Humanitas Scientific Report 2009/10

Scientific Report 2009 ›2010

Scientific Report 2009 ›2010 Results and Perspectives

Istituto Clinico Humanitas via Manzoni 56, 20089 Rozzano (Milano, Italy) Phone +39 02 8224 2445 Fax +39 02 8224 5101 www.humanitas.it

Scientific Report 2009 ›2010 Results and Perspectives

2

Humanitas commitment becomes stronger

The year 2009 included several important achievements for our Institute. Indeed, in the early months of the year its scientific and clinical activities were rigorously evaluated by the International Advisory Board, the International Joint Commission, and by the Ministry Commission for the renewal of our IRCSS (Istituto di ricovero e cura a carattere scientifico) status.

Thanks to our staff dedication and the obtained high quality standard of service and care, Humanitas once more established itself within the Italian scientific network of excellence as a highly regarded referral center for research and clinical care in the field of immuno-degenerative diseases. Between 2006 and 2009 our scientific production significantly increased as represented by the total impact factor elevation from 752 in 2006 to 1,587 points in 2009, with more than 30 papers in the highest ranking scientific journals.

Humanitas commitment and vocation to

translational research are becoming even stronger in 2010. We established for ourselves difficult clinical challenges which require an increasingly close and rapid link between laboratory data and clinical research to optimise the introduction timing into the practice of medicine. The project for a Translational Research Centre which includes a cell factory was started to fulfil these expectations.

These ambitious objectives warrant skills, partnerships, technologies, and economic support that has thus far characterised our personnel, scientific and clinical partnerships, financial institutions, and local community. I am extremely thankful to all of them, with the sincere hope that they will continue to support us in the enormous challenges we are willing to face.

Ivan Michele Colombo Vice President

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4

Practice-theory-practice: the virtuous cycle of translational research

Humanitas has been recognised as an Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) by the Italian Ministry of Health due to the manner in which it combines, between its various laboratories and operating units, basic clinical research and its application for the cure of gastroenterological and immunodegenerative diseases, which comprise chronic and autoimmune inflammatory pathologies – oncological, cardiovascular and neurological.

In particular, the efforts made by many research groups focus on immunology and inflammation, sectors that are leading players in the molecular biomedical revolution that has characterised the passage from the old millennium to the new. The hope today of tangible spin-offs for the cure of the sick flows from this revolution, which, with the support of technological development, sees the Humanitas laboratories abreast of the most advanced basic research centres in the world.

The challenge of the future must be tackled from two directions: on the clinical and educational fronts. We need to train doctors with a strong scientific foundation that allows them to use these new technologies both constructively and ethically; we must also ensure that the information that derives from research is not allowed to remain unused or simply to become the generator of impact factors. To paraphrase a famous film, the danger is that it will become “lost in translation”, whereas it should instead be drawn into a productive two-directional

relationship between the laboratory and the patient’s bed.

The guarantors that the label “translational”, attached to research, never becomes just “cosmetic” but remains an indicator of real clinical innovation, are the doctors-researchers who carry it out.

This synthesis of roles, represented by the abbreviation MD-PhD, is performed by doctors who devote themselves to scientific research for the benefit of the patient whom they treat and cure.

In Italy the road faced by institutions, and the incentivisation of MD-PhD pathways that generate these doctors, is very much an uphill one, but the Istituto Humanitas intends to make its own contribution to respond to the country’s deficiencies and scientific lag, and to take upon itself an international dimension, the only one that will ensure the collation of results and their continued acquisition.

The conditions for making this happen are the support and promotion of structures of excellence, the development and meritocratic reward of talent, so as to attract the best brains, whatever their origin, to preclinical and clinical research, and to create a healthy scientific climate where the doctors and researchers of the future may advance.

A l be rt o

Mant o vani

Scientific Director

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6

Clinical research to improve patient care

The Istituto Clinico Humanitas is a place where increasing amounts of time are devoted to clinical research. To dedicate itself to this, the institute had to undergo a period of preparation, an indispensable step in a new organisation: it is fundamental in order to create the right cultural background, to “enrol� the various skills required, to increase the quality of the treatment given, and to become a point of reference for patients.

Despite the difficulties created by the regulations governing a private health organisation, even if it is accredited, the prestige of Humanitas increased to the point where it was awarded the title Istituto di Ricovero e Cura a Carattere Scientifico. Additionally, the institute expanded its clinical research, as is shown by the yearly rise in the numbers of our researchers with scientific articles published in the international specialised literature, and in the constant increase of the impact factor.

The process is ongoing: we are satisfied at the results we have achieved but we are aiming at further improvement. Our next goal is to have the same maximum productivity level in clinical research for all Departments. In the past, growth has been greater in some areas than

others, but now it is becoming uniform because throughout the Humanitas clinics the attitude of our researchers and the understanding that treatment and research are closely related and that their development must be synergistic, are spreading more and more.

It is also essential that research is competitive and, necessarily, translational. In other words, it presupposes the continual exchange of information between the laboratory and the patient’s bed. This requires increasingly closer collaboration between basic research and clinical activity, and translates into a new way of thinking and working.

Also crucial to achieving continuously better results is innovation in all phases of the cure: in the radiological and endoscopic diagnostic techniques, in laparoscopic and robotic surgery, in radiotherapy, and in the development of new drugs and medical aids. And in this field, too, Humanitas is on the right path. And the challenge goes on.

A rmand o S ant o ro Director of Clinical Research

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Contents

10 The Istituto Clinico Humanitas

32 Translation research

a general hospital

and research centre

Immunity and inflammation

35

Cancer’s seventh hallmark

interview with alberto mantovani

Oncology

15

Humanitas and research

19 Humanitas and University education 20

International Medical School

21

Humanitas and International Quality

Accreditation

41 In Oncology, excellence

22

means research and innovation

Fondazione Humanitas per la Ricerca

24 The Ethics Committee

interview with armando santoro

Gastroenterology

45 Searching for the inflammatory genesis of tumours

interview with alberto malesci

49 Less gives more,

26 Clinical-scientific activities 28 Clinical activities 29 Research activities 8

30 Clinical & Research Departments

or at least better

interview with marco montorsi

53

dvanced mathematics at A the service of human health

interview with nicola dioguardi

57

Women’s health

78

Departments and teams

The goal: the all-round well-being and fulfilment of women

78 84

Clinical Area Scientific research and laboratories

86

Papers published 2009

interview with paolo emanuele levi setti

Internal Medicine

63

Two aims for new medical students: integrated learning and translational research

111 The Humanitas Group

in Italy

interview with mauro podda

Cardiology

67

In the third millenium, heart repair beats heart replacement interview with ettore vitali

71

Reaching the heart through the skin interview with patrizia presbitero

Pathology

75

Macroscopic, microscopic and molecular indices in the diagnostic jigsaw puzzle interview with massimo roncalli

9

The Istituto Clinico Humanitas: a general hospital and research centre

10

The Istituto Clinico Humanitas of Milan is the flagship of the Humanitas group, which is represented in Italy by Humanitas Gavazzeni in Bergamo, the Clinica Cellini in Turin, Humanitas Centro Catanese di Oncologia in Catania and Humanitas Mater Domini in Castellanza. The group is a network of hospitals distinguished by quality, research, high specialisation, a common medical culture and emphasis on human needs and qualities.

The major shareholder is Gruppo Techint, followed by UBI – Banca Popolare di Bergamo and Bracco Holding.

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Humanitas, a general hospital and research centre

Created in 1996 as a highly specialised general hospital, the Istituto Clinico Humanitas in Rozzano, South of Milan, is an Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), a hospital recognised by the Ministry of Health and the Region of Lombardy as a national centre of excellence distinguished by the quality of its health treatment and by its ability to transfer the results of its research and innovation into daily clinical practice.

Accredited with the Italian Health Service, the institute has 24 operating rooms, 5 angiographic rooms, 120 outpatients’ Clinics and 747 beds (of which 72 are in the medical, surgical and oncological day hospital, 28 in the intensive care unit, and 120 reserved for cardio-ortho-neuro-motor rehabilitation in an autonomous centre). It is equipped with a High Specialisation Emergency Centre, which attends over 55,000 patients yearly.

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With 747 beds (of which 72 are in the medical, surgical and oncological day hospital, 28 in the intensive care unit, and 120 reserved for cardio-orthoneuro-motor rehabilitation in an autonomous centre), 24 operating rooms, 5 angiographic rooms, and 120 outpatients’ Clinics, the institute is accredited with the Italian Health Service.

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Humanitas, a general hospital and research centre

Humanitas is the first italian general hospital to obtain quality certification from the Joint International Commission. Its diagnostic, therapeutic and rehabilitation work responds to the needs of local, national and international patients. Humanitas is presented as a case study to Harvard Business School students in the framework of its “Innovations in Health Care� course on the planning and management of high-quality healthcare services.

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Humanitas and research

15

Humanitas, a general hospital and research centre

Research is the driving force of scientific dynamics and essential for extending the breadth and depth of knowledge.

At Humanitas, research is an integral part of the training of physicians because of its natural interaction with clinical skills. Accordingly Fondazione Humanitas per la Ricerca was established with the aim of supporting and orienting basic and clinical research with a high scientific and technological profile, and promoting the training of young researchers in an international dimension.

Internationalisation is a key element in Humanitas’ research as it provides a point of reference and comparison with academics from all over the world.

The research laboratories, completed in 2007, are housed in a separate building which faces the Clinical Institute.

Nearly two hundred researchers work at the University Teaching and Research Centre using stateof-the-art technology such as two-photon microscopy and soon a cell factory. The group works in close collaboration with the more than 400 doctors in the hospital to identify the immunological and inflammatory mechanisms that underlie the formation and development of different pathologies that range from tumours to diseases of the gastro-intestinal tract and cardiovascular diseases like infarction and ictus.

Research at Istituto Clinico Humanitas

focuses

on inflammation and immunity. In particular, members of Istituto Clinico Humanitas have a long-standing interest in the mechanisms of innate immunity. Specific areas of research include chemokines and their receptors, members of the interleukin-1/toll-like receptor family and their regulation, humoral innate immunity receptors (i.e. pentraxins), the immunological synapse, and mechanisms of immunoregulation and angiogenesis in the gastrointestinal tract. Approaches utilised range from classical cellular immunology to post genomics techniques. The results of research activities are transferred to the clinic and feature as part of the interaction with industrial partners. The mission of Istituto Clinico Humanitas 16

includes training, in the context of a integrated cooperative effort with UniversitĂ degli Studi di

The integration of the hospital, laboratories and University creates the conditions for the formation of a figure that is rising increasingly in importance: the physician scientist (MD-PhD).

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Humanitas, a general hospital and research centre

Milano, both at a pre-doctoral and post-doctoral level. Research is supported by diverse sources of funding, including competitive public national and international granting agencies (e.g., the European Commission), charities (Associazione Italiana per la Ricerca sul Cancro, Telethon, Fondazione Cariplo, etc.) as well as industrial funding obtained through joint research projects, commercial availability of reagents and assays, and protection of intellectual property.

The research work of Humanitas is also carried out in collaboration with other national and international institutions, such as Fondazione Michele Rodriguez, which is dedicated to scientific quantitative measurements in medicine, Fondazione ARIEL (active in the field of infantile neuromotor sciences), and Fondazione Mercuriale, which is involved in biological and biomechanical research in the field of orthopaedics.

The mission of the Research Centre directed by Alberto Mantovani is unique in Italy. It works in partnership with centres of excellence like the University of Lovanio in Belgium, the Centro Nacional di Biotecnologia in Madrid, the Queen Mary School of Medicine in England, and the Institut Pasteur in Paris. Since 2006, Humanitas has also been part of the European Network of Immunology Institutes.

The work carried out by the researchers at Humanitas is monitored by an Advisory Board, one of whose members is the Nobel Prize winner Rolf Zinkernagel. The integration of the hospital, laboratories and University creates the conditions for the formation of a figure that is rising increasingly in importance: the physician scientist, a professional who has acquired the necessary methodology and precision by his or her work in the field, but who at the same time works in close contact with patients. The physician scientist is able to ensure continuity between the

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clinic and the laboratory in an educational setting.

Humanitas and University education Humanitas is a teaching centre for the 400 University students in the Schools of Medicine, Biotechnologies and Nursing affiliated with the UniversitĂ degli Studi of Milan, and is equipped with 14 classrooms for direct education, meeting rooms, open spaces, internet access and a multimedia library.

The new Centre and a separate independent academic track allowed the introduction of an innovative teaching method (problem based learning) for Medical students and achieved significant results. The goal is to improve the training of new doctors by placing them in a clinical environment in which model of care and assistance is a fundamental part of the teaching course.

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Humanitas, a general hospital and research centre

International Medical School Humanitas also hosts the International track of the Università degli Studi di Milano School of Medicine. This 6-year track combines a new problem-based approach to academic training with experience in clinics and research laboratory.

Pecularities of the Humanitas track include:

• an international profile: all classes are held in English and based on structured training problems. Critical contributions are made by numerous visiting professors from prestigious European and North American universities worldwideas part of coordinated exchange programmes

• innovative teaching methods including small study groups, problem-based learning, discussion of specific cases, problem solving

• highly integrated curricula: teaching activities and different courses are divided into longitudinal blocks starting from the first year, with closely linked, integrated contents that overcome the classical issues of anatomy, physiology, and clinics in a more pragmatic problem-driven approach

• targeted training for a subgroup of students in collaboration with the University other degree courses, inspired by the MD-PhD degree model for future physician scientists

• the initial reception of the students, to whom a highly specialized teaching service is offered by medical education professionals to create a sense of academic link between the teaching staff and the students.

The aim of this project is to define an educational path in which the MD trainees feel to be active parts of the life of the University, hospital and research center, while absorbing the culture and values of the setting and progressively developing their professional intelligence, creativity, and capacities for problem-solving and innovation. Ultimately, students will receive the necessary training to find their ideal path in the practice of medicine or research.

In this context, the international side of the training experience, which is created by the introduction of the students to different attitudes, cultures and languages, becomes an essential and distinctive aspect of the project which is expected to provide an enrmous advantage for the participating students.

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Visit its site www.mimed.it

Humanitas and International Quality Accreditation Ever since its inauguration, Humanitas has employed quality control systems based on the PDCA (Plan Do Check Act) approach, which represents a closed circle of quality improvement and allows to verify procedures and outcomes as part of a continuous process. Istituto Clinico Humanitas has always been compared to the most prestigious European hospitals and has taken part in various benchmarking projects to meet the challenge of the opening of the European Health System.

This process led to the decision to have the hospital’s management model certified by the Joint Commission International, one of the world’s most prestigious hospital certification bodies.

The Joint Commission International is one of the most advanced organisations of quality certification for healthcare facilities. In the United States it is the most important de facto reference for defining healthcare facilities from the points of view of patients and public healthcare systems alike. The organisation is also recognised in Europe and the rest of the world.

Joint Commission International has validated the Humanitas quality system, which is overseen by the Quality Management Committee to direct the process of continuous quality improvement, define indicators, propose corrective actions and check their effectiveness, to ultimately preside over quality-related issues.

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Humanitas, a general hospital and research centre

Fondazione Humanitas per la Ricerca The Fondazione Humanitas per la Ricerca is a nonprofit organisation that supports clinical and basic research in the field of immunology and inflammation, and its possible clinical applications in the cure of chronic inflammatory, autoimmune, oncological, cardiovascular and neurological diseases.

Studies made in close collaboration with the Humanitas general hospital in Milan, and with other Humanitas hospitals in Bergamo, Turin, Castellanza and Catania, have the aim of transferring the results of the research to the patient’s bedside, thanks to the continuous exchange of information between the laboratory and clinical activity.

During the phases of both original and translational research, the projects are characterised by the use of advanced technology ranging from whole genome profiling to molecular imaging.

The Fondazione Humanitas per la Ricerca is also committed to allowing young researchers to train in an international setting, and its activity is supported by national and international organisations like the European Commission, AIRC, Telethon, Fondazione Cariplo.

Visit its site www.humanitasresearch.org

Advisory board

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Charles Dinarello, MD

Fabio Cominelli, MD, PhD

Rolf Zinkernagel, MD, PhD

Lorenzo Moretta, MD

Professor of Medicine Division of Infectious Diseases

Professor of Internal Medicine and Microbiology

University of Zurich Zurich, Switzerland

University of Colorado Health Sciences Centre

Director, Digestive Health Centre of Excellence Division Head, Division of Gastroenterology and Hepatology University of Virginia

Research Director, Giannina Gaslini Pediatric Insitute Professor of General Pathology

Set up in 2005, the Fondazione Humanitas per la Ricerca, a nonprofit organisation that operates in the Humanitas University Research and Teaching Centre, has achieved significant results.

University Hospital Zurich Institute of Exp. Immunology

University of Genova Genova, Italy

In the context of the foundation – where young Italian and foreign researchers work with clinicians in close contact with some of the most important medical and research centres in the world – translational research

HUMANITAS LECTURES The Humanitas Lectures are a series of high-level scientific meetings in which the development and evolution of biomedical research at the service of human health is presented and discussed.

Promoted by Humanitas’s Scientific Direction, the lectures are organised in partnership with the Fondazione Humanitas per la Ricerca and the Università degli Studi of Milan with the aim of analysing key sectors in medical research.

The Humanitas Lectures benefit from the contributions of doctors and researchers who have played a fundamental role in their respective fields, and have to date included Rolf Zinkernagel, Malik Peiris, Silvio Garattini, Fabio Cominelli,

Marc Feldmann, Lodovico Balducci, Richard Blyton Devereux, Charles Dinarello, Giorgio Trinchieri, Fran Balkwill, Claudio Fiocchi and Lorenzo Moretta.

The speakers at the Humanitas Lectures in 2009 and 2010 have been: •Prof. Piero Anversa, Director of the Center for Regenerative Medicine Brigham & Womens’ Hospital-Harvard Medical School •Prof. Abul K. Abbas, Professor & Chairman, Pathology - University of California, San Francisco •Prof. M. Eric Gershwin, Chief Division of Rheumatology, Allergy, and Clinical Immunology - University of California, Davis School of Medicine

•Prof. Giuseppe Giaccone, Medical Oncology Branch, National Cancer Institute - National Institutes of Health Bethesda, MD - USA. •Prof. Antonio Lanzavecchia, Director of the Institute for Research in Biomedicine - Bellinzona, Switzerland Currently planned for 2 November 2010 is a lecture to be given by Prof.

Francoise Barre-Sinoussi, Director of the Regulation of Retroviral Infections Unit at the Pasteur Institute in Paris.

Prof. Barre-Sinoussi was awarded the Nobel Prize for Medicine in 2008 with Prof. Luc Montagnier for their discovery of the human immunodeficiency virus (HIV).

Rolf Zinkernagel during his Humanitas Lecture. Together with Peter C. Doherty, Zinkernagel received the 1996 Nobel Prize in Medicine for the discovery of how the immune system recognises virus-infected cells.

activities have been developed that benefit different clinical activities, such as Oncology, Cardiology, Surgery, Nephrology, Gastroenterology and Internal Medicine.

Many studies carried out in our laboratories have been published in the pages of leading scientific reviews, such as Gastroenterology, Lancet, Nature, Nature Immunology, Journal of Experimental Medicine, The New England Journal of Medicine, and PNAS. Some of these studies have opened the path to the perfection of innovative therapeutic strategies, for example, in the field of chronic

inflammatory bowel diseases and several forms of tumour.

Research is the best way to offer our patients what could be the most effective and innovative treatments for purposes of diagnosis and cure.

Our researchers study inflammation and alterations of the organism’s defence mechanisms that foster the development of very common diseases, such as digestive tumours, leukaemia, lymphomas, autoimmune diseases, heart ischemic diseases and stroke.

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Humanitas, a general hospital and research centre

The Ethics Committee Scientific research at the Istituto Clinico Humanitas is overseen by an independent Ethics Committee which acts as an Istitutional Review Board (IRB). The tasks of the Ethics Committee are designed to offer a public guarantee of the rights, safety and well-being of subjects who take part in clinical trials and basic studies before any study involving a human being is undertaken.

Established in 1998, the Ethics Committee, after a reorganisation of the prescriptive regulations, operates on the basis of precise rules fixed by legislation. In conformity with directions from the Ministry of Health, it has had competency in all the specialities offered by the Institute since 2009.

From 2007 to 2009 the Ethics Committee was involved only in gastroenterological research as ministerial regulations then in force limited its work to fields for which the IRCCS had obtained recognition.

The committee is composed of 11 members-elect who remain in office for three years. Members include experts in clinical, biostatistical and pharmacological experimentation and legal matters. Some members also have experience in primary care and nursing. Other ex-officio members of the Ethical Committee are the Scientific Director, Medical Director, Pharmaceutical Service Manager and the Secretary. It generally meets on a monthly basis and is presided over by Pier Giuseppe Torrani.

In conformity with the regulations in force, the Ethics Committee has its own set of rules that govern the methods with which it functions.

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During its sessions, the Ethics Committee makes an overall evaluation of a trial, paying special attention to informed consent, privacy report, insurance and economic coverage and any new experimental aspects. In multicentric clinical trials, the committee confirms, in collaboration with foreign institutes, that pertinent foreign standards are in accordance with their Italian equivalents.

In the performance of its duties, the Ethics Committee benefits from the collaboration of the Clinical Trials Office, which, for each trial, draws up a technical sheet that summarises the type of study being undertaken, the Operative Units and human resources that are to be involved, the expected number of patients, and any additional services required above and beyond those included in good clinical practice.

The Ethics Committee also provides support in current clinical practice. At the request of the physician in charge of the study, it draws up informed consents relating to subjects of particular ethical and legal delicacy, as it has done for assisted medical procreation, the collection of biological samples for future genetic research and, more in general, privacy.

It also formulates responses to complex ethical questions connected with assistance-related activities, with the aim of protecting and promoting the values of the human individual. It does so in an attempt to overcome difficulties that arise, due to either a lack of relevant legislation or, in situations where laws exist, to the rapid progress made in science compared to the ability of the legislator to crystallise subjects of great scientific and ethical complexity into a standard.

The Ethics Committee produces an annual report on the state of progress of individual research protocols and its own review activity.

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26

Clinical-scientific activities

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Clinical activities Outpatients

Inpatients 7,135

2007

2,196

2007

1,091,505

24,539 7,356

2008

2,362

24,964 6,969

200

400

600

800

1000

1200

2,302

15,948

2009

1,329,935

0

15,246

2008

1,175,990

2009

15,208

1400

25,219

0

5

10

15

20

thousands of patients

25

30

thousands of patients

total inpatients

emergency inpatients

rehabilitation inpatients

elective inpatients

Humanitas’ people 512

893

2007

893

1,704

2007 538

947

319

538

2008

947

1,804

2008 566

918

331

566

2009

918

2009

0

200

total people

28

299

512

400

physicians and researchers

600

healthcare support workers

800

staff

1000 0

1,815

1200 200

total people

1400 400

physicians and researchers

1600 600

1800 800

healthcare support workers

staff

2000 1000

1200

Research activities Published papers 2006

160

2007

172

2008 2006

197 160

2009 2007

289 172 0

50

100

150

200

2008

300

197

2009 2006 2007

250

289

752

0

50

100

150

200

724

250

300

Raw impact factor 2008 2006

752

2009 2007

2008

896

1,587

724 0

200

400

600

800

1,000

896

1,200

1,400

2009

1,600

1,587

0

200

400

600

800

1,000

1,200

1,400

1,600

The raw IF is the sum of the IF of each journal that publishes the paper with at least one name of an Istituto Clinico Humanitas doctor.

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Clinical & Research Departments oncology

Director: Armando Santoro BREAST UNIT

Director: Corrado Tinterri GENERAL � ONCOLOGIC SURGERY

Director: Roberto Doci ������� �������: Vittorio Lorenzo Quagliuolo MEDICAL ONCOLOGY � HAEMATOLOGY

Director: Armando Santoro PET � NUCLEAR MEDICINE

Director: Arturo Chiti

RADIOTHERAPY � RADIOSURGERY

Director: Marta Scorsetti THORACIC SURGERY

Director: Marco Alloisio

President

Gianfelice Rocca Vice President

Ivan Colombo Chief E�ecutive Officer

Luciano Ravera

Medical Director

Norberto Silvestri

gastroenterology

Director: Alberto Malesci

GASTROENTEROLOGY � DIGESTIVE ENDOSCOPY

Director: Alberto Malesci

DIGESTIVE ENDOSCOPY SERVICE

ADAPTIVE IMMUNITY

Group leader: Antonella Viola CELLULAR IMMUNOLOGY

Group leader: Paola Allavena CLINICAL & EXPERIMENTAL IMMUNOLOGY

Group leader: Domenico Mavilio CLINICAL PHARMACOLOGY

Group leader: Alfredo Gorio

EXPERIMENTAL IMMUNOPATHOLOGY

Group leader: Cecilia Garlanda

GASTROINTESTINAL IMMUNOPATHOLOGY

Group leader: Silvio Danese

COMMON RESEARCH SERVICES BIOBANK

Director: Alessandro Repici

GENERAL � MINIMALLY INVASIVE SURGERY

Director: Riccardo Rosati

GENERAL MEDICINE � HEPATOLOGY

Director: Maurizio Tommasini GENERAL SURGERY III

Director: Marco Montorsi ������� �������: Guido Torzilli ���������� �������: Alessandro Zerbi

internal medicine

Director: Mauro Podda DERMATOLOGY

Director: Marcello Monti DIALYSIS

Director: Salvatore Badalamenti EMERGENCY DEPARTMENT

Director: Salvatore Badalamenti

cardiovascular diseases

ENDOCRINOLOGY � DIABETOLOGY

CARDIAC SURGERY

GENERAL MEDICINE � NEPHROLOGY

Director: Ettore Vitali

Director: Giuseppe Tarelli CLINICAL CARDIOLOGY � HEART DECOMPENSATION � FAILURE TREATMENT CENTRE

Director: Patrizia Presbitero ECHOCARDIOGRAPHY

Director: Renato Maria Bragato

Director: Pietro Travaglini

Directors: Giorgio Graziani, Salvatore Badalamenti

GENERAL MEDICINE � PNEUMOLOGY

Director: Michele Ciccarelli INTERNAL MEDICINE

ELECTROPHYSIOLOGY � ELECTROSTIMULATION

Director: Mauro Podda

HAEMODYNAMICS, INVASIVE CARDIOLOGY � CORONARY CARE

Director: Bianca Marasini

Director: Maurizio Gasparini

Director: Patrizia Presbitero �������� ����: Elena Corrada

RHEUMATOLOGY

THROMBOSIS CENTRE

Director: Lidia Rota

VASCULAR SURGERY I

Director: Pier Luigi Giorgetti

VASCULAR SURGERY II

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Director: Maria Grazia Bordoni ANAESTHESIA � CARDIOSURGERY INTENSIVE CARE

Director: Angelo Bandera

diagnostic imaging

Director: Giorgio Brambilla

RADIOLOGY � DIAGNOSTIC IMAGING

Directors: Giorgio Brambilla, Luca Balzarini ECHOGRAPHY

Director: Paola Magnoni

F

orthopaedic surgery HEPATOBILIARY IMMUNOPATHOLOGY

Group leader: Pietro Invernizzi IMMUNOPHARMACOLOGY

Group leader: Barbara Bottazzi LEUKOCYTE BIOLOGY

Group leader: Massimo Locati LEUKOCYTE MIGRATION

Group leader: Silvano Sozzani MOLECULAR GASTROENTEROLOGY

Group leader: Luigi Laghi

MOLECULAR IMMUNOLOGY

Group leader: Antonio Sica

MOLECULAR PATHOLOGY

Group leader: Massimo Roncalli NATIONAL RESEARCH COUNCIL (CNR) HUMAN GENOME AND MEDICAL BIOTECHNOLOGIES

Group leaders: Paolo Vezzoni, Anna Villa

CELL FACTORY

general anaesthesia � intensive care department Director: Giovanni Bordone ANAESTHESIA I

Director: Franco Cancellieri ANAESTHESIA II

ARTHROSCOPIC SURGERY OF THE KNEE

Director: Enrico Arnaldi HAND SURGERY

Director: Alberto Lazzerini HIP & KNEE PROTHESIC SURGERY

Director: Guido Grappiolo

KNEE ORTHOPAEDICS & SPORT TRAUMATOLOGY

Director: Piero Volpi

PEDIATRIC & NEUROORTHOPAEDICS SURGERY

Director: Nicola Portinaro

SHOULDER, ELBOW & FOOT ARTHOSCOPIC SURGERY

Director: Alessandro Castagna ���� �������: Luigi Milano TRAUMATOLOGY

Director: Marco Berlusconi

Director: Vittorio Gavazzeni

neuroscience

gynaecology GYNAECOLOGY

Director: Domenico Vitobello GYNAECOLOGY & REPRODUCTIVE MEDICINE

Director: Paolo Emanuele Levi Setti

specialised divisions of surgery OPHTHALMOLOGY

Director: Paolo Vinciguerra OTORHINOLARYNGOLOGY

Director: Arturo Poletti

Director: Simona Marcheselli NEUROLOGY II

Piero Melodia

Research Advisory Board

rehabilitation

Rolf Zinkernagel (President) Charles Dinarello Fabio Cominelli Lorenzo Moretta

CARDIAC & RESPIRATORY REHABILITATION

Director: Stefano Aglieri

NEUROLOGIC REHABILITATION

Director: Bruno Bernardini

ORTHOPAEDIC REHABILITATION

Director: Stefano Respizzi

special diagnostic and treatment services LABORATORY TESTS

Director: Alessandro Montanelli PATHOLOGY

Director: Roberta Monzani

UROLOGY

Education

NEUROSURGERY

PLASTIC SURGERY II

Director: Pierpaolo Graziotti ������ �������: Alessandro Piccinelli

Armando Santoro

Director: Riccardo Rodriguez y Baena

PLASTIC SURGERY I

Director: Marco Klinger

Alberto Mantovani

Director: Eduardo Nobile Orazio

Director: Massimo Roncalli

Director: Simone Grappolini

Scientific Director

EMERGENCY NEUROLOGY & STROKE UNIT

Director: Stefano Respizzi Director: Paolo Emanuele Levi Setti

Nicola Dioguardi

Clinical Research Director

Director: Valentina Bellato ANAESTHESIA III

Scientific Superintendent

SURGICAL DAY HOSPITAL

Teams: page 78 Scientific publications: page 85 Updated to 31 May 2010

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Translational research

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Immunity and inflammation

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Cancer’s seventh hallmark

Interview with Alberto Mantovani

Alberto Mantovani is Professor of General Pathology at the Faculty of Medicine and Surgery at the Università degli Studi di Milano and, since 10 October 2005, Scientific Director of Humanitas.

Previously he was head of the Department of Immunology and Cellular Biology at the Mario Negri Pharmacological Research Institute in Milan. He is President of the Fondazione Humanitas per la Ricerca, which supports clinical and basic research with relation to immunology and its applications for the cure of chronic inflammatory, autoimmune, oncological, gastroenterological, cardiovascular and neurological diseases.

» One of the most interesting suggestions to emerge

from your lines of research is the existence of a close link between inflammation and cancer: are there any certainties on this topic?

During the last ten years attention has focused on the paradigm that assumes inflammation processes to be an essential part of the micro-environment of tumours. In spite of the great number of studies, however, we have not yet fully understood which molecules orchestrate the protumoral inflammation mechanisms, nor how to transfer our knowledge to clinical practice. What Massimo Locati is now doing in his Leukocyte Biology Laboratory is “gene mining”, in order to identify new actors and discover the role played by the old ones so that we can understand the molecular events that govern inflammation circuits in the tumoral micro-environment.

Recent evidence shows that the leukocytes that infiltrate tumours, tumour-associated macrophages (TAM) in particular, prefer to be localised in the hypoxic regions of the tumour where they acquire functions that favour tumoral angiogenesis. They create the ecological niche for the survival of tumoral cells, making them insensible to hormonal flows and encouraging the formation of metastasis.

» At one time it was believed that macrophages were

“on the scene of the crime” to help the organism fight the tumour: why are they now accused of being “accomplices” of the tumour itself?

Thirty years ago it was discovered that macrophages help the progression of the cancer in the manner described; with regard to their role, a paper called La mala educación of Tumor-Associated Macrophages: diverse pathways and new players has just been published in Cancer Cell.

Among the various mechanisms that activate TAMs, Antonio Sica, who is head of the Molecular Immunology Laboratory, is studying in particular the characterisation of the NF-kB system (Nuclear Factor kB), a transcriptional factor that is expressed by many solid tumours and which stimulates cell proliferation and resistance to apoptotic signals. NF-kB is also activated in cells of inflammatory infiltrates where it stimulates the production of cytokines and growth factors that cause cell proliferation and neo-angiogenesis. In murine experimental models it has been seen, for example, that TAMs that have the inhibitory protein p50 NF-kB in their nucleus are not

35

Cancer’s seventh hallmark Interview with Alberto Mantovani

« Tumour’s ability to build an

inflammation microenvironment may turn out to be cancer’s Achilles’ heel

»

able to perform effective antitumoral inflammation activity, and that, when the protein p50 NF-kB is suppressed, there is recovery of the inflammation function with the development of resistance to the growth of tumours of diverse origin (fibrosarcoma, melanoma, hepatocellular cancer and cancer of the colon rectum). Studies are therefore directed at identifying the tumoral mechanisms that induce nuclear p5O in the cells of the innate immune system so that the knowledge acquired can be translated into new pharmacological strategies to prevent their build up.

» What signals are macrophages activated by?

Leukocytes respond to chemokines. What signals attract macrophages are being studied by Innochem, a consortium of 15 scientific academic groups in Belgium, France, Germany, England, Italy, Poland, Switzerland, Spain and Israel, and by 6 groups in the pharmaceutical and biotechnological industries, which are advancing basic research and clinical experimentation at the same time. Recently the FDA and EMEA approved a chemokine inhibitor for clinical use on patients suffering from HIV and for the recruitment of stem cells in patients with tumours that are being subjected to bone-marrow transplant. Currently an inhibitor of the chemokine ligand 2 of the monocyte chemoattractant (or chemotactic) protein -1 family (MCP-1, CCL-2) against tumours is in phase 1 of testing. CCL2 recruits the monocytes, the T lymphocytes of memory and dendritic cells in sites of damaged tissue.

36

» So your research has helped to shed light on

the ability of a cancer to build an inflammation

micro-environment around itself that is ideal for its own proliferation.

Exactly so. We call it cancer’s “seventh hallmark”, which completes the class of its peculiar characteristics. Till now a tumour was known to have six characteristics: the ability to grow endlessly, autonomy of development (thanks to its own growth factors), insensibility to signals from the organism that block cell proliferation, the ability to escape apoptotic commands, high angiogenetic activity and the ability to colonise other organs (creating metastasis).

This new discovery might turn out to be cancer’s Achilles’ heel and to open the path to new therapeutic strategies.

» Is it possible to establish which comes first – the cancer or the inflammation?

The pathological connection is complex. For some tumours chronic inflammation is a risk factor (consider gastrointestinal tumours, for instance, a colonic tumour); in other cases, the same oncogenes that cause the cancer directly orchestrate an inflammation response as an amplification circuit of the six characteristics of the tumoral cells.

In addition, macrophages promote the dissemination of tumour cells. Currently the molecular basis of how that happens is being studied.

» Your studies show that it is its intrinsic

regulation that transforms the inflammation from a protective event to an event that promotes the cancer. How does that happen?

During the inflammation response, a key moment is the resolution of an inflammation: this is not a passive phenomenon that occurs “as a result of exhaustion”, but an active phenomenon governed by the so-called “brakes” or “scavengers” of the inflammation. The relationship that is under study is the one between the lack of resolution of the inflammation (i.e., its turning chronic) and the establishment of the cancer.

Massimo Locati’s laboratory is studying the mechanisms that govern the negative regulation of the inflammation response. His group is working on the identification of molecules that may suggest anomalous functions, braking functions, like the

receptors that bind a particular ligand and thus eliminate it without transducting any signal.

» Are you referring to the atypical receptors of the chemokines?

Yes, I am. A receptor is a membrane protein that, having recognised a particular ligand, mediates a biological response. In the 1990s, however, it was discovered that there are false receptors – decoy receptors – which act like a sort of molecular trap.

The one that has been best studied by Locati’s group is called D6 and is an atypical receptor that recognises high-affinity inflammation chemokines but does not induce transduction of the signal. On the contrary, it degrades the ligand. In this way it progressively reduces the free chemokines, modulating the defensive response and eventually interrupting it.

Absence of the inflammation’s negative regulator D6 determines the incapacity to resolve the inflammation response in many organs and encourages development of the tumour. Decoy receptors have been identified in lymphatic vessels, the skin, the heart, the lungs and the liver. The D6 receptor also intervenes in the syncytiotrophoblast during pregnancy, becoming a

sentinel in the interface between the mother and the foetus. When it is absent, the chemokines produced by a maternal immune response reach the placenta and can cause an abortion. That is what probably happens in the antiphosphilipid syndrome studied with P.L. Meroni from the Università degli Studi di Milano.

» Can we say, then, that D6 is a scavenger of chemokines? Do we know of any others?

The scavenger D6 is an important defence against female autoimmune pathologies. TIR8 is also a negative control mechanism that restricts activation of the above-mentioned transcriptional factor NF-kB, which is essential for the synthesis of inflammation molecules such as interleukin-l, Toll Like Receptors and other members of the family (IL-1R, IL-18R, TLR4, TLR9). Regulation of the inflammation cascade avoids the cascade being activated to excessive degree, as happens in chronic intestinal inflammation, cancerogenesis associated with inflammation, and in pulmonary tuberculosis.

» Is it already possible to speak of a therapeutic fall-out arising from these discoveries?

Unquestionably. Chemokines and their receptors are promising pharmacological targets. Massimo Locati’s laboratory has helped to identify a new class of receptor inhibitors, which are referred to as allosteric inhibitors. Now he is working on identifying the molecular mechanisms that underlie their function and on characterising their pharmacological profile.

Drugs have been created that block inflammation: anti-TNF antibodies to counter rheumatoid arthritis, Crohn’s disease, psoriatic arthritis; IL-1 inhibitors for arthritis in youths; a chemokine inhibitor to treat AIDS and the inflammatory diseases. Undergoing experimentation are IL-6 inhibitors to treat arthritis.

« The new discovery might open the path to innovative therapeutic strategies »

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Cancer’s seventh hallmark Interview with Alberto Mantovani

» Another important topic on the subject of

inflammation is that of pentraxins, a family whose most famous member is the C-reactive protein which is the most commonly used inflammation marker used in diagnosis.

Your group has discovered another molecule homologous to CRP called PTX3: how does it differ and what is its importance?

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PTX3 was identified in 1993: the more it is studied, the more we realise its importance from an immunological and clinical viewpoint due to its broad interactome, that is to say the range of possible ligands.

The laboratory headed by Barbara Bottazzi has the task of broadening the spectrum of recognised ligands and trying to understand the interactions of the protein. This knowledge path is new and important: we have cloned the gene, studied its regulation and created antibodies.

Unlike CRP, PTX3 is a long pentraxin, which differs from its best known homologue not only in its cell source but also in its chemical structure, as it has two different functional dominions.

CRP is a late inflammation marker because its synthesis is not local but occurs in the hepatic cells. Moreover, it has very low specificity. In the JUPITER study (Justification for the Use of Statins in Prevention: an Interventional Trial Evaluating Rosuvastatin), high sensitivity CRP was used as a cardiovascular risk marker. In reality it is not known if the measurement of C-reactive protein is relevant to pathogenesis.

Preclinical research has also revealed that, used as a marker, PTX3 may have a diagnostic role. A study carried out on 740 patients suffering from myocardial infarction showed that PTX3 is the only indicator able to predict death.

The long PTX3 pentraxin is an earlier marker and better reflects tissue damage because it comes from the tissue itself, where it is produced by macrophages, the lymphatic endothelium and dendritic cells. It is a multifunctional molecule: for example, it is of fundamental importance to women’s fertility and regulation of the innate immune response to pathogenic micro-organisms of bacterial, viral or fungal origin. It is also essential in resistance to Aspergillus fumigatus or Pseudomonas, with obvious consequences for those suffering from

cystic fibrosis or immune deficiencies associated with anti-tumoral therapies. Aspergillus affects between 10 and 35% of transplant patients or those who have undergone aggressive chemotherapy.

» Does this molecule also play a role in reproduction?

It is not surprising that such a role exists. After all, ovulation is an inflammation process. Allelic variants of the gene that expresses PTX3 are correlated with fertility: long pentraxin is a constituent of the extracellular matrix that protects the oocyte and it is an early marker of pre-eclampsia. These topics are being studied closely by Cecilia Garlanda’s group in the experimental immunopathology laboratory.

» What are the other basic research paths being followed in the Humanitas laboratories?

In the Human Genome and Medical Biotechnologies Laboratories they are studying what I call “opencast mining”, by which I mean that it is no longer necessary to explore in the dark now that there is the genome. Paolo Vezzoni and Anna Villa, researchers in the Humanitas CNR, are working on identifying the

top paper Mantovani A, Allavena P, Sica A, Balkwill F.

Cancer-Related Inflammation Nature. 2008; 454: 436-444.

molecular bases and treatment of autosomal recessive osteopetrosis. This is a serious genetic disease of the bones, fatal in the early years of life, which leads to macrocephalia and anaemia, blindness and deafness through compression of the bone marrow and the acoustic and optic nerves.

Strong links exist between bone and immunity, to the extent that a discipline has come into existence called osteoimmunology: osteoclasts and macrophages have in common the precursors in the haemopoietic stem cells, and this fact forms the basis of the treatment of the disease through bone marrow transplant, which needs to be carried out in the prenatal phase.

A second therapeutic hypothesis – still in the preclinical research phase – is directed at the mechanism that activates osteoclastogenesis. This is induced by parathormone, which stimulates osteoblasts to secrete the cytokine M-CSF and a protein called RANKL, molecules for which monocytes have a specific receptor. Interaction induces the monocytes to differentiate into osteoclasts. Lastly, the osteoblasts mitigate the action of RANKL by expressing a decoy receptor called OPG that associates with RANKL. The balance found between production of RANKL, M-CSF and OPG determines the level of osteoclastogenesis.

» Does your research also take you into the field of adaptive immunity?

Antonella Viola, head of the Humanitas Adaptive Immunity Laboratory and assistant Professor at Università degli Studi di Milano, works on what are known as immunological synapses, mechanisms with which the dendritic cells of the innate immune system activate adaptive immunity. This interaction functions at an insufficient level in tumours and Viola has discovered several molecular mechanisms of the defect in the dialogue between the two types of immunity.

« Strong links exist between

bone and immunity: a discipline has come into existence called osteoimmunology

»

The cells and mediators of inflammation form a major part of the tumour microenvironment. In some cancers, inflammatory conditions precede development of malignancy; in other cancers, oncogenic change drives a tumour-promoting inflammatory milieu. Whatever its origin, smouldering inflammation in the tumour microenvironment aids proliferation and survival of malignant cells, angiogenesis and metastasis; subverts adaptive immunity, and alters response to hormones and chemotherapeutic agents.

The unravelling of the molecular pathways of cancer-related inflammation (CRI) is generating novel therapeutic and diagnostic targets.

Among the other notable results achieved by our research groups is the paper published in Lancet Oncology in which solid data demonstrate how the density of CD3 and T lymphocytes (TIL, tumour-infiltrating lymphocytes) that infiltrate a cancer of the colon without involvement of the lymph nodes is a positive prognostic factor.

» The most distressing field in immunology is

autoimmunity. Why is it so important and who deals with it in Humanitas?

Autoimmunity is a set of pathologies that affects 20% of the population, mostly female. It is a real gender-related pathology, as Pietro Invernizzi and Carlo Selmi know. Both are MD-PhDs studying autoimmune diseases of the biliary ducts in the Hepatobiliary Immunopathology Laboratory.

In addition, the Clinical and Experimental Immunology Laboratory directed by Domenico Mavilio (MD-PhD) investigates the role of dendritic and NK (Natural Killer) innate immunity cells in autoimmune diseases. The attempt is to go beyond the current immunosuppressive therapeutic possibilities and develop specific therapeutic strategies. In order to work on this applied experimental research line, Mavilio’s team collaborates with the universities of Genova, Pavia and Padova and with the National Institutes of Health in Bethesda.

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Oncology

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Disease prevention, research and transfer of discoveries from the laboratory to the patient’s bed, and integrated use of new technologies: these are the challenges of oncology in Humanitas. Representing 20% of all sickness-related deaths, cancer is the second largest killer in Italy. However, progress in research and the extraordinary development of diagnostic tools and therapeutic strategies have produced results that were unforeseeable thirty years ago.

Research has opened new horizons for our understanding of the disease and, subsequently, its treatment. On one hand, discovery of the important role played by the tumour micro-environment, which supports cancer’s growth and proliferation, offers the hope of a new therapeutic strategy that strikes not only the tumour but also its microenvironment. On the other hand, new discoveries in the field of tumoral stem cells and a better understanding of the genetic mechanisms that occur around cancer cells allow, or will allow, therapy to center its specific target .

Treatments will be customised to match the tumour’s genic profile so as to improve both the patient’s prognosis and the tolerability of the cure.

In the fight against cancer, the patient is at the centre of an integrated vision that benefits from progress in surgical and radiotherapeutic techniques.

An example of the latest development at the service of the patient is RapidArc, a sophisticated computerised system connected to a linear accelerator that gives an extremely precise and rapid radiotherapy by describing an arc around the patient in just 70 seconds.

This innovative system allows modulated intensity treatments (IMRT) to be carried out, irradiating with extreme accuracy even very small lesions of complex form that are situated in deep zones that are otherwise difficult to reach. In Humanitas – the first centre in Italy to have RapidArc and one of the very few in Europe – this device is used alongside other pieces of radiotherapy equipment such as the 4-D, which fires at the tumour while taking account of the movement of the organs due to the patient’s breathing.

Prevention remains a fundamental goal in oncology.

With regard to two big killers – lung and colon cancers – Humanitas cooperates with other Italian centres to define prevention strategies that promote early diagnosis and healthy lifestyles, such as abstinence from smoking.

In Oncology, excellence means research and innovation Interview with Armando Santoro

Armando Santoro, who directs the Department of Medical Oncology and Haematology at Humanitas, has been director of the institute’s clinical research since 2007; since 2008 he has been a consultant to the Ministry of Health for the coordination of the National Oncological Plan, and since 2010 a member of the Superior Health Counsel. He is also a member of the Regional Oncological Commission and Rete Oncologica Lombarda (ROL).

» How has oncology evolved and what are the

perspectives for the discipline in the third millennium?

In recent years enormous progress has been made in oncology and haemato-oncology, in terms both of cure and improving patient survival. These successes are attributed to different factors. First and foremost, early diagnosis, thanks to large population screening and increasingly accurate diagnostic procedures. Second, the improvement of therapeutic results due to the introduction of more sophisticated therapeutic methodologies – i.e. the development of advanced oncological surgical techniques such as laparoscopic and robotic surgery, and the improvement in radiotherapy with the introduction of new techniques (gamma knife, tomotherapy, RapidArc), which enable increasingly accurate treatments. On the other hand the development of a whole series of new drugs (biological drugs and targeted therapies) have improved the therapeutic possibilities and the prognosis of many oncologic and haemato-oncologic diseases; these have allowed successes to be achieved in treating diseases for which previously we had no effective drugs.

At the same time needs have also changed and raised the bar of the challenge we face: the rise in the average age of the population has increased the incidence of oncological diseases, also bringing into the game the major problem of comorbidity, which involves the need for a therapeutic strategy that is both comprehensive and tailored on each individual patient.

However, as “comprehensive” also means complex, the need for a multi-disciplinary approach becomes essential: the oncologist should design an overall cure plan together with other specialists involved in patient treatment and with general practitioner to decrease the difficulties in treating comorbidity.

Finally, the success of oncological cures has increased the need for a dedicated approach for cancer survivors, requiring follow-up in terms of surveillance against disease relapse and second cancer, control of the effects of chemotherapy and a qualified psychological support.

» How does Humanitas fit into this challenge?

Humanitas is active in all sectors of oncology, starting from primary prevention with initiatives aimed to prevent anyone from becoming an oncological patient. In 2010 we launched an anti-smoking campaign aimed in particular at young people to warn them of the dangers associated with tobacco smoke, and for a few years now an Anti-smoking Centre has been operative where anyone wishing to quit is followed by a multi-

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In Oncology, excellence means research and innovation Interview with Armando Santoro

« Patients’ needs have changed and raised the bar of the challanges we face »

radiotherapy session duration.

Finally, Radiological Diagnostics directed by Luca Balzarini and Nuclear Medicine under Arturo Chiti are equipped at a very high level.

» And what about pharmacological therapy?

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specialist team. Furthermore, Humanitas offers a genetic counselling service for several tumour, such as breast and colo-rectal cancer. We are also active in advertising campaigns on the importance of lifestyle.

And on the subject of early diagnosis we are involved in screening for cancers of the colon, breast and cervix.

On the therapeutic front, the battle at Humanitas against cancer integrates old and new weapons, offering high specialties in all oncological diseases thanks to the creation of specific sections.

The Oncology Department at Humanitas uses highlevel surgeries: the General Oncological Surgery directed by Roberto Doci, which includes a section specifically dedicated to the surgery of sarcomas under the guidance of Vittorio Quagliuolo, and of a Gastroenteric and Artificial Nutrition Surgery directed by Luca Cozzaglio; the Thoracic Surgery run

by Marco Alloisio, which specialises in the treatment of primary lung cancer and lung metastases, as well as tumours of the pleura and mediastine; Senology headed by Corrado Tinterri, which uses innovative techniques like radio-guided surgery of the sentinel lymph node and non-palpable lesions localised using the ROLL technique. And Radiotherapy, directed by Marta Scorsetti, has an excellent arsenal, featuring three dedicated bunkers: advanced equipment gives maximum precision and selectivity of the damage to be inflicted on the tumoral tissue, thereby reducing collateral effects.

These instruments are a CT with mobile lasers for virtual simulation, three linear accelerators with software for precision positioning of the patient and distribution of doses synchronised with the patient’s respiration movements, and a radiosurgical technique called SBRT (Stereotactic Body Radiation Therapy), which is used in the treatment of small lesions in the brain, but also in the lung, liver, pancreas and biliary ducts. In addition, RapidArc software minimises

The application and testing of new drugs represents a large part of the activity of the Oncology and Haematology Unit. We are currently working with important international centres in New York, Boston, Tampa, Stanford, Amsterdam, Dublin and Marseille.

We have worked on many innovative molecules that today are in clinical use and we are involved in many experiments of new drugs to discover better therapeutic weapons and to be leaders in the development of oncological results.

This is also the case in haemato-oncology, where we are actively involved in the development of new molecules (i.e. monoclonal antibodies for lymphomas, and biological therapies for myeloma and leukemias) and new therapeutic and transplant procedures.

In the Cellular Therapies Section coordinated by Luca Castagna, Humanitas is able to perform the complete range of marrow transplants: autologous and allogeneic, from an identical donor and from a voluntary donor, to finish with haploidentical and cord blood transplants.

» With regard to patient treatment, what are the strengths of the Oncology Department?

In Humanitas our attention to the word “cancer” extends from streamlining and simplifying patients’ care pathways to the promptness of cure interventions and the diversification of the assistance offered in treating the patient’s needs: we have created specialist outpatient services, that tackle clinical and psychological aspects of cancer, for example, those created by early menopause or the desire to have children in a woman affected by breast cancer. Under the coordination of Raffaele Cavina, we will shortly be activating outpatient services dedicated to patients (not only and always the elderly) with multiple comorbidities and to “cured” oncological patients, like those who have been out of therapy for at least three years, for whose management there are no international guidelines. It is important to add to the definition of shared intervention strategies and

top paper Masci G, Tommaso L, Del Prato I , Orefice S, Rubino A, Gullo G, Zuradelli M, Sacco R, Alloisio M, Eboli M, Incarbone M, Giordano L, Roncalli M & Santoro A

Sinusal localization of nodal micrometastases is a prognostic factor in breast cancer personalised screening and follow-up.

A short while ago we also created a senology section specifically dedicated to the medical treatment of patients suffering from breast cancer, coordinated by Rosalba Torrisi.

» What are the plans of the Oncological Department at Humanitas?

Humanitas is always looking towards new research and innovation. In this respect we have already initiated a very close working relationship with all the Units involved, both inside and outside the Oncology Department. One example is Biobank directed by Daniela Pistillo, which is a collection of biological samples on which future research will be able to find predictive factors in treatment response.

With Adalberto Ibatici we are also starting up a cell factory to produce cells for therapy research in the oncological, cardiological, opthalmological and orthopaedic fields, wherever regenerative therapy is required; and we are also working with Paolo Pedrazzoli in the use of cellular therapies in specific malignancies. We have always been actively involved in the development of new molecules and in their testing from the earliest stages (the so-called Phase I trials). For this purpose we have created an ad hoc clinical pharmacology group coordinated by Paolo Zucali that will enable us to increase our development of antitumoral drugs.

Finally, we have given an enormous boost to molecular biology with doctors Lorenza Rimassa, Giovanna Finocchiaro, Luca Toschi and Nicola Personeni, who are involved in the identification of molecular and genetic factors that underlie cancer development and in the validation of prognostic and predictive biomarkers.

We have opened a Translational Oncology laboratory that focuses on these activities and its aim for 2011 is to create a Translational Oncology facility where all these scientific and experimental skills come together, with the purpose of taking a global approach to patient treatment and science.

Annals of Oncology. 2009; Oct 29.

Background: Breast cancer micrometastases are frequently found during pathological examination of sentinel lymph nodes and complete axillary lymph node dissection.

Despite this, their clinical relevance is still debated. The aim of this study is to investigate features that affect disease-free survival (DFS) and overall survival (OS) in patients with nodal micrometastases from breast cancer.

Material and methods: We retrospectively investigated the outcome of 122 patients with nodal micrometastases from breast cancer followed up for 60 months.

Results: At univariate analysis, worse DFS was related to features of primary tumor (multifocality P = 0.002; size >2 cm, P = 0.022; grade P = 0.022; absence of estrogen P < 0.001 and progesterone P < 0.001 receptors; HER-2 overexpression P = 0.006; vascular invasion P = 0.039; proliferative fraction ‡20% P = 0.034) and micrometastases (sinusal localization P = 0.010). Among the above-mentioned features, two were strongly associated with worse DFS in the multivariate model, i.e. negative receptorial status [hazard ratio (HR) = 11.24, 95% confidence interval (CI) 4.06– 31.09; P < 0.001] and sinusal localization of micrometastasis (HR = 3.66, 1.18–11.36; P = 0.025). The OS was influenced by multifocality (P < 0.001) and receptor status (P = 0.005).

Conclusion: Our results indicate that in patients affected by breast cancer, in addition to the well-known pathological features of primary tumor, sinusal localization of micrometastasis strongly impacts on the prognosis.

« It is important to add to the definition of shared intervention strategies and personalised screening and follow-up »

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Gastroenterology

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Over the past fe� years a new approach has been taken towards the gastroenteric tract, in which “foreign” microorganisms play a very important role. Inside our organism, made up of 100,000 billion cells, there are in addition at least 10 million billion such microorganisms. In the intestines, for example, microorganisms help us metabolically, behaving like “factories” that produce essential elements, and encourage the development and functioning of our immune system. The evolution of this system has been fundamentally aided by the selection of “good” microbes as opposed to those that represent a danger.

Moreover, genetic studies have shown that changes in our ability to recognise foreign microorganisms is a cause of the development of inflammatory bowel diseases like Crohn’s Disease and ulcerative

rectocolitis. Recent studies have demonstrated how defence cells in patients affected by Crohn’s Disease do not perform – as was believed – increased inflammatory activity but are in fact less able to respond to the microbes. This is a further confirmation of the fact that a delicate balance exists between the host organism and the microorganisms that become localised in the gastroenteric tract.

It is of fundamental importance, therefore, to deepen our knowledge of this situation, which in Humanitas is studied using a metagenomic approach. The aim of the studies in progress is to understand how and how much these microbes affect pathologies of the intestinal tract, and to what extent the use of probiotics can reduce or control the emergence of disease.

Searching for the inflammatory genesis of tumours » What is new in the therapy of inflammatory bowel Interview with Alberto Malesci

Alberto Malesci is head of the Department of Gastroenterology at Humanitas. He coordinates several research teams: the first group which is supervised

by Silvio Danese investigates pathogenesis of inflammatory bowel disease. The main team, lead by Luigi Laghi focuses on colorectal and pancreatic cancer translational research.

Alessandro Repici’s team develops and validates new diagnostic and therapeutic devices for digestive endoscopy.

Finally, physiopathology of gastroesophageal reflux disease (GERD) is being investigated in collaboration with Edoardo Savarino from University of Genoa.

disease?

The Research and Cure Centre for Inflammatory Bowel Disease, lead by Silvio Danese, is investigating a variety of novel therapeutic approaches.

At the cutting edge of translational research, the group is testing the possibility of inhibiting lymphangiogenesis in patients with ulcerative colitis and Crohn’s disease.

Furthermore, our group is focusing on the inhibition of pro-angiogenetic factors released by platelets, which are attracted by the endothelium cells of intestinal micro vessels.

Sponsored clinical research is also very active: we are testing new biological drugs, such as anti-VEGF-C polyclonal antibodies, the anti-interleukin 12/23 called Ustekinumab, and Vedalizumab. This last drug is a monoclonal antibody directed exclusively against a particular integrin, alpha(4)beta(7)integrin, and modulates the action of inflammatory cells in the gastro enteric tract without inducing systemic immunosuppression. Phase II studies have already been completed and it is now being tested versus placebo in Phase III, which should lead to its approval. An international multicentre study has also been concluded on the clinical effectiveness, versus placebo, of antibiotics released in gut in patients suffering from moderate Crohn’s disease and the results have been presented at Digestive Disease Week, an important convention held in New Orleans in the first week of May. Since November 2008, our centre has been reproposing the old budesonide, but in a new formulation whose coating allows the active principle to be released in the colon alone, thus minimising systemic effects. Finally, we participate in a study testing the effectiveness of lymphocytapheresis.

» Can you please explain the role played by VEGF? It is a tumoral growth factor as it has a role in regulating angiogenesis, which is implicated in the development of cachexia in patients with advanced cancer and which also has a pro-inflammatory action in chronic intestinal pathologies. Our Laboratory has studied the role of a molecular adhesion protein called JAM-A (Junctional Adhesion Molecule-A) expressed by epithelial and endothelial cells to maintain wall integrity, and regulate permeability to water and solutes and the normal exchange of epithelial cells. When levels of JAM-A fall or it is absent, as in chronic intestinal inflammation, cell death is accelerated

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Searching for the inflammatory genesis of tumours Interview with Alberto Malesci

and ulcers are created in the mucous membrane. The goal of the research is to design new drugs that restore the intestinal barrier. Also under study is the role of TREM-2 receptors (Triggering Receptor Expressed on Myeloid cells-2) in intestinal homeostasis.

» Is intestinal inflammation linked to tumour development?

Yes indeed. Our Laboratory is also studying a receptor called D6, which is part of the negative regulation system of chemokyne levels. It has been observed that the lack of D6 increases susceptibility to the emergence of adenocarcinoma in inflammatory bowel disease. Chronic inflammation creates the conditions for the development of neoplastic forms in the colon, prostate and liver. Communication between tumours and inflammation cells occurs through a circuit of pro-inflammatory mediators that include cytokines, chemokynes and metabolites. This pro-inflammation response can be triggered and maintained in the tumoral cells by activation of certain oncogenes.

The growth of the tumour is also influenced by the ‘tumoral microenvironment’, which consists of fibroblasts, cells of the immune system and endothelial cells, plus the components of the extracellular matrix.

» What about your additional research on translational oncology?

With regard to colon cancer, our research has several objectives. One is to identify new biological prognostic markers: as a fact, the conventional staging system does not answer the question whether chemotherapy should be used after surgery in subjects with a tumour that does not extend to the lymph nodes (stage II). It would be very useful to identify patients at higher risk of relapse among stage II patients, who have a 20-25% overall risk of metastasis. To this end, research is also looking at the local immune response of cancer.

» We know that you recently published on this

topic in Lancet Oncology: what did your study add to our knowledge?

46

The study confirmed the existence of an inverse ratio between the entity of the local immune response, represented by the density of T-lymphocytes at the invasive front of the tumour, and the development of

metachronous metastases after surgical resection.

However this worked only if the cancer had not spread to the lymph nodes. Suppression of T regulatory cells might become a therapeutical option.

» What decides if a tumour is metastatic or not?

The mechanism for distant organ metastasis is being studied. The crucial step seems to be the so-called epithelial mesenchymal transition (EMT). The epithelial cells ‘change’ to be able to enter the blood or the lymphatic vessels through which they reach their target organs, where they re-acquire their original characteristics. By the way, when micro satellite instability coexists, this capacity is lost. As a result, the micro satellite instable tumours are unlikely to progress to metastasis.

» What about pancreatic cancer?

This cancer still has a very poor prognosis and no real breakthrough has been achieved to the end of patient care.

Recently, the Cell Immunology Laboratory has studied the receptors of the chemokynes (such as CX3CR1) expressed by the pancreatic ductal carcinoma that are involved in the dissemination of neoplastic cells along the nerve fibres that cross the organ and retro-pancreatic nerve ganglions.

This dissemination leads to a post-surgery relapse. The research groups that together have managed to define neural tropism of the pancreatic carcinomatous cells are those run by Paola Allavena and Alberto Mantovani for Humanitas, and by Lorenzo Piemonti for San Raffaele. The project is to produce specific inhibitors that give a boost to the therapy of a killer disease that has so far been unstoppable.

« Chronic inflammation

creates the conditions for the development of neoplastic forms in the colon, prostate and liver

»

Âť To conclude our talk: which are the most recent innovations in digestive endoscopy?

Prototypes of new endoscopic instruments are being tested in our endoscopic unit. We are also testing two very new techniques for detecting areas of displasia or neoplasia in patients with inflammatory bowel disease.

These techniques are chromoendoscopy and narrow band imaging (NBI). Chromoendoscopy colours mucous to allow recognition of displastic or cancerous areas and NBI makes use of a new optical technology that identifies micro circle alterations in superficial neoplastic lesions.

Beside technological innovation, our unit is particularly voted to endoscopic resection of T1a and T1b esophageal tumours, whose success is largely operator dependent.

ÂŤ New drugs have a role

in regulating angiogenesis

Âť

47

Searching for the inflammatory genesis of tumours Interview with Alberto Malesci

top paper Laghi L, Bianchi P, Miranda E, Balladore E, Pacetti V, Grizzi F, Allavena P, Torri V, Repici A, Santoro A, Mantovani A, Roncalli M, Malesci A.

CD3+ cells at the invasive margin of deeply invading (pT3–T4) colorectal cancer and risk of post-surgical metastasis: a longitudinal study Lancet Oncol 2009; 10: 877–84

Background. The density of tumour-infi ltrating lymphocytes (TIL) has been proposed as an independent predictor of outcome in patients with colorectal cancer. However, the relative roles of TIL density, nodal status, and microsatellite instability (MSI) in predicting tumour progression to metachronous metastasis remain to be elucidated.

The aim of this study was to assess the relationship between the density of CD3+ TIL and the postsurgical occurrence of distantorgan metastases in a large series of patients with deeply invading and MSI-typed colorectal cancer.

Methods. Per cent areas of immunoreactivity due to CD3+ TIL at the invasive margin of the tumour (CD3+ TILIM) were measured by computer-assisted image analysis in 286 tissue specimens from pT3 or pT4 MSI-tested colorectal cancer. Tissue samples were taken from consecutive patients who underwent resection at the IRCCS Istituto Clinico Humanitas, Rozzano, Milan, Italy, from January, 1997, to November, 2004, for colorectal cancer with no evidence of metastasis at diagnosis. Occurrence of metachronous metastasis, disease-specifi c survival (DSS), and disease-free survival (DFS), were assessed retrospectively in relation to per cent immunoreactivity.

Findings. CD3+ TILIM density was higher in MSI colorectal cancer than in mismatch repair-systemprofi cient tumours (6·53% vs 2·19%; p<0·0001).

At Cox analysis, higher CD3+ TILIM densities, colonic site, and absence of nodal involvement were signifi cantly associated with a lower risk of metachronous metastasis, but only the interaction 48

between CD3+ TILIM density and N-stage was signifi cant on multivariate analysis (p=0·002). On separate analysis of node negative colorectal cancer, increasing percentage of CD3+ immunoreactive area progressively reduced the risk of metachronous metastasis (<1%, reference; 1–5%, HR 0·28, 95% CI 0·10–0·81, p=0·02; >5%, 0·06, 0·01–0·48, p=0·008). Conversely, no signifi cant association was seen between CD3+ immunoreactive area and risk of metachronous metastasis in node-positive colorectal cancer. Accordingly, CD3+ TILIM density was associated with a better DSS (p=0·01) and DFS (p=0·006) only in patients with node-negative colorectal cancer. In primary tumours that had progressed to metachronous metastasis, stage III tumours had higher CD3+ TILIM densities than stage II tumours (p=0·0004).

Interpretation. Metachronous metastases are unlikely to arise from node-negative colorectal cancers with a highdensity CD3+ TILIM, whereas high densities of CD3+ TILIM are not associated with the absence of postsurgical metastasis in patients with node-positive colorectal cancer. Our data suggest that densities of CD3+ TILIM cannot be used as an independent predictor of clinical outcome in patients with stage III colorectal cancer and, at least for now, the tumour-node-metastasis classifi cation should remain the preferred prognostic system. Our fi ndings are consistent with a relationship between nodal involvement and tumour immunoevasion.

Funding: MIUR (Ministero dell’Istruzione, dell’Università e della Ricerca), Target Project Oncologia 2006, and Alleanza Contro il Cancro.

Less gives more, or at least better

Interview with Marco Montorsi

Marco Montorsi is Professor of General Surgery at the Faculty of Medicine at the Università Statale di Milano and head of the Humanitas General Surgery Operating Unity III.

* (Torzilli G. Surgical technique: new advancements for expanding indications and safety: the Western experience.

Hepatobiliary Pancreat Surg 2009 Nov 7. [Epub ahead of print]; Torzilli G et al. One-stage ultrasonographically guided hepatectomy for multiple bilobar colorectal metastases: a feasible and effective alternative to the 2-stage approach.

Surgery 2009; 146: 60-71; Donadoni M et al. Experience with more than 500 minimally invasive hepatic procedures: a serious note of caution. Ann Surg 2009; 249: 1064-5; Muilenburg DJ et al. Surgery in the patient with liver disease. Anesthesiol Clin 2009; 27: 721-37; Torzilli G et al. Systematic Extended Right Posterior Sectionectomy: A Safe and Effective Alternative to Right Hepatectomy. Annals of Surgery 2008; 247: 603-611; Torzilli G et al. Anatomical segmental and subsegmental resection of the liver for hepatocellular carcinoma: a new approach by means of ultrasound-guided vessel compression.

Ann Surg 2010; 251: 229-35).

» Professor Montorsi, which area in General Surgery is of greatest interest?

First of all digestive surgery: hepatobiliopancreatic, oesophagogastric and colorectal. Then, sarcomas and rare tumours, in particular in the digestive field, are the subjects of multicentric research projects that we are involved in.

We are trying to ensure that everyone working in the Unit refines his or her skills in a particular field of surgery, thereby creating, even if not nominally, a series of high specialisations. Humanitas encourages the development of highly specialised skills: it is a University polyclinic with a wide range of advanced technology, where a large number of students and people training in specialisations are present and provide fundamental assistance to research, and where these very competences enable them to acquire broad clinical and assistance-related experience.

» What is your personal interest of study at your Operating Unit?

I would first mention diseases of the liver and the historical evolution of operating techniques. The principal innovation has been the use of ultrasound as a guide to planning operation strategy in terms of conservative resections using various types of procedures, including mini-invasive ones. The possibility of preserving the hepatic parenchyma, removing a portion of the organ lower than the lobe (segmentectomy and subsegmentectomy) and thus respecting the metabolic events produced in the liver, has opened new therapeutic horizons. A number of innovative surgical techniques have been proposed such as SERPS (Systematic Extended Right Posterior Sectionectomy), which consists in a conservative, but at the same time radical, modification to the classic right hepatectomy, exploiting the potential given by intraoperative ultrasonography.

Many studies published on the subject are by Guido Torzilli, Professor and Associate of General Surgery at the Università degli Studi di Milano and section head of Hepatic Surgery.* It should be remembered that Humanitas is the site of the European School of Surgical Ultrasonography (ESSU), the aim of which is practical and theoretical teaching of interventional ultrasonography in all fields of surgery.

» The tendency then is in the direction of increasingly less invasive surgery?

Over the last twenty years mini-invasive surgery has made great progress. The technological innovations that have made

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Less gives more, or at least better Interview with Marco Montorsi

« In many cases laparoscopy

is today the gold standard for surgical operations, even in Day Surgery

»

this leap in quality possible are evermore sophisticated image transmission systems, both analogue and digital, and dedicated instruments. In many cases laparoscopy is today the gold standard for surgical operations, even in Day Surgery. The advantages for patients are significant: minimum tissue damage, reduced postoperative pain, a shorter length of stay, and a faster recovery of normal activities. We have seen a continual effort to reduce the invasive nature of operations by reducing the extent and number of incisions. Thus another opening through which operations can be conducted has been rediscovered in the umbilicus: in mini-invasive surgery it is used as a port of access for one of the surgical instruments (the first trocar) and for the telecamera that allows surgeons to see the images of the operation on a monitor.

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» Are you referring to “scarless” cholecyst operations?

Yes. My team and that of Riccardo Rosati have carried out – among the first in Italy – this type of cholecystectomy using the umbilicus as a natural opening to perform the entire operation. This is unquestionably another step forward on the path of surgery that is increasingly respectful of the patient’s well-being. Time and experience will tell us whether this approach offers a real advantage to the patient, not only from the point of view of appearance but of function too, in comparison with traditional laparoscopic cholecystectomy.

» On 1 January 2009 the University Department of

Translational Medicine came into being, of which you are the director. What are its goals?

The name of the Department is a reference to our commitment to apply basic research findings in the clinic. One of the Department’s objectives is to activate research protocols in the most important clinical sectors, such as surgery of the liver and biliary ducts, inflammatory bowel disease, and mini-invasive surgery.

2010 will be the year of a vast multicentre research project on surgery of the hepatocarcinoma, and a

research protocol is ready on the use of microwave ablation as a technology to be used alongside radiofrequency ablation.

» Another of your particular interests is pancreatic surgery.

Since the start of this year Humanitas has been working with Alessandro Zerbi, who is particularly expert in this field of surgery. Humanitas is also the coordinating centre of a large multicentre study in Italy whose aim is to validate the use of biological supports in order to reduce the occurrance of fistulas after left pancreatectomy. Fistulisation is one of the most frequent complications in surgery of the pancreas.

A protocol for neo-adjuvant chemotherapy has been activated and is in its initial phase, which includes biological drugs for patients considered borderline resectable. The benefits of neo-adjuvant therapy have now been ascertained: partial response of the tumour to chemotherapy increases the possibility of tumour free resection margins and tests the sensitivity of the tumour to drugs. If the treatment required is pluripharmacological, it will be better tolerated before a duodenopancreatectomy (after which 40% of patients have complications); lastly, the fact that patients who have been operated successfully show recurrences means that micrometastases may be present even during initial phases of the disease and the neo-adjuvant therapy may help to control them.

» The University Centre for Research of

Oesophagogastric Diseases, directed by Riccardo Rosati, has just been opened. It reports to the Department and brings together all the skills in this field.

And they are skills of great international prestige: in Humanitas surgery of the oesophagus and stomach is conducted by surgeons of great experience such as Riccardo Rosati and Alberto Peracchia, senior consultant for mini-invasive surgery, to which great attention is paid and which is preferred, with the help of technological improvements.

Colonic and rectal surgery can now be performed under laparoscopy in 70-80% of cases, with the result that ostomies have decreased to 5%. The laparoscopic

technique also improves post-operative recovery and (probably) the long-term outcome. The hypothesis is that mini-invasive surgery preserves the immune system response in the post-operative phase and consequently may improve the long-term result.

On this subject, our Surgery Unit and Alberto Mantovani are working together on a comparative study between the immunological response to laparotomic or laparoscopic surgery, using various chemokines and pentraxin as a pathology marker.

Following the logic of the motto “small tumour, small operation”, further studies are being undertaken on the reliability of examination of the sentinel lymph node for tumours of the colon. It should be pointed out, however, that for the moment this procedure has given poorer results than in breast surgery.

» Marco Montorsi is the general coordinator of

fast track protocols that aim at allowing patients to be discharged in a few days.

Post-operative patient care is one of the most relevant aspects of surgery at Humanitas. The rapid discharge of a patient is the result of a series of factors, the most important of which is the informed involvement of the patient and his family. The principles of not eating prior to the operation and of intestinal preparation have been rethought; bladder catheterisation is of short duration and abdominal drainage can be omitted; nausea and post-operative pain are carefully monitored (to avoid negative repercussions on patient homeostasis, the supply of systemic opiates is prohibited in favour of epidural anesthesia).

Early feeding and mobilisation are incouraged.

Anaesthesia has also been reconsidered: in Humanitas there are two distinct anaesthesiological services: one specialised in major surgery and

« The benefits of neo-adjuvant

therapy have now been ascertained: partial response of the tumour to chemotherapy increases the possibility of tumour free resection margins

»

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Less gives more, or at least better Interview with Marco Montorsi

top paper Torzilli G, Procopio F, Cimino M, Del Fabbro D, Palmisano A, Donadon M, Montorsi M

Anatomical Segmental and Subsegmental Resection of the Liver for Hepatocellular Carcinoma. A New Approach by Means of Ultrasound-Guided Vessel Compression Ann Surg. 2010; 251: 229–235.

Background. Anatomic resection is considered the gold standard approach for liver resection in patients with hepatocellular carcinoma. The use of intraoperative ultrasound (IOUS) as guidance is indispensable in this sense but methods available up to now were rather complex and for that reason of limited use. We herein describe a novel technique for the demarcation of the resection area by means of IOUS-guided finger compression to systematically accomplish anatomic segmental and subsegmental resections.

Methods. Thirty-three patients met the eligibility criteria. This technique consisted in the demarcation of the resection area by IOUS-guided finger compression of the vascular pedicle feeding the tumor at the level closest to the tumor but oncologically suitable. Median age was 65 years (range, 36–81). There were 25 men and 8 women.

52

the other in day surgery. Epidural anaesthesia is preferred, when possible (abdominal laparoscopy, for example, requires a general anaesthetic); inhalation anaesthetics are reduced in favour of intravenous ones.

ERAS (Enhanced Recovery After Surgery) is a protocol already in use in colorectal and vascular surgery and is currently being activated also in urological, gynaecological and hepatobiliopancreatic surgery. This protocol requires periodic audits to update antibioticotherapy protocols in collaboration with Humanitas’s infectologists.

The result of these efforts is a reduction in surgical stress, which is translated into a rapid return to as normal a life as possible for the patient.

Median tumor number was 1 (range, 1–2); median tumor size was 2 cm (range, 1–10). Twenty-five (76%) patients had cirrhosis or chronic hepatitis, and 8 (24%) had steatosis (ClinicalTrials.Gov ID: NCT00829335).

Results. Procedure resulted feasible in all eligible patients, and demarcation area was obtained in all patients within 1 minute of bimanual IOUS-guided compression. There was no mortality or major morbidity: only 7 (21%) patients experienced minor morbidity. No blood transfusions were administered.

Conclusions. Systematic segmentectomy and subsegmentectomy by IOUSguided finger compression is a feasible, safe, and effective technique, which could be considered as a simpler alternative to those up to now proposed.

Advanced mathematics at the service of human health Interview with Nicola Dioguardi

» Professor Dioguardi, what is the programme of your laboratory that studies metric measurements in medicine?

The programme is to decrease subjective evaluation and hypothesis in the medical sciences.

» Your group has worked for some years on the

prototype of the Histological Metriser. What is it exactly?

Nicola Dioguardi, after a life spent teaching at Università Statale di Milano, is the Scientific Superintendent of Humanitas since 2005 and the Director of the Laboratory for the Study of Metric Measurements in Medicine since 2001.

The machine is an example of the output of this Laboratory’s programme. It was built with Carlo Russo, a doctor in information sciences, the statistician Emanuela Morenghi, and the biologists Barbara Franceschini, Sonia Di Biccari and Stefano Musardo. Musardo was a student in biology and today is a summa cum laude graduated doctor. Economic support was provided by the Rodriguez Foundation. The Histological Metriser is an effective and potentially operative instrument able to give a computerised appraisal in micrometers of the extent of inflammation, of the biliary microcanal system, fibrosis, neoangiogenesis and the quantisation of the structural disorder that they cause in the liver tissue. In four minutes for each histological section the machine produces 14 parameters that measure the determinants for analysis of chronic liver inflammations, of fibrosis, posthepatic, Laennechian cirrhosis and primary biliary cirrhosis. The fully automated Histological Metriser, which has been completely devised and built in Humanitas, reduces the physical and mental exertion of

53

Advanced mathematics at the service of human health Interview with Nicola Dioguardi

« In the Metriser we have

a machine that applies the quantitative scientific method to irregular histological phenomena

»

the operator, opens new vistas and identifies new parameters that can be used in hepatological clinic and research.

» What logical and mathematical model does it use?

Point dynamics, the geometry of behaviour and the geometry of irregular bodies are some aspects of a new view into theoretics and praxis of medical science whose aim is to reduce the use of hypothesis in clinical and in research environments. The logic adopted was suggested by the geometry of the dynamic behaviours that leads us to consider the vectorial magnitude of the quantities of interest and use them to measure the dynamic behaviour of the pathological processes.

» These are difficult concepts to understand…

54

What we propose in Humanitas relates to a theory based on the computer-aided construction of a general theoretical outline of chronic hepatic diseases that coincides with the dynamic behaviour inferred by clinical experience. The objective is to update our understanding of certain traditional behaviours. Our aim is to clarify in physical and geometrical terms the behaviour of the states of the phenomenic complex that determine certain hepatic diseases and to look for new information that will aid us in predicting their development. In summary, the theory we are creating is related to results obtainable from valuations of histologic structures of bioptic specimens using the theory of measurement that forms the basis both of our knowledge of the physical world, and of the creation of models that organise this knowledge.

» How do you apply the theory of dynamic evaluation to primitive biliary cirrhosis?

The intention is to study the determinants of chronic disease substituting the current criteria of evaluation useful only for comparative purposes suggested by static physics with quantitative measurements that define structural changes over time in accordance with dynamic criteria.

For example the current histological evaluation subdivides the long-standing course of primary biliary cirrhosis (PBC) into the four stages which delineate disease progression: inflammation, ductular regeneration, fibrosis, and tissue disorder.

However, analysing serial liver biopsies to monitor PBC enhancement has become uncommon due to the unsatisfactory standardisation of the current semiquantitative methodologies which remain largely dependent on the pathologist’s expertise.

Furthermore, all current histological criteria rely on the static branch of physics that limits the readouts to the actual state. The processes of evolution (past and future) are in a large sense considered only related to the increasing complexity of the collective behaviour of intrinsecally simple objects.

In addition, PBC staging is particularly unreliable during the intermediate stages of the disease when bile ductule destruction intersects with regeneration, inflammation becomes florid, and fibrosis increases.

As biopsy is the only manoeuvre that allows partially representative but direct observation of the liver tissue, but retains some risk even in skilled hands, we realised that measurement – which lies at the very core of liver description – might provide the point of departure for the construction of a liver tissue evaluation that could satisfy the need for a complete and precise automated mathematical method for the measurement of the PBC process progression.

Taking into consideration inflammation, CK7+ hepatic ducts, and fibrosis magnitude vectorial quantities, the state-of-the-art machine we have created on the basis of dynamic criteria: 1. gives the metrical state portrait of the PBC determinant liver structures; 2. identifies the dynamic point particle whose progressive change of position in the state space

determines the trajectory that describes the overall PBC process behaviour from α to ω; 3. a llows identification of the time of the process marked by fibrosis; 4. fi nds a significant relationship between the data obtained from the tectonic index; 5. s hows that the trajectory depicting the dynamics of PBC could be divided into three stadia: the first is characterised by low and high levels of CK7+ structures, in the second CK7+ bile ducts and fibrosis vary widely from low to high levels, indicating strong CK7+ ductule regeneration, while in the third CK7+ cells and fibrosis are maximal.

Given these propositions, we can say that the “measurement of dynamics” refers to the quantitative evaluation of changes in visible and measurable hepatic elements over time. The information and knowledge given are clear and repeatable, but they modify the observer’s interaction so profoundly that they generate prejudice and hostility.

« The information and knowledge given by the “measurement of dynamics” are clear and repeatable »

55

Women’s health

56

Gender medicine, which takes account of the differences and problems related to the patient’s sex, is one of the great challenges of this century. We have always thought of health in a sort of “asexual” way, but over recent years we have understood that gender, whether male or female, is in fact very important to medicine. For example, the management of a female cancer patient of reproductive age incurs particular problems due to the importance of being able to guarantee her a future pregnancy, and to monitor the effects of pregnancy and post-pregnancy on the disease itself.

And on the other hand because pathologies exist that are strictly tied to sex. Autoimmune (or immunodegenerative) diseases are paradigmatic: rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis affect mostly women and generally at a young age. Lupus, for instance, is approximately nine times more common among

women than men, and similar data can be found for rheumatoid arthritis. And the therapy for inflammatory bowel diseases – Crohn’s disease and ulcerative rectocolitis – in women brings a greater risk of osteoporosis.

However, sex also plays an important role in diseases that are not traditionally gender-related, such as cardiovascular diseases. Recent epidemiological observations have shown that there is an alarming increase in such pathologies among women, particularly after menopause. In Italy 120,000 women die each year from cardiovascular diseases, a mortality rate three times greater than that due to breast tumours. Acute myocardium infarction alone kills approximately 33,000 women a year.

It is Humanitas’s goal to be at the cutting-edge in medicine, and in gender research, particularly for the benefit of women.

The goal: the all-round well-being and fulfilment of women Interview with Paolo Emanuele Levi Setti

Paolo Emanuele Levi Setti, President of the Italian Society of Fertility, Sterility and Reproduction Medicine (SIFES e MR), has worked for Humanitas since 1996. He is Director of the Department of Gynaecology and Reproduction Medicine, which comprises the Gynaecology and Reproduction Medicine Operating Unit directed

by Levi Setti himself, and the Gynaecology Operating Centre directed by Domenico Vitobello.

» Two names and two missions for the Department that you direct?

Yes indeed: the Department has twin clinical activities, both strictly connected with research: • the prevention, diagnosis and therapy of couple infertility and of the conditions that reduce the possibilities of procreation, whether gynaecological or andrological.

• the prevention, diagnosis and therapy of benign and oncological female genital disease, with particular attention paid to new endoscopic technologies and the use of robotics.

In January 2008 an entire block was inaugurated dedicated to hi-tech assisted reproductive technology (ART) in its every aspect: oocytes collection, embryo culture, cryopreservation of gametes and embryos, surgical spermatozoa collection, endoscopic diagnosis and therapy of the utero-tubal pathologies in reproduction. In this type of surgical operation, a mini-invasive procedure can be much more radical with the use of optical equipment and entering devices with diameters much smaller than is usually possible using laparoscopic surgery. Attention is focused not only on the recovery of the patient and the reduction of complications but also on the aesthetic aspect”. This activity is supported by a counselling programme and outpatients’ services that integrate diagnostics and the activity of low-tech medically assisted procreation. The follow-up of couples and pregnancies is performed by two psychologists as part of the quality project called “Humanitas for Couples and Children Care Project (CCCP)”.

» What is the volume of activity of this Department?

The Humanitas ART Department has performed more than 20,000 assistance cycles (representing all the techniques used) and performs more than 2,500 assisted procreation procedures every year. As regards the prevention of infertility and the development of new technologies, the Department has one of the most experienced teams in the world when it comes to the cryopreservation of female gametes. In 2006 the results of the activities of the period 1989-2003 were published, which included 303 freezing cycles and 156 defreezing cycles (Levi Setti PE, Albani E, Novara PV, Cesana A, Morreale G. Cryopreservation of supernumerary oocytes in IVF/ICSI cycles. Human Reprod 2006; 21: 370-5) and in 2008 the data of 1,280 defreezing cycles

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The goal : the all-round well-being and fulfilment of women Interview with Paolo Emanuele Levi Setti

« A new line of research: rather

than freezing single oocytes, a part or the whole of the ovarian parenchyma is frozen

»

with different protocols of cryopreservation up to the end of 2007 were published, with the achievement of 144 pregnancies (Albani E, Barbieri J, Novara PV, Smeraldi A, Scaravelli G, Levi Setti PE. Oocyte Cryopreservation. Placenta 2008; 143-146). Our database includes more than 1,800 thawing cycles and more than 200 pregnancies, out of the about 1,000 pregnancies reported in the world. This activity has permitted us to carry out multicentre studies of great scientific importance in partnership with the Istituto Superiore di Sanità (ISS) (Borini A, Levi Setti PE, Anserini P, De Luca R, De Santis L, Porcu E, La Sala G, Ferraretti A, Bartolotti T, Coticchio G, Scaravelli G. Multicenter observational study on slow-cooling oocyte cryopreservation: clinical outcome. Fertil Steril 2010 in press).

» What are the advantages of the recent oocytes freezing techniques?

Cryopreservation of egg cells is fundamental for treating infertility, because it enables us to have a reserve of unused oocytes on which to repeat the attempt to have a pregnancy with a successive cycle of assisted fertilisation, without requiring further ovarian stimulation. Oocyte freezing can reduce the number of frozen embryos.

Moreover, in the field of infertility prevention, it is offered to patients of reproductive age affected by tumours (prevalently leukaemia or lymphomas, which more frequently have a good prognosis).

» 58

I s the freezing of oocytes an easily executed technique and does it use a well defined procedure?

There are several critical aspects with regard

to maintaining the integrity of the anatomicalfunctional microstructures of the cell: the oocytes could theoretically be preserved indefinitely in liquid nitrogen at –196°C, and then returned to normal body temperature, but the phases of freezing and defreezing can produce structural and functional damage to the cell. That can be avoided (though only partially) by the introduction of what are called cryoprotectant substances like saccharose. Comparative studies are being made between two techniques of cryopreservation: one using controlled rate slowcooling, which is programmed to follow a temperature reduction curve, and the other using rapid freezing, called vitrification (due to the appearance the cells take), which is thought to prevent oocytes being damaged by the formation of ice crystals, but which requires a higher concentration of chemical substances in the preparatory solution that possibly have a toxic effect on cells. Vitrification is, moreover, a technique that is very dependent on the person in charge of the operation: the result can be affected greatly by the smallest of modifications in the procedure.

Another line of research is carried out on freezing: rather than freezing single mature or immature oocytes (for every woman at least 10 oocytes need to be preserved), a part or the whole of the ovarian parenchyma is frozen.

Obviously, this method is the only one that can be used when we “try” to preserve future fertility in females who have a tumour during prepuberty, but it is also recommended for adult women with hormone-dependent tumours who should not be subjected to hormonal stimulation to obtain oocytes to freeze, or when the time available to obtain oocytes is very limited (for example, if chemotherapy needs to be started very shortly). Use of the word “try” is deliberate, as such a low number of births (no more than ten worldwide) have been recorded after the reimplantation of defrozen ovarian parenchyma, following the healing of a tumour.

» What, in general, is the rate of success for assisted fertilisation?

In Humanitas in 2009, 505 pregnancies were achieved using assisted procreation techniques, but a more detailed answer to this question needs

a premise: in parallel to the rates of success in spontaneous conceptions, the apex of which occurs for women aged 25, ART methods have a success rate that exceed 50% in women below the age of 30 but this percentage drops with increasing age. For example, in Lombardy, where the average age of women trying to have a child with medical assistance is higher than in the rest of Europe, the failure rate of assisted reproduction is very high. At the same time, the more advanced age of the women in question (plus the more extensive information available and their greater economic possibilities) encourage Lombard couples to seek help from centres abroad where the donation of female gametes is allowed.

« ART procedures have a

success rate that exceeds 50% in women below the age of 30

»

» Research into procreation and couple infertility

is progressing. Furthermore, the follow-up of the pregnancies’ outcome is important. How is the Humanitas Centre organised to handle this aspect?

One of the Department’s strong points is the clinical database of medical records and procedures which, for the protection of personal data, is held separately from the institute’s information systems. This archive was set up in 1996 and developed in a quality project called the Paperless Operative Unit. In 2009 this system won a Lombardy Region research competition on the computerisation of ART procedures. The archive contains more than 13,000 clinical files on couples, 3,440 pregnancies obtained using assisted fertilisation procedures, with an abortion rate of 17% (not dissimilar to the rate among spontaneous pregnancies if considered by age groups), and with roughly 20% of twin births. The chromosomal anomalies registered in aborted fetuses have shown a comparable incidence in both different techniques (ICSI and FIVET) and in miscarriages in spontaneous pregnancies (Bettio D et al. Chromosomal

59

The goal: the all-round well-being and fulfilment of women Interview with Paolo Emanuele Levi Setti

top paper Chiriva-Internati M, Nicoletta Gagliano N, Elena Donetti E, Costa F, Grizzi F, Franceschini B, Albani E, Levi-Setti PE, Gioia M, Jenkins M, Cobos E, and Kast WM. abnormalities in miscarriages after different assisted reproduction procedures. Placenta 2008; 29: S178-83).

Factors that cause serious infertility in men are an insurmountable obstacle to the success of assisted fertilisation. These are, moreover, often indicative of anomalies in the sex chromosomes and an epiphenomenon of a damaged gonad, with increased risk of a testicular tumour. Such a condition should receive early screening and a follow-up in its own right (Negri L et al. Cancer risk in male factor-infertility.

Eur J Cell Biol 2008; 87: 963-76).

» Can you give a figure for mini-invasive surgery on women?

60

In relation to the treatment of benign and oncological female genital diseases, the “figure” can be translated into a rate: mini-invasive surgery (which is always preferred) is used in 85% of cases, including in those for which the protocols of most of the other Centres recommend laparotomic surgery.

By the use of robot technology, mini-invasive surgery can be radical in many procedures beyond conventional limits, due to better visibility and instrumentation that can reach very restricted spaces. The arrival of Domenico Vitobello in the management of the Gynaecology Operating Unit in July 2009 introduced robotics as the preferred method in gynaecological surgery.

Once diagnosed, the approach taken to a tumour is based on the joint opinions of the surgeon, the radiotherapist and the medical oncologist.

Nor should oncological prevention been forgotten, a pride of the Department, which is applied to the uterine cervix, endometrium and ovary. It makes use of echography, the cytogenetics laboratory, and the HPV vaccine programme. But the Department does not just concentrate on tumours: ageing of the female population, together with a longer active age, has focused attention on uro-gynaecological diseases that were at one time neglected. Surgery of the pelvic statics and urinary incontinence is a growing activity of the Department under the direction of Marco Balestri.

Finally, in 2009 a female genital and senology outpatients’ section was opened also to non-EC women, given the cultural facilitation enabled by the prevalence of women on the medical staff.

Sperm protein 17 is expressed in the sperm fibrous sheath Journal of Translational Medicine.

2009; 7: 61.

Background. Sperm protein 17 (Sp17) is a highly conserved mammalian protein characterized in rabbit, mouse, monkey, baboon, macaque, human testis and spermatozoa. mRNA encoding Sp17 has been detected in a range of murine and human somatic tissues. It was also recognized in two myeloma cell lines and in neoplastic cells from patients with multiple myeloma and ovarian carcinoma.

These data all indicate that Sp17 is widely distributed in humans, expressed not only in germinal cells and in a variety of somatic tissues, but also in neoplastic cells of unrelated origin.

Methods. Sp17 expression was analyzed by immunocytochemistry and transmission electron microscopy on spermatozoa.

Results. Here, we demonstrate the ultrastructural localization of human Sp17 throughout the spermatozoa flagellar fibrous sheath, and its presence in spermatozoa during in vitro states from their ejaculation to the oocyte fertilization.

Conclusion. These findings suggest a possible role of Sp17 in regulating sperm maturation, capacitation,acrosomal reaction and interactions with the oocyte zona pellucida during the fertilization process.

Further, the high degree of sequence conservation throughout its N-terminal half, and the presence of an A-kinase anchoring protein (AKAP)-binding motif within this region, suggest that Sp17 might play a regulatory role in a protein kinase A-independent AKAP complex in both germinal and somatic cells.

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Internal Medicine

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Two aims for new medical students: integrated learning and translational research Interview with Mauro Podda

Mauro Podda is a Full Professor of Internal Medicine at the Università degli Studi di Milano and also the coordinator for the twoyear course in Internal Medicine.

As a teacher, Professor Podda is recognised for his willingness to help students and overcome established customs.

» How would you describe the Istituto Clinico

Humanitas in relation to your academic role?

Humanitas hosts the second three-year period of the School of Medicine of my University and activities of medical assistance (its primary mission), research and teaching here coexist and benefit from each another. At first Humanitas was dependent on the San Paolo School location but now it recently became independent in its organization. In January 2010 the University approved the project to institute an entire 6-year track at Humanitas, in which teaching would be given esclusively in English and be based on experimental methods. This step will open the teaching – which has now moved out of its experimental stage – to international students.

» What are the proposed experimental methods and what improvements are expected?

Over the past year, the Humanitas Medical School track has implemented a teaching approach that had already been consolidated in some universities in North Europe and the United States. In particular, individual courses are more closely integrated from an interdisciplinary point of view and the teaching methodology is based on significantly fewer formal lessons while the active student participation is encouraged throughout the course.

To this end the students are divided into small groups for problem-solving purposes, which are designed to encompass, via a problem-based solving (PBL) approach, physiopathological, clinical and therapeutic information on very common or potentially serious complaints (as in the case of back or chest pain, respectively). This approach is based on previous demonstrations that an active participation reinforces the memory and long-term learning, as well as stimulates interest, curiosity, and, most important, doubt. One of the major examples of this approach is the Maastricht University in Holland and it is of particular interest that the University homepage states: “Tomorrow’s doctors must be able to manage any medical problem. Their education has to prepare them to be fully-fledged problem solvers who can rely on a broad knowledge base and the ability to gain access to new knowledge. The programme structure is varied and internationally oriented. From the beginning, students are confronted with aspects of real medical practice”. To me this seems a sort of illuminated manifesto of the ideas that underlie the Humanitas location of the Medical School of our University.

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Two aims for new medical students: integrated learning and translational research Interview with Mauro Podda

« Between one’s genetic factors

and environmental factors I would favour the former as a major determinant of autoimmunity

»

» Beside clinics and teaching, the third side of the University is, necessarily, research. For thirty years you have dedicated your efforts to investigate primary biliary cirrhosis as a paradigmatic autoimmune disease.

Primary biliary cirrhosis is a prototype and an excellent model for the study of autoimmune diseases. As an example, it affects women ten times more often than men and it has allowed us to open the chapter on sex chromosome abnormalities as a cause of female predominance of almost all autoimmune diseases.

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» Is autoimmunity a matter of nature or nurture, then?

In the choice between one’s genetic structure and environmental factors, I would favour the former as the major determinant. To illustrate my opinion with a metaphor, driving on a motorway can create the risk of having an accident (environmental factor) but driving against traffic (genetic factors) makes this risk enormously higher! The loss of one of the two X chromosomes that all female cells have (an event linked with increasing age) is called monosomy X and women with autoimmune diseases have a high number of circulating cells which manifest this monosomy.

In addition, there are observations of inactivation or duplication of chromosome X and on the role of these chromosomic changes in an individual’s susceptibility to autoimmunity.

» The role of monosomy X was confirmed in three

different autoimmune diseases affecting mainly women, yet complex problems do not have simple solutions. Is this correct?

Unfortunately this is quite correct. Further information

top paper Lleo A, Selmi C, Invernizzi P, Podda M, Coppel RL, Mackay IR, Gores GJ, Ansari AA, Van de Water J, Gershwin ME

on polygenic diseases (as in autoimmune diseases) will only result from the study of millions of small modifications (polymorphisms) of the entire genome, which is one current research path. These studies are being carried out in the Hepatobiliary Immunopathology Laboratory run by Pietro Invernizzi and Carlo Selmi (both of whom are clinical researchers in the Clinical Medicine Operating Unit that I direct) in collaboration with Eric Gershwin, a world-famous immunologist at the University of California in Davis. Other research interests include the mechanisms of onset of biliary duct cancer and the factors that lead to the presence of autoimmune diseases in only one subject between genetically identical twins. This last subject is another approach to complex diseases using naturally occurring models.

» Another research path is clinical epidemiology,

which studies the prevalence of autoimmune liver diseases in the general population.

An early and interesting rationale for this research project was the difference between 10:1 and 3:1 occurring between the female preponderance of primary biliary cirrhosis and its specific autoantibodies in the general population. This suggests a possible flaw in the selection of diagnosed cases: indeed, could we investigate women differently in the knowledge that they are more predisposed to autoimmunity? The next studies, of which many are being carried out in partnership with eminent colleagues abroad, will shed new light on the true impact of these conditions which are currently considered as rare.

» It seems that gender medicine, i.e., the study of

diagnostic and prognostic differences linked to sex, could hold an important key to autoimmunity.

Once again, I agree with your view, though we should talk about sex rather than gender, as this latter term indicates the individual’s social rather than biological characteristics. Autoimmune diseases are the paradigm of sex-related medicine. Even bearing in mind the possible diagnostic bias I mentioned, diseases like rheumatoid arthritis, systemic lupus erythematosus, and primary biliary cirrhosis affect women more commonly than men, thus suggesting that sex-related factors are indeed relevant in the initiation and perpetuation of the chronic inflammatory state.

Apotopes and the Biliary Specificity of Primary Biliary Cirrhosis Hepatology 2009; 49: 871-879.

Primary biliary cirrhosis (PBC) is characterized by antimitochondrial antibodies (AMAs), directed to the E2 component of the pyruvate dehydrogenase complex (PDC-E2). Notwithstanding the presence of mitochondria in virtually all nucleated cells, the destruction in PBC is limited to small intrahepatic bile ducts. The reasons for this tissue specificity remain unknown, although biliary epithelial cells (BECs) uniquely preserve the PDC-E2 epitope following apoptosis. Notably, PBC recurs in an allogeneic transplanted liver, suggesting generic rather than host PBC– specific susceptibility of BEC. We used cultured human intrahepatic BECs (HIBECs) and other well-characterized cell lines, including, HeLa, CaCo-2 cells, and nontransformed human keratinocytes and bronchial epithelial cells, to determine the integrity and specific localization of PDC-E2 during induced apoptosis. All cell lines, both before and after apoptosis, were tested with sera from patients with PBC (n 3 0), other autoimmune liver and rheumatic diseases (n 20), and healthy individuals (n 20) as well as with a mouse monoclonal antibody against PDC-E2 and AMA with an immunoglobulin A isotype.

PDC-E2 was found to localize unmodified within apoptotic blebs of HIBECs, but not within blebs of various other cell lineages studied. The fact that AMA-containing sera reacted with PDC-E2 on apoptotic BECs without a requirement for permeabilization suggests that the autoantigen is accessible to the immune system during apoptosis.

Conclusion: Our data indicate that the tissue (cholangiocyte) specificity of the autoimmune injury in PBC is a consequence of the unique characteristics of HIBECs during apoptosis and can be explained by exposure to the immune system of intact immunoreactive PDC-E2 within apoptotic blebs.

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Cardiology

66

Since the end of the last century, the greatest progress in medicine has been in the cardiovascular field. According to a research published in the New England Journal of Medicine, between 1960 and 2000 the reduction in cardiovascular mortality has lengthened the average lifespan by 7 years. This benefit has derived from a more precise use of drugs, the efficacy of new and perfected drugs such as statins, technological innovation, the miniaturisation of biomedical devices, and the increasingly less invasive nature of operating techniques. Today the challenge has moved to a different level: first, the development and use of advanced technologies and minimally invasive techniques, in both the interventional (stents, biological valves) and surgical (miniaturised ventricular assist devices) fields.

Second, the shift in the battle against cardiovascular diseases to the realm of human behaviour, with the encouragement of better lifestyles like a healthier

diet and a tobacco-free life. Humanitas’s antismoking efforts – carried out through an information campaign targeted especially at the young – have had a strong impact not only in the fight against cancer but also against cardiovascular diseases, for which smoking is a serious risk factor. A major challenge is represented by the assimilation into the clinical practice of discoveries made in preclinical research like the transfer to the bedside of new inflammation markers like C-reactive protein and its “parent” PTX3. The latter was discovered and developed in Humanitas.

Large cooperative studies, such as JUPITER, based on thousands of patients, are considered milestones and contribute to modify the way medicine is practised.

Humanitas’ goal is to continue to create innovation, through the introduction of new inflammation markers and its participation in joint projects underlying medical progress, without ever losing sight of the individual nature and needs of each patient.

In the third millennium, heart repair beats heart replacement Interview with Ettore Vitali

Since 2008 Ettore Vitali has been head of the Cardiovascular Department at Humanitas Gavazzeni in Bergamo, and since 2009 head of the Cardiovascular Department at the Istituto Clinico Humanitas in Rozzano. This Department coordinates many Operating Units: Cardiac Surgery, Haemodynamics, Electrophysiology and Clinical Cardiology with the addition of the outpatients’ Departments of Echocardiographic Diagnostics and Vascular Surgery.

» What directions are cardiology and cardiac surgery taking today? And where does Humanitas stand in all this?

Like in many other medical branches, the cardiovascular field is undergoing rapid changes, thus new directions have to be addressed by future cardiologists. The rules of this evolution are dictated by demographic changes: in the near future there will be a new epidemiology, dealing with increasingly elderly patients suffering prevalently from degenerative pathologies. This will alter both the technical and ethical terms of cardiological treatment. On one hand, scientific societies will have to focus their guidelines on this profile of patient, on the other, doctors will have to step outside of their hyperspecialisations and return not only to curing patients, but to looking after them from every aspect. Keeping this in mind we have to start an integrated process, not only within the Department – as has already occurred between the clinical cardiologist, the electrophysiologist and the interventional cardiologist – but also outside, with other specialists like diabetologists and primary-care physicians. Heart failure is a typical example of this need for a long-term homecare based system. In just this field in Humanitas we are arranging an agreement with VIDAS for people suffering from endstage heart failure.

» You have described the evolution of demand; in your opinion, what are the more advanced solutions in the interventional field?

Regarding heart failure, the future will be further characterised by ventricular assist devices (VADs) and artificial hearts due to the increasing shortage of donors.

Less invasive cardiac surgical techniques are being evolved in order to minimise the biological impact of surgery and, consequently, patient suffering. New horizons are opening up in the field of heart valve replacement with new biological prostheses, which can be implanted either transapically or transfemorally.

Furthermore, the trends in cardiology have shifted from replacement to repair. For example, in the case of heart valve disease and surgery of the thoracic aorta, repair rather than replacement has the advantage of avoiding prosthetic endocarditis, thromboembolic or haemorrhagic complications (from oral anticoagulation) for mechanical prostheses, and of structural degeneration in the case of bioprostheses. The patient’s pharmacological treatment is

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In the third millennium, heart repair beats heart replacement Interview with Ettore Vitali

« Less invasive cardiac surgical

techniques are being evolved in order to minimise the biological impact of surgery and, consequently, patient suffering

»

also becoming increasingly personalised: an example is the next oral anticoagulant to be released, which has a shorter half-life to better control any haemorrhagic complications, and does not require regular blood samples to check the INR thanks to the stability of its effect.

» What exactly are VADs? LVADs (left ventricular assist devices) are batteryoperated mechanical pumps whose purpose is to compensate a seriously failing cardiac pump.

Their improvements in the last 20 years have been extraordinary: from the first pumps made available in 1988, which weighed 2kg, research has now developed the CircuLite, the smallest PCS (partial circulatory support device) available, which can pump three litres of blood per minute, thus increasing the total cardiac capacity. Furthermore it is minimally invasive: implanted with a small incision in the thorax, it can even be used in young patients affected by moderate dilated myocardiopathies of different etiologies to further prevent the exhaustion of the myocardium.

» Heart surgery is becoming less invasive and more conservative. Is this the path being followed in Humanitas?

Certainly. Giuseppe Tarelli’s team deals with all heart surgery. These operations are performed either using the traditional approach, or the minithoracotomical or ministernotomical approach (surgical incisions less than 10 cm in length).

» Regarding transcatheter aortic valve 68

replacement, in addition to the surgical transapical approach there is a transfemoral technique practised in Humanitas by the

Interventional Cardiology Unit headed by Patrizia Presbitero. What do the two options have in common and how do they differ?

Both procedures are implemented without the need for extracorporeal circulation, thus can be offered to patients of advanced age or with serious concomitant pathologies, for whom traditional surgery is not advisable. In common with international societies, the Italian Cardiac Surgery Society considers surgical replacement of the aortic valve the gold standard for severe aortic stenosis. Thus risk assessment is crucial for patient selection.

Percutaneous transfemoral implantation of the aortic valve is performed against the normal circulation flow: it is a minimally invasive approach but it might develop into an atrioventricular block due to pressure on the septum. Left ventricular transapical surgery allows implantation of an Edwards aortic valve by a thin catheter inserted through a minithoracotomy of 4-5 cm, proceeding in the direction of blood flow. For this reason it is easier in stenosis.

» Returning to heart failure, which is one of the

most dangerous cardiological threats today, is there a third therapeutic option in addition to pharmacology and surgery?

The third option is electrophysiological, using the cardiac resynchronisation technique, which, by means of a pacemaker (to treat brachycardia) and biventricular defibrillators (for tachycardia), eliminates the delay between the two ventricular chambers. After they are electrically resynchronised, they become mechanically synchronised which improves the contractile efficacy. This procedure is carried out by the Electrophysiology and Electrostimulation Operating Unit directed by Maurizio Gasparini. In some moderate cases, implantation of heart devices may induce regression of the disease, as published by the Gasparini team in the American Heart Journal in 2008. Studies by Gasparini’s team on the treatment of cardiac failure associated with atrial fibrillation (30-40% of the cases of failure) led to modification of the operating guidelines in Europe and America, with the extension of the use of biventricular electrostimulators to this type of patient too.

» What are the sizes and functions of biventricular devices?

They have been miniaturised over the years and have been given a series of added functions, so that now the patient is monitored like in a continuous Holter, and it is even possible to interrupt a ventricular arrhythmia in 70% of cases, with stimuli faster than the arrhythmia itself sent by the defibrillator to the ventricle. Recent technical innovations record information on the device’s operation (e.g., battery power low or damaged catheters) but also on arterial pressure, the patient’s physical activity and the quantity of fluids retained by the patients (and thus the emergence of an acute pulmonary edema).

« Heart failure will be increasingly dominated by ventricular assist devices and artificial hearts »

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70

Reaching the heart through the skin

Interview with Patrizia Presbitero

Patrizia Presbitero, an expert in interventional cardiology and adult surgically treated or non-surgically treated congenital heart disorders, is currently the head of the Interventional Cardiology and Clinical Cardiology and Intensive Coronary Care Unit at Humanitas Hospital.

Âť How does the interventional cardiologist work?

The interventional cardiologist, measuring pressures and saturations and injecting contrast in cardiac chambers and coronaries, makes precise diagnosis of most cardiac disorders; at the same time, he may intervene to reopen obstructed coronary arteries or to close interatrial or interventricular defects. His aim is to implement a more or less definitive therapy for many heart diseases, particularly coronary artery diseases.

In addition, a new frontier has been opened in this discipline, with interventions on the heart valves. Since many years we are able do dilate with balloons stenotic valves with fusion of the commissures. Now we are able, using percutaneous methods, to insert a biological aortic valve (made of bovine or porcine tissue anchored to a metal stent), which functionally replaces the native stenotic valve, which is not removed but squashed against the walls of the aorta. Percutaneous valve substitution avoids the risks linked with advanced age and comorbidity of open-heart intervention, as well as the risk of limited duration of the simple valvular dilation using a balloon. We are also working on making catheters smaller for insertion of the valves: we have come down from a diameter of 1.5 cm to one of 0.8 cm, thereby making access easier through arteries that may be narrow or, particularly among the elderly, calcified and stenosed.

Âť Is the percutaneous method the only mini-invasive way to replace the aortic valve? And why is there not an equivalent procedure for the mitral valve?

For mitral valve replacement currently two problems remain to be overcome: one regards the dimensions of the mitral ring, which are much greater than the ones of the aortic ring and therefore require a much larger valve, and the other concerns the anchorage of the valve to the native ring, which is much more difficult for the mitral valve, because the valve is supported by papillary muscles and chordae tendineae.

Without extracorporeal circulation, a biological aortic valve can be positioned in the beating heart either percutaneously through the femoral arteries (or, more rarely, the subclavian arteries) by interventional cardiologists. In my unit we perform approximately fiftysixty such procedures a year, but they are raising.

Alternatively, the valve can be positioned surgically on a beating heart by means of transapical left ventricular

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Reaching the heart through the skin Interview with Patrizia Presbitero

« Patients suffering

from advanced age and comorbidity can avoid open heart operations

»

generation of medicated stents (called Drug Eluting Stents, DES), which release active principles that inhibit cell proliferation and therefore help to prevent restenosis. In most of the second generation DES the polymer which carries the drug attached to the stent disappears after few days giving less inflammation in the vessel wall.

» How does restenosis occur? access with a small thoracic incision of 4-5 cm made by the heart surgeons in the haemodynamics room.

» You have studied the “gender paradox” closely.

This refers to women who, though requiring angioplasty and the positioning of stents in worse basic conditions or with greater risk factors than men, may enjoy the same or even better results. Can you tell us about it?

The gender paradox is a very interesting topic, to the extent that a large multicentre research study is currently being carried out on the characteristics of myocardium infarction in women, and in which we are taking part.

It is known that women are disadvantaged as regards diagnosis and treatment of coronary heart disease.

Diagnosis is often not timely, either because the symptoms are atypical or because the significance of the symptoms is underestimated. In addition, coronary arteries in women are difficult to treat either with interventional cardiology or with cardiac surgery because they are smaller and dissect more easily. The process of atherosclerosis, which emerges after menopause, is more rapid than in men and therefore probably the plaques are unstable and more often give acute coronary syndromes. Until more dedicated instruments have been developed (very small and flexible stents and balloons), complications used to occur more frequently in procedures performed on women.

» Are the stents used today always medicated?

72

Very often, in roughly 70% of cases, because restenosis is much less frequent with the drug eluting stents (8%) than with unmedicated bare metal stents (30%). We are now using the second

Restenosis is rarely a recurrence of the coronary disease but more often a process similar to cicatrisation. Unsurprisingly, it has been defined as the organism’s response to the controlled injury induced by angioplasty. Moreover, platelets aggregation around the stent leads to the formation of blood clots.

» Within how much time can thrombosis appear?

Usually within the first six months, during which time the patient must undergo double anti-platelets treatment, using aspirin and clopidogrel. The risk of thrombosis is also lessened by the different structure of current stents, which have a smaller mesh and polymers that induce less endothelial inflammation.

They also exist without polymers. In addition for few months new and more potent antiplatelet agents have been available in our hospital, to be used in patients at high thrombotic risk.

» What examinations exist for checking what

happens in the vessel after the stent has been positioned?

Traditionally intracoronary echography is used, which gives a very good view of the vessel wall but less of what is inside the vessel lumen. Today we have a new technique called Optical Computed Tomography, which is based on the use of light rather than ultrasounds. This allows sight of the vessel endothelium and whatever is inside the vessel lumen, for example, blood clots. In addition, this instrument allows a very good view of the mesh of the stent and the extent to which it has undergone endothelisation.

This is a completely new piece of equipment here at Istituto Humanitas.

» So, have bare metal stents been completely abandoned?

No, in some cases they are recommended rather than

medicated stents: for example, when angioplasty is required in subjects who are going to be operated for other reasons (e.g., for a tumour) and who therefore cannot continue double anti-platelets treatment for a long period. Or in thrombotic situations such as acute myocardial infarctions (provided that the subject is not diabetic) because bare metal stents are less thrombogenic.

Âť The possibility of coating the simple balloon

with anti-proliferation drugs for angioplasty has been mooted. Is this still just experimental or is it actually in use?

We have already carried out some procedures with paclitaxel-eluting balloons in our centre. These were created to treat restenosis of DES and can today be

used in stenosis of native coronary artery.

Still undergoing experimentation are reabsorbable stents, which would be useful in cases of extensive lesions in order to preserve the coronary tree for a possible future bypass surgery and to avoid filling all the coronary arteries with metal.

All the topics we have discussed are considered in detail on the haemodynamics and interventional cardiology course at Humanitas, now in its sixth edition. Over the four days that the course is held, examinations are made of clinical cases of complex coronary artery disease, of complications caused by cardiac catherisation and PCI, of percutaneous valve replacement, and prevention of cryptogenic ischemic stroke through closure of the patent ovale foramen.

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Pathology

74

Over the last ten years we have seen an epochal change in Pathology: this discipline has moved from a traditional morphological vision to a molecular type approach, thanks to which the pathologist has available new markers and helps to classify diseases in a manner that goes well beyond their exterior aspects.

One of the most illuminating examples is tumours, which, thanks to this new approach, are today not only classified on the basis of their site, but also according to their molecular â&#x20AC;&#x153;signatureâ&#x20AC;?. Each tumour has a precise molecular characteristic that, just like a signature, distinguishes it from neoplasias that affect the same organ in another patient, and which until a short while ago were considered identical. This is an important step in the direction of personalised therapies. Identification of a tumour with a particular molecular signature is the first step to attacking its cells with carefully targeted therapies, which today are represented by new

biological drugs. In this way it is now possible to cure, in a different but more specific and effective way, patients who have the same disease and who before could only receive a single therapy, one that was the same for all patients.

This does not mean that morphological analysis is a prerogative of the past. And the microscope, far from being obsolete, makes use of highly advanced technologies that permit quantitative evaluation of disease morphology and which integrate the morphology itself with analysis of molecular changes.

In this general scenario, Humanitas not only uses cutting-edge imaging techniques (confocal microscopy, two photon microscopy) and integrates morphological analysis with molecular techniques, it works to transfer as many of the results obtained in research as possible to clinical practice. And, far from being a mere user of innovative markers, it plays an active role in the identification of new markers and diagnostic instruments.

Macroscopic, microscopic and molecular indices in the diagnostic jigsaw puzzle Interview with Massimo Roncalli

» What does this mean exactly, Professor Roncalli?

It means studying pathologies by associating molecular data to the morphological aspect and researching into indicators that help to produce diagnoses that are increasingly objective and filled with clinical information.

» Molecular biology is one of the aspects of

professional knowledge that has increased disproportionately, to the point of being studied only by specialists and superspecialists: how has University teaching changed?

Massimo Roncalli is Professor of Pathology at the Università Statale di Milano and in Humanitas is head of the Pathology Operating Unit and Molecular Pathology Laboratory.

His principal field of research is inflammatory, pre-tumoral and tumoral (which represents 70% of his publications) hepatic pathology. He uses a clinical anatomical approach supported by molecular technologies.

The aim of teaching has changed: if it’s not possible to teach the whole body of medical knowledge, new doctors must be put in a position to know how to acquire the advances in their discipline, and how to differentiate notions that are certain (at least temporarily) from those that have not been validated by authoritative studies.

» Does the incentive of new technologies prompt many youngsters to enter research?

Perhaps it would be like that research doctorates do not attract graduates in medicine, mainly because of the low salary. In fact, research positions are increasingly taken by biotechnologists and biologists despite the excellent laboratories to support research and the cultural stimulus given by international working partnerships. For example, in the PhD school of Molecular Medicine at Milan University, on whose steering committee Humanitas sits, a statute requires students to work as active researchers on the project their group is working on, and they are encouraged to undertake part of their thesis work in laboratories abroad, preferably in a group that has a working relation with the Milan-based research group.

» What degree of importance does research have in your field?

Despite the pressure for diagnostic work, it is a lot, if we consider that between 2000 and 2010 the impact factor reached was 424, with an average of 5 points per article published.

» Does the liver remain the most important subject of this research?

Important but certainly not the only one. For example, there are many cases of rare pathologies, such as

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Macroscopic, microscopic and molecular indices in the diagnostic jigsaw puzzle Interview with Massimo Roncalli

« We must teach new doctors

how to deal with a body of professional knowledge that has increased disproportionately

»

sarcomas and mesothelioma. On the subject of the latter, we are currently in a peak phase. It should not be forgotten that in addition to professional exposure to asbestos there is also environmental exposure, which is not always counted. The fact that the latency of the tumour ranges from 15 to 30 years does not make identification of the cause easy. But other very important pathologies mean we work every day on their diagnostics and research, for instance, carcinoma of the breast, diagnosis and therapy of which have recently been successfully implemented in Humanitas, thanks partly to our spirit of interdisciplinary collaboration.

» What are your future lines of research?

Returning to the liver, one of our next research lines will be the validation of a panel of diagnostic markers (Di Tommaso, L. The application of

markers (HSP70 GPC3 and GS) in liver biopsies is useful for detection of hepatocellular carcinoma. J Hepatol. 2009; 50: 756-754) in order to achieve early identification of hepatocarcinomas in the cirrhotic liver, which is more sensitive and specific than radiology. A cancerous lesion of small size may be suspected from close examination of the vascularisation, but for certain diagnosis of the tumour and the nodules that precede it, various recognition patterns are needed, both morphological and molecular. We are currently working on this with the group headed by Y.N. Park at Yonsei University in Seoul, and Luigi Terracciano at the Hospital University in Basel.

Another research project is the identification of predictors of the behaviour of neoplasias, such as microRNA (miRNA) or short non-coding RNA, which may be correlated with the regulation of oncogenes or tumoral suppressors, and thus to the behaviour of a tumour. These short RNA molecules have the advantage of not suffering degradation from the action of formalin and can thus be searched out even on archive material.

Our team, with Luca Di Tommaso and Annarita Destro – who dedicate part of their time to research in synergy with the entire group, but I would like to mention the names of Drs Rahal, Colombo and Fernandes – has always worked very closely with oncologists in the belief that molecular data might be the key to recognition of sensitivity to chemotherapeutics and new biological drugs (Baryshnikova et al. Molecular alterations in spontaneous sputum of cancer-free heavy smokers: results from a large screening program.

Clinical Cancer Research 2008; 14: 1913-9).

» Can diagnosis therefore be thought of as a puzzle?

76

Very much so. The task of the pathologist is fascinating and difficult. It is like the reconstruction of a jigsaw puzzle where the diagnosis is made up of many pieces representing data of various morphological, immunohistochemical, molecular biological and clinical nature, which must be ordered in a rational manner. Nothing can be left to chance because behind every diagnosis there is a patient.

To conclude, my team has a transversal presence in diagnostics and in the research work of other groups working on gastroenteric, soft tissues, urology and respiratory oncology. From this same standpoint, we are working on possible predictors of the sensitivity of a tumour to drugs, with special attention to the new biological anti-angiogenics like sorafenib, which is active against liver cancer, on which an article has recently been published in the New England Journal of Medicine, one of whose authors was Armando Santoro (Llovet JM et al. Sorafenib in Advanced Hepatocellular Carcinoma. New Engl J Med 2008; 359: 378-90). Moreover, our laboratory is working with Antonio Sica and Alberto Mantovani on the study of experimental models of hepatocarcinogenesis.

« The task of the pathologist is

fascinating and difficult.

It is like the reconstruction of a jigsaw puzzle where the diagnosis is made up of many pieces

»

top paper Di Tommaso L, Destro A, Seok JY, Balladore E, Terraciano E, Sangiovanni A, Iavarone M, Colombo M, Jang JJ, Eu E, Jin SY, Morenghi E, Park YN, Roncalli M

The application of markers (HSP70 GPC3 and GS) in liver biopsies is useful for detection of hepatocellular carcinoma Journal of Hepatology 2009; 50: 746–754.

Background/Aims. Liver biopsy for hepatocellular carcinoma (HCC) detection is largely restricted to small hepatocellular lesions, which are often morphologically challenging, requiring careful distinction between dysplastic nodules (highgrade) and well-differentiated HCC. Methods. We investigated the diagnostic accuracy of a panel of markers (HSP70 GPC3 and GS), previously tested in resection specimens, in a series of liver biopsies of large regenerative nodules (n = 13), low-grade dysplastic nodules (n = 21), high-grade dysplastic nodules (n = 50), very well-differentiated (VWD) (n = 17), well-differentiated (WD-G1) (n = 40) and G2-3 (n = 35) HCC. Results. Almost all cases of large regenerative and

low-grade dysplastic nodules did not stain while highgrade dysplastic nodules showed 1 marker (22%) but never 2 or 3. For HCC detection the overall accuracy of marker combination was 60.8% (3 markers) and 78.4% (2 markers) with 100% specificity. When restricted to VWD + WD-G1 HCC the accuracy was 57% (3 markers) and 72.9% (2 markers) with 100% specificity.

Conclusions. This panel proved useful to detect welldifferentiated HCC in biopsy. Two immunoreactive markers (out of 3) are recommended as the most valuable diagnostic combination for HCC detection.

The diagnostic accuracy of the panel could be improved using additional markers, as suggested by studies of expression profiling in other human models.

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Departments and teams Clinical Area Updated to 31 May 2010

Cardiovascular Department director: Ettore Vitali CARDIAC SURGERY division director: Giuseppe Tarelli Alessandro Barbone Enrico Citterio Pietro Malvindi Giuseppe Raffa Diego Ornaghi (•) Fabrizio Settepani

CLINICAL CARDIOLOGY division director: Patrizia Presbitero Tiziana Ammaturo Monica Bocciolone (•) Sara Cioccarelli Franco Fea Augusto Foresti Veronica Fusi Daniela Guiducci Manuel Marconi (•) Barbara Nardi Roberta Paliotti Sergio Potenza Michele Randazzo Francesca Regalia Cinzia Santucciu Maria Luisa Stella Luisa Ulian CLINICAL CARDIOLOGY AND HEART DECOMPENSATION AND FAILURE TREATMENT CENTRE division director: Patrizia Presbitero Maurizio Mangiavacchi Silvia Galvanin Daniela Pini ECHOCARDIOGRAPHY division director: Renato Maria Bragato (*) Physician dealing with activity in the Research laboratories too (**) Research staff

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(•) Head of unit

Mirko Curzi Aurelio Sgalambro

ELECTROPHYSIOLOGY AND ELECTROSTIMULATION division director: Maurizio Gasparini Carlo Ceriotti Paola Galimberti Angelica Montorio HAEMODYNAMICS, INVASIVE CARDIOLOGY AND CORONARY CARE division director: Patrizia Presbitero Cristina Barbaro Guido Belli (•) Elena Corrada (coronary care) Gabriele Luigi Gasparini Marco Mennuni (*) Ruggiero Mango (*) Paolo Pagnotta (•) Dennis Zavalloni Parenti Marco Luciano Rossi Daniela Soregaroli (**) VASCULAR SURGERY I division director: Pier Luigi Giorgetti Elisa Casabianca Andrea Odero Giorgio Luca Poletto Athos Popovich VASCULAR SURGERY II division director: M. Grazia Bordoni Vittorio Danesino Paolo Spada ANAESTHESIA AND CARDIOSURGERY INTENSIVE CARE division director: Angelo Bandera Graziano Cortis Pietro Ferrara Licia Melis Maria Cristina Soriano Rodrigo Paolo Francesco Tosi Maria Maddalena Visigalli (•)

Diagnostic Imaging Department

Gastroenterology Department

director: Giorgio Brambilla

director: Alberto Malesci

RADIOLOGY AND DIAGNOSTIC IMAGING division directors: Giorgio Brambilla, Luca Balzarini

GASTROENTEROLOGY AND DIGESTIVE ENDOSCOPY division director: Alberto Malesci

Cristiana Bonifacio Sara Galli Sara Imparato Romano Lutman (•) Paolo Malerba (•) Lorenzo Monti Federica Mrakic Sposta Vittorio Pedicini Alessandra Pestalozza Dario Poretti Manuel Profili Elisa Rognone Felice Rognone (•) ECHOGRAPHY division director: Paola Magnoni Marina Canevini Pasquale De Nittis Cristiana Magnaghi

Silvio Danese (*) Luigi Laghi (*) Paolo Dario Omodei (•) Beatrice Salvioli Giuseppe Strangio DIGESTIVE ENDOSCOPY service division director: Alessandro Repici Alessandra Carlino Nico Pagano Paoletta Preatoni Giacomo Rando Fabio Romeo

GENERAL AND MINIMALLY INVASIVE SURGERY division director: Riccardo Rosati Fabio Baticci (•) Ugo Elmore (•) Pietro Dante Muselli Alberto Peracchia Uberto Fumagalli Romario (•) Clemente Verrusio GENERAL MEDICINE AND HEPATOLOGY division director: Maurizio Tommasini Roberto Ceriani (•) Luca Contu Giovanni Covini (•) Maria Gioia Lea Pich

General Anaesthesia and Intensive Care Department director: Giovanni Bordone General anaesthesia and intensive care Department Alessandra Alfano Enrico Arosio (•) Jana Balazova Gian Michele Battistini Gabriella Brancato Stefania Brusa Stefania Cantoni Cristina Carlino Vincenzo Cesina Renato Coluccia Paola Matilde De Pietri Orazio Difrancesco Cristina Dominoni Nadia Fusilli Alessandro Gaggianese Donatella Girardello (•) Enrico Giustiniano Sabrina Malara Silvia Eleonora Malossini Gian Luca Marinelli Juan Carlos Pastore Francesco Pellegrino Laura Rocchi Nadia Ruggieri Giorgio Signoroni M. Rosaria Spoto (•) Guido Turio Anaesthesia I division director: Franco Cancellieri

GENERAL SURGERY III division director: Marco Montorsi

Anaesthesia II division director: Valentina Bellato

Stefano Bona (•) Francesca Gavazzi Antonino Spinelli Guido Torzilli (hepatic surgery) Daniele Del Fabbro Angela Palmisano Alessandro Zerbi (pancreatic surgery)

Anaesthesia III division director: Vittorio Gavazzeni

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Gynaecology Department

Internal Medicine Department

director: Paolo E. Levi Setti

DERMATOLOGY division director: Marcello Monti

GYNAECOLOGY division director: Domenico Vitobello Antonio Accardi Marco Balestri (•) Barbara Bianchini Gianluigi Bresciani Cinzia Bulletti Nicola Fattizzi GYNAECOLOGY AND REPRODUCTIVE MEDICINE division director: Paolo Emanuele Levi Setti Elena Albani Veronica Arfuso (*) Annamaria Baggiani Renzo Benaglia Sonia Castelli (*) Alessia De Mita Raffaella De Cesare Alessandra Drovanti Serena Galliera (*) Valeria Liprandi Luciano Negri Laura Sacchi Cristian Specchia Elena Zannoni

director: Mauro Podda

Luca Livio Mancini Stefania Motta Francesco Sacrini dialysis division director: Salvatore Badalamenti Silvia Finazzi Silvia Santostasi EMERGENCY DEPARTMENT division director: Salvatore Badalamenti Gianluigi Citterio Ilmari Cuevas Cairo Carlo Fedeli Giovanni Giorgino Elisabetta Lavezzi Silvia Oldani Stefano Ottolini Antonio Voza Antonella Zedde ENDOCRINOLOGY AND DIABETOLOGY division director: Pietro Travaglini Paolo Colombo GENERAL MEDICINE AND NEPHROLOGY division directors: Giorgio Graziani, Salvatore Badalamenti

(*) Physician dealing with activity in the Research laboratories too (**) Research staff

80

(•) Head of unit

Claudio Angelini (•) Paola Arosio Cesare Berra (•) Albania Calvetta Laura Cosmai Marco Mirani Rosa Pedale Claudio Ponticelli

GENERAL MEDICINE AND PNEUMOLOGY division director: Michele Ciccarelli Massimo Crippa Alberto Grassi Alfonso Maiorino Lucia Testoni INTERNAL MEDICINE division director: Mauro Podda Ilaria Bianchi (*) Pietro Invernizzi (*) Francesca Meda (*) Carlo Francesco Selmi (*) RHEUMATOLOGY division director: Bianca Marasini Enrico Brunetta (*) Marco Sergio Massarotti Domenico Mavilio (*) Francesca Uboldi THROMBOSIS Centre division director: Lidia Rota Monica Bacci Anna Colombo Monica Demarco Paola Ferrazzi Luca Librè Corrado Lodigiani Grazia Loredana Mendolicchio Ilaria Quaglia

Neuroscience Area

Oncology Department

EMERGENCY NEUROLOGY AND STROKE UNIT division director: (ad interim) Simona Marcheselli

BREAST UNIT division director: Corrado Tinterri

Manuel Corato Michele Dileone Barbara Stival NEUROLOGY II division director: Eduardo Nobile Orazio Claudia Giannotta Fabrizia Terenghi Francesco Tuccillo NEUROSURGERY division director: Riccardo Rodriguez y Baena Enrico Aimar Eugenio Benericetti Paolo Gaetani (•) Daniel Levi Martin Lorenzetti Federico Pessina Alessandro Sacchelli Flavio Tancioni (•)

director: Armando Santoro

Claudio Andreoli Marco Eboli Wolfgang Gatzemeier (•) Sergio Orefice Arianna Rubino Carlo Marco Rossetti Andrea Sagona GENERAL AND ONCOLOGIC SURGERY division director: Roberto Doci Antonella Ardito Pietro Francesco Bagnoli Andrea Brocchi Luca Cozzaglio (•) Leandro Gennari Chiara Erminia Mussi Vittorio Lorenzo Quagliuolo (sarcoma surgery ) MEDICAL ONCOLOGY AND HAEMATOLOGY division director: Armando Santoro Antonella Anastasia Monica Balzarotti (*) Maria Grazia Banfi Alexia Bertuzzi Giuseppe Biancofiore Stefania Bramanti Carlo Carnaghi (*) Luca Castagna (•) Raffaele Cavina (•) Fabio De Vincenzo Giovanna Finocchiaro Isabella Garassino Adalberto Ibatici Massimo Magagnoli Giovanna Masci Rita Mazza Manuela Mencaglia Andrea Nozza Paolo Pedrazzoli (•) Nicola Personeni Tiziana Pressiani

Lorenza Rimassa (•) Luca Rubino (*) Barbara Sarina Francesco Sclafani Simona Secondino Matteo Simonelli Licia Vanessa Siracusano Elisa Stroppa Elisabetta Todisco (**) Rosalba Torrisi (•) Luca Toschi Mariachiara Tronconi Marialuisa Valente (*) Paolo Andrea Zucali (•) Monica Zuradelli Monica Bertossi (**) Elisa Crotti (**) Barbara Ercoli (**) Rita Finotto (**) Laura Giordano (**) Natalia Locopo (**) Emanuela Marenghi (**) PET AND NUCLEAR MEDICINE division director: Arturo Chiti Gianluigi Ciocia Giovanna Pepe Marcello Rodari Giovanni Tosi RADIOTHERAPY AND RADIOSURGERY division director: Marta Scorsetti Mario Bignardi Caterina Bressi Simona Castiglioni Paola Lattuada Pietro Mancosu Pierina Navarria Sara Pentimalli Angelo Tozzi Gaetano Urso THORACIC SURGERY division director: Marco Alloisio Umberto Cariboni Giorgio Maria Ferraroli Maurizio Valentino Infante Alberto Testori (•)

81

Orthopaedic Area Arthroscopic SURGERY of the knee division director: Enrico Arnaldi Adriano Baldi Andrea Bruno Massimo De Donato Paolo Dupplicato Alexander Kirienko Paolo Pesenti

HAND SURGERY division director: Alberto Lazzerini Matilde Cacianti Luciana Marzella Ilaria Papini Zorli Davide Smarrelli Fabiana Zura Puntaroni HIP AND KNEE PROsTHEtIC SURGERY division director: Guido Grappiolo Franco Astore Emanuele Caldarella Gianluca Cusmà Federico Della Rocca Matteo Carlo Ferrari Damiano Ricci Marco Scardino Francesco Traverso knee ORTHOPAEDICS and sport traumatology division director: Piero Volpi co-head: Matteo G.M. Denti

Rehabilitation Department PEDIATRIC AND NEUROORTHOPAEDICS SURGERY division director: Nicola Portinaro Maurizio Mori Artemisia Panou Francesco Pelillo

shoulder, elbow and foot arthroscopic surgery division director: Alessandro Castagna Ignazio Bagnoli Mario Borroni Giacomo Delle Rose Antonio Giardella Leonardo Maradei (•) Nikolaos Markopoulos Luigi Milano (foot surgery) Mario Randelli Paolo Renato Rolla

TRAUMATOLOGY division director: Marco Berlusconi Matteo Cavanna Federico Chiodini Lorenzo Di Mento Davide Marchettini Antonella Pieroni Josè Antonio Puchol Incertis Ivano Scarabello

Corrado Bait Matteo Cervellin Emanuele Prospero

(*) Physician dealing with activity in the Research laboratories too (**) Research staff

82

(•) Head of unit

director: Stefano Respizzi Cardiac & Respiratory Rehabilitation division director: Stefano Aglieri Anna Beretta Alessandro Eusebio Ornella Riccardi Neurologic Rehabilitation division director: Bruno Bernardini Marta Arleo Giovanna Cerina Carla Corsini Sara Ghirmai Marco Augusto Pagani Verusca Gasparroni

Orthopaedic Rehabilitation division director: Stefano Respizzi Barbara Baroni Maria Cristina D’Agostino Antonio Frizziero Gianluca Stefano Galimberti Lucio Genesio

Special Diagnostic and Treatment Services

Specialised Divisions of Surgery

LABORATORY TESTS division director: Alessandro Montanelli

OPHTHALMOLOGY division director: Paolo Vinciguerra

UROLOGY division director: Pierpaolo Graziotti

Elena Albè Elena Bernasconi Fabrizio Ivo Camesasca Carlo Castellani Marco Criscito Alessandra Di Maria Marco Gramigna Alessandro Randazzo Mario Romano Pietro Rosetta Maria Ingrid Torres Munoz

Alessio Benetti Giovanni Cordima Guido Giusti (•) Vincenzo Inneo Luisa Pasini Roberta Peschechera Alessandro Piccinelli (kidney surgery) Alessandro Pizzocaro Mauro Seveso Gianluigi Taverna (•) Silvia Zandegiacomo De Zorzi

Barbara Barbieri Daniela Bettio Simona Brambilla Elena Bredi Concetta De Luca Erminia Casari Elisabetta Corsi Antonella Ferrario Rossana Mineri Marta Monari Serenella Valaperta PATHOLOGY division director: Massimo Roncalli Silvia Armenia Andrea Bornati Paola Bossi Piergiuseppe Colombo (•) Annarita Destro Luca Di Tommaso Valentina Fabbris Bethania Fernandes Barbara Fiamengo Sofia Manara Cornelia Navligu Daoud Rahal (•) Paola Spaggiari

OTORHINOLARYNGOLOGY division director: Arturo Poletti Fabio Bertone Giovanni Colombo Gioavanni Cugini Susanna Di Pietro Luca Malvezzi Stefano Miceli Vanessa Rossi PLASTIC SURGERY I division director: Simone Grappolini Alessandra Veronesi

SURGICAL DAY HOSPITAL division director: Roberta Monzani Marco Babbini Diego Beltrutti Francesco Carrera Laura Crozzoli Michele De Ruvo Chiara Ferrari Annarita La Rocca Oreste Davide Montino Rossana Peretti Maria Del Carmen Rodriguez Beatrice Rossi Claudio Sacchi Alessandro Scafella

PLASTIC SURGERY II division director: Marco Klinger Fabio Caviggioli Silvia Giannasi Ombretta Nucca

83

Departments and teams Scientific research and laboratories

Scientific superintendence

Updated to 31 May 2010

Scientific Direction and Research Laboratories

director: Nicola Dioguardi Sonia Di Biccari Barbara Franceschini Carlo Russo

director: Alberto Mantovani Annunciata Vecchi

Clinical research director: Armando Santoro

Clinical trials office director: Michele Tedeschi Clara Caccialanza Alessandra GiampĂ Francesco Minuti

Adaptive Immunity group leader: Antonella Viola Fabio Anselmi Debora Avella Javier Cibella Rita Contento Marino Kallikourdis Cristina Mazzon Sara Morlacchi Adelaida Sarukhan Cristiana Soldani Anna Elisa Trovato Mary Wang Lucia Zanotti Cellular Immunology group leader: Paola Allavena Marco Erreni Giovanni Germano Federica Marchesi Samantha Pesce

Clinical and Experimental Immunology group leader: Domenico Mavilio (2) Stefania Bonaldo Luisa Bozzo Enrico Brunetta (2) Kelly Lorraine Hudspeth Clinical Pharmacology group leader: Alfredo Gorio Stephana Carelli

(1) MD-PhD. In addition to research s/he works as a clinician in Gastroenterology (2) MD-PhD. In addition to research he works as a clinician in Rheumatology (3) MD-PhD. In addition to research he works as a clinician in Internal Medicine

84

(*) staff

Experimental Immunopathology group leader: Cecilia Garlanda Elisa Barbati Edoardo Bonavita Sebastien Jaillon Federica Moalli Fabio Pasqualini Nadia Polentarutti Gastrointestinal Immunopathology group leader: Silvio Danese (1) Carmen Correale Gionata Fiorino Patrizia Naccarato Emanuela Sala Stefania Vetrano Hainalka Szabo Orsola Sociale (*) Hepatobiliary Immunopathology group leader: Pietro Invernizzi (3) Francesca Bernuzzi Ana Lleo De Nalda Carlo Francesco Selmi (3) Immunopharmacology group leader: Barbara Bottazzi Ivan Cuccovillo Livja Deban Antonio Inforzato Marina Sironi Sonia Valentino

Leukocyte Biology group leader: Massimo Locati Raffaella Bonecchi Elena Borroni Cinzia Cancellieri Graziella Curtale Massimiliano Mirolo Laura Mori Bedsheba Nachimuthu Benedetta Savino Nina Machado Torres

Leukocyte Migration group leader: Silvano Sozzani Annalisa Del Prete Michel Ruiz Rosquete Safyie Gonzalvo Feo Molecular Gastroenterology group leader: Luigi Laghi (1) Gianluca Basso Paolo Bianchi Giuseppe Celeste Di Caro Giuseppe Lucia Fini Fabio Grizzi Loredana Scalisi (*) Molecular Immunology group leader: Antonio Sica

Biobank Daniela Pistillo Giorgia Ceva Grimaldi Valentina Paleari Alice Pezzoni Cell Factory Nadia Sessarego Valentina Poletto common research services Achille Anselmo Chiara Buracchi Andrea Doni Stefano Mantero Monica Rimoldi Luca Zammataro

Paola Larghi Laura Strauss Maria Grazia Totaro Molecular Pathology group leader: Massimo Roncalli Silvia Armenia Annarita Destro National Research Council (CNR) Human Genome and Medical Biotechnologies group leaders: Paolo Vezzoni, Anna Villa Maria Elena Caldana Barbara Cassani Francesca Faggioli Francesca Ficara Maria Luisa Focarelli Michela Frascoli Matteo Guerrini Nadia Lo Iacono Veronica Marrella Cristina Panaroni Alessandra Pangrazio Marianna Paulis Samantha Scaramuzza Cristina Sobacchi Dario Strina Lucia Susani Barbara Tondelli

85

Papers published 2009

At 31 March 2010

* = Corresponding author

Cardiovascular Department Cardiac Surgery

Gasparini M*, Regoli F, Galimberti P, Ceriotti C, Cappelleri A.

Settepani F, Szeto WY, Bergonzini M, Barbone A, Citterio E, Berwick D, Gallotti R, Bavaria JE.

Reimplantation Valve-Sparing Aortic Root Replacement for Aortic Root Aneurysm in the Elderly: Are We Pushing the Limits?

Cardiac resynchronization therapy in heart failure patients with atrial fibrillation.

Europace. 2009 Nov;11 Suppl 5:v82-6.

Raw IF (2008): 1.706

Normalized IF: 2

Interact Cardiovasc Thorac Surg. 2009 Jul;9(1):113-6. Epub 2009 Apr 28.

Dickstein K, Bogale N, Priori S, Auricchio A, Cleland JG, Gitt A, Limbourg T, Linde C, van Veldhuisen DJ, Brugada J; Scientific Committee; National Coordinators: (Dickstein K, Priori S, Auricchio A, Bogale N, Brugada J, Cleland JG, Derumeaux G, Gitt A, Gras D, Komajda M, Limbourg T, Linde C, Morgan J, van Veldhuisen DJ, Fruhwald F, Strohmer B, Goethals M, Vijgen J, Trochu JN, Gras D, Kindermann M, Stellbrink C, McDonald K, Keane D, Gal TB, Glikson MG, Metra MM, Gasparini M, Maass A, Jordaens L, Alings M, Larsen AI, Faerestrand S, Delgado J, Lluis Mont LM, Persson H, Gadler F, Brunner-La Rocca HP, Osswald S, Squire L, Morgan J).

Raw IF (2008): 0

The European cardiac resynchronization therapy survey.

J Card Surg. 2009 Mar 23. [Epub ahead of print] Raw IF (2008): 0.754

Normalized IF: 1

Settepani F, Bergonzini M, Barbone A, Citterio E, Basciu A, Ornaghi D, Gallotti R, Tarelli G.

Reimplantation valve-sparing aortic root replacement with the Valsalva graft: what have we learnt after 100 cases?

Normalized IF: 0.1

Eur Heart J. 2009 Oct;30(20):2450-60. Epub 2009 Aug 31.

Catena E, Sozzi F, Trunfio S, Montrasio E, Nonini S, Tarelli G.

Left ventricular pseudoaneurysm associated with septal ventricular rupture following myocardial infarction.

J Cardiovasc Med (Hagerstown). 2010 Feb;11(2):140-2. Epub 2009 Dec 4.

Raw IF (2008): 0

Normalized IF: 0.1

Electrophysiology and Electrostimulation Cardiac resynchronisation therapy in patients with atrial fibrillation.

Heart. 2009 Jan;95(1):83; author reply 83-4.

Letter to the Editor (results) Normalized IF: 3

Gasparini M*, Menozzi C, Proclemer A, Landolina M, Iacopino S, Carboni A, Lombardo E, Regoli F, Biffi M, Burrone V, Denaro A, Boriani G.

A simplified biventricular defibrillator with fixed long detection intervals reduces implantable cardioverter defibrillator (ICD) interventions and heart failure hospitalizations in patients with non-ischaemic cardiomyopathy implanted for primary prevention: the RELEVANT [Role of long dEtection window programming in patients with LEft VentriculAr dysfunction, Non-ischemic eTiology in primary prevention treated with a biventricular ICD] study.

86

Normalized IF: 1.6

Boriani G, Gasparini M, Landolina M, Lunati M, Biffi M, Santini M, Padeletti L, Molon G, Botto G, De Santo T, Valsecchi S; InSync/InSync ICD Italian Registry Investigators.

Effectiveness of cardiac resynchronization therapy in heart failure patients with valvular heart disease: comparison with patients affected by ischaemic heart disease or dilated cardiomyopathy. The InSync/InSync ICD Italian Registry.

Eur Heart J. 2009 Sep;30(18):2275-83. Epub 2009 Jun 10.

Gasparini M*, Regoli F.

Raw IF (2008): 4.964

Raw IF (2008): 8.917

Raw IF (2008): 8.917

Normalized IF: 8

Proclemer A, Ghidina M, Facchin D, Rebellato L, Corrado D, Gasparini M, Gregori D.

Use of implantable cardioverter-defibrillator in inherited arrhythmogenic diseases: data from Italian ICD Registry for the years 2001-6.

Pacing Clin Electrophysiol. 2009 Apr;32(4):434-45.

Raw IF (2008): 1.59

Normalized IF: 1

Schwab JO, Gasparini M, Lunati M, Proclemer A, Kaup B, Santi E, Ligorio G, Klersy C, DE Sousa J, Okreglicki A, Arenal A, Wijffels M, Lemke B.

Avoid delivering therapies for nonsustained fast ventricular tachyarrhythmia in patients with implantable cardioverter/defibrillator: the ADVANCE III Trial.

Eur Heart J. 2009 Nov;30(22):2758-67. Epub 2009 Jun 29.

J Cardiovasc Electrophysiol. 2009 Jun;20(6):663-6. Epub 2009 Jan 9.

Raw IF (2008): 8.917

Raw IF (2008): 3.798

Normalized IF: 8

Normalized IF: 6

Catanzariti D, Lunati M, Landolina M, Zanotto G, Lonardi G, Iacopino S, Oliva F, Perego GB, Varbaro A, Denaro A, Valsecchi S, Vergara G; Italian Clinical Service Optivol-CRT Group: (Tavazzi L, Landolina M, Rordorf R, Savastano S, Lunati M, Frigerio M, Oliva F, Vergara G, Maines M, Cazanzariti D, Vassanelli C, Zanotto G, Lonardi G, Visentin E, Perego G, Brambilla I R, Santini M, Ricci R, Speca G, Agricola T, Cassese M, Iacopino S, Proclemer A, Facchin D, Ravazzi P, Diotallevi P, Ometto R, Bonanno C, Rauhe W, Pescoller F, Gasparini M, Ceriotti C, Regoli F, Sassara M, Turreni F, Pappone C, Pappone A, Paglino G, Bernasconi M, Guenzati G, Padeletti L, Pieragnoli P, Gaita F, Bocchiardo M, Scaglione M, Curnis A, Bontempi L, Botto G, Luzi M, Perrone C, Zorzi A, Mantovani G, Bertocchi P, Massa R, Golzio P, Amellone C, Gavazzi A, Cant첫 F, Senni M, Sorgato A, Pezzali M, Capella G, Fornerone R, Pasqualini M, Pozzetti D, Lombroso S, Petrucci E, Di Girolamo E, Sabatini P, Sprito P, Molini D, Gelmini P, Bignotti T, Senatore G, Trapani G, Giuggia M, Zanetta M, Perucca A, Parravicini U).

Monitoring intrathoracic impedance with an implantable defibrillator reduces hospitalizations in patients with heart failure.

Haemodynamics and Interventional Cardiology Rossi ML*, Zavalloni D, Gasparini GL, Mango R, Belli G, Presbitero P.

The first report of late stent thrombosis leading to acute myocardial infarction in patient receiving the new endothelial progenitor cell capture stent.

Int J Cardiol. 2009 Jan 8. [Epub ahead of print] Letter to the Editor (comment) Raw IF (2008): 3.121

Normalized IF: 0.8

Pagnotta P, Briguori C, Saluzzo CM, Presbitero P.

Endovascular treatment of traumatic bilateral internal carotid artery dissection.

J Invasive Cardiol. 2009 Jan;21(1):E6-8.

Raw IF (2008): 0

Normalized IF: 0.1

Pacing Clin Electrophysiol. 2009 Mar;32(3):363-70.

Raw IF (2008): 1.59

Normalized IF: 0.4

Task Force members, Brignole M, Vardas P, Hoffman E, Huikuri H, Moya A, Ricci R, Sulke N, Wieling W; EHRA Scientific Documents Committee, Auricchio A, Lip GY, Almendral J, Kirchhof P, Aliot E, Gasparini M, Braunschweig F; Document Reviewers, Lip GY, Almendral J, Kirchhof P, Botto GL; EHRA Scientific Documents Committee.

Indications for the use of diagnostic implantable and external ECG loop recorders.

Europace. 2009 May;11(5):671-87.

Raw IF (2008): 1.706

Normalized IF: 2

CRT Survey Scientific Committee: Dickstein K, Priori S, Auricchio A, Terradellas JB, Cleland J, Derumeaux G, Gras D, Komajda M, Linde C, Morgan J, van Veldhuisen DJ, Gitt A, Bogale N, Fruhwald F, Strohmer B, Goethals M, Vijgen J, Gal TB, Glikson M, McDonnald K, Keane D, Metra M, Gasparini M, Persson H, Gadler F, Trochu JN, Gras D, Maass A, Jordaens L, Larsen AI, Faerestrand S, Brunner-La Rocca HP, Osswald S, Kindermann M, Stellbrink C, Delgado J, Mont L, Squire I, Morgan J.

European cardiac resynchronization therapy survey: rationale and design.

Eur J Heart Fail. 2009 Mar;11(3):326-30.

Raw IF (2008): 3.398

Normalized IF: 6

Belli G.

Survival benefit after percutaneous treatment of chronic total coronary occlusions.

Eur Heart J. 2009 Feb;30(4):506; author reply 506-7.Epub 2009 Jan 23.

Letter to the Editor (comments) Raw IF (2008): 8.917

Normalized IF: 1.6

Ribichini F, Tomai F, De Luca G, Boccuzzi G, Presbitero P, Pesarini G, Ferrero V, Ghini AS, Pastori F, De Luca L, Zavalloni D, Soregaroli D, Garbo R, Franchi E, Marino P, Minelli M, Vassanelli C.

A multicenter, randomized study to test immunosuppressive therapy with oral prednisone for the prevention of restenosis after percutaneous coronary interventions: cortisone plus BMS or DES versus BMS alone to eliminate restenosis (CEREADES) - study design and rationale.

J Cardiovasc Med (Hagerstown). 2009 Feb;10(2):192-9.

Raw IF (2008): 0

Normalized IF: 0.1

Presbitero P, Lanzone AM, Albiero R, Lisignoli V, Zavalloni Parenti D, Gasparini GL, Lodigiani C, Barbaro C, Fappani A, Barberis G, Rossi ML, Pagnotta P.

Anatomical patterns of patent foramen ovale (PFO): do they matter for percutaneous closure?

Minerva Cardioangiol. 2009 Jun;57(3):275-84.

Raw IF (2008): 0

Normalized IF: 0.1

87

Papers published 2009

Pagnotta P, Briguori C, Presbitero P.

Arteriovenous fistula complicating directional atherectomy of the popliteal artery.

J Cardiovasc Med (Hagerstown). 2009 Oct;10(10):798-800.

Raw IF (2008): 0

Normalized IF: 0.1

Zavalloni D, Bossi P, Rossi ML, Gasparini GL, Lisignoli V, Presbitero P.

Inflammatory substrate with eosinophils may be present in bare-metal stent thrombosis.

J Cardiovasc Med (Hagerstown). 2009 Dec;10(12):942-3.

Raw IF (2008): 0

Normalized IF: 0.1

Rossi ML*, Zavalloni D, Presbitero P.

Reply to the article by Wendel HP et al.: Endothelial progenitor cell capture stents - Hype or hope (IJC-D09-01313)?

Int J Cardiol. 2009 Aug 25. [Epub ahead of print] Letter to the Editor (comments) Raw IF (2008): 3.121

Normalized IF: 0.8

Presbitero P.

The gender paradox.

EuroIntervention. 2009 Jan;4(4):415, 417. No abstract available.

Raw IF (2008): 0

Normalized IF: 0.1

Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA; PLATO Investigators (Presbitero P), Freij A, Thorsén M.

Ticagrelor versus clopidogrel in patients with acute coronary syndromes.

N Engl J Med. 2009 Sep 10;361(11):1045-57. Epub 2009 Aug 30.

Raw IF (2008): 50.017

Normalized IF: 3

Lettieri C, Savonitto S, De Servi S, Guagliumi G, Belli G, Repetto A, Piccaluga E, Politi A, Ettori F, Castiglioni B, Fabbiocchi F, De Cesare N, Sangiorgi G, Musumeci G, Onofri M, D’Urbano M, Pirelli S, Zanini R, Klugmann S; LombardIMA Study Group: (Sganzerla P, Savasta C, Guagliumi G, Musumeci G, Fiocca L, Niccoli L, Ettori F, Onofri M, Bortolini F, Gentilini C, Ferrari G, Cattaneo L, Valentini P, Pirelli S, Passamonti E, Vandoni P, Falcone C, Galdangelo F, Politi A, Piatti L, Tiberti G, De Servi S, D’Urbano M, Zanini R, Lettieri C, Tomasi L, Klugmann S, Pirola R, Colombo P, Sesana G, Bartorelli A, Fabbiocchi F, Fiorentini C, Bedogni F, Salvadè P, Viecca M, Piccaluga E, Marzegalli M, Caprari M, Sponzilli C, Colombo A, Sangiorgi G, Aranzulla T, Colombo V, Bramucci E, Repetto A, Rovelli G, Presbitero P, Corrada E, Belli G, Maiello L, Pitì A, Castiglioni B, Garducci S, Zaro T, De Cesare N.)

Emergency percutaneous coronary intervention in patients with ST-elevation myocardial infarction complicated by out-of-hospital cardiac arrest: early and medium-term outcome.

Am Heart J. 2009 Mar;157(3):569-575.e1. Epub 2008 Dec 20.

88

Raw IF (2008): 4.285

Normalized IF: 6

Myocardial Infarction Genetics Consortium: Kathiresan S, Voight BF, Purcell S, Musunuru K, Ardissino D, Mannucci PM, Anand S, Engert JC, Samani NJ, Schunkert H, Erdmann J, Reilly MP, Rader DJ, Morgan T, Spertus JA, Stoll M, Girelli D, McKeown PP, Patterson CC, Siscovick DS, O’Donnell CJ, Elosua R, Peltonen L, Salomaa V, Schwartz SM, Melander O, Altshuler D, Ardissino D, Merlini PA, Berzuini C, Bernardinelli L, Peyvandi F, Tubaro M, Celli P, Ferrario M, Fetiveau R, Marziliano N, Casari G, Galli M, Ribichini F, Rossi M, Bernardi F, Zonzin P, Piazza A, Mannucci PM, Schwartz SM, Siscovick DS, Yee J, Friedlander Y, Elosua R, Marrugat J, Lucas G, Subirana I, Sala J, Ramos R, Kathiresan S, Meigs JB, Williams G, Nathan DM, MacRae CA, O’Donnell CJ, Salomaa V, Havulinna AS, Peltonen L, Melander O, Berglund G, Voight BF, Kathiresan S, Hirschhorn JN, Asselta R, Duga S, Spreafico M, Musunuru K, Daly MJ, Purcell S, Voight BF, Purcell S, Nemesh J, Korn JM, McCarroll SA, Schwartz SM, Yee J, Kathiresan S, Lucas G, Subirana I, Elosua R, Surti A, Guiducci C, Gianniny L, Mirel D, Parkin M, Burtt N, Gabriel SB, Samani NJ, Thompson JR, Braund PS, Wright BJ, Balmforth AJ, Ball SG, Hall AS; Wellcome Trust Case Control Consortium, Schunkert H, Erdmann J, Linsel-Nitschke P, Lieb W, Ziegler A, König I, Hengstenberg C, Fischer M, Stark K, Grosshennig A, Preuss M, Wichmann HE, Schreiber S, Schunkert H, Samani NJ, Erdmann J, Ouwehand W, Hengstenberg C, Deloukas P, Scholz M, Cambien F, Reilly MP, Li M, Chen Z, Wilensky R, Matthai W, Qasim A, Hakonarson HH, Devaney J, Burnett MS, Pichard AD, Kent KM, Satler L, Lindsay JM, Waksman R, Epstein SE, Rader DJ, Scheffold T, Berger K, Stoll M, Huge A, Girelli D, Martinelli N, Olivieri O, Corrocher R, Morgan T, Spertus JA, McKeown P, Patterson CC, Schunkert H, Erdmann E, Linsel-Nitschke P, Lieb W, Ziegler A, König IR, Hengstenberg C, Fischer M, Stark K, Grosshennig A, Preuss M, Wichmann HE, Schreiber S, Hólm H, Thorleifsson G, Thorsteinsdottir U, Stefansson K, Engert JC, Do R, Xie C, Anand S, Kathiresan S, Ardissino D, Mannucci PM, Siscovick D, O’Donnell CJ, Samani NJ, Melander O, Elosua R, Peltonen L, Salomaa V, Schwartz SM, Altshuler D.

Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants.

Nat Genet. 2009 Mar;41(3):334-41. Epub 2009 Feb 8.

Raw IF (2008): 30.259

Normalized IF: 15

Erdmann J, Grosshennig A, Braund PS, König IR, Hengstenberg C, Hall AS, Linsel-Nitschke P, Kathiresan S, Wright B, Trégouët DA, Cambien F, Bruse P, Aherrahrou Z, Wagner AK, Stark K, Schwartz SM, Salomaa V, Elosua R, Melander O, Voight BF, O’Donnell CJ, Peltonen L, Siscovick DS, Altshuler D, Merlini PA, Peyvandi F, Bernardinelli L, Ardissino D, Schillert A, Blankenberg S, Zeller T, Wild P, Schwarz DF, Tiret L, Perret C, Schreiber S, El Mokhtari NE, Schäfer A, März W, Renner W, Bugert P, Klüter H, Schrezenmeir J, Rubin D, Ball SG, Balmforth AJ, Wichmann HE, Meitinger T, Fischer M, Meisinger C, Baumert J, Peters A, Ouwehand WH; Italian Atherosclerosis, Thrombosis, and Vascular Biology Working Group (Rossi ML); Myocardial Infarction Genetics Consortium; Wellcome Trust Case Control Consortium; Cardiogenics Consortium, Deloukas P, Thompson JR, Ziegler A, Samani NJ, Schunkert H.

New susceptibility locus for coronary artery disease on chromosome 3q22.3.

Nat Genet. 2009 Mar;41(3):280-2. Epub 2009 Feb 8.

Raw IF (2008): 30.259

Normalized IF: 3

Diagnostic Imaging Department

Gastroenterology Department

Radiology and Diagnostic Imaging

Gastroenterology and Digestive Endoscopy

Pedicini V, Poretti D, Mauri G, Trimboli M, Brambilla G, Sconfienza LM, Cornalba G, Sardanelli F.

Management of post-surgical biliary leakage with percutaneous transhepatic biliary drainage (PTBD) and occlusion balloon (OB) in patients without dilatation of the biliary tree: preliminary results.

Eur Radiol. 2009 Nov 5. [Epub ahead of print] Raw IF (2008): 3.651

Normalized IF: 6

Livraghi T.

Single HCC smaller than 2 cm: surgery or ablation: Interventional oncologistâ&#x20AC;&#x2122;s perspective.

J Hepatobiliary Pancreat Surg. 2009 Nov 5. [Epub ahead of print] Raw IF (2008): 1.914

Normalized IF: 4

Repici A.

Endoscopic submucosal dissection: established, or still needs improving?

Gastrointest Endosc. 2009 Jan;69(1):16-8. No abstract available.

Raw IF (2008): 7.367

Normalized IF: 8

Scaldaferri F, Sans M, Vetrano S, Correale C, Arena V, Pagano N, Rando G, Romeo F, Potenza AE, Repici A, Malesci A, Danese S*.

The role of MAPK in governing lymphocyte adhesion to and migration across the microvasculature in inflammatory bowel disease Eur J Immunol. 2009 Jan;39(1):290-300.

Raw IF (2008): 4.865

Normalized IF: 6

Cennamo V, Fuccio L, Repici A, Fabbri C, Grilli D, Conio M, Dâ&#x20AC;&#x2122;Imperio N, Bazzoli F.

Timing of precut procedure does not influence success rate and complications of ERCP procedure: a prospective randomized comparative study.

Gastrointest Endosc. 2009 Mar;69(3):473-479.

Raw IF (2008): 7.367

Normalized IF: 4

Bruno M, Carucci P, Repici A, Pellicano R, Mezzabotta L, Goss M, Magnolia MR, Saracco GM, Rizzetto M, De Angelis C.

The Natural History of Gastrointestinal Subepithelial Tumors Arising From Muscularis Propria: An Endoscopic Ultrasound Survey.

J Clin Gastroenterol. 2009 Apr 3. [Epub ahead of print] Raw IF (2008): 2.775

Normalized IF: 2

Fiorino G, Allez M, Malesci A, Danese S.

Review article: anti TNF-alpha induced psoriasis in patients with inflammatory bowel disease.

Aliment Pharmacol Ther. 2009 May 1;29(9):921-7. Epub 2009 Feb 10.

Raw IF (2008): 3.71

Normalized IF: 6

De la Motte C, Nigro J, Vasanji A, Rho H, Kessler S, Bandyopadhyay S, Danese S, Fiocchi C, Stern R.

Platelet-derived hyaluronidase 2 cleaves hyaluronan into fragments that trigger monocyte-mediated production of proinflammatory cytokines.

Am J Pathol. 2009 Jun;174(6):2254-64. Epub 2009 May 14.

Raw IF (2008): 5.697

Normalized IF: 3

89

Papers published 2009

Pace F, Antinori S, Repici A.

What is new in esophageal injury (infection, druginduced, caustic, stricture, perforation)?

Curr Opin Gastroenterol. 2009 Jul;25(4):372-379.

Raw IF (2008): 3.877

Normalized IF: 6

Bruno M, Bosco M, Carucci P, Pacchioni D, Repici A, Mezzabotta L, Pellicano R, Fadda M, Saracco GM, Bussolati G, Rizzetto M, De Angelis C.

Preliminary experience with a new cytology brush in EUS-guided FNA. Gastrointest Endosc. 2009 Dec;70(6):1220-4. Epub 2009 Aug 8.

Gullo L, Laghi L, Migliori M, Lucrezio L, Bianchi P, Randolph AE, Mantovani V, Bastagli L, Pezzilli R, Malesci A.

Raw IF (2008): 7.367

SPINK1 and PRSS1 mutations in benign pancreatic hyperenzymemia.

Laghi L*, Bianchi P, Miranda E, Balladore E, Pacetti V, Grizzi F, Allavena P, Torri V, Repici A, Santoro A, Mantovani A, Roncalli M, Malesci A.

Pancreas. 2008 Jul;37(1):31-5.

Raw IF (2008): 2.708

Normalized IF: 4

Normalized IF: 4

CD3+ cells at the invasive margin of deeply invading (pT3-T4) colorectal cancer and risk of post-surgical metastasis: a longitudinal study.

Danese S*, Angelucci E.

Lancet Oncol. 2009 Sep;10(9):877-84. Epub 2009 Aug 3.

New and emerging biologics in the treatment of infl ammatory bowel disease: quo vadis?

Raw IF (2008): 13.283

Gastroentérologie Clinique et Biologique (2009) 33, Suppl. 3, S217—S227

Szabò H, Fiorino G, Spinelli A, Rovida S, Repici A, Malesci AC, Danese S.

Raw IF (2008): 1.033

Review article: Anti-fibrotic agents for the treatment of Crohn’s disease - lessons learned from other diseases.

Normalized IF: 1

Vetrano S, Danese S.

The role of JAM-A in inflammatory bowel disease: unrevealing the ties that bind.

Normalized IF: 10

Aliment Pharmacol Ther. 2010 Jan 15;31(2):189-201.

Epub 2009 Oct 13 Raw IF (2008): 3.71

Normalized IF: 6

Ann N Y Acad Sci. 2009 May;1165:308-13.

Raw IF (2008): 2.303

Normalized IF: 6

Angelucci E, Orlando A, Ardizzone S, Guidi L, Sorrentino D, Fries W, Astegiano M, Sociale O, Cesarini M, Renna S, Cassinotti A, Marzo M, Quaglia A, Sergi MD, Simondi D, Vernia P, Malesci A, Danese S.

Internet use among inflammatory bowel disease patients: an Italian multicenter survey.

Vetrano S, Borroni EM, Sarukhan A, Savino B, Bonecchi R, Correale C, Arena V, Fantini M, Roncalli M, Malesci A, Mantovani A, Locati M, Danese S*.

The lymphatic system controls intestinal inflammation and inflammation-associated colon cancer through the chemokine decoy receptor D6.

Gut. 2009 Oct 20. [Epub ahead of print] Raw IF (2008): 9.766

Normalized IF: 8

Eur J Gastroenterol Hepatol. 2009 Sep;21(9):1036-41.

Raw IF (2008): 2.08

Normalized IF: 2

Repici A*, Pellicano R, Strangio G, Danese S, Fagoonee S, Malesci A.

Emerging Biologics in the Treatment of Inflammatory Bowel Disease: What is Around the Corner?

Curr Drug Targets. 2009 Nov 17. [Epub ahead of print]

Endoscopic mucosal resection for early colorectal neoplasia: pathologic basis, procedures, and outcomes.

Raw IF (2008): 4.187

Dis Colon Rectum. 2009 Aug;52(8):1502-15.

Efficacy of TNF Antagonists Beyond One Year in Adult and Pediatric Inflammatory Bowel Diseases: A Systematic Review.

Raw IF (2008): 2.615

Normalized IF: 6

Uitdehaag MJ, Hooft JE, Verschuur EM, Repici A, Steyerberg EW, Fockens P, Kuipers EJ, Siersema PD.

A fully-covered stent (Alimaxx-E) for the palliation of malignant dysphagia: a prospective follow-up study.

Gastrointest Endosc. 2009 Dec;70(6):1082-9.

Epub 2009 Jul 28.

90

Fiorino G, Rovida S, Correale C, Danese S*.

Raw IF (2008): 7.367

Normalized IF: 4

Normalized IF: 6

Oussalah A, Danese S, Peyrin-Biroulet L.

Curr Drug Targets. 2009 Nov 17. [Epub ahead of print] Raw IF (2008): 4.187

Normalized IF: 6

Danese S*, Vetrano S, Zhang L, Ploplis VA, Castellino FJ.

The protein C pathway in tissue inflammation and injury: pathogenic role and therapeutic implications.

Blood. 2009 Dec 17. [Epub ahead of print] Raw IF (2008): 10.432

Normalized IF: 8

van Boeckel PG, Repici A, Vleggaar FP, Solito B, Rando G, Cortelezzi C, Rossi M, Pagano N, Malesci A, Siersema PD.

A new metal stent with a controlled-release system for palliation of malignant dysphagia: a prospective, multicenter study.

Gastrointest Endosc.2009. [Epub ahead of print] Raw IF (2008): 7.367

Normalized IF: 8

Hassan C, Pickhardt PJ, Kim DH, DI Giulio E, Zullo A, Laghi A, Repici A, Iafrate F, Osborn J, Annibale B.

Systematic review: distribution of advanced neoplasia according to polyp size at screening colonoscopy.

Peyrin-Biroulet L, Cieza A, Sandborn WJ, Kostanjsek N, Kamm MA, Hibi T, LĂŠmann M, Stucki G, Colombel JF and the IPNIC group (S. Danese)

Disability in inflammatory bowel diseases: Developing ICF core sets for patients with inflammatory bowel diseases based on the international classification of functioning, disability, and health.

Inflamm Bowel Dis. 2010 Jan;16(1):15-22. Epub 2009 Jul16.

Raw IF (2008): 4.975

Normalized IF: 1.2

Scaldaferri F, Correale C, Gasbarrini A, Danese S.

Aliment Pharmacol Ther. 2010 Jan 15;31(2):210-7. Epub 2009 Oct 8.

Molecular signaling blockade as a new approach to inhibit leukocyte-endothelial interactions for inflammatory bowel disease treatment.

Raw IF (2008): 3.71

Cell Adh Migr. 2009 Jul-Sep;3(3):296-9. Epub 2009 Jul 2.

Normalized IF: 3

Raw IF (2008): 0

Normalized IF: 0.1

Grassini M, Battaglia E, Verna C, Niola P, Repici A, Corazzi N, Bassotti G.

Improvement of functional bloating by an enterovaccine: a preliminary study.

Rev Esp Enferm Dig. 2009 Sep;101(9):619-22.

Raw IF (2008): 1.263

General Surgery iii

Normalized IF: 0.5

De Angelis C, Mangone M, Bianchi M, Saracco G, Repici A, Rizzetto M, Pellicano R.

Rottoli M, Bona S, Rosati R, Elmore U, Bianchi PP, Spinelli A, Bartolucci C, Montorsi M.

An update on AIDS-related cholangiopathy.

Laparoscopic Rectal Resection for Cancer: Effects of Conversion on Short-Term Outcome and Survival.

Minerva Gastroenterol Dietol. 2009 Mar;55(1):79-82.

Review.

Ann Surg Oncol. 2009 May;16(5):1279-86. Epub 2009 Feb 28.

Raw IF (2008): 0

Normalized IF: 0.1

Rey JF, Repici A, Kuznetsov K, Boyko V, Aabakken L.

Optimal preparation for small bowel examinations with video capsule endoscopy.

Raw IF (2008): 3.898

Normalized IF: 6

Donadon M, Botea F, Belliappa V, Montorsi M, Torzilli G.

Experience With More Than 500 Minimally Invasive Hepatic Procedures: A Serious Note Of Caution.

Dig Liver Dis. 2009 Jul;41(7):486-93. Epub 2009 Jan 20.

Ann Surg. 2009 Jun;249(6):1064-5; author reply 1065-6.

Letter to the Editor (comments)

Raw IF (2008): 2.577

Raw IF (2008): 8.46

Normalized IF: 4

Normalized IF: 1.6

Suffat LP, Fronda G, Maglione V, Righi D, Doriguzzi A, Repici A, De Paolis P.

Torzilli G, Donadon M, Cimino M, Del Fabbro D, Procopio F, Botea F.

Cholangioscopic management of intrahepatic papillomatosis unsuitable for surgical treatment.

Systematic Subsegmentectomy by UltrasoundGuided Finger Compression for Hepatocellular Carcinoma in Cirrhosis.

Ann Ital Chir. 2009 Jan-Feb;80(1):35-8.

Raw IF (2008): 0

Normalized IF: 0.1

Ann Surg Oncol. 2009 Jul;16(7):1843. Epub 2009 Apr 30.

Raw IF (2008): 3.898

Normalized IF: 6

Pellicano R, Oliaro E, Fagoonee S, Astegiano M, Berrutti M, Saracco G, Smedile A, Repici A, Leone N, Castelli A, Luigiano C, Fadda M, Rizzetto M.

Torzilli G, Procopio F, Botea F, Marconi M, Del Fabbro D, Donadon M, Palmisano A, Spinelli A, Montorsi M.

Clinical and biochemical parameters related to cardiovascular disease after Helicobacter pylori eradication.

One-stage ultrasonographically guided hepatectomy for multiple bilobar colorectal metastases: a feasible and effective alternative to the 2-stage approach.

Int Angiol. 2009 Dec;28(6):469-73.

Surgery. 2009 Jul;146(1):60-71.

Raw IF (2008): 1.418

Normalized IF: 1

Raw IF (2008): 3.389

Normalized IF: 6

91

Papers published 2009

Torzilli G, Procopio F, Palmisano A, Cimino M, Del Fabbro D, Donadon M, Montorsi M.

Torzilli G*, Donadon M, Palmisano A, Marconi M, Procopio F, Botea F, Del Fabbro D, Cappellani A, Montorsi M.

New technique for defining the right anterior section intraoperatively using ultrasound-guided finger counter-compression.

Ultrasound guided liver resection: does this approach limit the need for portal vein embolization?

J Am Coll Surg. 2009 Aug;209(2):e8-11. Epub 2009 Jun 25.

Raw IF (2008): 3.692

Normalized IF: 6

Hepatogastroenterology. 2009 Sep-Oct;56(94-95):1483-90.

Raw IF (2008): 0.68

Normalized IF: 1

Torzilli G*, Palmisano A, Procopio F, Cimino M, Botea F, Donadon M, Fabbro DD, Montorsi M

Santambrogio R, Opocher E, Zuin M, Selmi C, Bertolini E, Costa M, Conti M, Montorsi M.

A New Systematic Small for Size Resection for Liver Tumors Invading the Middle Hepatic Vein at its Caval Confluence: Mini-Mesohepatectomy.

Ann Surg. 2010 Jan;251(1):33-9. Epub 2009 Oct 24.

Surgical Resection Versus Laparoscopic Radiofrequency Ablation in Patients With Hepatocellular Carcinoma and Child-Pugh Class A Liver Cirrhosis.

Raw IF (2008): 8.46

Ann Surg Oncol. 2009 Sep 1. [Epub ahead of print]

Normalized IF: 8

Raw IF (2008): 3.898

Normalized IF: 6

Torzilli G*, Botea F, Donadon M, Cimino M, Del Fabbro D, Palmisano A.

Minimesohepatectomy for Colorectal Liver Metastasis Invading the Middle Hepatic Vein at the Hepatocaval Confluence.

Ann Surg Oncol. 2009 Oct 23. [Epub ahead of print] Raw IF (2008): 3.898

Normalized IF: 6

Torzilli G, Procopio F, Cimino M, Fabbro DD, Palmisano A, Donadon M, Montorsi M.

Anatomical Segmental and Subsegmental Resection of the Liver for Hepatocellular Carcinoma: A New Approach by Means of Ultrasound-Guided Vessel Compression.

Mini Invasive Surgery Repici A, Fumagalli U, Malesci A, Barbera R, Gambaro C, Rosati R.

Endoluminal Fundoplication (ELF) for GERD Using EsophyX: a 12-Month Follow-up in a Single-Center Experience.

J Gastrointest Surg. 2009 Nov 10. [Epub ahead of print] Raw IF (2008): 2.311

Normalized IF: 6

Ann Surg. 2010 Feb;251(2):229-35. Epub 2009 Oct 15.

Raw IF (2008): 8.46

Normalized IF: 8

Torzilli G.

Surgical technique: new advancements for expanding indications and safety: The Western experience.

J Hepatobiliary Pancreat Surg. 2009 Nov 7. [Epub ahead of print] Raw IF (2008): 1.914

Normalized IF: 4

Spinelli A*, Szabo H, Montorsi M.

Intestinal fibrosis in Crohnâ&#x20AC;&#x2122;s disease: medical treatment or surgery?

Curr Drug Targets. 2009 Nov 17. [Epub ahead of print] Raw IF (2008): 4.187

Normalized IF: 6

Gynaecology Department Reproductive Medicine Chiriva-Internati M, Gagliano N, Donetti E, Costa F, Grizzi F, Franceschini B, Albani E, Levi-Setti PE, Gioia M, Jenkins M, Cobos E, Kast WM.

Muilenburg DJ, Singh A, Torzilli G, Khatri VP.

Sperm protein 17 is expressed in the sperm fibrous sheath.

Surgery in the patient with liver disease.

J Transl Med. 2009 Jul 15;7:61.

Anesthesiol Clin. 2009 Dec;27(4):721-37.

Raw IF (2008): 2.917

Raw IF (2008): 0

Normalized IF: 4

Normalized IF: 0.1 Bulletti C, Montini A, Setti PL, Palagiano A, Ubaldi F, Borini A.

Muilenburg DJ, Singh A, Torzilli G, Khatri VP.

92

Surgery in the patient with liver disease.

Vaginal parturition decreases recurrence of endometriosis.

Med Clin North Am. 2009 Sep;93(5):1065-81.

Fertil Steril. 2009 Jun 12. [Epub ahead of print]

Raw IF (2008): 2.214

Raw IF (2008): 4.167

Normalized IF: 3

Normalized IF: 3

Intensive Care Department and General Anaesthesia

Internal Medicine Department

Anaestesia and GIT

General Medicine & Hepatology

Giustiniano E, Cancellieri F, Battistini GM, Dominoni C, Brancato G, Spoto MR.

Cazzaniga M, Salerno F, Borroni G, Ceriani R, Stucchi G, Guerzoni P, Casiraghi MA, Tommasini M.

Positive end-expiratory pressure during infrarenal aortic clamping limits hemodynamic impairment risk.

Prediction of asymptomatic cirrhosis in chronic hepatitis C patients: accuracy of artificial neural networks compared with logistic regression models.

J Cardiovasc Med (Hagerstown). 2009 Mar;10(3):282-7.

Raw IF (2008): 0

Normalized IF: 0.1

Carlino C, Pastore JC, B attistini GM, Cancellieri F, De Caria D, Ruggieri N, Bordone G, Bellato V*.

Training resident anesthesiologists in adult challenging intubation comparing Truview EVO2 and Macintosh laryngoscope: a preliminary study.

Minerva Anestesiol. 2009 Oct;75(10):563-7. Epub 2009 May 21.

Raw IF (2008): 1.627

Normalized IF: 2

Taccone P, Pesenti A, Latini R, Polli F, Vagginelli F, Mietto C, Caspani L, Raimondi F, Bordone G, Iapichino G, Mancebo J, GuĂŠrin C, Ayzac L, Blanch L, Fumagalli R, Tognoni G, Gattinoni L; Prone-Supine II Study Group.

Collaborators (64): Gattinoni L, Tognoni G, Fumagalli R, Latini R, Pesenti A, Taccone P, Malacrida R, Valsecchi MG, Suter P, Barlera S, Polli F, Milani V, Amigoni M, Scanziani M, Serio C, Cabello B, Lisi A, Valetti MT, Marchesi G, Cerchiari E, Cilloni N, Gordini G, Maioli A, Servadio G, Greco S, Solca M, Ronzoni G, Beck E, Pallavicini FB, Ardidi E, Radrizzani D, Porta V, Castelli A, Colombo R, Russo R, Savioli M, Zaniboni M, Noto A, Rossi N, Tagliabue P, Rialp G, Trabanco S, Pittoni G, Bonaccorso G, Michielan F, Gagliardi G, Braschi A, Rodi G, Botazzi A, Peta M, Bellato V, Gavazzeni V, Salati G, Bottari W, Capra C, Frattini F, Dan M, Zaro G, Borelli M, Ferraris S, Rossi S, Marafon S, Gallioli G, Muttini S.

Prone positioning in patients with moderate and severe acute respiratory distress syndrome: a randomized controlled trial.

Eur J Gastroenterol Hepatol. 2009 Jun;21(6):681-7.

Raw IF (2008): 2.08

Normalized IF: 2

General Medicine & Pneumology Maggi S, Siviero P, Gonnelli S, Schiraldi C, Malavolta N, Nuti R, Crepaldi G; EOLO Study Group.Collaborators (108): Angeli A, De Rose V, Cravero M, Fantino S, Isaia G, Baldi S, Cisari C, Ronco M, Rocchetta PA, Polla B, Mondavio M, Ferraro G, Bianchi G, Bonaria M, Versace F, Vacca N, Calitro M, Iaffaldano A, Muratore M, Mandurino L, Cesareo di Lecce S, Maugeri D, Distefano S, Fiore CE, Di Maria G, Frisina N, Girbino G, Rossetto S, Rossetto G, Pedrazzoni M, Cuomo A, Francesco T, Potena A, Biondi M, Fiorenti F, Malavolta N, Fagiani A, Del Forno L, Colaneri A, De Felice A, De Matthaeis G, Di Matteo L, Cortese G, Mancini G, Tubaldi A, Pozone M, Fiore Donati A, Sfrappini M, Olori G, Silveri F, Subiaco S, Laatte VM, Ricciardi C, Noverino L, Tallarico L, Del Puente A, Zedda A, Borg ML, Longobardi U, Cerqua R, Califano M, Aversa A, Battaglia E, Santi I, Caratozzolo O, Tenca P, Davoli C, Bosio G, Cavaiani P, Alessandrini A, Rondena M, Grechi A, Galimberti G, Ciccarelli M, Giustina A, Cantucci C, Giannini S, Zuin R, Bertoldo F, Ferrari M, Adami S, Cipriani A, Sella D, Schinella D, Mazza F, Di Virgilio R, Santelli G, Tartarelli G, Vincenti R, Bertolucci D, Torrini A, Di Munno O, Paggiaro P, Sabadini L, Naldi M, Brandi ML, Pistoleri M, Nuti R, Frediani B, Rottoli P, Cecchetti R, Faloppa C, Bancheri C, Trequatrini T, Falaschi P, Mariotta S, Napoletano C, Dominaci M.

Osteoporosis risk in patients with chronic obstructive pulmonary disease: the EOLO study.

J Clin Densitom. 2009 Jul-Sep;12(3):345-52.

Raw IF (2008): 1.983

Normalized IF: 0.4

JAMA. 2009 Nov 11;302(18):1977-84.

Raw IF (2008): 31.718

Normalized IF: 15

General Medicine & Nephrology Graziani G, Montanelli A, Brambilla S, Balzarini L.

Nephrogenic systemic fibrosis an unsolved riddle.

J Nephrol. 2009 Mar-Apr;22(2):203-7.

Raw IF (2008): 1.211

Normalized IF: 1

Ponticelli C*, Graziani G, Montanari E.

Ureteral Endometriosis: A Rare and Underdiagnosed Cause of Kidney Dysfunction.

Nephron Clin Pract. 2009 Nov 3;114(2):c89-c94. [Epub ahead of print] Raw IF (2008): 1.715

Normalized IF: 2

93

Papers published 2009

Ponticelli C.

Recurrence of focal segmental glomerular sclerosis (FSGS) after renal transplantation.

Nephrol Dial Transplant. 2010 Jan;25(1):25-31. Epub 2009 Oct 28.

Raw IF (2008): 3.568

Normalized IF: 6

Lleo A, Selmi C, Invernizzi P, Podda M, Coppel RL, Mackay IR, Gores GJ, Ansari AA, Van de Water J, Gershwin ME.

Apotopes and the biliary specificity of primary biliary cirrhosis.

Hepatology. 2009 Mar;49(3):871-9.

Raw IF (2008): 11.355

Normalized IF: 4

Ponticelli C, Alberighi OD.

Haemophagocytic syndrome – a life-threatening complication of renal transplantation.

Invernizzi P.

Nephrol Dial Transplant. 2009 Sep;24(9):2623-7. Epub 2009 Jun 12.

J Autoimmun. 2009 Aug;33(1):1-2. Epub 2009 May 2.

Raw IF (2008): 3.568

Normalized IF: 6

Salvadori M, Scolari MP, Bertoni E, Citterio F, Rigotti P, Cossu M, Dal Canton A, Tisone G, Albertazzi A, Pisani F, Gubbiotti G, Piredda G, Busnach G, Sparacino V, Goepel V, Messa P, Berloco P, Montanaro D, Veroux P, Federico S, Bartezaghi M, Corbetta G, Ponticelli C.

Everolimus With Very Low-Exposure Cyclosporine A in De Novo Kidney Transplantation: A Multicenter, Randomized, Controlled Trial.

Future directions in genetic for autoimmune diseases.

Raw IF (2008): 7.881

Normalized IF: 8

Selmi C, Gershwin ME.

The retroviral myth of primary biliary cirrhosis: Is this (finally) the end of the story?

J Hepatol. 2009 Aug;51(2):412-3; author reply 414-5. Epub 2009 May 15. Letter to the editor (comment) Raw IF (2008): 7.056

Normalized IF: 1.6

Transplantation. 2009 Nov 27;88(10):1194-1202.

Raw IF (2008): 3.816

Normalized IF: 6

Ponticelli C.

Azathioprine (AZA) or Mycophenolate in Renal Transplant Recipients?

Agmon-Levin N, Ram M, Barzilai O, Porat-Katz BS, Parikman R, Selmi C, Gershwin ME, Anaya JM, Youinou P, Bizzaro N, Tincani A, Tzioufas AG, Cervera R, Stojanovich L, Martin J, Gonzalez-Gay MA, Valentini G, Blank M, SanMarco M, Rozman B, Bombardieri S, De Vita S, Shoenfeld Y.

Am J Transplant. 2009 Dec 2. [Epub ahead of print] No abstract available. Letter to the Editor (comment)

Prevalence of hepatitis C serum antibody in autoimmune diseases.

Raw IF (2008): 6.559

J Autoimmun. 2009 May-Jun;32(3-4):261-6.

Epub 2009 Apr 8.

Normalized IF: 1.2

Raw IF (2008): 7.881

Ponticelli C, Meroni PL.

Normalized IF: 4

Kallikreins and lupus nephritis.

J Clin Invest. 2009 Apr;119(4):768-71.

Raw IF (2008): 16.559

Normalized IF: 15

Raw IF (2008): 2.971

Invernizzi P, Pasini S, Selmi C, Gershwin ME, Podda M.

Female predominance and X chromosome defects in autoimmune diseases.

J Autoimmun. 2009 Aug;33(1):12-6. Epub 2009 Apr 7.

Normalized IF: 8

Tanaka A, Nezu S, Uegaki S, Kikuchi K, Shibuya A, Miyakawa H, Takahashi SI, Bianchi I, Zermiani P, Podda M, Ohira H, Invernizzi P°, Takikawa H°.

Vitamin D receptor polymorphisms are associated with increased susceptibility to primary biliary cirrhosis in Japanese and Italian populations.

J Hepatol. 2009 Jun;50(6):1202-9. Epub 2009 Mar 5.

94

Raw IF (2008): 7.056

Old and rising stars in the lymphoid liver.

Semin Immunopathol. 2009 Sep;31(3):279-82. Epub 2009 Jul 15.

Internal Medicine

Raw IF (2008): 7.881

Selmi C, Podda M, Gershwin ME.

Normalized IF: 8

(°) These authors equally contributed to this work

Normalized IF: 4

Selmi C, Gershwin ME.

The role of environmental factors in primary biliary cirrhosis.

Trends Immunol. 2009 Aug; 30(8):415-20.

Epub 2009 Jul 28.

Raw IF (2008): 9.91

Normalized IF: 8

Zhong B, Strnad P, Selmi C, Invernizzi P, Tao GZ, Caleffi A, Chen M, Bianchi I, Podda M, Pietrangelo A, Gershwin ME, Omary MB.

Keratin variants are overrepresented in primary biliary cirrhosis and associate with disease severity.

Hepatology. 2009 Aug;50(2):546-54.

Raw IF (2008): 11.355

Normalized IF: 8

Niro G.A., Poli F., Andriulli A., Bianchi I., Bernuzzi F., Caliari L., Fontana R., Gioffreda D., Valvano M.R., Podda M., Invernizzi P*.

TNF-α Polymorphisms in Primary Biliary Cirrhosis: A Northern and Southern Italian Experience Ann. N.Y. Acad. Sci. 1173: 557–563 (2009).

Raw IF (2008): 2.303

Normalized IF: 6

Selmi C, Meda F, Kasangian A, Invernizzi P, Tian Z, Lian Z, Podda M, Gershwin ME.

Experimental evidence on the immunopathogenesis of primary biliary cirrhosis.

Cell Mol Immunol. 2010 Jan;7(1):1-10. Epub 2009 Dec 23.

Raw IF (2008): 0

Normalized IF: 0.1

Invernizzi P. Coufal M, Invernizzi P, Gaudio E, Bernuzzi F, Frampton GA, Onori P, Franchitto A, Carpino G, Ramirez JC, Alvaro D, Marzioni M, Battisti G, Benedetti A, Demorrow S.

Geoepidemiology of autoimmune liver diseases.

J Autoimmun. 2009 Dec 23. [Epub ahead of print]

Increased local dopamine secretion has growth promoting effects in cholangiocarcinoma.

Raw IF (2008): 7.881

Int J Cancer. 2009 Sep 30. [Epub ahead of print]

Selmi C, Tsuneyama K.

Raw IF (2008): 4.734

Normalized IF: 6

Lleo A, Invernizzi P, Gao B, Podda M, Gershwin ME.

Definition of human autoimmunity -autoantibodies versus autoimmune disease.

Autoimmun Rev. 2009 Dec 3. [Epub ahead of print] Raw IF (2008): 5.371

Normalized IF: 6

Normalized IF: 8

Nutrition, geoepidemiology, and autoimmunity.

Autoimmun Rev. 2009 Dec 4. [Epub ahead of print] Raw IF (2008): 5.371

Normalized IF: 6

Selmi C, Lleo A, Pasini S, Zuin M, Gershwin ME.

Innate immunity and primary biliary cirrhosis.

Curr Mol Med. 2009 Feb;9(1):45-51.

Raw IF (2008): 5.254

Normalized IF: 6

Agmon-Levin N, Shapira Y, Selmi C, Barzilai O, Ram M, Szyper-Kravitz M, Sella S, Katz BS, Youinou P, Renaudineau Y, Larida B, Invernizzi P, Gershwin ME, Shoenfeld Y.

Marzioni M., Invernizzi P., Candelaresi C., Maggioni M., Saccomanno S., Selmi C., Rychlicki C., Cassani B., Miozzo M., Pasini S., Fava G., Alpini G., Benedetti A.

A comprehensive evaluation of serum autoantibodies in primary biliary cirrhosis.

Human cholangiocarcinoma development is

J Autoimmun. 2009 Nov 6. [Epub ahead of print] Raw IF (2008): 7.881

Normalized IF: 4

associated with dysregulation of opioidergic modulation of cholangiocyte growth.

Digest Liver Dis. 2009;41:523-33.

Raw IF (2008): 2.577

Barak V, Selmi C, Schlesinger M, Blank M, Agmon-Levin N, Kalickman I, Gershwin ME, Shoenfeld Y.

Selmi C.

Serum inflammatory cytokines, complement components, and soluble interleukin 2 receptor in primary biliary cirrhosis.

Ann N Y Acad Sci. 2009 Sep;1173:239-42.

A new year in autoimmunity.

Raw IF (2008): 2.303

J Autoimmun. 2009 Nov-Dec;33(3-4):178-82. Epub 2009 Oct 28.

Selmi C.

Raw IF (2008): 7.881

What is hot in autoimmunity.

Normalized IF: 8

Normalized IF: 4

Normalized IF: 6

Acta Reumatol Port. 2009 Oct-Dec;34(4):580-8.

Giorgini A, Capsoni F, Podda M, Lleó A, Battezzati PM, Ongari AM, Selmi C, Benetti A, Malinverno F, Rossaro L, Gershwin ME, Zuin M.

Treatment with PEG-interferon and ribavirin for chronic hepatitis C increases neutrophil and monocyte chemotaxis.

Probiotics and immunity.

J Gastroenterol. 2009;44(1):26-46. Epub 2009 Jan 22. Review.

Normalized IF: 4

Normalized IF: 3 Kawai T, Hosoya N, Moritoki Y, Kajiyama Y, Watanabe M, Takai A, Selmi C, Gershwin ME, Miyakawa H, Kikuchi K.

Invernizzi P, Gershwin ME.

The genetics of human autoimmune disease.

J Autoimmun. 2009 Nov-Dec;33(3-4):290-9. Epub 2009 Aug 13.

Raw IF (2008): 7.881

Normalized IF: 0.1

Borchers AT, Selmi C, Meyers FJ, Keen CL, Gershwin ME.

Raw IF (2008): 3.117

Ann N Y Acad Sci. 2009 Sep;1173:847-57.

Raw IF (2008): 2.303

Raw IF (2008): 0

Normalized IF: 8

Autoantibody IgG subclasses to recombinant antigens and the role of bacterial stimuli in primary biliary cirrhosis.

Hepatol Res. 2009 Sep;39(9):874-81. Epub 2009 Jul 13.

Raw IF (2008): 1.562

Normalized IF: 1

95

Papers published 2009

Bhat A, Selmi C, Naguwa SM, Cheema GS, Gershwin ME.

Currents Concepts on the Immunopathology of Amyloidosis.

Clin Rev Allergy Immunol. 2009 Jul 21. [Epub ahead of print] Raw IF (2008): 3,533

Normalized IF: 6

Matthias T, Pfeiffer S, Selmi C, Eric Gershwin M.

Diagnostic Challenges in Celiac Disease and the Role of the Tissue Transglutaminase-Neo-Epitope.

Rheumatology Uboldi F, Carlo-Stella N*, Belloli L, Massarotti M, Marasini B.

Glucose blood levels after intra-articular steroid injection in diabetic and non-diabetic patients.

Clin Rheumatol. 2009 Apr;28(4):491-2. Epub 2009 Jan 24.

Letter to the Editor (results) Raw IF (2008): 1.559

Normalized IF: 1

Clin Rev Allergy Immunol. 2009 Jul 23. [Epub ahead of print]

Massarotti M, Marasini B.

Raw IF (2008): 3.533

Successful treatment with etanercept of a patient with psoriatic arthritis after adalimumab-related hepatotoxicity

Normalized IF: 3

European Association for the Study of the Liver: Beuers U°, Boberg KM°, Chapman RW°, Chazouillères O°, Invernizzi P°, Jones DE°, Lammert F°, Parès A°, Trauner M°.

EASL Clinical Practice Guidelines: management of cholestatic liver diseases.

J Hepatol. 2009 Aug;51(2):237-67. Epub 2009 Jun 6.

Raw IF (2008): 7.056

Normalized IF: 8

(°) These authors equally contributed to this work

Int J Immunopathol Pharmacol. 2009 Apr-Jun;22(2):547-9.

Letters to the Editor (results) Raw IF (2008): 2.793

Normalized IF: 2

Marasini B, Conciato L, Belloli L, Massarotti M.

Systemic sclerosis and cancer.

Int J Immunopathol Pharmacol. 2009 Jul-Sep;22(3):573-8.

Raw IF (2008): 2.793

Normalized IF: 4

Migliore A, Bizzi E, Laganà B, Altomonte L, Zaccari G, Granata M, Canzoni M, Marasini B, Massarotti M, Massafra U, Ranieri M, Pilla R, Martin LS, Pezza M, Vacca F, Galluccio A.

The safety of anti-TNF agents in the elderly.

Int J Immunopathol Pharmacol. 2009 Apr-Jun;22(2):415-26.

Raw IF (2008): 2.793

Thrombosis Centre Pezzini A, Grassi M, Del Zotto E, Lodigiani C, Ferrazzi P, Spalloni A, Patella R, Giossi A, Volonghi I, Iacoviello L, Magoni M, Rota LL, Rasura M, Padovani A.

Common genetic markers and prediction of recurrent events after ischemic stroke in young adults.

Neurology. 2009 Sep 1;73(9):717-23.

Raw IF (2008): 7.043

Normalized IF: 8

Carlo-Stella N, Belloli L, Barbera R, Gambaro C, Rando G, Malesci A, Marasini B.

Gastroesophageal reflux and lung disease in systemic sclerosis.

Am J Respir Crit Care Med. 2009 Jun 15;179(12):1167; author reply 1167-8.

Letters to the editor (comments) Raw IF (2008): 9.792

Normalized IF: 1.6

Di Micco P*, D’Uva M, Lodigiani C, Rota LL.

Marasini B, Massarotti M.

Thrombophilia and repeated fertilisation and embryo transfer failure: An open issue.

What rheumatologists should know about gout and cardiovascular disease.

Thromb Haemost. 2010 Feb 1;103(2):472-3. Epub 2009 Dec 18.

Letter to the editor (comment).

J Rheumatol. 2009 Apr;36(4):854-5.

Letters to the editor (comments)

Raw IF (2008): 3.803

Raw IF (2008): 3.282

Normalized IF: 1.2

Lodigiani C*, Ferrazzi P, Di Micco P, Librè L, Genovese S, Quaglia I, Rota LL.

Is there a relationship between factor V Leiden and type 2 diabetes?

J Transl Med. 2009 Jun 26;7:52.

96

Normalized IF: 2

Raw IF (2008): 2.917

Normalized IF: 4

Normalized IF: 0.8

Neuroscience Area

Nobile-Orazio E, Terenghi F, Cocito D, Gallia F, Casellato C.

Emergency Neurology & Stroke Unit Micieli G*, Marcheselli S, Tosi PA.

Safety and efficacy of alteplase in the treatment of acute ischemic stroke.

Vasc Health Risk Manag. 2009;5(1):397-409.

Raw IF (2008): 0

Normalized IF: 0.1

Oral methotrexate as adjunctive therapy in patients with multifocal motor neuropathy on chronic IVIg therapy.

J Peripher Nerv Syst. 2009 Sep;14(3):203-5.

Letters to the editor (results) Raw IF (2008): 2.8

Normalized IF: 2

Nobile-Orazio E*, Giannotta C, Briani C.

Anti-ganglioside complex IgM antibodies in multifocal motor neuropathy and chronic immunemediated neuropathies.

J Neuroimmunol.2009 . [Epub ahead of print]

Neurology ii

Raw IF (2008): 3.159

Nobile-Orazio E, Terenghi F, Giannotta C, Gallia F, Nozza A.

Serum vegf levels in poems syndrome and in immunemediated neuropathies.

Neurology. 2009 Mar 17;72(11):1024-6.

Raw IF (2008): 7.043

Normalized IF: 8

Galassi G, Girolami F, Nobile-Orazio E, Funakoshi K, Ariatti A, Odaka M.

Acute hand weakness as a regional variant of GuillainBarré syndrome.

Letters to the editor (results) Eur J Neurol. 2009 Mar;16(3):e49.

Normalized IF: 4

Nobile-Orazio E.

Antigenic Determinants in IgM Paraprotein-Related Neuropathies.

Clin Lymphoma Myeloma. 2009 Feb;9(1):107-9.

Raw IF (2008): 1.596

Normalized IF: 1

Cocito D, Paolasso I, Antonini G, Benedetti L, Briani C, Comi C, Fazio R, Jann S, Matà S, Mazzeo A, Sabatelli M, NobileOrazio E; on behalf of The Italian Network for CIDP Register.

A nationwide retrospective analysis on the effect of immune therapies in patients with chronic inflammatory demyelinating polyradiculoneuropathy.

Eur J Neurol. 2009 Oct 23. [Epub ahead of print]

Raw IF (2008): 2.732

Normalized IF: 2

Raw IF (2008): 2.732

Normalized IF: 4

RMC Trial Group (Nobile-Orazio E).

Umapathi T, Hughes RA, Nobile-Orazio E, Léger JM.

Randomised controlled trial of methotrexate for chronic inflammatory demyelinating polyradiculoneuropathy (RMC trial): a pilot, multicentre study.

Immunosuppressant and immunomodulatory treatments for multifocal motor neuropathy.

Lancet Neurol. 2009 Feb;8(2):158-64. Epub 2009 Jan 10.

Raw IF (2008): 5.182

Raw IF (2008): 14.27

Cochrane Database Syst Rev. 2009 Jan 21;(1):CD003217.

Normalized IF: 3

Normalized IF: 10

Padua L, Briani C, Jann S, Nobile-Orazio E, Pazzaglia C, Morini A, Mondelli M, Ciaramitaro P, Cavaletti G, Cocito D, Fazio R, Santoro L, Galeotti F, Carpo M, Plasmati R, Benedetti L, Schenone A, Marchettini P, Cruccu G.

Validation of the Italian version of the Neuropathic Pain Symptom Inventory in peripheral nervous system diseases.

Neurol Sci. 2009 Apr;30(2):99-106. Epub 2009 Feb 6.

Raw IF (2008): 1.435

Normalized IF: 1

CI-PERINOMS Study Group: Cavaletti G, Cornblath DR, Postma TJ, Merkies IS, Argyriou A, Boogerd W, Briani C, Bruna J, Faber CG, Grisold W, Heimans JJ, Kalofonos H, KrarupHansen A, Koeppen S, Lauria G, Leandri M, Mielke S, NobileOrazio E, Pace A, Padua L, Plasmati R, Psimaras D, Ros T, Schenone A, Stragliotto G, Galimberti S, Valsecchi MG.

van Nes SI, Vanhoutte EK, Faber CG, Garssen M, van Doorn PA, Merkies IS; PeriNomS Study Group: (Bennett D, van den Berg LH, Van den Bergh PY, Cornblath DR, Dalakas M, Devigili G, van Doorn PA, Faber CG, Gorson KC, Hadden RD, Hahn AF, Hartung HP, Hughes RA, Lauria G, Léger JM, Lewis RA, Lunn MP, Merkies IS, Nobile-Orazio E, Notermans NC, Padua L, Reilly MM, Smith B).

Improving fatigue assessment in immune-mediated neuropathies: the modified Rasch-built fatigue severity scale.

J Peripher Nerv Syst. 2009 Dec;14(4):268-78.

Raw IF (2008): 2.8

Normalized IF: 0.8

Neurosurgery Di Ieva A, Barolat G, Tschabitscher M, Rognone E, Aimar E, Gaetani P, Tancioni F, Lorenzetti M, Crotti FM, Rodriguez Baena R, Warnke JP.

CI-PERINOMS: chemotherapy-induced peripheral neuropathy outcome measures study.

Lumbar Arachnoiditis and Thecaloscopy: Brief Review and Proposed Treatment Algorithm.

J Peripher Nerv Syst. 2009 Jun;14(2):69-71.

Cen Eur Neurosurg. 2009 Dec 21. [Epub ahead of print]

Raw IF (2008): 2.8

Normalized IF: 2

Raw IF (2008): 0

Normalized IF: 0.1

97

Papers published 2009

Oncology Department

Castagna L, Bramanti S, Balzarotti M, Sarina B, Todisco E, Anastasia A, Magagnoli M, Mazza R, Nozza A, Giordano L, Rodari M, Rinifilo E, Chiti A, Santoro A.

General and Oncologic Surgery Farinella E, Cirocchi R, La Mura F, Morelli U, Cattorini L, Delmonaco P, Migliaccio C, De Sol AA, Cozzaglio L, Sciannameo F.

Feasibility of laparoscopy for small bowel obstruction.

Predictive value of early 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) during salvage chemotherapy in relapsing/refractory Hodgkin lymphoma (HL) treated with high-dose chemotherapy.

Br J Haematol. 2009 May;145(3):369-72. Epub 2009 Mar 5.

Raw IF (2008): 4.478

Normalized IF: 6

World J Emerg Surg. 2009 Jan 19;4:3.

Raw IF (2008): 0

Normalized IF: 0.1

Gianotti L, Braga M, Biffi R, Bozzetti F, Mariani L; GlutamItaly Research Group of the Italian Society of Parenteral, and Enteral Nutrition: (Capuano G, Lembo R, Sabbatini A, Cozzaglio L, Coladonato M, Rocchetti S, Beneduce A, Tamini N, Coppola S, Pirovano R, Cipolat L, Geretto P, Borghi F, Di Cosmo L, Vuolo G, Amerio ML, Bianchi S, Pogliano B, Marino B, Amerio GM, Terranova ML, Leonello G, Rivoli G, Farinella E.)

Perioperative intravenous glutamine supplemetation in major abdominal surgery for cancer: a randomized multicenter trial.

Ann Surg. 2009 Nov;250(5):684-90.

Raw IF (2008): 8.46

Zucali PA, De Vincenzo F, Simonelli M, Santoro A.

Future developments in the management of malignant pleural mesothelioma.

Expert Rev Anticancer Ther. 2009 Apr;9(4):453-67.

Raw IF (2008): 2.296

Normalized IF: 2

Zuradelli M*, Masci G, Biancofiore G, Gullo G, Scorsetti M, Navarria P, Tancioni F, Berlusconi M, Giordano L, Santoro A.

High incidence of hypocalcemia and serum creatinine increase in patients with bone metastases treated with zoledronic acid.

Oncologist. 2009 May;14(5):548-56. Epub 2009 May 2.

Raw IF (2008): 6.63

Normalized IF: 6

Normalized IF: 1.6 Rimassa L*, Santoro A.

Sorafenib therapy in advanced hepatocellular carcinoma: the SHARP trial.

Medical Oncology and Haematology

Expert Rev Anticancer Ther. 2009 Jun;9(6):739-45.

Raw IF (2008): 2.296

Anastasia A, Giglio F, Mazza R, Sarina B, Todisco E, Bramanti S, Castagna L.

Early discharge after high-dose melphalan and peripheral blood stem cell reinfusion in patients with hematological and non-hematological disease.

Leuk Lymphoma. 2009 Jan;50(1):80-4 Raw IF (2008): 1.939

Normalized IF: 2

Cappuzzo F, Varella-Garcia M, Rossi E, Gajapathy S, Valente M, Drabkin H, Gemmill R.

MYC and EIF3H Coamplification Significantly Improve Response and Survival of Non-small Cell Lung Cancer Patients (NSCLC) Treated with Gefitinib.

J Thorac Oncol. 2009 Apr;4(4):472-8.

Raw IF (2008): 3.508

Normalized IF: 6

Stroppa E*, Bertuzzi A, Di Comite G, Mussi C, Lutman RF, Barbato A, Santoro A.

Phase I study of non-pegylated liposomal doxorubicin in combination with ifosfamide in adult patients with metastatic soft tissue sarcomas.

Invest New Drugs. 2009 Jul 7. [Epub ahead of print] Raw IF (2008): 3.396

Sorafenib is active on lung metastases from synovial sarcoma.

Letters to the editor (results) Annals of Oncology 2009 20(2):386-387;

98

Raw IF (2008): 4.935

Normalized IF: 6

Gregorc V, Santoro A, Bennicelli E, Punt CJ, Citterio G, Timmer-Bonte JN, Caligaris Cappio F, Lambiase A, Bordignon C, van Herpen CM.

Phase Ib study of NGR-hTNF, a selective vascular targeting agent, administered at low doses in combination with doxorubicin to patients with advanced solid tumours.

Br J Cancer. 2009 Jul 21;101(2):219-24. Epub 2009 Jun 30.

Raw IF (2008): 4.846

Basso U, Brunello A, Bertuzzi A, Santoro A.

Normalized IF: 2

Normalized IF: 6

Simonelli M*, Banna GL, Santoro A.

Thymoma associated with myasthenia and autonomic anti-Hu paraneoplastic neuropathy.

Tumori. 2009 Mar-Apr;95(2):243-7.

Normalized IF: 3

Raw IF (2008): 0.791

Normalized IF: 1

Cappuzzo F*, Marchetti A, Skokan M, Rossi E, Gajapathy S, Felicioni L, Del Grammastro M, Sciarrotta MG, Buttitta F, Incarbone M, Toschi L, Finocchiaro G, Destro A, Terracciano L, Roncalli M, Alloisio M, Santoro A, Varella-Garcia M.

de Azambuja E, McCaskill-Stevens W, Francis P, Quinaux E, Crown JP, Vicente M, Giuliani R, Nordenskjöld B, Gutiérez J, Andersson M, Vila MM, Jakesz R, Demol J, Dewar J, Santoro A, Lluch A, Olsen S, Gelber RD, Di Leo A, Piccart-Gebhart M.

Increased MET gene copy number negatively affects survival of surgically resected non-small-cell lung cancer patients.

The effect of body mass index on overall and diseasefree survival in node-positive breast cancer patients treated with docetaxel and doxorubicin-containing adjuvant chemotherapy: the experience of the BIG 02-98 trial.

J Clin Oncol. 2009 Apr 1;27(10):1667-74. Epub 2009 Mar 2.

Raw IF (2008): 17.157

Normalized IF: 15

Castagna L*, Sarina B, Todisco E, Magagnoli M, Balzarotti M, Bramanti S, Mazza R, Anastasia A, Bacigalupo A, Aversa F, Soligo D, Giordano L, Santoro A.

Breast Cancer Res Treat. 2010 Jan;119(1):145-53. Epub 2009 Sep 3.

Raw IF (2008): 5.684

Normalized IF: 3

Allogeneic stem cell transplantation compared with chemotherapy for poor-risk Hodgkin lymphoma.

Brusamolino E, Bacigalupo A, Barosi G, Biti G, Gobbi PG, Levis A, Marchetti M, Santoro A, Zinzani PL, Tura S.

Biol Blood Marrow Transplant. 2009 Apr;15(4):432-8. Epub 2009 Feb 12.

Classical Hodgkin’s lymphoma in adults: guidelines of the Italian Society of Hematology, the Italian Society of Experimental Hematology, and the Italian Group for Bone Marrow Transplantation on initial work-up, management, and follow-up.

Raw IF (2008): 3.732

Normalized IF: 6

Bearz A, Garassino I, Tiseo M, Caffo O, Soto-Parra H, Boccalon M, Talamini R, Santoro A, Bartolotti M, Murgia V, Berretta M, Tirelli U.

Activity of Pemetrexed on brain metastases from Non-Small Cell Lung Cancer.

Lung Cancer. 2009 Jul 24. [Epub ahead of print] Raw IF (2008): 2.97

Normalized IF: 6

Garassino I*, Gullo G, Orefice S, Tondulli L, Masci G, Salvini P, Eboli M, Di Tommaso L, Giordano L, Alloisio M, Roncalli M, Santoro A.

Outcome of T1N0M0 breast cancer in relation to St. Gallen risk assignment criteria for adjuvant therapy.

Haematologica. 2009 Apr;94(4):550-65. Epub 2009 Mar 10.

Raw IF (2008): 5.978

Normalized IF: 3

Leidner RS, Fu P, Clifford B, Hamdan A, Jin C, Eisenberg R, Boggon TJ, Skokan M, Franklin WA, Cappuzzo F, Hirsch FR, Varella-Garcia M, Halmos B.

Genetic Abnormalities of the EGFR Pathway in African American Patients With Non-Small-Cell Lung Cancer.

J Clin Oncol. 2009 Nov 20;27(33):5620-6. Epub 2009 Sep 28.

Raw IF (2008): 17.157

Normalized IF: 7.5

Breast. 2009 Aug;18(4):263-6. Epub 2009 Aug 13.

Raw IF (2008): 2.155

Normalized IF: 4

BIG 1-98 Collaborative Group°, Mouridsen H, Giobbie-Hurder A, Goldhirsch A, Thürlimann B, Paridaens R, Smith I, Mauriac L, Forbes JF, Price KN, Regan MM, Gelber RD, Coates AS.

Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer.

N Engl J Med. 2009 Aug 20;361(8):766-76.

Raw IF (2008): 50.017

Normalized IF: 3

Cappuzzo F*, Tallini G, Finocchiaro G, Wilson RS, Ligorio C, Giordano L, Toschi L, Incarbone M, Cavina R, Terracciano L, Roncalli M, Alloisio M, Varella-Garcia M, Franklin WA, Santoro A.

Insulin-like growth factor receptor 1 (IGF1R) expression and survival in surgically resected nonsmall-cell lung cancer (NSCLC) patients.

Ann Oncol. 2009 Sep 18. [Epub ahead of print] Raw IF (2008): 4.935

Normalized IF: 6

(°)A. Santoro member of the BIG 1-98 Group Agnelli G, Gussoni G, Bianchini C, Verso M, Mandalà M, Cavanna L, Barni S, Labianca R, Buzzi F, Scambia G, Passalacqua R, Ricci S, Gasparini G, Lorusso V, Bonizzoni E, Tonato M; on behalf of the PROTECHT Investigators (A. Santoro).

Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study.

Lancet Oncol. 2009 Oct;10(10):943-9. Epub 2009 Aug 31.

Raw IF (2008): 13.283

Normalized IF: 2

Ferreri AJ, Reni M, Foppoli M, Martelli M, Pangalis GA, Frezzato M, Cabras MG, Fabbri A, Corazzelli G, Ilariucci F, Rossi G, Soffietti R, Stelitano C, Vallisa D, Zaja F, Zoppegno L, Aondio GM, Avvisati G, Balzarotti M, Brandes AA, Fajardo J, Gomez H, Guarini A, Pinotti G, Rigacci L, Uhlmann C, Picozzi P, Vezzulli P, Ponzoni M, Zucca E, Caligaris-Cappio F, Cavalli F; on behalf of the International Extranodal Lymphoma Study Group (IELSG).

High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial.

Lancet. 2009 Oct 31;374(9700):1512-20. Epub 2009 Sep 18 Raw IF (2008): 28.409

Normalized IF: 15

99

Papers published 2009

Ceresoli GL, Zucali PA, Gianoncelli L, Lorenzi E, Santoro A.

Second-line treatment for malignant pleural mesothelioma.

Cancer Treat Rev. 2009 Oct 28. [Epub ahead of print] Raw IF (2008): 4.729

Normalized IF: 6

Varella-Garcia M, Diebold J, Eberhard DA, Geenen K, Hirschmann A, Kockx M, Nagelmeier I, Rüschoff J, Schmitt M, Arbogast S, Cappuzzo F.

EGFR fluorescence in situ hybridisation assay: guidelines for application to non-small-cell lung cancer.

J Clin Pathol. 2009 Nov;62(11):970-7.

Masci G*, Di Tommaso L, Del Prato I, Orefice S, Rubino A, Gullo G, Zuradelli M, Sacco R, Alloisio M, Eboli M, Incarbone M, Giordano L, Roncalli M, Santoro A.

Raw IF (2008): 2.342

Sinusal localization of nodal micrometastases is a prognostic factor in breast cancer.

Predictive value of EGFR and HER2 overexpression in advanced non-small-cell lung cancer.

Ann Oncol. 2009 Oct 29. [Epub ahead of print] Raw IF (2008): 4.935

Normalized IF: 6

Peck-Radosavljevic M, Greten TF, Lammer J, Rosmorduc O, Sangro B, Santoro A, Bolondi L.

Consensus on the current use of sorafenib for the treatment of hepatocellular carcinoma.

Hirsch FR, Varella-Garcia M, Cappuzzo F.

Oncogene. 2009 Aug;28 Suppl 1:S32-7. Review.

Raw IF (2008): 7.216

Normalized IF: 8

Soria JC, Shepherd FA, Douillard JY, Wolf J, Giaccone G, Crino L, Cappuzzo F, Sharma S, Gross SH, Dimitrijevic S, Di Scala L, Gardner H, Nogova L, Papadimitrakopoulou V.

Eur J Gastroenterol Hepatol. 2009 Nov 24. [Epub ahead of print]

Efficacy of everolimus (RAD001) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors.

Raw IF (2008): 2.080

Ann Oncol. 2009 Oct;20(10):1674-81. Epub 2009 Jun 23.

Normalized IF: 1

Raw IF (2008): 4.935 Marchetti A, Milella M, Felicioni L, Cappuzzo F, Irtelli L, Del Grammastro M, Sciarrotta M, Malatesta S, Nuzzo C, Finocchiaro G, Perrucci B, Carlone D, Gelibter AJ, Ceribelli A, Mezzetti A, Iacobelli S, Cognetti F, Buttitta F.

Clinical implications of KRAS mutations in lung cancer patients treated with tyrosine kinase inhibitors: an important role for mutations in minor clones.

Neoplasia. 2009 Oct;11(10):1084-92.

Raw IF (2008): 5.191

Normalized IF: 3

Castagna L, Bramanti S, Levis A, Michieli MG, Anastasia A, Mazza R, Giordano L, Sarina B, Todisco E, Gregorini AI, Santoro A.

Pegfilgrastim versus filgrastim after high-dose chemotherapy and autologous peripheral blood stem cell support.

Raw IF (2008): 4.935

A randomized phase III study comparing adjuvant 5-fluorouracil/folinic acid with FOLFIRI in patients following complete resection of liver metastases from colorectal cancer.

Ann Oncol. 2009 Dec;20(12):1964-70. Epub 2009 Jun 30.

Normalized IF: 6

Metro G, Cappuzzo F.

Emerging drugs for small-cell lung cancer.

Expert Opin Emerg Drugs. 2009 Dec;14(4):591-606.

Raw IF (2008): 3.08

Chiti A.

Evaluation of response: is (18)F-FDG PET the answer?

Eur J Nucl Med Mol Imaging. 2009 May;36(5):733-4.

Raw IF (2008): 4.532

Normalized IF: 6

Chiti A.

A portrait of the scientist as a young woman: Comments after the first EANM Young Investigators’ Meeting.

Eur J Nucl Med Mol Imaging. 2009 Oct;36(10):1697-8.

Normalized IF: 6

Normalized IF: 6

Ychou M, Hohenberger W, Thezenas S, Navarro M, Maurel J, Bokemeyer C, Shacham-Shmueli E, Rivera F, Kwok-Keung Choi C, Santoro A.

Raw IF (2008): 4.935

Normalized IF: 3

Nuclear Medicine

Raw IF (2008): 4.532

Ann Oncol.2009 . [Epub ahead of print]

100

Normalized IF: 4

Normalized IF: 4

Bayele HK, Chiti A, Colina R, Fernandes O, Khan B, Krishnamoorthy R, Ozdağ H, Padua RA.

Isotopic biomarker discovery and application in translational medicine.

Drug Discov Today. 2009 Dec 28. [Epub ahead of print] Raw IF (2008): 6.618

Normalized IF: 6

Clerici F, Del Sole A, Chiti A, Maggiore L, Lecchi M, Pomati S, Mosconi L, Lucignani G, Mariani C.

Differences in hippocampal metabolism between amnestic and non-amnestic MCI subjects: automated FDG-PET image analysis.

Q J Nucl Med Mol Imaging. 2009 Dec;53(6):646-57. Epub 2009 Oct 7.

Raw IF (2008): 2.64

Normalized IF: 2

Alkureishi LW, Burak Z, Alvarez JA, Ballinger J, Bilde A, Britten AJ, Calabrese L, Chiesa C, Chiti A, de Bree R, Gray HW, Hunter K, Kovacs AF, Lassmann M, Leemans CR, Mamelle G, McGurk M, Mortensen J, Poli T, Shoaib T, Sloan P, Sorensen JA, Stoeckli SJ, Thomsen JB, Trifiro G, Werner J, Ross GL; European Association of Nuclear Medicine Oncology Committee; European Sentinel Node Biopsy Trial Committee.

Lucignani G, Orunesu E, Cesari M, Marzo K, Pacei M, Bechi G, Gori A, Gaito S, Clerici M, Chiti A.

Joint practice guidelines for radionuclide lymphoscintigraphy for sentinel node localization in oral/oropharyngeal squamous cell carcinoma.

Raw IF (2008): 4.532

Ann Surg Oncol. 2009 Nov;16(11):3190-210.

Raw IF (2008): 3.898

Normalized IF: 6

Alkureishi LW, Burak Z, Alvarez JA, Ballinger J, Bilde A, Britten AJ, Calabrese L, Chiesa C, Chiti A, de Bree R, Gray HW, Hunter K, Kovacs AF, Lassmann M, Leemans CR, Mamelle G, McGurk M, Mortensen J, Poli T, Shoaib T, Sloan P, Sorensen JA, Stoeckli SJ, Thomsen JB, Trifiro G, Werner J, Ross GL; European Association of Nuclear Medicine Oncology Committee; European Sentinel Node Biopsy Trial Committee.

Joint practice guidelines for radionuclide lymphoscintigraphy for sentinel node localization in oral/oropharyngeal squamous cell carcinoma.

Eur J Nucl Med Mol Imaging. 2009 Nov;36(11):1915-36.

Raw IF (2008): 4.532

Normalized IF: 6

Chakera AH, Hesse B, Burak Z, Ballinger JR, Britten A, Caracò C, Cochran AJ, Cook MG, Drzewiecki KT, Essner R, Even-Sapir E, Eggermont AM, Stopar TG, Ingvar C, Mihm MC Jr, McCarthy SW, Mozzillo N, Nieweg OE, Scolyer RA, Starz H, Thompson JF, Trifirò G, Viale G, Vidal-Sicart S, Uren R, Waddington W, Chiti A, Spatz A, Testori A; European Association of Nuclear Medicine-European Organisation for Research and.

EANM-EORTC general recommendations for sentinel node diagnostics in melanoma.

FDG-PET imaging in HIV-infected subjects: relation with therapy and immunovirological variables.

Eur J Nucl Med Mol Imaging. 2009 Apr;36(4):640-7. Epub 2008 Dec 11.

Normalized IF: 6

Oncological Gynaecology Tozzi R*, Lavra F, Cassese T, Campanile RG, Pedicini V, Bignardi M, Scorsetti M, Bertuzzi A.

Laparoscopic debulking of bulky lymph nodes in women with cervical cancer: indication and surgical outcomes.

BJOG. 2009 Apr;116(5):688-92. Epub 2009 Feb 10.

Raw IF (2008): 3.101

Normalized IF: 6

Radiotherapy and Radiosurgery Bignardi M, Cozzi L, Fogliata A, Lattuada P, Mancosu P, Navarria P, Urso G, Vigorito S, Scorsetti M.

Critical Appraisal of Volumetric Modulated Arc Therapy in Stereotactic Body Radiation Therapy for Metastases to Abdominal Lymph Nodes.

Int J Radiat Oncol Biol Phys. 2009 Dec 1;75(5):1570-7. Epub 2009 Oct 31.

Raw IF (2008): 4.639

Normalized IF: 6

Scorsetti M*, Facoetti A, Navarria P, Bignardi M, De Santis M, Ninone SA, Lattuada P, Urso G, Vigorito S, Mancosu P, Del Vecchio M.

Eur J Nucl Med Mol Imaging. 2009 Oct;36(10):1713-42.

Hypofractionated stereotactic radiotherapy and radiosurgery for the treatment of patients with radioresistant brain metastases.

Raw IF (2008): 4.532

Anticancer Res. 2009 Oct;29(10):4259-63.

Normalized IF: 6

Raw IF (2008): 1.39

Normalized IF: 1

Sathekge M, Maes A, Al-Nahhas A, Rubello D, Chiti A.

What impact can fluorine-18 fluorodeoxyglucose PET/computed tomography have on HIV/AIDS and tuberculosis pandemic?

Nucl Med Commun. 2009 Apr;30(4):255-7.

Raw IF (2008): 1.706

4D-PET data sorting into different number of phases: a NEMA IQ phantom study.

J Appl Clin Med Phys. 2009 Oct 28;10(4):2917.

Normalized IF: 2

Perrino M, Vannucchi G, Vicentini L, Cantoni G, Dazzi D, Colombo C, Rodari M, Chiti A, Beck-Peccoz P, Fugazzola L.

Outcome predictors and impact of central node dissection and radiometabolic treatments in papillary thyroid cancers < or =2 cm.

Endocr Relat Cancer. 2009 Mar;16(1):201-10. Epub 2008 Dec 23.

Raw IF (2008): 5.236

Mancosu P, Sghedoni R, Bettinardi V, Fioroni F, Aquilina MA, Grassi E, Fazio F, Borasi G, Gilardi MC.

Normalized IF: 3

Raw IF (2008): 1.225

Normalized IF: 2

Mancosu P, Navarria P, Bignardi M, Cozzi L, Fogliata A, Lattuada P, Santoro A, Urso G, Vigorito S, Scorsetti M.

Re-irradiation of metastatic spinal cord compression: A feasibility study by volumetric-modulated arc radiotherapy for in-field recurrence creating a dosimetric hole on the central canal.

Radiother Oncol. 2009 Dec 17. [Epub ahead of print] Raw IF (2008): 3.99

Normalized IF: 6

101

Papers published 2009

Mancosu P, Cantone MC, Veronese I, Giussani A

Spatial distribution of beta extremity doses in nuclear medicine: A feasibility study with thin alpha-Al(2) O(3):C TLDs. Phys Med. 2010 Jan;26(1):44-48. Epub 2009 Apr 7.

Raw IF (2008): 0.698

Normalized IF: 1

Breast Unit Tinterri C, Gatzemeier W, Zanini V, Regolo L, Pedrazzoli C, Rondini E, Amanti C, Gentile G, Taffurelli M, Fenaroli P, Tondini C, Sacchetto G, Sismondi P, Murgo R, Orlandi M, Cianchetti E, Andreoli C.

Conservative surgery with and without radiotherapy in elderly patients with early-stage breast cancer: A prospective randomised multicentre trial.

Breast. 2009 Dec;18(6):373-7. Epub 2009 Nov 11.

Raw IF (2008): 2.155

Normalized IF: 4

Arthroscopic Surgery of the Shoulder Conti M, Garofalo R, Delle Rose G, Massazza G, Vinci E, Randelli M, Castagna A.

Post-operative rehabilitation after surgical repair of the rotator cuff.

Musculoskelet Surg. 2009 Apr;93 Suppl 1:S55-63.

Raw IF (2008): 0

Normalized IF: 0.1

Castagna A, Delle Rose G, Borroni M, Markopoulos N, Conti M, Maradei L, Garofalo R.

Modified MacLaughlin procedure in the treatment of neglected posterior dislocation of the shoulder.

Musculoskelet Surg. 2009 Apr;93 Suppl 1:S1-5.

Raw IF (2008): 0

Thoracic Surgery

Normalized IF: 0.1

Falvella FS, Galvan A, Frullanti E, Spinola M, Calabrò E, Carbone A, Incarbone M, Santambrogio L, Pastorino U, Dragani TA.

Porcellini G, Campi F, Pegreffi F, Castagna A, Paladini P.

Transcription Deregulation at the 15q25 Locus in Association with Lung Adenocarcinoma Risk.

J Bone Joint Surg Am. 2009 Nov;91(11):2537-42.

Clin Cancer Res. 2009 Mar 1;15(5):1837-42. Epub 2009 Feb 17.

Raw IF (2008): 6.488

Normalized IF: 3

Infante M, Cavuto S, Lutman FR, Brambilla G, Chiesa G, Ceresoli G, Passera E, Angeli E, Chiarenza M, Aranzulla G, Cariboni U, Errico V, Inzirillo F, Bottoni E, Voulaz E, Alloisio M, Destro A, Roncalli M, Santoro A, Ravasi G; DANTE Study Group:Cavuto S, Alloisio M, Bottoni E, Cariboni U, Errico V, Ferraroli G, Incarbone M, Infante M, Inzirillo F, Ravasi G, Ruzzante D, Testori A, Voulaz E, Balzarini L, Brambilla G, Imparato S, Lutman F, Pedicini V, Poretti D, Ragucci P, Chiesa G, Guanella G, Meroni A, Passera E, Rizzi A, Angeli E, Torda E, Zanello A, Giuseppe A, Caruso M, Chiarenza M, Barishnykova E, Bianchi P, Destro A, Gribaudi G, Roncalli M, Chiti A, Ciocia G, Rodari M, Cavina R, Cappuzzo F, Ceresoli G, Garassino I, Santoro A, Zucali P, Navarria P, Scorsetti M, Ciccarelli M, Paracchini E, Voza A, Alessandrini A, Tedeschi M, Morenghi E.

A randomized study of lung cancer screening with spiral computed tomography: three-year results from the DANTE trial.

Am J Respir Crit Care Med. 2009 Sep 1;180(5):445-53. Epub 2009 Jun 11.

Raw IF (2008): 9.792

FGFR4 Gly388Arg polymorphism may affect the clinical stage of patients with lung cancer by modulating the transcriptional profile of normal lung.

Int J Cancer. 2009 Jun 15;124(12):2880-5.

Raw IF (2008): 4.734

Predisposing factors for recurrent shoulder dislocation after arthroscopic treatment.

Raw IF (2008): 3.313

Normalized IF: 3

Dierickx C, Ceccarelli E, Conti M, Vanlommel J, Castagna A.

Variations of the intra-articular portion of the long head of the biceps tendon: a classification of embryologically explained variations.

Raw IF (2008): 1.827

Normalized IF: 4

Orthopaedics I Morandi A, Dupplicato P, Sansone V.

Results of distal metatarsal osteotomy using absorbable pin fixation.

Foot Ankle Int. 2009 Jan;30(1):34-8.

Raw IF (2008): 1.061

Normalized IF: 2

Normalized IF: 8

Falvella FS, Frullanti E, Galvan A, Spinola M, Noci S, De Cecco L, Nosotti M, Santambrogio L, Incarbone M, Alloisio M, Calabrò E, Pastorino U, Skaug V, Haugen A, Taioli E, Dragani TA.

102

Orthopaedic Area

Normalized IF: 3

Pediatric Orthopaedics Portinaro N*, Panou A, Gagliano N, Pelillo F.

D.D.S.H.: developmental dysplasia of the spastic hip: strategies of management in cerebral palsy. A new suggestive algorithm.

Hip Int. 2009 Jan-Mar;19 Suppl 6:S69-74.

Raw IF (2008): 0.215

Normalized IF: 1

Pelillo F*, De Sanctis N, Benazzo F, Portinaro N.

Vinciguerra P, Albè E, Trazza S, Seiler T, Epstein D.

Slipped Upper Femoral Epiphysis (SUFE): to do or not to do in sufe.

Intraoperative and postoperative effects of corneal collagen cross-linking on progressive keratoconus.

Hip Int. 2009 Jan-Mar;19 Suppl 6:S13-7.

Arch Ophthalmol. 2009 Oct;127(10):1258-65.

Raw IF (2008): 0.215

Normalized IF: 1

Gagliano N, Pelillo F, Chiriva-Internati M, Picciolini O, Costa F, Schutt RC Jr, Gioia M, Portinaro N.

Expression profiling of genes involved in collagen turnover in tendons from cerebral palsy patients.

Connect Tissue Res. 2009;50(3):203-8.

Raw IF (2008): 1.113

Normalized IF: 6

Randazzo A, Vinciguerra P.

Chronic macular edema medical treatment in IrvineGass syndrome: case report.

Eur J Ophthalmol. 2009 Oct 21. [Epub ahead of print] Raw IF (2008): 1.01

Normalized IF: 2

Normalized IF: 2

Colombo G, Dalle-Donne I, Giustarini D, Gagliano N, Portinaro N, Colombo R, Rossi R, Milzani A.

Cellular redox potential and hemoglobin S-glutathionylation in human and rat erythrocytes: A comparative study.

Blood Cells Mol Dis. 2009 Dec 4. [Epub ahead of print] Raw IF (2008): 2.749

Raw IF (2008): 3.242

Normalized IF: 2

Plastic Surgery ii Ottaviani F, Capaccio P, Villani F, Banderali M, Pruneri G, Klinger M, Pignataro L.

Bona Fide Primary Merkel Cell Carcinoma of an Intraparotid Lymph Node in a HIV-Positive Patient.

Int J Surg Pathol. 2009 Jan 14. [Epub ahead of print] Raw IF (2008): 0.879

Normalized IF: 1

Klinger M*, Caviggioli F, Villani F, Forcellini D, Klinger F.

Gynecomastia and Tuberous Breast: Assessment and Surgical Approach.

Surgical Area

Aesthetic Plast Surg. 2009 Sep;33(5):786-7. Epub 2009 Jun 11.

Letter to the Editor (results)

Ophthalmology

Raw IF (2008): 0.782

Vinciguerra P*, Albè E, Trazza S, Rosetta P, Vinciguerra R, Seiler T, Epstein D.

Refractive, Topographic, Tomographic, and Aberrometric Analysis of Keratoconic Eyes Undergoing Corneal Cross-Linking.

Ophthalmology. 2009 Mar;116(3):369-78. Epub 2009 Jan 22.

Raw IF (2008): 5.296

Normalized IF: 6

Vinciguerra P, Camesasca FI, Bains HS, Trazza S, Albè E.

Normalized IF: 1

Klinger M*, Caviggioli F, Banzatti B, Fossati C, Villani F.

Ectodermal dysplasia with amastia: a case of one-step reconstruction.

Case Report Med. 2009;2009:927354. Epub 2009 May 4.

Raw IF (2008): 0

Normalized IF: 0.1

Villani F, Caviggioli F, Klinger F, Klinger M.

Re: Rehabilitation of irradiated head and neck tissues by autologous fat transplantation.

Photorefractive keratectomy for primary myopia using NIDEK topography-guided customized aspheric transition zone.

Plast Reconstr Surg. 2009 Dec;124(6):2190-1; author reply 2191.

J Refract Surg. 2009 Jan;25(1 Suppl):S89-92.

Raw IF (2008): 2.591

Raw IF (2008): 1.914

Letter to the Editor (comment) Normalized IF: 1.2

Normalized IF: 4 Klinger M, Caviggioli F, Forcellini D, Villani F.

Koller T, Iseli HP, Hafezi F, Vinciguerra P, Seiler T.

Scheimpflug imaging of corneas after collagen crosslinking.

Scars: a review of emerging and currently available therapies.

Plast Reconstr Surg. 2009 Jul;124(1):330.

Letter to the Editor (comment)

Cornea. 2009 Jun;28(5):510-5.

Raw IF (2008): 1.853

Normalized IF: 2

Raw IF (2008): 2.591

Normalized IF: 1.2

103

Papers published 2009

Klinger M, Villani F, Klinger F, Gaetani P, Rodriguez Y Baena R, Levi D.

Anatomical variations of the occipital nerves: implications for the treatment of chronic headaches.

Plast Reconstr Surg. 2009 Nov;124(5):1727-8.

Letters to the editor (comments) Raw IF (2008): 2.591

Normalized IF: 1.2

Caviggioli F, Vinci V, Salval A, Klinger M.

Human adipose-derived stem cells: isolation, characterization and applications in surgery.

ANZ J Surg. 2009 Nov;79(11):856.

Letter to the Editor (comments) Raw IF (2008): 1.388

Special Diagnostic and Treatment Services Analysis Laboratories Mineri R, Ghilardi G, Brambilla S, Sarno T, Bologna M, Valaperta S, Montanelli A.*

The genetic variant of lactase persistence C/T (13910) and blood glucose control in tyoe 1 diabetes mellitus patients.

Mediterr J Nutr Metab (2009) 1:181-185 Raw IF (2008): 0

Normalized IF: 0.1

Normalized IF: 0.8 Venci A, Bettio D.

Tetrasomy 5p mosaicism due to an additional isochromosome 5p in a man with normal phenotype.

Am J Med Genet A. 2009 Dec;149A(12):2889-91.

Urology

Raw IF (2008): 2.555

Taverna G, Colombo P, Grizzi F*, Franceschini B, CevaGrimaldi G, Seveso M, Giusti G, Piccinelli A, Graziotti P.

Fractal analysis of two-dimensional vascularity in primary prostate cancer and surrounding non-tumoral parenchyma.

Pathol Res Pract. 2009;205(7):438-44. Epub 2009 Feb 20.

Raw IF (2008): 1.029

Normalized IF: 1

Giusti G*, Piccinelli A, Maugeri O, Benetti A, Taverna G, Graziotti P.

Normalized IF: 4

Pathology Romagnoli S, Fasoli E, Vaira V, Falleni M, Pellegrini C, Catania A, Roncalli M, Marchetti A, Santambrogio L, Coggi G, Bosari S.

Identification of Potential Therapeutic Targets in Malignant Mesothelioma Using Cell-Cycle Gene Expression Analysis.

Am J Pathol. 2009 Mar;174(3):762-70. Epub 2009 Feb 13.

Percutaneous nephrolithotomy: tubeless or not tubeless?

Raw IF (2008): 5.697

Urol Res. 2009 Jun;37(3):153-8. Epub 2009 Mar 27.

Kim H, Oh BK, Roncalli M, Park C, Yoon SM, Yoo JE, Park YN.

Raw IF (2008): 1.615

Large liver cell change in hepatitis B virus-related liver cirrhosis.

Normalized IF: 2

Normalized IF: 3

Hepatology. 2009 Sep;50(3):752-62.

Raw IF (2008): 11.355

Normalized IF: 4

Di Tommaso L, Destro A, Seok JY, Balladore E, Terracciano L, Sangiovanni A, Iavarone M, Colombo M, Jang JJ, Yu E, Jin SY, Morenghi E, Park YN, Roncalli M.

The application of markers (HSP70 GPC3 and GS) in liver biopsies is useful for detection of hepatocellular carcinoma.

J Hepatol. 2009 Apr;50(4):746-54. Epub 2008 Dec 25.

Raw IF (2008): 7.056

Normalized IF: 8

Leidi M, Gotti E, Bologna L, Miranda E, Rimoldi M, Sica A, Roncalli M, Palumbo GA, Introna M, Golay J.

M2 macrophages phagocytose rituximab-opsonized leukemic targets more efficiently than m1 cells in vitro.

J Immunol. 2009 Apr 1;182(7):4415-22.

104

Raw IF (2008): 6

Normalized IF: 3

Patriarca C, Colombo P, Pio Taronna A, Wesseling J, Franchi G, Guddo F, Naspro R, Macchi RM, Giunta P, Di Pasquale M, Parente M, Arizzi C, Roncalli M, Campo B.

Cell discohesion and multifocality of carcinoma in situ of the bladder: new insight from the adhesion molecule profile (e-cadherin, Ep-CAM, and MUC1).

J Surg Pathol. 2009 Apr;17(2):99-106. Epub 2008 Nov 19.

Raw IF (2008): 0.879

Normalized IF: 1

Augello C, Caruso L, Maggioni M, Donadon M, Montorsi M, Santambrogio R, Torzilli G, Vaira V, Pellegrini C, Roncalli M, Coggi G, Bosari S.

Inhibitors of apoptosis proteins (IAPs) expression and their prognostic significance in hepatocellular carcinoma.

BMC Cancer. 2009 Apr 27;9:125.

Raw IF (2008): 3.087

Normalized IF: 4

International Consensus Group for Hepatocellular NeoplasiaThe International Consensus Group* for Hepatocellular Neoplasia. *The International Consensus Group for Hepatocellular Neoplasia consists of: Masamichi Kojiro, Ian R. Wanless, Venancio Alves, Sunil Badve, Charles Balabaud, Pierre Bedosa, Prithi Bhathal, Paulette Bioulac-Sage, Elizabeth M. Brunt, Alastair D. Burt, John R. Craig, Amar Dhillon, Linda Ferrell, Stephen A. Geller, Zackary D. Goodman, Annette S. H. Gouw, Maria Guido, Maha Guindi, Prodromos Hytiroglou, Masayoshi Kage, Fukuo Kondo, Masutoshi Kudo, Gregory Y. Lauwers, Masayuki Nakano, Valerie Paradis, Young-Nyun Park, Alberto Quaglia, Massimo Roncalli, Tania Roskams, Boris Ruebner, Michiie Sakamoto, Romil Saxena, Neil D. Theise, Swan Thung, and Dina Taniakos.

Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia.

Hepatology. 2009 Feb;49(2):658-64. Erratum in: Hepatology. 2009 Mar;49(3):1058.

Raw IF (2008): 11.355

Normalized IF: 8

Surgical Day Hospital Monzani R.

General or locoregional anesthesia for elective carotid endarterectomy: which local anesthetic can we use?

Minerva Anestesiol. 2009 Jan-Feb;75(1-2):1-2.

Raw IF (2008): 0

Normalized IF: 0.1

105

Papers published 2009

Research Laboratories Bottazzi B, Garlanda C, Cotena A, Moalli F, Jaillon S, Deban L, Mantovani A. Dal Secco V, Soldani C, Debrat C, Asperti-Boursin F, Donnadieu E, Viola A, Sarukhan A.

Tunable chemokine production by antigen presenting dendritic cells in response to changes in regulatory T cell frequency in mouse reactive lymph nodes.

PLoS One. 2009 Nov 6;4(11):e7696.

Raw IF (2008): 0

Normalized IF: 0.1

The long pentraxin PTX3 as a prototypic humoral pattern recognition receptor: interplay with cellular innate immunity.

Immunol Rev. 2009 Jan;227(1):9-18.

Raw IF (2008): 11.761

Normalized IF: 8

Mantovani A.

Cancer: Inflaming metastasis.

Nature. 2009 Jan 1;457(7225):36-7.

Raw IF (2008): 31.434

Normalized IF: 15

Augusto JF, Onno C, Blanchard S, Dubuquoi S, Mantovani A, Chevailler A, Jeannin P, Subra JF.

Fumagalli F, Madaschi L, Caffino L, Marfia G, Di Giulio AM, Racagni G, Gorio A.

Acute spinal cord injury reduces brain derived neurotrohic factor expression in rat hippocampus.

Neuroscience. 2009 Mar 31;159(3):936-9.

Raw IF (2008): 3.556

Normalized IF: 6

Lesma E, Sirchia SM, Ancona S, Carelli S, Bosari S, Ghelma F, Montanari E, Di Giulio AM, Gorio A.

The methylation of the TSC2 promoter underlies the abnormal growth of TSC2 angiomyolipoma-derived smooth muscle cells.

Detection of anti-PTX3 autoantibodies in systemic lupus erythematosus.

Rheumatology (Oxford). 2009 Apr;48(4):442-4. Epub 2009 Feb 12.

Raw IF (2008): 4.136

Normalized IF: 2

Tondelli B, Blair HC, Guerrini M, Patrene KD, Cassani B, Vezzoni P, Lucchini F.

Fetal Liver Cells Transplanted in Utero Rescue the Osteopetrotic Phenotype in the oc/oc Mouse.

Am J Pathol. 2009 Mar;174(3):727-35. Epub 2009 Feb 13.

Raw IF (2008): 5.697

Normalized IF: 6

Borroni EM, Bonecchi R*.

Am J Pathol. 2009 Jun;174(6):2150-9. Epub 2009 May 14.

Shaping the gradient by nonchemotactic chemokine receptors.

Raw IF (2008): 5.697

Cell Adh Migr. 2009 Apr;3(2):146-7. Epub 2009 Apr 24.

Normalized IF: 6

Raw IF (2008): 0

Normalized IF: 0.1

Bonecchi R, Galliera E, Borroni EM, Corsi MM, Locati M, Mantovani A.

Chemokines and chemokine receptors: an overview.

Front Biosci. 2009 Jan 1;14:540-51.

Grizzi F.

Raw IF (2008): 3.308

Pirfenidone: A Potential Therapeutic Option in the Treatment of Liver Fibrosis.

Borroni EM, Bonecchi R, Mantovani A, Locati M*.

Clin Exp Pharmacol Physiol. 2009 Oct;36(10):961-2. Epub 2009 Jul 24.

Raw IF (2008): 2.196

Normalized IF: 4

Grizzi F, Taverna G, Muzzio PC.

On the morphological complexity of bone texture.

106

Normalized IF: 4

Chemoattractant receptors and leukocyte recruitment: more than cell migration.

Sci Signal. 2009 Feb 24;2(59):pe10.

Raw IF (2008): 0

Normalized IF: 0.1

Mantovani A*, Sica A, Allavena P, Garlanda C, Locati M.

Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009 Sep;108(3):311-2.

Tumor-associated macrophages and the related myeloid-derived suppressor cells as a paradigm of the diversity of macrophage activation.

Letters to the editor (comments)

Hum Immunol. 2009 May;70(5):325-30. Epub 2009 Feb 21.

Raw IF (2008): 1.581

Normalized IF: 0.8

Raw IF (2008): 3.061

Normalized IF: 4

Souza DG, Amaral FA, Fagundes CT, Coelho FM, Arantes RM, Sousa LP, Matzuk MM, Garlanda C, Mantovani A, Dias AA, Teixeira MM.

The Long Pentraxin PTX3 Is Crucial for Tissue Inflammation after Intestinal Ischemia and Reperfusion in Mice.

Am J Pathol. 2009 Apr;174(4):1309-18. Epub 2009 Mar 12.

Raw IF (2008): 5.697

Role of the chemokine scavenger receptor D6 in balancing inflammation and immune activation.

Methods Enzymol. 2009;460:231-43.

Raw IF (2008): 2.312

Normalized IF: 4

Normalized IF: 3

Bazzoni F, Rossato M, Fabbri M, Gaudiosi D, Mirolo M, Mori L, Tamassia N, Mantovani A, Cassatella MA, Locati M.

Induction and regulatory function of miR-9 in human monocytes and neutrophils exposed to proinflammatory signals.

Proc Natl Acad Sci U S A. 2009 Mar 31;106(13):5282-7. Epub 2009 Mar 16.

Raw IF (2008): 9.38

Borroni EM, Buracchi C, Savino B, Pasqualini F, Russo RC, Nebuloni M, Bonecchi R, Mantovani A, Locati M.

Normalized IF: 8

Erreni M, Bianchi P, Laghi L, Mirolo M, Fabbri M, Locati M, Mantovani A, Allavena P.

Expression of chemokines and chemokine receptors in human colon cancer.

Methods Enzymol. 2009;460:105-21.

Raw IF (2008): 2.312

Normalized IF: 4

Kuscher K, Danelon G, Paoletti S, Stefano L, Schiraldi M, Petkovic V, Locati M, Gerber BO, Uguccioni M.

Albanesi C, Scarponi C, Pallotta S, Daniele R, Bosisio D, Madonna S, Fortugno P, Gonzalvo-Feo S, Franssen JD, Parmentier M, De PitĂ O, Girolomoni G, Sozzani S.

Synergy-inducing chemokines enhance CCR2 ligand activities on monocytes.

Chemerin expression marks early psoriatic skin lesions and correlates with plasmacytoid dendritic cell recruitment.

Raw IF (2008): 4.865

Eur J Immunol. 2009 Apr;39(4):1118-28.

Normalized IF: 3

J Exp Med. 2009 Jan 16;206(1):249-58. Epub 2008 Dec 29.

Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A*.

Raw IF (2008): 15.463

Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability.

Normalized IF: 7.5

Maina V, Cotena A, Doni A, Nebuloni M, Pasqualini F, Milner CM, Day AJ, Mantovani A, Garlanda C*.

Coregulation in human leukocytes of the long pentraxin PTX3 and TSG-6.

J Leukoc Biol. 2009 Jul;86(1):123-32. Epub 2009 Apr 23.

Raw IF (2008): 4.605

Normalized IF: 6

Riva F*, Polentarutti N, Tribbioli G, Mantovani A, Garlanda C, Turin L.

The expression pattern of TIR8 is conserved among vertebrates.

Vet Immunol Immunopathol. 2009 Sep 15;131(1-2):44-9.

Epub 2009 Mar 24.

Raw IF (2008): 1.907

Normalized IF: 6

Salogni L, Musso T, Bosisio D, Mirolo M, Jala VR, Haribabu B, Locati M, Sozzani S.

Activin A induces dendritic cell migration through the polarized release of CXCL12 and CXCL14.

Blood. 2009 Jun 4;113(23):5848-56. Epub 2009 Apr 1.

Raw IF (2008): 10.432

Normalized IF: 4

Carcinogenesis. 2009 Jul;30(7):1073-81. Epub 2009 May 25.

Raw IF (2008): 4.93

Normalized IF: 6

Wagenaar JF, Goris MG, Gasem MH, Isbandrio B, Moalli F, Mantovani A, Boer KR, Hartskeerl RA, Garlanda C, van Gorp EC.

Long pentraxin PTX3 is associated with mortality and disease severity in severe Leptospirosis.

J Infect. 2009 Jun;58(6):425-32. Epub 2009 Apr 18.

Raw IF (2008): 3.089

Normalized IF: 4

Oliviero B, Varchetta S, Paudice E, Michelone G, Zaramella M, Mavilio D, De Filippi F, Bruno S, Mondelli MU.

Natural Killer Cell Functional Dichotomy in Chronic Hepatitis B and Chronic Hepatitis C Virus Infections.

Gastroenterology. 2009 Sep;137(3):1151-60, 1160.e1-7. Epub 2009 May 24.

Raw IF (2008): 12.591

Normalized IF: 5

Savino B, Borroni EM, Machado Torres N, Proost P, Struyf S, Mortier A, Mantovani A, Locati M, Bonecchi R.

Pentraxins: Multifunctional proteins at the interface of innate immunity and inflammation.

Recognition versus adaptive upregulation and degradation of CC chemokines by the chemokine decoy receptor D6 are determined by their N-terminal sequence.

Biofactors. 2009 Mar;35(2):138-45.

J Biol Chem. 2009 Sep 18;284(38):26207-15. Epub 2009 Jul 24.

Deban L, Bottazzi B, Garlanda C, de la TorreYM, Mantovani A*.

Raw IF (2008): 1.23

Normalized IF: 1

Raw IF (2008): 5.52

Normalized IF: 6

107

Papers published 2009

Porta C, Larghi P, Rimoldi M, Grazia Totaro M, Allavena P, Mantovani A, Sica A.

Cellular and molecular pathways linking inflammation and cancer.

Immunobiology. 2009;214(9-10):761-77. Epub 2009 Jul 17.

Raw IF (2008): 3.461

Normalized IF: 6

Norata GD, Marchesi P, Pulakazhi Venu VK, Pasqualini F, Anselmo A, Moalli F, Pizzitola I, Garlanda C, Mantovani A, Catapano AL.

Deficiency of the Long Pentraxin PTX3 Promotes Vascular Inflammation and Atherosclerosis.

Circulation. 2009 Aug 25;120(8):699-708. Epub 2009 Aug 10.

Raw IF (2008): 14.595

Normalized IF: 10

Ma YJ, Doni A, Hummelshoj T, Honore C, Bastone A, Mantovani A, Thielens NM, Garred P.

Synergy between ficolin-2 and PTX3 boost innate immune recognition and complement deposition.

J Biol Chem. 2009 Oct 9;284(41):28263-75. Epub 2009 Jul 24.

Raw IF (2008): 5.52

Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation.

J Leukoc Biol. 2009 Nov;86(5):1065-73. Epub 2009 Sep 9.

Raw IF (2008): 4.605

Normalized IF: 6

Mantovani A.

The yin-yang of tumor-associated neutrophils.

Cancer Cell. 2009 Sep 8;16(3):173-4.

Raw IF (2008): 24.962

Normalized IF: 15

Noris M, Cassis P, Azzollini N, Cavinato R, Cugini D, Casiraghi F, Aiello S, Solini S, Cassis L, Mister M, Todeschini M, Abbate M, Benigni A, Trionfini P, Tomasoni S, Mele C, Garlanda C, Polentarutti N, Mantovani A, Remuzzi G.

The Toll-IL-1R Member Tir8/SIGIRR Negatively Regulates Adaptive Immunity against Kidney Grafts.

Immunol. 2009 Oct 1;183(7):4249-60. Epub 2009 Sep 4.

Raw IF (2008): 6.00

Normalized IF: 6

Normalized IF: 6

Brunetta E, Fogli M, Varchetta S, Bozzo L, Hudspeth KL, Marcenaro E, Moretta A, Mavilio D*.

The decreased expression of Siglec-7 represents an early marker of dysfunctional natural killer cell subsets associated with high levels of HIV-1 viremia.

Blood. 2009 Oct 29;114(18):3822-30. Epub 2009 Aug 26.

Raw IF (2008): 10.432

Solinas G, Germano G, Mantovani A, Allavena P*.

Normalized IF: 8

Lech M, Avila-Ferrufino A, Allam R, Segerer S, Khandoga A, Krombach F, Garlanda C, Mantovani A, Anders HJ.

Resident dendritic cells prevent postischemic acute renal failure by help of single Ig IL-1 receptor-related protein.

J Immunol. 2009 Sep 15;183(6):4109-18. Epub 2009 Aug 19.

Raw IF (2008): 6.00

Normalized IF: 3

Sozzani S, Mantovani A. Porta C, Rimoldi M, Raes G, Brys L, Ghezzi P, Di Liberto D, Dieli F, Ghisletti S, Natoli G, De Baetselier P, Mantovani A, Sica A.

Tolerance and M2 (alternative) macrophage polarization are related processes orchestrated by p50 nuclear factor {kappa}B.

Immunobiology. 2009;214(9-10):729. Epub 2009 Jul 7.

Proc Natl Acad Sci U S A. 2009 Sep 1;106(35):14978-83. Epub 2009 Aug 17.

Raw IF (2008): 3.461

Raw IF (2008): 9.38

Villa A, Guerrini MM, Cassani B, Pangrazio A, Sobacchi C.

Normalized IF: 8

TIR8/SIGIRR: an IL-1R/TLR family member with regulatory functions in inflammation and T cell polarization.

Trends Immunol. 2009 Sep;30(9):439-46. Epub 2009 Aug 21.

Raw IF (2008): 9.91

Normalized IF: 8

Mantovani A*, Garlanda C, Locati M.

Macrophage Diversity and Polarization in Atherosclerosis. A Question of Balance.

Arterioscler Thromb Vasc Biol. 2009 Oct;29(10):1419-23.

Epub 2009 Aug 20.

Raw IF (2008): 6.858

Normalized IF: 6

Infantile malignant, autosomal recessive osteopetrosis: the rich and the poor.

Garlanda C*, Anders HJ, Mantovani A.

108

Diversity and plasticity of the innate immune response. Preface.

Normalized IF: 6

Calcif Tissue Int. 2009 Jan;84(1):1-12. Epub 2008 Dec 12.

Raw IF (2008): 2.737

Normalized IF: 4

Schinke T, Schilling AF, Baranowsky A, Seitz S, Marshall RP, Linn T, Blaeker M, Huebner AK, Schulz A, Simon R, Gebauer M, Priemel M, Kornak U, Perkovic S, Barvencik F, Beil FT, Del Fattore A, Frattini A, Streichert T, Pueschel K, Villa A, Debatin KM, Rueger JM, Teti A, Zustin J, Sauter G, Amling M.

Impaired gastric acidification negatively affects calcium homeostasis and bone mass.

Nat Med. 2009 Jun;15(6):674-81.

Raw IF (2008): 27.553

Normalized IF: 7.5

Pangrazio A, Caldana ME, Sobacchi C, Panaroni C, Susani L, Mihci E, Cavaliere ML, Giliani S, Villa A, Frattini A.

May L, Kuningas M, van Bodegom D, Meij HJ, Frolich M, Slagboom PE, Mantovani A, Westendorp RG.

Characterization of a novel Alu-Alu recombinationmediated genomic deletion in the TCIRG1 gene in five osteopetrotic patients.

Genetic Variation in Pentraxin (PTX) 3 Gene Associates with PTX3 Production and Fertility in Women.

J Bone Miner Res. 2009 Jan;24(1):162-7.

Raw IF (2008): 6.443

Normalized IF: 6

Biol Reprod. 2009 Oct 21. [Epub ahead of print] Raw IF (2008): 3.469

Normalized IF: 3

Panaroni C, Gioia R, Lupi A, Besio R, Goldstein SA, Kreider J, Leikin S, Vera JC, Mertz EL, Perilli E, Baruffaldi F, Villa I, Farina A, Casasco M, Cetta G, Rossi A, Frattini A, Marini JC, Vezzoni P, Forlino A.

Garlanda C, Maina V, Cotena A, Moalli F.

In utero transplantation of adult bone marrow decreases perinatal lethality and rescues the bone phenotype in the knockin murine model for classical, dominant osteogenesis imperfecta.

J Reprod Immunol. 2009 Dec;83(1-2):128-33. Epub 2009 Nov 8.

Blood. 2009 Jul 9;114(2):459-68. Epub 2009 May 4.

Raw IF (2008): 10.432

Normalized IF: 8

Mazzolari E, Forino C, Razza A, Porta F, Villa A, Notarangelo LD.

A single-center experience in 20 patients with infantile malignant osteopetrosis.

Am J Hematol. 2009 Aug;84(8):473-9.

Raw IF (2008): 2.126

Normalized IF: 1

Blair HC, Yaroslavskiy BB, Robinson LJ, Mapara MY, Pangrazio A, Guo L, Chen K, Vezzoni P, Tolar J, Orchard PJ.

The soluble pattern recognition receptor pentraxin-3 in innate immunity, inflammation and fertility.

Raw IF (2008): 2.778

Normalized IF: 4

Brunetta E, Fogli M, Varchetta S, Bozzo L, Hudspeth KL, Marcenaro E, Moretta A, Mavilio D.

Chronic HIV-1 viremia reverses NKG2A/NKG2C ratio on natural killer cells in patients with human cytomegalovirus co-infection.

AIDS. 2010 Jan 2;24(1):27-34. Epub 2009 Nov 11.

Raw IF (2008): 5.46

Normalized IF: 6

Cassatella MA, Locati M, Mantovani A*.

Never underestimate the power of a neutrophil.

Immunity. 2009 Nov 20;31(5):698-700.

Osteopetrosis with micro-lacunar resorption because of defective integrin organization.

Raw IF (2008): 20.579

Lab Invest. 2009 Sep;89(9):1007-17. Epub 2009 Jun 22.

Bottazzi B*, Doni A, Garlanda C, Mantovani A.

Raw IF (2008): 4.58

An Integrated View of Humoral Innate Immunity: Pentraxins as a Paradigm.

Normalized IF: 3

Cetin I, Cozzi V, Papageorghiou AT, Maina V, Montanelli A, Garlanda C, Thilaganathan B.

First trimester PTX3 levels in women who subsequently develop preeclampsia and fetal growth restriction.

Annu Rev Immunol. 2009 Dec 7. [Epub ahead of print] Raw IF (2008): 41.059

Macrophage fusion cuisine.

Raw IF (2008): 1.356

Blood. 2009 Nov 19;114(21):4609-10.

Raw IF (2008): 10.432

Mantovani A, Locati M.

Orchestration of macrophage polarization.

Blood. 2009 Oct 8;114(15):3135-6.

Raw IF (2008): 10.432

Normalized IF: 8

Ward J, Davis Z, DeHart J, Zimmerman E, Bosque A, Brunetta E, Mavilio D, Planelles V, Barker E.

HIV-1 Vpr triggers natural killer cell-mediated lysis of infected cells through activation of the ATR-mediated DNA damage response.

PLoS Pathog. 2009 Oct;5(10):e1000613. Epub 2009 Oct 2.

Raw IF (2008): 9.125

Normalized IF: 4

Normalized IF: 15

Sica A, Mantovani A.

Acta Obstet Gynecol Scand. 2009;88(7):846-9.

Normalized IF: 1

Normalized IF: 15

Normalized IF: 8

Pangrazio A, Pusch M, Caldana E, Frattini A, Lanino E, Tamhankar PM, Phadke S, Gonzalez Meneses Lopez A, Orchard P, Mihci E, Abinun M, Wright M, Vettenranta K, BariĂŚ I, Melis D, Tezcan I, Baumann C, Locatelli F, Zecca M, Horwitz E, Ben Mansour LS, Van Roij M, Vezzoni P, Villa A, Sobacchi C.

Molecular and clinical heterogeneity in CLCN7dependent osteopetrosis: report of 20 novel mutations.

Hum Mutat. 2010 Jan;31(1):E1071-E1080. Epub 2009 Dec 1.

Raw IF (2008): 7.033

Normalized IF: 8

109

Papers published ich 2009

de Kruif MD, Limper M, Sierhuis K, Wagenaar JF, Spek CA, Garlanda C, Cotena A, Mantovani A, Ten Cate H, Reitsma PH, van Gorp EC.

PTX3 predicts severe disease in febrile patients at the emergency Department.

J Infect. 2009 Dec 2. [Epub ahead of print] Raw IF (2008): 3.089

Normalized IF: 2

Dander E, Balduzzi A, Zappa G, Lucchini G, Perseghin P, Andrè V, Todisco E, Rahal D, Migliavacca M, Longoni D, Solinas G, Villa A, Berti E, Mina PD, Parma M, Allavena P, Biagi E, Rovelli A, Biondi A, D’Amico G.

Interleukin-17-Producing T-Helper Cells as New Potential Player Mediating Graft-Versus-Host Disease in Patients Undergoing Allogeneic Stem-Cell Transplantation.

Transplantation. 2009 Dec 15;88(11):1261-1272.

Raw IF (2008): 3.816

Normalized IF: 6

Mantovani A, Savino B, Locati M, Zammataro L, Allavena P, Bonecchi R.

The chemokine system in cancer biology and therapy.

Cytokine Growth Factor Rev.2009. [Epub ahead of print] Raw IF (2008): 7.022

Normalized IF: 8

Hagemann T, Biswas SK, Lawrence T, Sica A, Lewis CE.

Regulation of macrophage function in tumors: the multifaceted role of NF-kappaB. Blood. 2009 Apr 2;113(14):3139-46. Epub 2009 Jan 26. Review.

Raw IF (2008): 10.432

Recalcati S, Locati M, Marini A, Santambrogio P, Zaninotto F, De Pizzol M, Zammataro L, Girelli D, Cairo G.

Differential regulation of iron homeostasis during human macrophage polarized activation.

Eur J Immunol. 2009 Dec 28. [Epub ahead of print] Raw IF (2008): 4.865

Synergistic up-regulation of MCP-2/CCL8 activity is counteracted by chemokine cleavage, limiting its inflammatory and anti-tumoral effects.

Eur J Immunol. 2009 Mar;39(3):843-57.

Raw IF (2008): 4.865

Normalized IF: 3

Normalized IF: 6

Focarelli ML, Soza S, Mannini L, Paulis M, Montecucco A, Musio A.

Claspin inhibition leads to fragile site expression.

Genes Chromosomes Cancer. 2009 Dec;48(12):1083-90.

Raw IF (2008): 3.925

Normalized IF: 6

Balkwill F, Mantovani A.

Foreword.

Cytokine Growth Factor Rev. 2009 Dec 22. [Epub ahead of print] Raw IF (2008): 7.022

Struyf S, Proost P, Vandercappellen J, Dempe S, Noyens B, Nelissen S, Gouwy M, Locati M, Opdenakker G, Dinsart C, Van Damme J.

Normalized IF: 4

Normalized IF: 8

Pucci F, Venneri MA, Biziato D, Nonis A, Moi D, Sica A, Di Serio C, Naldini L, De Palma M.

A distinguishing gene signature shared by tumorinfiltrating Tie2-expressing monocytes, blood “resident” monocytes, and embryonic macrophages suggests common functions and developmental relationships.

Blood. 2009 Jul 23;114(4):901-14. Epub 2009 Apr 21.

Kim J, Koh JK, Lee EY, Park JA, Kim HA, Lee EB, Garlanda C, Cotena A, Song YW.

Raw IF (2008): 10.432

Serum levels of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) and pentraxin 3 (PTX3) as markers of infection in febrile patients with systemic lupus erythematosus.

Lech M, Skuginna V, Kulkarni OP, Gong J, Wei T, Stark RW, Garlanda C, Mantovani A, Anders HJ.

Clin Exp Rheumatol. 2009 Sep-Oct;27(5):773-8.

J Pathol. 2009 Dec 22. [Epub ahead of print]

Raw IF (2008): 2.364

Normalized IF: 2

Albini A, Brigati C, Ventura A, Lorusso G, Pinter M, Morini M, Mancino A, Sica A, Noonan DM.

Angiostatin anti-angiogenesis requires IL-12: the innate immune system as a key target.

J Transl Med. 2009 Jan 14;7:5.

Raw IF (2008): 2.917

110

Normalized IF: 2

Normalized IF: 4

Lack of SIGIRR/TIR8 aggravates hydrocarbon oilinduced lupus nephritis.

Raw IF (2008): 5.121

Normalized IF: 3

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Scientific Report Š Istituto Clinico Humanitas July 2010 Communication manager: Walter Bruno Editorial coordination: Humanitas: Michele Tedeschi, Monica Florianello Zadig, Milano: Giulia Candiani Graphic design: Luisa Goglio, Brescia Photographs: Marco Capovilla, Milano Paolo Carlini, Milano Renzo Chiesa, MIlano Humanitas Press Office

Printed in July 2010

by Tipografia F.lli Verderio, Milano

Scientific Report 2009 ›2010

Scientific Report 2009 ›2010 Results and Perspectives

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