Scientific Report 2010/2011

Scientific Report 2010 ›2011 Results and Perspectives Scientific Report 2010 ›2011

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 2010 ›2011

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Scientific Report 2010 ›2011 Results and Perspectives

Contents

Istituto Clinico Humanitas: general hospital and research center

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International scientific cooperation

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30 Translation research

14 Research in Humanitas 18 Cooperation networks 20

Clinical innovation: the Humanitas Cancer Center

78 Departments and teams 78 Clinical Area

29 Clinical-scientific activities

84 Scientific Research and Laboratories 86 Papers published 2010 86 Preclinical Research 92 Translational research 100 Clinical research

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Cardiology

58 New cardiologists for a new cardiology

Immunity and inflammation

62 A protein coming

32 New insights on immunity and their translation from benchside to bedside

interview with alberto mantovani

“weaker sex�

interview with mauro podda

Oncology

from the past to predict heart disease

interview with cecilia garlanda

Orthopaedics

66 The rich and the poor interview with anna villa

42 Humanitas Cancer

36 The diseases of the

i nterview with ettore vitali

Center: oncologydevoted, researchoriented, patientdedicated

72 The shoulder: an

interview with armando santoro

unstable balance between complexity and imperfection interview with alessandro castagna

52 Cancer and inflammation: the two sides of the coin

interview with paola allavena

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Istituto Clinico Humanitas: general hospital and research center 6

Offering the best affordable care has always been the mission of Humanitas. “Everyday – says Ivan Colombo, Vice President of Humanitas – hundreds of professionals – i.e. doctors, researchers, nurses, technicians and other staff – work towards this goal. Humanitas encompasses a highly specialized general hospital, a world top-ranking scientific research, and a training center. This allows to apply biomedical cutting-edge research results to curing patients with minimal delays, within a continuous process of innovation and improvement.

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Humanitas: general hospital and research center

The patient is at the center as a person, with his/her own wholeness and complexity, which goes beyond one single disease, or a combination of diseases. Patients nowadays increasingly choose – particularly through the Internet – a hospital according to its quality and to how complete its services are. This is why it is necessary to meet the patients’ health needs with an approach that combines cure, pre-clinical and clinical research, specialist competence and multidisciplinary therapeutic pathways. The aim of the foundation is to safeguard the quality of life of the patients (whatever their illness) and their families. It works towards this purpose with the Hospital doctors and nurses and programmes focussing on the practical, emotional and psychological needs of the patients and their families, thus making the medical care more complete.

Nowadays, advances in medicine and the increasing complexity of patients set an important challenge for general hospitals, i.e. to create dedicated centers for diseases which are socially relevant to a greater extent, to focus in terms of prevention, cure and research.

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9

Humanitas: general hospital and research center

This challenge is worldwide intended, to change the essence of bigger health centers. “It is through this perspective – Colombo continues – that the Cancer Center at Humanitas has been developed as a structure including highly specialist competence against cancer located within a general hospital, so as to provide a 360 degree feedback. Our effort towards integration is also translated as the ability to create a system and involve different types of competence: this is the reason why we have and promote the coexistence of institutions with specific and apparently very different missions under the same roof, i.e. Humanitas and Humanitas Cancer Center as far as assistance is concerned, but also Fondazione Humanitas and Fondazione Ariel, and the Università di Milano for teaching and training (including the new international degree course), as well as the Consiglio Nazionale delle Ricerche and the Fondazione Humanitas per la Ricerca in the research sector.

Fondazione Humanitas supports patients with chronic diseases and their families by dedicated programs and properly trained caregiving volunteers.

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Castellanza Humanitas Mater Domini

Bergamo Humanitas Gavazzeni

www.materdomini.it

www.humanitasgavazzeni.it

Research FONDAZIONE HUMANITAS PER LA RICERCA www.humanitasricerca.org

Torino Clinica Cellini www.clinicacellini.it

Take care FONDAZIONE HUMANITAS www.fondazionehumanitas.it FONDAZIONE ARIEL www.fondazioneariel.it

Rozzano Istituto Clinico Humanitas www.humanitas.it

Catania Humanitas Centro Catanese di Oncologia www.humanitascatania.it

The Humanitas Group in Italy The Istituto Clinico Humanitas is the flagship of the Humanitas Group, an Italian hospital network distinguished by its quality, research, high specialisation, common medical culture and emphasis on the humanization of care.

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An integrated general hospital with a high specialisation Emergency Center Humanitas is an Istituto di Ricovero e Cura a carattere scientifico (IRCCS, a Scientific Institute of Inpatient Care). In other words, a multi-specialty and highly integrated general hospital with 747 beds (of which 75 are in the medical, surgical, and oncological day-hospital and 28 in the intensive care unit, while 120 beds are reserved to cardio-ortho-neuro-motor rehabilitation in a separate building), 24 operating theatres, 5 angiographic rooms, and 120 outpatients clinics.

Istituto Clinico Humanitas is accredited by the Italian National Health Service.

Its diagnostic and therapeutic activities meet people requirements at a local, national, and international level with over 140,000 patients from all Italian Regions and from abroad followed each year.

Moreover, it is equipped with a high specialisation Emergency Center, attended by over 55,000 patients every year.

The “Humanitas case study” was presented to Harvard University MBA 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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The hospital as a teaching site

“MIMed”, International Medical School

Humanitas is a teaching center of the Università degli Studi di Milano. Specifically, it hosts the courses of the University School of Medicine, the International Medical School (www.mimed.it), the courses in Biotechnology and Nursing Schools.

“MIMed” was designed to combine academic training, experience in hospital, and research laboratory environments. Adopting an innovative approach, at least in traditional Italian teaching, but in line with the most advanced international academic standards, the study course combines lectures held in English with original teaching methods where students play an active role and are largely responsible for their own learning.

Interactions with teachers, a broad spectrum of experience in the field, a solid clinical tutoring system, small study groups, problem-based learning and problem-solving are the main features of the learning process.

International scientifi c cooperation The challenge of integrating assistance, research and training is played on international grounds: “this implies being confronted with the best international institutions at all levels (i.e. assistance, research and training) in order to attract and train the best minds, whether from Italy or elsewhere, who are going to be doctors and scientists of the future” – explains Alberto Mantovani, Scientific Director of Humanitas.

There is a close link between the quality of treatments, research and training. Generally speaking, patients are expected to be treated better where research is performed and centers of clinical excellence are thus also dedicated to training and research. An international training is the best way for young doctors to get in touch with most advanced progress and to keep up-todate and develop critical thinking. Besides, innovative teaching methodologies – i.e. problem oriented study groups, discussion and analysis of case studies taken from the daily clinical practice – stimulate doctors to develop analysis and reflection skills through the interaction with their teachers and practical experience in the hospital and in labs, as well as with the clinicians and researchers who tutor them. All this is designed to ultimately offer the best possible assistance to patients. This is why we have been strongly committed with the Università degli Studi di Milano (with Medical and Nursing School academic courses taking place at Humanitas) to create the International Medical School, an international degree course in Medicine.

13

Humanitas: general hospital and research center

The challenge we are facing now is to work with the Università degli Studi di Milano in order to add a new track for MD-PhDs, to conform to international standards. These professionals will work between the hospital and the laboratory, thus combining the rigor of research through a continuous contact with the patients, who can benefit from discoveries and results of the most advanced research”.

Research in Humanitas Scientific research is the field where the power of Humanitas to be well-known internationally is put to the test. Mantovani continues: “We have had positive results so far. Scientists from all over the world are hosted in our laboratories (see map on page 16). The year 2010 has seen our scientific productivity increase constantly in quality, so that quality levels remained very high, as indicated by the bibliometric indexes: a total of 1,750 Impact Factor points over the 12-month period, with a consistent focus in the immunodegenerative area, where we are recognised as an IRCCS by the Italian government. We are convinced that this is a crucial field for contemporary medicine, in that it has a strong impact on different clinical areas, ranging from cancer to cardiovascular,

14

Humanitas lectures include a series of top level scientific meetings organised in partnership with the Università degli Studi di Milano. These lectures represent a focus on the development and the evolution of the biomedical research at the service of human health. It has to be mentioned, among the speakers, the Nobel Prize awardees Prof. Rolf Zinkernagel and Prof. Françoise BarréSinoussi (in the picture with Prof. Alberto Mantovani).

Translational Research Humanitas’ scientific and research activity has always been characterised by an enormous potential for the translation of findings from benchside to bedside, implying a close integration and exchange of data between laboratory and hospital wards, crucial to promptly transfer the results of its reasearch into everyday clinical practice.

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Humanitas: general hospital and research center

inflammatory and autoimmune diseases. We obtained important results which range from basic discoveries to quality clinical studies which analyze and validate diagnostic and therapeutic procedures. Thanks to the use of genomics techniques in different areas at the patient’s service, it has been possible to identify possible targets in areas of diagnostic and therapeutic interventions for autoimmune diseases (as in the case of primary biliary cirrhosis), and to validate targeted therapies which – in the case of tumours – are guided by molecular characteristics. Nevertheless, several challanges remain. First, we need to translate the advancements obtained in genomics and post-genomics into diagnostic and therapeutic innovation at the patient’s service. Second, we are expected to focus on gender medicine, which deals with gender-related problems and differences, with particular reference to the female sex. The results we have obtained so far tell us that we are on the right track using bi-directional cooperation between research efforts at the benchside and at the bedside. Ultimately, we must transfer laboratory data to patients and let patients drive our lab efforts.

UK 2

canada 1

cuba 4 mexico 1

croatia 2

spain 4

russian federation 1

poland 2 Hungary 1

france 3

usa 1

romania 1

india 3

colombia 1

Brazil 4

bolivia 1

argentina 1

16

germany 1

netherlands 1

Geographical distribution of foreign researchers at Humanitas, during the years 2009-2011 Total 36

china 1

Fondazione Humanitas per la Ricerca

Research and Teaching Center

Fondazione Humanitas per la Ricerca is involved in supporting clinical and basic studies on pathophysiology of immunological defense mechanisms and the risk factors for several diseases, among which chronic inflammatory, cancer, cardiovascular, and neurological diseases.

The research activity of Fondazione Humanitas is monitored by an Advisory Board whose chairman is the Nobel Prize awardee Prof. Rolf Zinkernagel.

At the University Research and Teaching Center which is fully integrated with the Clinical Institute counterpart, over 200 researchers have been working with cutting-edge technology such as the recently acquired two-photon microscope, and a cell factory which is currently under construction. The group operates in close collaboration with the hospital 400 physicians on the identification of inflammation mechanisms at the outset of the processes and in the area of development of various diseases that range from tumours, through to disorders of the gastrointestinal tract, and to cardiovascular diseases e.g. myocardial infarction and stroke.

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Humanitas: general hospital and research center

Cooperation networks Scientific research grows naturally in a natural dimension (which is boundless by nature), and progresses towards the cure of patients. This is why it is fundamental that Humanitas takes part to global cooperation networks. As Ivan Colombo explains, “we want to be challenged on this field, where efforts have been made over the past few years, from the point of view of assessment as well. For us, assessment is not only passion, but true culture. This led Humanitas to be the first general hospital to be accredited by the Joint Commission International and to be endowed with an Advisory Board for basic research whose chairman is the Nobel Prize awardee Prof. Rolf Zinkernagel. The international Advisory Board includes doctors and researchers from the most important Reasearch Centers in the world, with which we share clinical and research activities, particularly of the Humanitas Cancer Center.

The intensity and proactive character of international relationships at Humanitas is illustrated by the ability to be part (or promoters, or leaders) of highly competitive EUsponsored projects, although these represent only a small portion of our international dimension. We are currently working on projects with the United States and with Eastern countries, in particular with Singapore�.

Quality and International accreditation 18

Humanitas is the first Italian general hospital to have been certified

by Joint Commission International.

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Humanitas: general hospital and research center

Clinical innovation: the Humanitas Cancer Center Collaboration at an international level is crucial also in clinical practice. Humanitas has established significant collaborations with national and international top-ranking hospitals and the continuous effort to implement the most advanced technologies has led to outstanding results in the treatment of cancer, gastrointestinal, cardiovascular, neurological and immunological diseases.

Concerning our mission against cancer, plenty of clinical research trials designed for the application and testing of new candidate drugs rely on scientific collaborations with important centers in the US and Europe including but non limited to New York, Boston, Tampa, Stanford, Amsterdam, Dublin and Marseille.

“Humanitas has always been a first-tier institution in the battle against cancer – explains Armando Santoro, Director of the Humanitas Cancer Center – a committment which has found in

Humanitas Cancer Center a firmer affirmation and a further impulse towards the future: a large and top-level multi-specialty hospital with dedicated outpatient clinics, services and innovative therapeutic pathways for oncological conditions merges with last-generation technologies and individually personalised therapeutical approaches, to warrant a 360 degree assistance to our patients without overlooking the possibilities of personalised medical care. Our aim is the ultimate focus against cancer – thanks to professional skills, high-specialty competence, technologies and

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therapeutical pathways – together with comprehensive care offered to patients, as only a general hospital can afford, able to meet every demand not only for oncological problems, but also for internal medicine (e.g. cardiological, rehabilitative, and emergency medicine) and psychology.

The needs of the modern patient and his/her central position drive the evolution of hospital care, from a the traditional management of assets (mostly based on beds, operatory theatres, outpatients clinics) towards a more patient-centered approach based on the specific condition to be cured.

For the patient, this shift results in a multidisciplinary approach and multispecialty assistance – performed by clinical oncologists, surgeons, radiotherapists, and, in addiction, psychologists – to offer a comprehensive approach to take care of the person as a whole. Moreover, the composition of the team, to include clinical researchers (MD-PhDs) allows for translational research, and – as a consequence – the most advanced therapies to be transferred to the bedside.

One fundamental aspect of this approach is the follow up for disease-free patients and home care and support for those who have failed to respond to treatments. This continuity of medical care is reinforced by the offer of a two-way communication between doctors and patients and on-line services to simplify the patient’s relationship with our center.

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Humanitas: general hospital and research center

At Humanitas Center, research, which is crucial to optimize both research and treatment, is widely spread and inspires every step of care: from the prevention and the screening programmes, to imaging and endoscopic diagnostic procedures, all the way to the development of new drugs and supportive therapies through laparoscopic and robotic surgery and pioneer exemples.

Humanitas challenge for the future is to enforce cooperations at all levels. We are cooperating with other national and international networks of exellence, including the hematological and the oncological networks operating in Lombardy. As an exemple Humanitas (a network itself) has now become part of the broader INCARE (ICH Network in CAncer REsearch) with the main aim of promoting research. We are working to achieve that the Humanitas Cancer Center becomes in the near future a Comprehensive Cancer Center which follows the numerous US examples. In this ambitious and realistic view this would be a local and global reference�.

ireland UK

sweden

denmark

belgium

Countries involved in international cooperation networks

netherlands germany austria

usa

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portugal

switzerland

france

croatia

japan

Technology and innovation Humanitas is a general hospital with a strong tendency for an interdisciplinary, integrated approach and high specialization. From cardiac surgery to orthopaedics, from oncosurgery to neurosurgery, the most advanced standards at an international level are offered, as well as up to date technologies.

Among these, radiotherapy, with last generation nuclear accelerators – which include TrueBeam, the first and the only one in Italy – operating at high speed and allowing for an extremely fast and precise treatment. Moreover, Humanitas is equipped with a robotic surgical system to treat cardiac arrhythmias, a 3 Tesla nuclear magnetic resonance and a PET-CT. It also stands out because of the role of robotic surgery, which represents the new frontier in minimally invasive surgery.

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Humanitas Cancer Center Advisory Board Members Köln, Germany

Andreas Engert Köln University Clinic Dublin, Ireland

John Crown St. Vincent University Hospital Boston, Usa

Eric Van Custern

Harvard Medical School and Dana-Farber Cancer Institute

University Hospital Gasthuisberg

Silvia Formenti Antonella Surbone

Ruprecht Karl University and Salem-Hospital

Leuven, Belgium

Kenneth C. Anderson

New York, Usa

Heidelberg, Germany

Markus Büchler

milan, Italy

Alberto Costa European School of Oncology

Tokyo, Japan

Masatoshi Makuuchi Tokyo University

New York University School of Medicine

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Humanitas Cancer Center’s figures 200 health professionals (physicians, surgeons, psychologists, physicists, and biologists) 200 nursing professionals 200 clinical and basic researchers 30,000 patients per year, 40% from Regions other than Lombardy 300 clinical trials and projects aimed to develop new therapeutical options in the last 3 years

The Center 30,000 sqm 300 beds 120 outpatient clinics 20 operating theatres 1 Translational Research Center with a Biobank, a Cell Factory, Molecular Biology and Clinical Pharmacology labs 30 million Euro investments in technology, research and reception with a receptive structure for patients’ relatives

Last generation technology equipment for diagnosis and treatment 4 linear accelerators for radiotherapy, included the innovative TrueBeam accelerator PET-CT and a cyclotron for radiopharmaceutical production 4 CTs 5 NMRs, included a 3 Tesla NMR 1 Da Vinci Surgical System

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www. cancercenter.it

27

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Clinical-scientific activities Clinical activities Outpatients 2007

Inpatients 2007

1,091,505

2008

2008

1,175,990

2009 2010

1,200

24,901

2010

1,292,447 1,100

24,964

2009

1,246,415

1,000

24,539

0

1,300

200 23,0

400

600

800

23,5

1000

24,0

24,785 1200

1400

24,5

25,0

thousands of patients

thousands of patients

Humanitas’ people Total people 2007

1,704

2008

1,793

2009

1,811

2010

1,880

1,000

1,150

1,300

1,450

1,600

1,750

1,900

total people

18%

31,7% 597

337

Staff 50,3%

Physicians and researchers

946

Healthcare support workers

2010

100% = 1,880

Research activities Published papers 2007

Raw impact factor*

172

2008

2007

197

2009

2008

2010

349 50

100

150

200

250

896

2009

289

0

724

300

350

1,587

2010 400

published papers

1,727 0

400

800

1,200

1,600

2,000

raw impact factor

* 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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Translational research Immunity and inflammation Oncology Cardiology Orthopaedics

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Immunity and inflammation benchside

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New insights on immunity and their translation from benchside to bedside they involve a broad range of medical branches.

Interview with Alberto Mantovani

Professor of General Pathology at the Faculty of Medicine and Surgery at the Università degli Studi di Milano and Scientific Director of Humanitas

IMMUNOLOgIC and inflammatory mechanisms are at the root of a remarkable variety of human conditions, which range from immunological and autoimmune diseases to cancer and cardiovascular diseases. This revolutionary evidence has been acquired only recently, and nowadays the immunological component is advocated more often.

» Which immunological and infl ammatory

mechanisms are being mostly investigated at Humanitas?

At Humanitas the biggest efforts in research are focused on the understanding and on the deep knowledge of the mechanisms of what is referred to as innate immunity which represents the first-line physiologic defense. Moreover, it amplifies selfprotective processes and triggers immune responses.

For instance, the sentinel cells whose aim is to start the engine of immunity are paralyzed in tumours.

The link between cancer and inflammation and the balance of various population of cells is exhaustively discussed in the interview with Paola Allavena.

» We are referring to new and promising research

sectors, and the researchers at Humanitas have had the merit of gaining an insight on their scientifi c importance and wide scope, in that

Our choice has followed or even anticipated a general trend in this field. Besides, we have emphasized not only this aspect, but also human disease patterns. The former may be synthesized with the saying “learning from the patient for the patient”.

We proudly believe that we have once again anticipated a main tendency, i.e. going back to human models as a preferential experimental system to promote science and medicine. This is in agreement with recent outstanding positions. Specifically, I am referring to an authoritative paper by Mark Davis published in Immunity which calls immunologists for a greater focus on humans.

In addition, the focus on mechanisms underlying immunity and inflammation has a broad impact on chronic degenerative diseases ranging from cancer to atherosclerosis

» What approach do you think is most eff ective to explore the connection between infl ammation/ immunity and disease?

We are adopting and we will continue to adopt a broad spectrum of approaches, which we apply throughout the process, from molecules to humans. I am referring to molecular biology methods, genetic technologies in parallel with classical cellular immunology and studies in humans.

Innovation and translation are our key words and represent the basic condition for the newest knowledge to be transferred to clinical practice.

We have been using technologies such as transcriptional profiles as discovery and research tools, allowing us continuous updating and a unique possibility to access the “open cast mining” of the genome. This is the way to find new molecules and their association to human diseases.

Generally speaking and in extremely simple terms, we are living our experience as scientists in the post-genomic age. The interest is and will be mostly focused on downstream processes and mechanisms of control. The question will be about how the gene expression is modulated. In the case of immunity, the issue will be how the potential of a gene affects a certain immunological disease.

We will continue to work in this area, specifically

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Immunity and inflammation | Benchside Interview with Alberto Mantovani

studying those small mRNA called miR; miR are a recently discovered level of fine tuning of gene expression.

» Which problems do we have to face?

hIghLIghT

We have to face the diversity of inflammatory and innate immunity responses. We are used to indicate with the term inflammation a wide variety of conditions, very different even by intuition.

Inflammation associated to cancer initiation and progression is typically smouldering and not very apparent; differently to an inflammatory respiratory disease – i.e. asthma – or even to that peculiar inflammation associated to atherosclerotic processes.

Regardless of the same word used to indicate both in dictionary terms, we have to define these differences in molecular terms. In particular we have contributed to the identification of inflammation as a a key component of the tumour microenvironment, a so called 7th hallmark of cancer.

Another problem we have to face is gender medicine.

We want to find the reason why women show a higher

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Humanitas hosts the Cure and Research Center for Inflammatory Bowel Disease, led by Silvio Danese. The center is part of the Gastroenterology Department, led by Alberto Malesci.

risk of autoimmune diseases compared to men. Once given an answer to this big question, we will hopefully be able to address these diseases specifically. These aspects are being dealt with in the interview with Mauro Podda.

Again, with reference to the aforementioned group of diseases, our genetic studies – still ongoing but not far from the clinical experimental phase in a near future – on a rare autoimmune disease identified a potential therapeutic target.

» It is certainly fundamental to reach the clinical

experimental phase, since it means approaching the patient’s bedside and responds to your vocation for traslational research.

In fact, the last problem – but actually the most crucial – we have, is to transfer the results from our labs to clinical practice and to the patient’s bedside. Studying genetic diseases is particularly helpful in finding new therapeutic options. Several research groups at Humanitas have achieved brilliant and promising results.

Let me mention those by Marinos Kallikurdis on WHIM

New ascent of the Infl ammatory Bowel Disease pathophysiology

«It is now clear that Crohn’s disease (CD) and ulcerative colitis (UC) represent two distinct forms of chronic inflammatory bowel disease (IBD) and, as such, have different causes and pathogenic mechanisms. Our laboratory is actively investigating several aspects of disease pathogenesis.

Firstly, we are investigating the role of the protein C system as an unexpected player in maintaining epithelial barrier integrity and immune homeostasis.

Secondly, we are actively studying the role of the lymphatic system as an entirely new component of IBD pathogenesis. In particular, we are focusing on leukocyte exit from the intestine. Similar aspects are under investigation regarding colitis-associated colon cancer, as cancer similarly relies on the lymphatic system for metastasis.

Thirdly, we are observing stem-cell homing, and are currently trying to understand the mechanisms of stem cell recruitment in the inflamed intestine, in order to improve the engraftment and their homing to the gut.

All these areas of investigation are carried out at bench level, but always with a view to developing novel therapeutic approaches, so as to identify new means thanks to which we can target and cure CD and UC patients.»

top paper Biswas SK, Mantovani A.

Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm

hIghLIghT

syndrome – a rare congenital immunodeficiency disorder characterized by chronic neutropenia causing warts, hypogammaglobulinemia, and infections – or by Anna Villa on Wiskott Aldrich syndrome – again a rare immune deficiency with a X-linked recessive transmission, characterized by eczema, thrombocytopenia, and bloody diarrhea.

Osteopetrosis, another rare inherited condition, is the topic of the interview with Anna Villa, in which the role of genetic studies to develop appropriate and effective therapies becomes evident.

Our ability to innovate and to apply state-of-the-art research approaches will be tried out on classical autoimmune diseases – e.g. lupus and rheumatoid arthritis – inflammatory bowel diseases, autoimmune liver diseases. All conditions which are being actively studied by research groups at Humanitas, such as those led by Silvio Danese and Nicola Dioguardi.

Natural Killer (NK) lymphocytes, are important effectors of the innate immune system against viral infections and cancer. Domenico Mavilio, group leader of the Clinical Immunology

Nat Immunol. 2010 Oct;11(10):889-96.

Epub 2010 Sep 20.

Raw IF (2009): 26 Normalized IF: 15

Abstract Plasticity is a hallmark of cells of the myelomonocytic lineage. In response to innate recognition or signals from lymphocyte subsets, mononuclear phagocytes undergo adaptive responses. Shaping of monocyte-macrophage function is an essential component of resistance to pathogens, tissue damage and repair. The orchestration of myelomonocytic cell function is a key element that links inflammation and cancer and provides a paradigm for macrophage plasticity and function. A better understanding of the molecular basis of myelomonocytic cell plasticity will open new vistas in immunopathology and therapeutic intervention.

The promises of NK cells in diagnostics and treatment

«Our laboratories are conducting two important projects aimed at translating research programs on NK cells directly from the laboratory bench to the patient’s bedside. First of all, we are taking advantage of the intrinsic anti-tumoural NK cell potential by developing a protocol of allogeneic NK cell adoptive transfer therapy in patients with acute leukemia and lymphomas who undergo haploidentical hematopoietic bone marrow transplantations. This clinical trial relies on the hypothesis that alloreactive NK cells can both contribute to the eradication of leukemia blasts in the recipient, thus escaping or reducing the preparative regimen, and, on the other hand, to eliminate residual host dendritic cells and T lymphocytes, thus preventing graft-versus-host disease and graft rejection, respectively. Secondly, we have reported – alongside other researchers – that NK cells from HIV-1 infected patients in late stages of the disease are highly defective in their anti-viral and anti-tumour functions, thus contributing to the onset of all those opportunistic infections and tumours that characterize the acquired immune-deficiency syndrome (AIDS). Moreover, the presence of dysfunctional and pathologic NK cell subsets at different stages of HIV-1 infection correlates with the functional status of this innate immune cell compartment. On these assumptions, we are undertaking a multi-centric clinical trial to establish whether the analysis of NK cell phenotype can be used as a novel clinical biomarker that characterizes the clinical stages of the HIV-1 infection accurately, tracks the effectiveness of antiretroviral therapy, and evaluates the immune-competence in HIV-1 infected subjects.»

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Immunity and inflammation bedside

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The diseases of the “weaker sex”

Interview with Mauro Podda

Director of the Humanitas Internal Medicine Department

SEX AND GENETICS are necessarily linked in medicine and particularly in autoimmune diseases, which are the third most common group of diseases in the world, following cancer and heart disease.

Autoimmune diseases affect an estimated 5-10% of the general population, while representing an intriguing paradigm for this link. Since the first reports on these conditions, a striking female predominance with a female to male (F:M) prevalence ratio as high as 10:1 has been consistently described.

This epidemiological aspect is relevant for both research and clinical practice, and is probably due to either genetics or epigenetics. Moreover, inherited and environmental components interplay in a balance whose mechanisms are not yet completely defined.

» What is a typical clinical approach towards a disease where one sex prevails?

First of all, allow me to say that gender differences in medicine expose a physician to the risk of enormous bias. When suspecting an autoimmune disease in a patient, in the case of a woman, doctors usually tend to investigate thoroughly – sometimes even insistently – this diagnostic suspicion – because of the high a priori probability.

Considering the disease model we are mostly interested in, i.e. primary biliary cirrhosis – an

uncommon condition characterized by the presence of serum anti-mitochondrial antibodies (AMA) and by a progressive destruction of intrahepatic bile ducts resulting in chronic cholestatis and, ultimately, fibrosis and cirrhosis – we found a female to male prevalence ratio in our patients as high as 10:1.

I am referring to the prevalence ratio as apparent in clinical practice. The difference in prevalence ratio as estimated by AMA positivity is less clearcut: about 3:1 or 4:1 and may thus confirm the importance of our bias as a certain amount of male patients is lost on the way from diagnostics to clinical observation.

» What role does the information on X and Y

chromosomes play in the onset of the disease?

The X chromosome contains about 1,000 genes, many of which involved in the immune system homeostasis and immune tolerance.

Nevertheless, in autoimmune diseases a candidate gene has not been identified and the reason for the female preponderance of these conditions remains unclear. Thus, a mechanistic explanation based on a cause-effect relation – the presence of alterations in the X chromosome copy number or structural abnormalities leading to autoimmune disease – is too simplistic.

Indeed, X monosomy is described in women with autoimmune disease. Our group was the first to demonstrate a high X monosomy rate in peripheral blood mononuclear cells of women with primary biliary cirrhosis, autoimmune thyroid diseases, and scleroderma. Monosomy is a paraphysiological condition, being normally present in 0.5-2% of the cells of a healthy woman. In women with primary biliary cirrhosis, this rate can reach 8-10%. And it is likely to increase progressively with age – interestingly, the incidence of most autoimmune disease increases with age as well.

Another mechanism is the inactivation of the X chromosome, by virtue of which women are functional mosaics for X-linked genes. This multistep process is aimed at maintaining an equal dosage between males and females of X chromosome genes, and results in random inactivation of X-linked genes with respect to their parental derivation (expected to be 50% each). It is well known that at least 15% of X-linked genes are capable of escaping X

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Immunity and inflammation | Bedside Interview with Mauro Podda

chromosome inactivation in healthy women and thus to express genes from both X chromosomes. Some studies have suggested that women with specific female-preponderant autoimmune disease manifest a skewed X chromosome inactivation pattern.

However, even if epigenetic changes are so crucial in autoimmune diseases, their identification is lacking or – at least – very difficult to obtain.

» And which role do environment and genetics play in this scenario?

hIghLIghT

Autoimmune diseases have to be considered

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The Autoimmunity and Metabolism Unit has been recently established within the Department of Medicine, chaired

by Mauro Podda.

The Laboratory is coordinated by Carlo Selmi, Assistant Professor of the University of Milan and physician scientist of Humanitas.

multifactorial, and the burden of inheritance and environment is controversial.

An amount of evidence supports the determinant role of genetic factors, with up to 80-90% predominance of genetics. And, quite simply, in the absence of a genetic alteration the disease does not manifest.

The role of genetics is also demonstrated by studies in identical twins, where our data showed a rate of concordance for primary biliary cirrhosis higher (60-70%) than in dizygotic twins (which are approximately 50% identical in their DNA sequence).

On the other hand, the remaining 30% implies a

Finding the greater common factor between autoimmune and metabolic disorders «Our Unit includes senior physician scientists with laboratory and clinical expertise in Internal Medicine and Rheumatology/Clinical Immunology. It is designed to tackle different, and yet common grounds of the immunomediated chronic diseases sharing an autoimmune or chronic inflammatory pathogenesis with special emphasis on metabolic pathways. We are particularly intrigued by well established examples of organspecific (i.e. autoimmune thyroid disease or cholangitis, type I diabetes) as well as systemic (i.e. systemic lupus erythematosus, scleroderma) conditions and their link with metabolic features. An excellent example of the new paradigm associated with metabolic dysfunctions is provided by obesity and the corollarium of manifestations recognized in the metabolic syndrome. Indeed, there is now growing evidence that the strict interplay of adipose tissue features and chronic inflammation coexists with insulin resistance to determine the proinflammatory status that characterizes all features of the syndrome, as well as the elevated cardiovascular risk. All chronic inflammatory conditions are considered complex or multifactorial, as supported by the reported genomic associations resulting from the most recent genome-wide studies. Autoimmunity and Metabolism Unit work is based on the hypothesis that these conditions share numerous features that require a coordinated approach, as represented clearly by the striking female predominance, the incomplete concordance among monozygotic twins, and the variable prevalence and incidence rates in different geographical areas (coined geoepidemiology). Ongoing projects investigate (i) the population-based prevalence and incidence rates of chronic inflammatory and autoimmune conditions, (ii) the impact of environmental and metabolic factors (with a specific emphasis on nutrition) on the immune function and the putative role of these factors in determining disease onset, (iii) the resulting epigenetic differences in the effector lymphocyte populations from unique series of monozygotic twins discordant for complex diseases such as scleroderma, primary biliary cirrhosis, primary sclerosing cholangitis, and inflammatory bowel disease.»

necessary environmental component. To confirm this hypothesis further, the concordant twin sets often manifest a different disease phenotype, which may be explained by the lack of exposition to the same trigger or to a different timing in the disease progression. A combination of environmental factors in genetic predisposition is anyway necessary albeit some data seem to point to the causative role of infectious agents and xenobiotics. Lastly, recent but growing evidence has pointed towards the role of nutritional factors in autoimmunity.

Âť What do you think is the most constructive

approach to identify the role of genetics, environment and other causative factors for such complex diseases?

Studying the epidemiology of autoimmune complex

diseases is useful to determine the impact of the different causative factors, which are mainly environmental. Descriptive epidemiology provides rough data to be analyzed, and which allow to formulate a research hypothesis. But epidemiology itself is subject to bias, as in the case of variable prevalence rates of autoimmune diseases in different geographical areas which may be well adjusted by the physician awareness. Higher prevalence and incidence rates have been described in Northern European countries (particularly the UK and Scandinavian countries) compared to Mediterranean areas. They could be the results of either a true geoepidemiological divergence or of different methodologies of case finding. In more recent studies the previously reported North-South gradient is no more apparent. Moreover, it is difficult to establish whether the ethnic differences in prevalence rates

39

hIghLIghT

Immunity and inflammation | Bedside Interview with Mauro Podda

40

The recently opened Center for Autoimmune Liver Diseases is a paradigmatic model of the translational science activities in Humanitas. The center, led by Pietro Invernizzi, is part of the Division of Internal Medicine, led

by Mauro Podda.

A 360-degree study of autoimmune liver diseases

«The Center is a tertiary referral center and one of the largest centers for autoimmune liver disease in Europe. It follows an active program of basic and clinical research in hepatobiliary autoimmune disease, i.e., primary biliary cirrhosis (PBC) and primary sclerosing cholangitis, based on the availability of an unique population of patients». As Invernizzi points out: «A group of basic and clinical scientists are working together on projects ranging from basic science (research lines are active on etiopathogenetic aspects also based on appropriate experimental models), through the preclinical development of novel therapies, to clinical research (identification of novel diagnostic and prognostic markers; clinical trials to evaluate better therapies; a clinical epidemiology observatory to monitor national and international prevalence and incidence). Such a 360-degree commitment allows both to dissect the underlying pathogenic mechanisms and to result in an improvement in the patients’ health. In this way, basic research results are translated into better clinical management and therapies. As an example, last year the Center concluded a unique genome-wide study on PBC showing that PBC is associated with a genetic variant of the interleukin 12 (IL-12) gene (Nature Genetics 2010;42:658-60). Only a few months later, an international clinical trial to evaluate the efficacy of a anti-IL-12 monoclonal antibody was activated.»

reflect only the effects of genetics or include a role for migratory fluxes or even the effects of pollution and various environmental influences. Our group has recently concluded the largest epidemiological study thus far on primary biliary cirrhosis. The multivariate statistical analysis demonstrated that – besides having a first-degree relative with the disease, also a history of recurrent urinary tract infections, past smoking or the use of hormonereplacement therapy and (even if marginally) the use of nail polish – were associated with a higher risk of the disease.

» Could you provide an example of studies

which progress from laboratory research to clinical practice at Humanitas?

Our genetic studies identified variations of interleukin 12 (IL-12) genes underlying a risk association with primary biliary cirrhosis.

Interleukins (ILs) are naturally occurring proteins that regulate the immune system and immunemediated inflammatory disorders.

Until now primary biliary cirrhosis has been treated with a drug – ursodeoxycholic acid – able to slow its progression but not to cure it. Alternatively, a recent biological drug called ustekinumab is a human monoclonal antibody, directed against interleukin 12 (IL-12), and interleukin 23 (IL-23) and seems effective in blocking the inflammatory response through the suppression of these cytokines. It is has been already tested in the treatment of psoriasis with a good safety and efficacy profile.

There is a major problem, however, with drugs of this type which act at different levels of the immune system: the risk to unbalance the mechanism of immunity per se. In fact, drugs are not generally so selective to “press just one single button” useful for the therapeutic effect we are looking for. In the case of ustekinumab, serious and common adverse effects, specifically immunosuppression and predispostion to infection or cancer, have not been described.

I believe that this example provides an exhaustive and complete paradigm of translational research from the laboratory to clinical application.

top paper Liu X, Invernizzi P, Lu Y, Kosoy R, Lu Y, Bianchi I, Podda M, Xu C, Xie G, Macciardi F, Selmi C, Lupoli S, Shigeta R, Ransom M, Lleo A, Lee AT, Mason AL, Myers RP, Peltekian KM, Ghent CN, Bernuzzi F, Zuin M, Rosina F, Borghesio E, Floreani A, Lazzari R, Niro G, Andriulli A, Muratori L, Muratori P, Almasio PL, Andreone P, Margotti M, Brunetto M, Coco B, Alvaro D, Bragazzi MC, Marra F, Pisano A, Rigamonti C, Colombo M, Marzioni M, Benedetti A, Fabris L, Strazzabosco M, Portincasa P, Palmieri VO, Tiribelli C, Croce L, Bruno S, Rossi S, Vinci M, Prisco C, Mattalia A, Toniutto P, Picciotto A, Galli A, Ferrari C, Colombo S, Casella G, Morini L, Caporaso N, Colli A, Spinzi G, Montanari R, Gregersen PK, Heathcote EJ, Hirschfield GM, Siminovitch KA, Amos CI, Gershwin ME, Seldin MF.

Genome-wide metaanalyses identify three loci associated with primary biliary cirrhosis Nat Genet. 2010 Aug;42(8):658-60.

Epub 2010 Jul 18.

Raw IF (2009): 34.284 Normalized IF: 15

Abstract A genome-wide association screen for primary biliary cirrhosis risk alleles was performed in an Italian cohort. The results from the Italian cohort replicated IL12A and IL12RB associations, and a combined metaanalysis using a Canadian dataset identified newly associated loci at SPIB (P = 7.9 x 10(11), odds ratio (OR) = 1.46), IRF5-TNPO3 (P = 2.8 x 10(-10), OR = 1.63) and 17q12-21 (P = 1.7 x 10(-10), OR = 1.38).

41

Oncology bedside

42

Humanitas Cancer Center: oncology-devoted, research-oriented, patient-dedicated Interview with Armando Santoro

intended as a polyclinic where oncology plays a crucial but not exclusive role.

There are potential advantages in this choice, particularly when considering the introduction of specialist structures where the four main tools against cancer can be implemented, i.e.: prevention, assistance, research, and innovation.

» Modern clinical research is likely to be multifaceted as a consequence of this complex scenario.

Director of Humanitas Cancer Center

IF WE LOOK at the ranking of the top 15 American Medical Research Institutes, only 3 are specialized in a single area, while all the others are large multispecialty hospitals that devoted most of their resources to oncology. Humanitas Cancer Center, which was opened in November 2010 within the hospital, is exclusively devoted to oncology. Its aim is to gather and expand all existing competence and excellence, reconciling research with clinical activity at the highest standard levels.

» Which challenges for clinical activity do you

foresee, and in which direction do you think clinical assistance will evolve?

The main challenge in modern medicine is to face the increasing number of oncologic patients and their comorbidities, as a direct consequence of population aging and longer lifetime expectancy. In particular, comorbidities introduce complexity in everyday clinical activity. Cancer and other diseases often coexist in elderly people. However, this is true not only for elderly patients, but also for middle age and – increasingly – young patients. Surprisingly, management of patients with comorbidities is not taken into consideration in guidelines and flow charts and is substantially neglected even by research.

Thus, a big effort is needed to satisfy emerging assistential requirements. A cancer center has to be

Surely, there are multiple aspects to be considered in clinical research. Among these, I would like to focus on at least two. The first is the traditional clinical research based on large controlled clinical trials, aimed at assessing and comparing treatments in terms of effectiveness. This is a research approach we cannot prescind from, even if in recent years a new kind of research – translational research – has powerfully appeared. Translational research implies an intense and bidirectional interplay between the bench and bedside. Such approach allows the identification of the molecular and genetic alterations which are at the base of the disease, ultimately leading to the development of new drugs as, for instance, biological agents and targeted therapies.

» Which new developments can arise from these two branches of research?

Intriguing, and yet demanding changes may be expected. For instance, the progressive identification of clinically relevant molecular abnormalities will allow us to classify cancer types based on their biological characteristics rather than according to conventional pathological parameters. A situation comparable to that occurring in the case of a rare disease, which will open the issue of clinical research in low incidence tumours.

But the ideal kind of research depends on an even wider open question from this emerging scenario: nowadays, we are living in an era of globalization where research is mainly subsidized and supported by pharmaceutical companies in order to register new drugs. This obviously implies that medical research is – at the most – funded and registrationdirected; this is, in fact, essential to discover and test

43

Oncology | Bedside Interview with Armando Santoro

new therapeutic molecules. But there is the need to support free and independent research as well, hopefully thanks to public funds. In any case, an optimal balance of the system is difficult to achieve.

leaders in all oncology areas. It exerts its control and, where necessary, expresses criticism about our activity; but, at the same time, it helps stimulating new solutions in clinical assistance and research.

» What is the most effective approach in modern

» What are the most recent and innovative

I would like to start by saying that there is no more place and time for single players. Modern medicine stands on teams, multidisciplinarity, collaboration and integration. This approach, an innovative mental approach, is aimed at optimizing both clinical activity and research. We must learn to cooperate – overcoming our individualism – at all levels, not only among specialists in the same fields, e.g. oncologists with oncologists, but also oncologists with lab researchers or clinicians in different specialties.

Moreover, we need to cooperate with external, national and international, resources to expand all existing competence and excellence. A great deal of work in this direction is already being done, but we are planning to intensify it further. For instance, we have nominated a board including 10 key opinion

A large lab area – a translational research center – completely devoted to oncology is about to be opened.

This lab will host innovative facilities: a Biobank, a Cell Factory, a Laboratory of Clinical Pharmacology and a laboratory of Molecular Biology, and will help the center to expand greatly.

Our Biobank, which is already operative, hosts a collection of biological samples (each individually linked to its clinical data) that is growing day by day.

We have collected over 4,000 samples of various tissues, both neoplastic and non-neoplastic. In the near future, they will allow us to develop promising research projects, e.g. identifying predictive factors in the response to a treatment, prognostic markers but also to perform projects and studies which at the moment are still unpredictable.

HIGHLIGHT

clinical activity?

44

Humanitas hosts the Unit for Liver Surgery, led by Guido Torzilli.

The Unit is part of the Division of General Surgery III, led by Marco Montorsi.

projects and initiatives at Humanitas now?

No one can be refused liver surgery

«Hepatic resection remains the treatment of choice for most liver tumours. Nevertheless, its feasibility is often compromised by the need to remove a consistent portion of the liver itself in order to obtain a complete tumour clearance. Over the years – thanks to ultrasound guidance – our Unit has devised techniques, that are able to overcome these drawbacks and allow us to offer a surgical treatment to patients otherwise not suitable for that.

Clinical research is now oriented towards affirming this policy among the surgical community by coordinating and conducting international multicentric surveys able to highlight the potentiality of this approach on the long-term outcome of the patients on a wider and international setting.

Furthermore, having provided enough evidence concerning the feasibility and effectiveness of this approach both for primary and metastatic liver tumours, another goal is now to insert it in a well established multidisciplinary setting which is able to recognize its advantages in terms of expanded indication and safety, to emphasize its benefits, and to provide guidelines».

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Oncology | Bedside Interview with Armando Santoro

hIghLIghT

We are activating a Cell Factory, which will be able to produce molecules for immunotherapy and vaccinotherapy or cells for regenerative therapy research in oncology, cardiology, ophthalmology, orthopaedics and for cellular therapy in cancer. We are dealing with one of the future challenges for medicine – medicine for the future, but the future is today.

We are also investing a big part of our efforts in Clinical Pharmacology in order to convey the important message that it is necessary to develop new drugs and to test them from the earliest stages. Our research is oriented towards Clinical Pharmacology in oncology and in haematology, following a long-lasting tradition of excellence.

46

At Humanitas Cancer Center Luca Toschi coordinates the translational research on lung cancer, which is specifically focused on finding new prognostic markers, able to predict both the sensitivity and the resistance to an antitumour therapy.

» Which are going to be the most important technological innovations in the fi eld of diagnostics?

While traditional cytomorphological diagnosis will maintain its potentiality, technological innovation will offer extraordinary opportunities in oncology, e.g. the identification of molecular and genetic factors at the base of cancer development and the validation of prognostic and predictive biomarkers. As mentioned above, we have invested a great deal in Molecular Biology and Cellular Biology, whose integration in the new translational oncology center will produce highly competitive research also at an international level.

Personalized therapy against a harsh enemy

«Lung cancer is the leading cause of cancer deaths worldwide and survival rates are poor. This is primarily due to the lack of both effective screening tools for disease detection at an early stage and curative therapies for patients with advanced disease. Today, thanks to the wealth of knowledge about the molecular biology of lung cancer, we can start exploring the potential of personalized therapies for this disease, particularly for patients with lung adenocarcinoma. Recent studies show that as many as 50% of lung adenocarcinomas have activating mutations in known oncogenes against which novel therapeutic agents have been developed. Early clinical trials suggest that targeted oral agents have less toxicity and greater benefit than chemotherapy but only when administered to patients with the specific mutated oncogene.

Our research activity is currently focused on the identification of biological predictors of sensitivity and resistance to selected anti-cancer agents, including third generation cytotoxic compounds and novel tyrosine kinase inhibitors. In fact, our research is mainly oriented towards identifying reliable tools to assist the clinician in selecting those patients that might derive a substantial benefit from specific agents and, at the same time, to exclude from treatment those subjects who are unlikely to respond, thus avoiding unnecessary costs and unwanted toxicities. Another research area of interest is represented by the identification of lung cancer patients who might be suitable candidates for the anti-cancer immunotherapies that are being developed in our institution. In fact, we are currently investigating the prevalence of immunological biomarkers in surgically resected lung cancer in order to understand in-depth the mechanisms of anticancer immune response in this disease, tumour escape from immunological surveillance, and their prognostic role.»

Âť What you have mentioned so far demonstrates great attention and a great effort for innovation. In order to do good research, is it necessary to innovate?

This is exactly what we have been trying to do in the past years. Following this direction, it will not be so difficult to establish what has to be expected from research even if it will imply great efforts and conspicuous investments.

Nuclear Medicine is impressively expanding its potentiality, especially in terms of integration with CT and NMR, evaluation of response to treatment and radiation therapy planning.

PET is increasingly being used as a tool for biological characterization rather than for diagnosis. These innovative applications are made possible through the availability of both new radiopharmaceuticals and state of-the-art instruments (PET-CT or PET-NMR).

Radiology is extraordinarily expanding its potentialities, which were previously restricted to a diagnostic activity. Nowadays, by contrast, they are increasingly pursuing therapeutic objectives.

Âť Could you provide a significant example of these new applications, or other examples of innovation within medical or surgical treatment?

Well, in terms of new applications, it is impossible not to mention the innovative TrueBeam technology which offers a radically different approach for treating cancer with image-guided radiotherapy. True Beam is an advanced accelerator for the treatment of lung, breast, prostate, head- and neck, and other types of cancer, in that it enables the delivery of larger doses in smaller spaces. Clinicians can perform radiosurgery procedures with exceptional ease, precision, and

47

hIghLIghT

Oncology | Bedside Interview with Armando Santoro

48

Humanitas hosts a Unit for Research in Thoracic Surgical Oncology led by Maurizio Infante.

The Unit is part of the Division of Thoracic and MiniInvasive Surgery led

by Marco Alloisio.

Close-to-zero impact for lung cancer surgery

«Surgery is the mainstay of lung cancer management and of many intrathoracic malignancies – says Alloisio –.

However, smoking-related diseases have a considerable impact and a noticeable fraction of lung cancer patients die from consequences of surgery on their cardiovascular function rather than from cancer recurrence. In addition, recurrence rates are still high. Clinical research in our Unit is now carrying out several projects. We are focused on reducing the impact of surgical resection by performing minimally invasive (VATS), robotic surgery and lung-sparing techniques.

We promote this approach nationwide by offering technical training courses.

Lung cancer screening by spiral CT will detect more early-stage lung cancer cases among heavy smokers, amenable to resection with such techniques. Actually, we have been involved in lung cancer screening research since 2001 with the DANTE trial, the first randomized trial to have compared screening with spiral CT versus no screening, and we are now part of a European network that is going to establish and measure the potential benefits of this strategy. Moreover, lung cancer cases are being studied in conjunction with the Research Department in order to explore the role of tumour microenvironment in disease progression and outcome, and to develop new multimodal treatment approaches. Our Unit is also exploring the benefit of performing pleurectomy-decortication instead of EPP in the management of malignant pleural mesothelioma with a multimodality approach.»

speed, with most treatments taking only a few minutes a day. This makes it possible to offer greater comfort to our patients by shortening treatments, and to improve precision by reducing tumour motion during dose delivery.

Humanitas has been the first – and until now the only – oncologic center in Italy and the second in Europe to be equipped with these devices. Moreover, besides conventional laparoscopic surgery, we are also developing robotic techniques. In fact, technologies are contributing to less demolitive surgical procedures, shorter post operative recovery and fewer surgical complications even in severely advanced cases.

» How is it possible to manage most eff ectively all these opportunities for modern treatment techniques?

hIghLIghT

At Humanitas Cancer Center, repositioning patients

Humanitas Cancer Center hosts the Section of Bone Marrow Transplantation and Cell Therapy, led by Luca Castagna.

at the center of the whole healthcare process is a priority, with the goal of assuring the highest standards of care and improving assistance, as well as taking on an active role in research using the most innovative techniques.

Additionally, better communication and access to reliable information are needed for efficient daily clinical activity. When patients receive a shocking diagnosis, they give up hopes and feel lost.

Communication helps restoring their landmarks.

For this purpose, the Humanitas web site (www.cancercenter.it) is being constantly updated not only by our staff but also by patients and their relatives.

An important challenge to obtain is continuity of care. To achieve this aim we are building up diagnostic and therapeutic tracks, which can be activated directly by each patient with a simple

How to facilitate bone marrow or stem cells transplantation

«Bone marrow transplantation is the treatment of choice for many hematological malignancies. In Humanitas we perform autologous transplantation after high-dose chemotherapy, mainly in lymphoma and myeloma. In this setting, we participate in national and international studies to identify which patients should be treated with this approach. We are also evaluating drugs that could reduce side effects (such as mucositis) and enhance tolerance. On the other hand, we are studying – in collaboration with the Radiotherapy Department – the application of a new modality of total body irradiation, limited to bone marrow (total marrow irradiation, TMI), which is able to spare normal tissues, to reduce side effects, and to enhance anti-tumoural activity. Furthermore, high-dose chemotherapy is used for non-malignant diseases, such as refractory Crohn disease, in collaboration with the Gastroenterology Department.

Another area of clinical research is allogeneic stem cell transplantation. In this field, we are particularly committed to the treatment of acute leukemias, as well as refractory lymphomas. A new development target is represented by haploidentical bone marrow transplantation, where the donor is a family member partially matched with the patient. This allows for the availability of a donor for almost all patients and, as a consequence, the feasibility of an allogeneic transplantation.

Finally, in collaboration with the Immunology Lab, directed by Domenico Mavilio, we are studying immune reconstitution after transplantation.»

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hIghLIghT

Oncology | Bedside Interview with Armando Santoro

Humanitas Cancer Center hosts the Unit of Clinical Pharmacology, led by Paolo Andrea Zucali. The unit is part of the Department of Oncology and Hematology, led by Armando Santoro.

Mandatory change-over of the anti-cancer weaponry «The discovery of new drugs is mandatory in order to develop new therapeutic strategies and to improve the survival of cancer patients. Moreover, the identification of reliable predictors of the efficacy of treatment is crucial for the clinical routine, in order to maximize therapeutic efficacy and minimize inappropriate treatment, thus leading to tailored therapies for the individual patient.

In pre-clinical setting we are currently investigating the effects of several antiangiogenic drugs on cell lines of different tumour types, the mechanisms through which resistance occurs, and the mediators implicated in this event. Furthermore, considering the current knowledge on escape mechanisms, we are testing several drug combination strategies targeted to overcome the resistance to anti-angiogenic therapy itself.

In clinical setting, we are evaluating safety and tolerability of the following new drugs: • ARQ 736 (a B-RAF inhibitor) in patients with advanced solid tumours carrying BRAF mutations; • ARQ 197 (a c-MET inhibitor) in patients with hepatocyte carcinoma; • ARQ 197 or lapatinib (an EGFR and Her2 inhibitor) in combination with sorafenib (a multi tirosin-kinase inhibitor) in patients with advanced solid tumours; • high doses of NGR-h-TNF (an anti-angiogenic drug) in patients with advanced solid tumours; • PF-03446962 (a mAb directed to ALK 1) or ARQ 197 in combination with carboplatin and pemetrexed in patients with malignant pleural mesothelioma; • LDK378 (an ALK kinase inhibitor) in patients with advanced solid tumours characterized by genetic abnormalities in anaplastic lymphoma kinase (ALK).

Finally, with the aim of improving the activity and efficacy of current chemotherapy regimens, we are developing pharmacogenetic trials to identify predictors of efficacy of treatments, especially in rare tumours such as malignant pleural mesotheliomas and thymomas.»

50

call and can take him/her from the screening and diagnostic phase to the treatment. These pathways can even be extended to the follow up period, when they can proceed into two different directions.

The first direction includes most patients with good outcomes – either surviving with disease or diseasefree – which are enrolled in follow-up programs and are treated for any cancer and/or treatment-

related condition. The second path is for the fewer patients with a bad prognosis for whom home care and support must be guaranteed, paying particular attention to end-of-life care.

Continuity of care means continuity in home care as well. Where there is good medicine, there is good research. Our main mission is good medicine, good clinical activity.

hIghLIghT

As part of the Division of General and Oncological Surgery, Humanitas Cancer Center also hosts the Sarcoma Unit. Both the Division and the Unit are led by Vittorio Quagliuolo.

A multidisciplinary approach to the treatment of sarcoma

«Sarcomas are a very rare and heterogeneous group of tumours that arise predominantly from the embryonic mesoderm but can also arise from the ectoderm.

The surgical approach remains the treatment of choice, but a multidisciplinary approach to the management of either localized or metastatic disease may require one or all three treatment modalities (i.e. chemotherapy, radiation, and surgery). Clinical research is now oriented towards affirming this policy among the scientific community, by coordinating and conducting national and international multicentric protocols with the aim of confirming that this kind of approach could improve the patients’ clinical outcomes.

In Italy two multicentric studies are going to be carried out: the former will deal with preoperative and histotype oriented chemo- or chemo/radiotherapy for the treatment of soft tissue sarcomas of the extremities, while the latter will evaluate preoperative radiotherapy for retroperitoneal sarcomas.»

top paper Sarina B, Castagna L, Farina L, Patriarca F, Benedetti F, Carella AM, Falda M, Guidi S, Ciceri F, Bonini A, Ferrari S, Malagola M, Morello E, Milone G, Bruno B, Mordini N, Viviani S, Levis A, Giordano L, Santoro A, Corradini P.

Allogeneic transplantation improves the overall and progression-free survival of Hodgkin’s lymphoma patients relapsing after autologous transplantation: a retrospective study based on the time of HLA typing and donor availability Blood. 2010 May 6;115(18):3671-7. Epub 2010 Mar 10.

Raw IF (2009): 10.555 Normalized IF: 8

Abstract Hodgkin lymphoma relapsing after autologous transplantation (autoSCT) has a dismal outcome. Allogeneic transplantation (alloSCT) using reduced intensity conditioning (RIC) is a salvage option, but its effectiveness is still unclear. To evaluate the role of RIC alloSCT, we designed a retrospective study based on the commitment of attending physicians to perform a salvage alloSCT; thus, only Hodgkin lymphoma patients having human leukocyte antigen-typing immediately after the failed autoSCT were included. Of 185 patients, 122 found an identical sibling (55%), a matched unrelated (32%) or a haploidentical sibling (13%) donor; 63 patients did not find any donor. Clinical features of both groups did not differ. Two-year progression-free (PFS) and overall survival (OS) were better in the donor group (39.3% vs 14.2%, and 66% vs 42%, respectively, P < .001) with a median follow-up of 48 months. In multivariable analysis, having a donor was significant for better PFS and OS (P < .001). Patients allografted in complete remission showed a better PFS and OS. This is the largest study comparing RIC alloSCT versus conventional treatment after a failed autoSCT, indicating a survival benefit for patients having a donor.

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Oncology benchside

52

Cancer and inflammation: the two sides of the coin Interview with Paola Allavena

Our group is focused on innate immunity and its relation to neoplastic progression. What we need is to study not only the neoplastic cells, but the microenvironment of a solid tumour as a whole, where different cell types – fibroblasts, endothelial cells, cells of the immune system – cohabit and interact with tumour cells under the influence of a variety of transcriptional factors, inflammatory cytokines and chemokines, and matrix proteins.

» Could you provide a brief but eloquent

description of this micro-environment?

Group leader of the Cellular Immunology Research Laboratory

THE LINK between cancer and inflammation dates back to the observations of Rudolf Virchow late in the XIX century, who noticed the presence of inflammatory leukocytes in neoplastic tissues.

Nowadays however, we are facing an extremely complex scenario, where it is necessary to study the two sides of the coin at the same time, i.e. the ability of immune system (alias inflammation) to both promote and prevent oncogenesis. Human colorectal cancer represents a paradigm for this link, and several groups have been extensively researching in this field.

» How would you defi ne the complex connection between infl ammation/immunity and cancer?

Immunity has a twofold role in cancer. Specifically, a distinction between the positive role – defensive against cancer – of adaptive immunity and the mostly negative role of innate immunity has to be drawn.

Innate immunity and mostly chronic inflammation are protumoural responses which trigger neoplastic processes.

Chronic inflammation leads the development – for instance – of colon, prostate and liver cancer. The gastrointestinal tract where a number of chronic inflammatory conditions – collectively referred to as Inflammatory Bowel Disease (IBD) – predispose to cancer development, is an interesting model.

Cancer shows an extraordinary ability to surround itself with an inflammatory micro-environment ideal for its own progression. Immune-competent cells that infiltrate tumours – mostly lymphocytes and macrophages – exert opposite influences on tumour growth and progression in a delicate and intricate balance. Not only leukocytes are a source of inflammatory mediators. Transformed epithelial cells are themselves able to secrete factors of the inflammatory response that act on the other cells: leukocytes, endothelial cells, and fibroblasts, in this way promoting a reactive microenvironment.

It is now established that the genetic lesions causing cancer (oncogenes) trigger and maintain in the tumoural cells this pro-inflammation response.

» Is your research activity specifi cally

oriented towards any aspects of this microenvironment?

We are particularly interested on a specific population of cells involved in the innate immunity known as tumour-associated macrophages (TAM).

It is the most abundant immune population in the tumour microenvironment, where it can represent up to 50% of the neoplastic mass.

TAM originate from blood monocytes recruited at the tumour site by chemokines secreted by the neoplastic cells. TAM are major players in the connection between inflammation and cancer and create the ecological niche for many critical steps in cancer development: nurturing the tumour, promoting angiogenesis, helping cancer cells to spread to distant sites, suppressing adaptive immunity.

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Oncology | Benchside Interview with Paola Allavena

A link has been proven in human tissues and in animal models between TAM abundance and tumour growth or metastatic processes. Higher levels of TAM are often – although not always – correlated with a worst prognosis, whereas lower macrophage infiltration into the tumour mass with inhibition of tumour growth.

» How is the study of the complexity of the micro-environment carried out?

In order to carry out a thorough study and create hypotheses, we use either preclinical experimental models or biological specimens from the patients.

There we study the cells or soluble mediators which play a part in inflammation and cancer. We also look for new molecules expressed in the tumour microenvironment which are absent in the normal tissues.

These may serve as markers useful for diagnosis and prognosis, and perhaps as targets of therapeutic approaches.

Otherwise, to obtain a wide and comprehensive

picture of the micro-environment we can analyze the gene expression profiling studying in one chip up to 28.000 genes. This method provides a bulk of data to be furtherly selected and studied in depth in a large number of tumour samples.

Anyway, the experimental approach entails a constant bidirectional talk from lab research to clinical observation and vice versa. The interrelation of basic studies and clinical parameters, such as patient response to therapy and time of disease-free survival, provides indication whether the predicted hypotheses can be confirmed, or suggests to shift to new hypotheses. In our work, the reliability of results – in terms of stringent statistical data based on the law of large numbers and long follow-up time – is crucial.

» Are there any recent data from which it is

possible to describe the “defensive” role of immunity and the interplay between research and clinical practice?

Let us start with an example of adaptive – i.e.

left: Lymphatic and haematic vessel network in the colon; lymphatic vessels are shown in white, endothelial junctions in red. right: Reconstruction of tracheal lymphatic and haematic vessels (experimental model). Haematic vessels are shown in green, lymphatic vessels in white.

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Oncology | Benchside Interview with Paola Allavena

defensive even against cancer – immunity, which was recently published by the group of Luigi Laghi on Lancet Oncology, one of the most authoritative publications in the field. The study demonstrates in colorectal cancer that the high density of CD3+ T lymphocytes at the invasive margin of the mass is associated with a lower risk of metastases after surgical resection and, consequently, a better prognosis (however, this holds true only when the cancer has not spread to the lymph nodes, i.e.

patients in stage II). These results can be considered useful to identify among stage II patients – who have a 20-25% overall risk of metastasis and whose most appropriate treatment is controversial – those at higher risk of relapse, and to establish whether chemotherapy is appropriate in terms of survival. They are in line with our mission: to progress towards making what is normally referred to as accessible customized therapy, able to match the patient’s profile in order to improve efficacy

Recruitment of fibroblasts (green) and macrophages (red) in a fìbrotic liver (experimental model). Nuclei are shown in blue.

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and safety of a treatment, and definitely improve prognosis.

Obviously, things are more complex: in general, T lymphocytes correspond to good – or at least better – prognosis, while macrophage-induced inflammation leads to tumour progression.

» Could you provide an example of the other side of immunity?

As far as “the other side of the coin” is concerned, we are currently working on a series of research projects, on – once more – colorectal cancer and on pancreatic cancer: to date, at least two papers on these topics have been submitted.

The fundamental concept is that several molecules, e.g. inflammatory chemokines, induce cell mobilization, not exclusively of leukocytes, but also cancer cell mobilization. Chemokines and their receptors monitor and regulate cell traffic and play a major role in metastatic processes, as diffusion, tissue infiltration, and distant metastatization.

Gastrointestinal tumour cells express chemokine receptors and we are studying their expression in relation to the patient clinical outcomes.

It’s noteworthy that the possibility to observe both sides of the coin – adaptive and innate immunity –

and to collect information on inflammatory mediators expressed in the reactive mediator behavior in the same microenvironment offers the unique opportunity to cross-check different data and delineate a more exhaustive picture.

» Is it likely that your results will find an

application in clinical practice in the near future?

The study of tumour microenvironment may suggest new therapeutic options not only directed against tumour cells – as traditionally done with chemotherapy – but also aimed at modulating the microenvironment itself. TAM, for example, may be considered as an attractive target for novel anticancer therapies. It can be hypothesized that tumour progression may be affected by a block of these cells or their activity. We are currently studying compounds that selectively target macrophages.

One of these compounds is very interesting because it is an anti-tumour agent and thus offers the dual opportunity to hit both the neoplastic cells and the macrophages.

Chemokines and their receptors are promising pharmacological targets as well. They will be probably used in selected cases and in combination therapies to lower the inflammatory microenvironment.

top paper Solinas G, Marchesi F, Garlanda C, Mantovani A, Allavena P.

Inflammation-mediated promotion of invasion and metastasis Cancer Metastasis Rev. 2010 Jun;29(2):243-8.

Raw IF (2009): 9.345 Normalized IF: 8 Abstract Inflammation has been suggested to represent the seventh hallmark of cancer. Myelomonocytic cells are a key component of cancer-related inflammation. Tumor-associated macrophages and their mediators affect key elements in the multistep process of invasion and metastasis, from interaction with the extracellular matrix to the construction of a pre-metastatic niche. Evidence indicating that inflammatory mediators affect genetic stability and cause persistent epigenetic alterations suggests that inflammatory components of the tumour microenvironment impact on fundamental mechanisms responsible for the generation of metastatic variants.

These results provide impetus for efforts aimed at translating cancer-related inflammation into diagnosticprognostic markers and innovative therapeutic strategies.

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Cardiology bedside

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New cardiologists for a new cardiology

Interview with Ettore Vitali

disease, from the haemodynamist, to the cardiac surgeon, to – obviously – the clinical cardiologist.

» The central role of the patient is an issue which is put into practice in patient management policy at Humanitas

Director of the Humanitas Cardiovascular Diseases Department

ThE ChALLENgE for clinical research in cardiology is to retrieve, and at the same time renew, a crucial approach in cardiology, and – generally speaking – in modern medicine: the patient’s central role in the process of care.

» Which new perspectives do you envisage for a cardiologist’s bedside activity?

Before entering into details about the progression in clinical research and the development of new technologies, let me introduce a widespread but not generalized, and yet rather revolutionary phenomenon that is occurring in cardiology. It may be that also other specialties will follow this trend.

Anyway, cardiology is already ahead of them in that it is already patient-oriented and collaborative.

A good example comes from the recently published Guidelines on myocardial revascularization, developed by a joint board of experts selected from two different scientific societies, the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS).

These guidelines are the first to bring together both disciplines involved in coronary revascularization, i.e. non-interventional and interventional cardiology.

Besides, the task force which has joined to write them is a good example of each physician’s profile involved in the management of coronary heart

The central role of the patient has always been the mission of Humanitas and is already the mission of Humanitas Cancer Center, whose success is an exciting challenge. As Director of the Department of Cardiovascular Diseases, I undertake the same challenge in my field: teaching to individual artists – as Italian doctors are – how to work in a team with a trainer. In order to win, it is not enough to use the skills of a single person, but it is also fundamental to create a working group. Besides, this creates the foundations for the doctors and researchers who are going to work after us in the future.

» Can we outline your main steps of clinical research in cardiology?

Clinical research in cardiology is focused on heart failure and on minimally invasive cardiac surgery.

In regard to heart failure, more and more advanced Ventricular Assisted Devices (VADs) are being developed. These are battery-operated mechanical pumps – the state-of-the-art device is not heavier than 25 grams and not larger than a pair of centimeters – engineered to compensate for reduced cardiac output in severe heart failure. Humanitas is the first and only Italian center which, alongside few others over the world, is able to perform this operation. This most advanced device has so far been implanted on about forty patients worldwide.

Collaboration and intertalk with basic researchers is crucial. In fact, studying the changes in inflammatory mediators and cells in response to a disease could suggest assessing their modifications following a cardiosurgical procedure. Heart surgery offers big opportunities to basic research, thanks to at least two extraordinary experimental models: extracorporeal circulation and long-term ventricular assistance.

Both these conditions allow to study changes in inflammatory mediators and cells in response to a disease. In addition, one could suggest assessing their modifications following a cardiosurgical procedure.

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Cardiology | Bedside Interview with Ettore Vitali

Specifically, it has been well known for forty years that extracorporeal circulation – which affects physiology – is endowed with a potent immunosuppressive effect.

Thus, basic research in heart failure is still fertile.

familiar with, could be extremely useful in clinical cardiology.

» How important is research on new diagnostics

The second branch I was referring to is the miniinvasive surgical approach. The minimisation of the procedure impact is its driving force. There is no doubt that heart valve replacement is the most relevant application of mini-invasivity in cardiac surgery. Percutaneous transcatheter valve implantation is nowadays performed in restricted subgroups of patients, although more extensive indications are expected in a near future.

In addition, as far as future is concerned, it will depend on a new generation of clinicians – who do not exist as yet, but will be trained by ourselves – who will have a new combination of characteristics and competences in their technical and cultural background. The challenge of Humanitas is to instruct, train and let work professionals who are able to face the forty years to come.

in this field?

Advances in diagnostics are of fundamental importance, since they allow for an earlier treatment.

Let me give the example of organ damage in heart failure – in which case accurate markers cannot be relied upon for measurement. Implanting a VAD in a patient with heart failure means to remove the cause of the organ damage – which depends on the length of the disease – but only marginally modify his shortand long-term prognosis, life expectancy included – which, conversely, does not depend on the length of the disease. Today I can establish liver, kidney, or lung damage just at the moment of VAD implantation and on the basis of a clinical evaluation. A marker as PTX3, which researchers at Humanitas are very

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» What is the second research branch you were referring to?

» Does it mean you are going back to a global

perspective as it used to be once as opposed to a specialist perspective?

It is not simply that. I do agree on a global perspective, but medicine nowadays is the medicine of the 3rd millennium. On the way between miniinvasive surgical techniques and the creation of new professionals, we are going to acquire the ability to be doctors again. Doctors must abandon their own hyperspecializations and come back to a comprehensive care. This aspect of the profession is similar to what occurred when I graduated, where the patient was central: this is not the case nowadays. The center now is performance, which is not a cure.

» How is it possible to spread the results of clinical research on a wide scale?

Again, I am referring to ESC/EACTS joint guidelines.

What’s novel is that they emphasize a multidisciplinary approach for deciding which procedure should be used.

A team of intellectually honest and open-minded practitioners who are able to redefine their professional role is needed. They have to address the question of what’s best for the patient – the patient centrality – in a multidisciplinary dialogue and discussing specific cases.

This problem does not emerge inside a hospital as Humanitas – or any other hospital with highlyspecialized units – where the only requirement for specialists is learning how to work in a team.

Evidence-based clinical trials clearly recommend the closest integration among interventional cardiologists, other specialists, and clinicians. The objective is to analyze the individual case as a whole – overcoming individualisms.

Moreover, European joint guidelines provide detailed suggestions for patients with co-morbidities, an increasing population, especially in general hospitals.

In addition, they dedicate a chapter to the process of decision-making for patients which outlines what to explain to the patient, how to do it and when, in order to let him play an active part in the decisional process.

top paper Gasparini M, Steinberg JS, Arshad A, Regoli F, Galimberti P, Rosier A, Daubert JC, Klersy C, Kamath G, Leclercq C.

Resumption of sinus rhythm in patients with heart failure and permanent atrial fibrillation undergoing cardiac resynchronization therapy: a longitudinal observational study Eur Heart J. 2010 Apr;31(8):976-83. Epub 2010 Jan 12.

Raw IF (2009): 9.800 Normalized IF: 8 Abstract Aims: To investigate the temporal patterns, predictors, and prognostic impact of spontaneous sinus rhythm resumption (SRR) of heart failure (HF) patients with permanent atrial fibrillation (AF) treated with cardiac resynchronization therapy (CRT).

Methods and results: This multicentre, retrospective, longitudinal study analysed 330 consecutive HF patients with permanent AF treated with a CRT device (mean age 70 +/- 9 years, male 83%, ischaemic aetiology 44%, NYHA class III-IV 93%, mean QRS duration 167 +/- 40 ms, and mean ejection fraction 26 +/- 7%). Clinical, echocardiographic, and outcome data were collected during follow-up. Thirtyfour patients experienced SRR after CRT (10.3%) at a median 4-month follow-up. The strongest independent predictors were end-diastolic diameter (EDD) [hazard ratios (HR) 4.03, 95% confidence intervals (95% CI) 1.43-11.36, P = 0.008], post-CRT QRS <or=150 ms (HR 2.63, 95% CI 1.02-6.67, P = 0.05), left atrium (LA) diameter <or=50 mm (HR 4.76, 95% CI 1.72-11.82, P = 0.002), and atrioventricular junction (AVJ) ablation (HR 4.27, 95% CI 1.54-11.84, P = 0.02).

The coexistence of three predictors vs. zero to two predictors increased by 3.5-fold the likelihood of SRR; while the presence of all four factors improves the probability by a factor of 5.7-fold. Sinus rhythm resumption was associated with a significantly better long-term survival (log rank P = 0.03).

Conclusion: One in every 10 HF patients with permanent AF may experience SRR after CRT. Baseline EDD <or=65 mm, CRT

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Cardiology benchside

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A protein coming from the past to predict heart disease Interview with Cecilia Garlanda

during the phylogenesis, from arthropods to mammals and no deficiency state has been described in nature.

» Surely, there must be a reason why they

remained highly conserved in evolution?

Group leader of the Experimental Immunopathology Research Laboratory

PTx3 IS A PROTEIN of the pentraxin family, exactly as the C-reactive protein (CRP), and was discovered in the Nineties by Alberto Mantovani’s group, then characterized and developed with the contribution of Humanitas. It has been highly conserved during the evolution, which suggests a survival advantage.

While research is continuously being carried out to understand the in-depth meaning of its increase in various inflammatory conditions – the question is whether it represents a harmful or a protective pathophysiological response – the determination of PTX3 in biological fluids has been proposed as a useful and reliable diagnostic and prognostic marker.

» In which area of cardiological research is your group more active?

Our mission in the cardiovascular field – but the results could be extended to different medical sectors – is to do research on biomarkers. This project started at the beginning of the Nineties when we characterized pentraxin-3 (PTX3), a cytokineinducible molecule expressed in a variety of tissues in response to inflammation, whose gene is located on chromosome 3 in humans.

Pentraxins are a superfamily of proteins, some of which act as acute phase proteins, and can be classified as short pentraxins – such as the CRP – or long pentraxins such as PTX3. They are conserved

These observations possibly indicate that pentraxins play an essential and vital role, most probably in innate immunity, whose mechanisms are still to be exhaustively defined.

Their biological meaning – causative or reactive – in the pathogenesis of the disease has been debated for a long time. However, their prompt and massive response to inflammation or to cardiac injury suggests a marked protective reaction rather than a harmful effect. Besides, this hypothesis is supported by strong evidence. It has to be stated in advance that, differently from CRP, whose regulation has not been conserved during the evolution, thus making the direct translation of research results and conclusions from experimental models to humans difficult, gene organization and regulation of PTX3 allow us to address the question of its pathophysiologic role in models. As a consequence, we have been able to prove the protective effect of PTX3 in various conditions.

In experimental models, high PTX3 levels confer resistance to sepsis. Moreover, in in vivo and in vitro models we described PTX3 interactions with different component complements, and their modulating effect on the activation of the three complement pathways, which – again – indicated a defensive function.

Concerning the role of PTX3 in acute myocardial infarction and atherosclerosis, our data in both experimental models show that PTX3 deficiency is associated to increased tissue damage, inflammation, and severity of the pathological condition. These results suggest that PTX3 plays a protective role in these cardiovascular diseases.

» It seems that your research activity has not focused exclusively on cardiology, but – as results increasingly appeared – has been spreading among other areas.

Exactly. Over the years we have been working to develop a variety of tools for PTX3 study and research.

We generated monoclonal antibodies (MoAb),

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Cardiology | Benchside Interview with Cecilia Garlanda

Immunohistochemical distribution and cellular production of PTX3 in AMI (acute myocardial infarction) patients

recombinant proteins, and developed an ELISA test for its assay in biological fluids (plasma or serum) in physiological and pathological conditions. We also established the normal reference range (the cut cuff is set at 2 ng/ml). After that, we studied PTX3 level changes in our patients.

1

» What did you observe? Have you come across

any particular scenarios or any different patterns depending on the disease?

PTX3 levels show a 10-100 fold change in infectious diseases. We observed a correlation with the severity of the condition – therefore with the disease prognosis – rather than with its origin, as well as a lack of correlation with CRP levels. We verified the prognostic value of PTX3 in septic shock, tuberculosis, dengue virus, and meningococcal disease. In addition, we studied inflammatory non-infectious disease, namely autoimmune disorders (i.e. vasculitis and arthritis), but also chronic renal insufficiency, and – obviously – cardiovascular diseases (i.e. atherosclerosis, acute myocardial infarction, and chronic heart failure). In these cases the increase is less clear-cut, generally not exceeding one order of magnitude. Also, in these patients PTX3 levels correlate with the severity of the condition.

For instance, in acute myocardial infarction the highest concentrations are observed in more compromised patients, and levels correlate with patient mortality.

» Interestingly, most of the conditions you have mentioned are characterized by an impressive involvement of the endothelium.

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The endothelium is a crucial site of PTX3 production.

Immunohistochemistry performed at sites of inflammation constantly shows a positivity of endothelial cells. In addition, other cells participate to PTX3 production, as demonstrated by its abundance at sites of leukocyte infiltration. Neutrophil granulocytes can store PTX3 in their granules, thus being able to promptly release the protein in response to an inflammatory trigger, without the interposition of transcription and synthesis necessary in other cells.

The fast increase in PTX3 levels is partially due to granulocyte contribution.

» How does this protein behave? What are its modifications like?

PTX3 dramatically increases after an inflammatory signal. Specifically, an acute phase signal. Blood concentrations rise already after a 6-8 hour period and usually peak after 48 hours. In comparison, CRP increase occurs significantly later, after 24-48 hours.

A big difference between PTX3 and the traditional circulating markers of inflammations is their tissue origin and hence the timing to react. In fact, while CRP is a late inflammation marker because its synthesis is not local but occurs in the hepatic cells and is mediated by interleukin-6 (IL-6), PTX3 is an earlier marker and reflects tissue damage better because it comes from the tissue itself, where it is produced mainly by the endothelium, but also by granulocytes, macrophages and dendritic cells and, in any case, by a variety of cells of resident and innate immunity. Besides, recovery to a normal range occurs rapidly. This pattern of response – fast increase and equally fast recovery – is ideal for diagnostic applications. To this aim, the peak value is the most indicative parameter.

» Speaking of which, what diagnostic applications do you envisage?

Going back to cardiovascular diseases, recent studies outlined a diagnostic and prognostic application for PTX3 in myocardial infarction, where its potentiality is apparent since it is able to predict death. Indeed, the relevance of PTX3 as a diagnostic tool has been investigated in cardiovascular pathology because of its homology to CRP. However, PTX3 measurement in biological fluids is characterized by high accuracy.

Panel 1: 24-36 hour-old AMI. PTX3 staining is observed in most granulocytes (in brown) infiltrating myocardial cells.

Panel 2: 36 hour-3 days old AMI. PTX3 staining is found in the cytoplasm of macrophages (in brown).

Panel 3: 3-10 days old AMI. PTX3 expression is found in the endothelium (in brown).

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Moreover, information obtained by PTX3 measurement could be complementary to those obtained by CRP measurement. Its use applies also to cardiovascular diagnosis. In acute myocardial infarction with ST elevation, PTX3 levels peak early (6 to 8 hours from symptom onset) and compared to well established markers including CRP itself, NT-proBNP and troponin T, emerges as the only independent predictor of 3 month mortality. We also found a significant correlation with cardiovascular mortality at three months after a major cardiac event. In addition, in cardiovascular diseases it has been clarified again that these changes reflect a tentative protective pathophysiologic response rather than a more pronounced aggression.

» What about another diagnostic application

“ready” to be translated into clinical practice?

PTX3 is an early marker of pre-eclampsia.

In this condition, a relevant endothelial dysfunction – and pregnancy itself implies an endothelial perturbation and is characterized by slight PTX3 increase – is reported, which provokes the excessive maternal inflammatory response to pregnancy and the placental damage.

PTX3 plasma assay in a selected subgroup of pregnant women at risk may be proposed at the third trimester of gestation to estimate the risk of preeclampsia.

top paper Deban L, Russo RC, Sironi M, Moalli F, Scanziani M, Zambelli V, Cuccovillo I, Bastone A, Gobbi M, Valentino S, Doni A, Garlanda C, Danese S, Salvatori G, Sassano M, Evangelista V, Rossi B, Zenaro E, Constantin G, Laudanna C, Bottazzi B, Mantovani A.

Regulation of leukocyte recruitment by the long pentraxin PTX3 Nat Immunol. 2010 Apr;11(4):328-34. Epub 2010 Mar 7.

Raw IF (2009): 26 Normalized IF: 15 Abstract Pentraxins are a superfamily of conserved proteins involved in the acute-phase response and innate immunity.

Pentraxin 3 (PTX3), a prototypical member of the long pentraxin subfamily, is a key component of the humoral arm of innate immunity that is essential for resistance to certain pathogens. A regulatory role for pentraxins in inflammation has long been recognized, but the underlying mechanisms remain unclear. Here we report that PTX3 bound P-selectin and attenuated neutrophil recruitment at sites of inflammation. PTX3 released from activated leukocytes functioned locally to dampen neutrophil recruitment and regulate inflammation. Antibodies have glycosylation-dependent regulatory effect on inflammation. Therefore, PTX3, which is an essential component of humoral innate immunity, and immunoglobulins share functional outputs, including complement activation, opsonization and, as shown here, glycosylation-dependent regulation of inflammation.

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Orthopaedics benchside

66

The rich and the poor

Interview with Anna Villa

Group leader of Human Genome Research Laboratory

ThIS TITLE is particularly appropriate to describe the latest knowledge about osteopetrosis, a rare but severe genetic disease, often fatal in childhood.

At Humanitas Anna Villa and Paolo Vezzoni’s teams have been working for years on this disease, not only looking for a cure against its dramatic course, but also taking up the challenge to explain its molecular mechanisms. The outstanding results they obtained come from a constant comparison of lab data with clinical observation. This bidirectional crosstalk led to conclude that actually osteopetrosis is a group of different conditions with a similar clinical picture in whom osteoclasts are the defective cells. Interestingly, in osteopetrosis, recent studies have shown two different patterns of osteoclast dysfunction: they are many but inefficient in the “rich forms” of the disease, while they are quite few in the “poor forms”.

» What is osteopetrosis, and how does it

manifest? Why is it an interesting example of genetic disease?

Osteopetrosis, also termed as marble bone disease, is a rare heritable disease (approximately 1 in 400,000 births) characterized by increased bone density. In addition to high bone density it is characterized by propensity to fractures, short stature, no marrow cavity, pancytopenia, blindness and deafness.

The most severe forms are inherited through an

autosomal recessive transmission and associated with diminished life expectancy, with most untreated children dying in the first decade. The benign types show an onset in adulthood and life expectancy is not shortened. Actually malignant infantile autosomal recessive osteopetrosis can now be classified in several subsets with some peculiar clinical aspects.

The clinical distinction settled at the beginning of the last century between a dominant (benign) form and a recessive (malignant) form has successively found evidence in genetic studies.

» What are the most recent results in terms of

osteopetrosis-related genetics, and how has Humanitas contributed to their achievement?

From the Nineties onwards, some genes responsible for autosomic recessive osteopetrosis have been tested and mapped. Our group identified 3 among the 6 genes and collaborated with two groups (Canadian and Belgian) to describe the other two forms. They mapped the gene in the murine genoma, we sequenced the mutation/the gene in the human genoma.

» More specifi cally, what are the bones of a

person aff ected by osteopetrosis like, and what is the role of osteoclasts?

Osteoclasts are large multinuclear cells which originate from monocytes and participate to bone metabolism. In human recessive osteopetrosis bone resorption is prevented due to a defect in osteoclasts.

This is where we refer to the difference between rich and poor, in that we also distinguish between osteoclast-rich forms and osteoclast-poor forms in the disease. The former arise from a defective function, – i.e. the inability to perform bone resorption by those mature, multinucleated, but nonfunctional cells – the latter from a failure in osteoclast differentiation.

For several years, researchers in bone genetic diseases have been puzzled by the fact that human osteopetroses presented a normal or even elevated number of osteoclasts. In actual fact, the first five genes identified in human recessive osteopetrosis were all involved in the effector function of mature osteoclasts. Taken together, all the osteoclast-rich forms account for about 70% of cases.

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Orthopaedics | Benchside Interview with Anna Villa

» How did you find out about the remaining 30%?

A few clues to the existence of other forms in which differentiation steps were involved, slowly accumulated. The first observation, though rarely reported, was that some patients did not show any osteoclasts in their bone biopsies. Additionally, monocytes from these patients failed to differentiate into multinucleated osteoclasts, corroborating the histological data.

Moreover, osteopetrosis due to both these mechanisms was found in spontaneous and artificially created mouse mutants. In the last 15 years a number of experimental models have become available with defects in the production and differentiation of osteoclasts.

» What are – if any – the consequences of

this difference between osteoclast-rich and osteoclast-poor osteopetrosis on clinical practice?

The molecular dissection of autosomic recessive osteopetrosis has prognostic and therapeutic implications.

Historically, the treatment for osteclast-rich osteopetrosis has been classical bone marrow transplant, often performed with purified hematopoietic stem cells. Since in osteopetrosis skeletal deformities start before birth and they are not easily reversed, it is necessary the in utero approach with a prenatal transplant: early hematopoietic stem cell (HSC) transplantation is raccomended. Its application is so far very limited.

By contrast, we saw in our clinical practice that some patients did not respond to bone marrow

right: Osteoclasts (the nuclei are shown in blue; integrin aVb3 stains red, actin stains green) are large bone cells associated with absorption and turn-over of mineralized matrix/bone.

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on next page: in vitro image of a differentiated osteoclast (the nucleus is shown in blue; integrin aVb3 stains red, actin stains green).

transplant and – after two years – their conditions kept worsening in spite of the fact that the cells had grafted. We therefore started from the observations of a British team who associated the lack of response to transplant with the absence of osteoclasts in the bone biopsy.

After selecting from our large series a few patients whose bone biopsy was negative for the presence of osteoclasts and who were negative for mutations in the five genes responsible for osteoclast-rich osteopetrosis, we studied a short list of candidate genes. Among these, we sequenced RANKL gene and found a mutation in four patients. The gene product is a soluble cytochine, produced mainly by mesenchymal cells (which were not transplanted in our patients), driving osteclast differentiation. We concluded that RANKL-dependent osteopetrotic patients truly represent an osteoclast-poor subset.

» Is there any alternative treatment for patients who do not respond well to bone marrow transplant?

Even if RANKL-dependent patients do not respond to transplant, the knowledge of the molecular basis of their disease has opened the road to new therapeutic opportunities, from mesenchymal stem cell transplantation to administration of soluble

RANKL cytokine, in exactly the same way it has been done for years with insulin in diabetes.

» What has to be expected in the near future in

terms of know-how and cure for this disease?

We can say that six forms of osteopetrosis are known at present but – chances are – many more might exist. Our team is able to carry out a molecular

analysis of all the genes that have been identified. In our cohort of more than 230 automosomic recessive patients, all types of mutation are present but a relevant quote of DNA samples is negative for all identified mutations.

» Alongside with deficiencies in the bone

metabolism, immune alterations are present in

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Orthopaedics | Benchside Interview with Anna Villa

some patients who suffer from osteopetrosis.

Are the two factors related or is this a mere coincidence?

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It is not a coincidence. Indeed, bone and immunity are strictly linked to the extent that a new field of study, whose name is osteoimmunology, has recently come into existence. This link may be easily explained since osteoclasts (the cells involved in osteopetrosis mentioned above) and macrophages (cells with a crucial role in the immune response) share a common precursor, the haemotopoietic stem cell. The efficacy of bone marrow transplant in certain subtypes of osteopetrosis is the direct consequence of this common background. Moreover, a lot of interactions between immunity and bone are emerging. RANKL knockout mice have long been known to display both

top paper Chouery E, Pangrazio A, Frattini A, Villa A, Van Wesenbeeck L, Piters E, Van Hul W, Coxon FP, Schouten T, Helfrich M, Lefranc G, MĂŠgarbanĂŠ A.

A new familial sclerosing bone dysplasia J Bone Miner Res. 2010 Mar;25(3):676-80.5 Raw IF (2009): 6.043 Normalized IF: 6 Abstract Osteoscleroses are a heterogeneous group of bone remodeling disorders characterized by an increase in bone density. Here we report on a consanguineous Lebanese family in which two sisters, aged 39 and 36 years, exhibit a severe genu varum, a square-face appearance, high forehead, slight proptosis of the eyes, symmetric enlargement of the jaw, protruding chin, and short stature. Bone X-rays showed the presence of hyperostosis of the cranial base and vault with increased density of the orbits, hyperostosis of the bones, thickening of the cortices, diaphyseal modeling defects, cortical thickening of the medullary cavity, mild enlargement of the medullary cavity of the short long bones, short femoral necks, increased width of the ribs, and narrow interpedicular distances of the lower lumbar spine. Osteodensitometry showed values 200% to 300% above values for age. A cervical MRI revealed the presence of a diffuse osteosclerosis with calcification of the posterior vertebral ligament and a narrow canal between C2 and T2. Blood test results were unremarkable. Serum osteocalcin levels were in the normal range, whereas high values of serum C-telopeptide were noted. A bone biopsy showed only the presence of compact bone and did not allow for histomorphometric analysis. Molecular studies excluded genes known to be involved in sclerosing bone dysplasias as the cause of this condition. In vitro analysis of osteoclast function indicated that contrary to most cases of autosomal recessive osteopetrosis, osteoclasts both formed and resorbed but exhibited a small decrease in resorptive activity compared with osteoclasts generated from normal control individuals.

Differential diagnoses are discussed, and the possibility that this may be a novel clinical entity is raised.

osteopetrosis and immune defects. The interplay between the two systems has proved to be wider, with the identification of several other molecules which lead to defect both in bone remodeling and in the immune response, when mutated.

What is clear now is that clinicians and researchers can no longer focus on a single system or tissue, but they have to take into account the interactions between them.

Âť It can be said that the experience of your

group both at national and international level allows you to be considered an authoritative reference when it comes to research and cure for osteopetrosis.

So far, we have collected in our biobank 250-300

DNA samples where molecular defects have been diagnosed for all known genes, not only for the genes identified by us. We collected and stored all the data of the patients who have undergone transplant, and classified them according to the affected gene. As far as molecular diagnosis is concerned, we cover all Italian case studies, but we also receive samples from all over the world.

We are currently part of the European Group for Blood and Marrow Transplantation (EBMT).

We have also coordinated a European study within the rare diseases network on transplant conditioning, on which we are working with a German and a French group. Transplant conditioning is a vital but very hazardous step in this disease.

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Orthopaedics bedside

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The shoulder: an unstable balance between complexity and imperfection Interview with Alessandro Castagna

However, it has not yet completed the evolution to be perfectly adequate to its functional requirements.

» Do the considerations you have just made apply to the lesions you have to treat in your common practice?

THE SHOULDER is a highly complex and delicate joint that can be affected by non-traumatic disorders in young and otherwise healthy subjects.

This is why such a sophisticated mechanism needs to be handled with utmost expertise, so as to guarantee long term and definite outcomes thanks to the most advanced techniques.

Instability is one of the most common disorders of the shoulder. It can be considered an intrinsic pathophysiological condition of the shoulder, since this joint is prone to dislocation and subluxation, tipically in young and active people, related to sport trauma but also in predisposed subjects.

The other relevant chapter of the shoulder pathology is represented by rotator cuff tears. Actually, the four shoulder tendons that constitute the rotator cuff are undersized for their functions. This is especially true for the supraspinatus tendon and in a certain amount for the infraspinatus tendon. They can be compared to a fabric, which progressively wears out and becomes thinner and thinner. Once a tendon has worn out, pain and function loss occur. Generally, rotator cuff disorders are not traumatic. Nevertheless, they might be observed in middle-aged or young patients, who are usually active subjects and seldom sportsmen.

» The shoulder joint in brief: a frail, ineffi cient,

» Why only recently surgery of the shoulder has

The shoulder can be affected by a variety of disorders. It is the joint with the widest range of motion in the human body. In addition, it is endowed with the most complex biomechanics to meet demanding requests, from lifting or throwing heavy weights up to fine motor movements, controlling hand motion in the tridimensional space. To this aim, the needed mobility is conversely predisposing this joint to a somewhat limited degree of stability.

Theoretically, its stability is guaranteed by the interaction between soft tissues (i.e. capsule, ligaments, labrum and rotator cuff tendons) and bone structures (i.e. humeral head and glenoid).

One cannot forget that a few million years ago the shoulder was a ball and socket joint, practically identical to the hip joint, which has evolved – with the passage from quadrupedism to bipedism – to a joint capable of motion in multiple number of axes.

Surgical procedures for shoulder instability have been considered critical due to their unfulfilling outcomes, which has led to a certain delay in carrying out the procedure themselves. In fact, through the decades, several techniques have been employed for the treatment of instability, but with a rather high rate of recurrence or poor functional outcome (significant mobility restriction). Outcome of some procedures was not only not resolutive, but even increasing shoulder disability in a long term due to a glenohumeral osteo-arthritis.

Surgical treatment of rotator cuff tears still not perfect is generally aiming good results on pain and function with special regards in the mid-aged and elderly population. The younger patient may get the best outcome if treated without waiting too long. Retraction and hypotrophy of torn rotator cuff tendons and muscles that occur with time lead to a

Director of Shoulder, Elbow, and Foot Arthroscopic Surgery Division

far from perfect and sophisticated mechanism.

received a relevant impulse?

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Orthopaedics | Bedside Interview with Alessandro Castagna

clinical and biological poorer result. However, this has ceased to be the norm, thanks to great advances in shoulder surgical procedures.

» How is it possible to tackle the issue of lesions?

Today it has become feasible. Charles Neer (just passed away) was a true giant of shoulder surgery, which started with developing the concepts and principles involved in shoulder surgery in the Seventies and Eighties. Since then, procedures have evolved consistently in recent years, then the advent of shoulder arthroscopy gave an extraordinary boost and contributed to a better knowledge of pathophysiology.

Nowadays, many traditional open techniques have been replaced by arthroscopic techniques, which allow to identify intra-articular lesions more easily, are less invasive than traditional surgery and do not significantly alter normal anatomy. However, it has been lately noticed, that also arthroscopic techniques – even when performed correctly and with the most modern tools – are sometimes not able to provide the perfect solution.

Treatment of shoulder instability might have a higher recurrence rate in special condition (i.e. glenoid bony deficiency or poor capsular tissue) when compared with some other techniques.

Rotator cuff “retear” may also occur whatever technique is used.

» Does this mean that it is not merely a problem of surgical techniques?

74

Recently the investigation has moved from surgical technique towards pathophysiology, i.e. to the quality of the biological tissue that may affect – as a consequence – the healing process.

In fact, the low quality of the tissue to be repaired can lead to surgical failure, even when the operative technique has been carried out correctly.

Research is now very much focused on developing aids and supports helping the healing process after a surgical procedure.

For instance, biological patches to enhance healing of the rotator cuff have been studied at Istituto Ortopedico Rizzoli in Bologna in cooperation with Istituto Clinico Humanitas. The research on materials is directed towards both optimizing strength properties and stimulating biological responses, which can be obtained with intra-articular injections of growth factors or allograft and xenograft bioscaffolds. The latter are particularly promising.

Among allografts, acellular human dermal matrix processed from human cadaver skin to maintain an intact collagen structure while avoiding allergogenic effects is an option. The extracellular matrix behaves as a blotter which gathers cells so that they can be organized in a patch.

Considering xenografts, porcine small intestinal sub mucosa materials have been adovcated for use in rotator cuff augmentation, but have shown a low mechanical strength. They are sterilized multi-

layer laminates of porcine collagen, which is then processed to be freed from cellular or immunological DNA components.

» You are referring to extremely sophisticated material, which is difficult to obtain.

Unquestionably, and there is also a relevant difficulty in obtaining use authorizations and registrations which represents an adjunctive obstacle for clinical practice. Particularly in Italy – as well as in Germany, and as opposed to the United Kingdom and United States – where certain human cadaveric acellular matrix are considered allograft transplants. Thus, porcine-derived materials are mostly employed, and their experimental use has now proceeded to a phase II study. As you can see, progress is carrying on, and difficulties must be overcome to the patient’s advantage.

» In short, there are much more favorable

prospects for patients with shoulder problems, both in terms of easier intervention and of

results. What advice can you provide for people who suspect to suffer from or suffer from rotator cuff or shoulder problems?

Nowadays three innovative elements favor our practice: local anesthesia, arthroscopy, and daysurgery, allowing for shorter procedure times and better management. Since many indications and counter-indications are still being refined, I would like to keep my distance from over-enthusiasm: shoulder surgery has still to be carried out in few highly specialized centers.

A first good piece of advice is listening to the symptoms (dull or aching pain, stiffness, joint noises and a compromised motion range) and contacting an experienced specialist. Which, in turn, has either to have in-depth knowledge of the recent literature, the relevant semeiology, and the individual pathoanatomy, or to consider the patient’s demands, expectations, and desired functional levels. Risks and potential benefits must be instilled in the patient. It is clear that the focus is on the patient rather than on the disease.

top paper Castagna A, Garofalo R, Cesari E, Marcopoulos N, Borroni M, Conti M.

Anterior and posterior internal impingement: an evidence-based review Br J Sports Med. 2010 Apr;44(5):382-8.

Abstract Over the last decade, the concept of internal impingement has continued to evolve, and the frequency with which this condition is recognised continues to increase.

This syndrome should be clearly differentiated from the classical (external) impingement that is thought to be caused by compression of the subacromial bursa, long head of the biceps tendon and rotator cuff (RC) by the coraco-acromial arch. Internal (posterosuperior) impingement syndrome is typified by a painful shoulder due to impingement of the soft tissue, including the RC, joint capsule and the posterosuperior part of the glenoid. The aetiology

Raw IF (2009): 2.547 Normalized IF: 6

of this syndrome is unclear, but hypotheses include anterior shoulder instability or micro-instability, contracture of the posterior capsule, reduced humeral retroversion and scapular dyskinesis. Non-operative therapy represents the first line of treatment for this syndrome and includes the management of pain, stretching of the posterior capsule and a muscle strengthening programme. Surgical treatment should only be considered when conservative management fails. A number of different surgical procedures have been proposed, but the results are variable. The success rate is generally improved when the subtle instability, associated with internal impingement, is also addressed.

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Clinical & Research Departments

Board of Directors President

Scientific Superintendent

Gianfelice Rocca

Nicola Dioguardi

Vice President

Scientific Director

Ivan Colombo

Alberto Mantovani

Chief Executive Officer

Clinical Research Director Humanitas Cancer Center Director

Luciano Ravera

Armando Santoro Medical Director

Norberto Silvestri

Education

Research Advisory Board

Piero Melodia

Rolf Zinkernagel (President) Charles Dinarello Fabio Cominelli Lorenzo Moretta

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Departments and teams Clinical Area Updated to February 2011

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

CLINICAL CARDIOLOGY division director: Patrizia Presbitero Tiziana Ammaturo Monica Bocciolone (•) Sara Cioccarelli (°) Franco Fea Augusto Foresti (°) Veronica Fusi Daniela Guiducci Manuel Marconi (•) Giuseppe Mariani Barbara Nardi Roberta Paliotti Sergio Potenza (°) Michele Randazzo Cinzia Santucciu Maria Luisa Stella Luisa Ulian CLINICAL CARDIOLOGY AND HEART DECOMPENSATION AND FAILURE TREATMENT CENTRE division director: Patrizia Presbitero

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

Laura Ardino (***) Silvia Galvanin Maurizio Mangiavacchi Daniela Pini

(**) Research staff (***) Research nurse (•) Head of unit (°) Consultant

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■ Divisions that join in the Humanitas Cancer Center

ECHOCARDIOGRAPHY division director: Renato Maria Bragato 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) (•) Giuseppe Ferrante (*) Gabriele Luigi Gasparini 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 Giuseppe Carella 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

DIAGNOSTIC radiology

GASTROENTEROLOGY AND DIGESTIVE ENDOSCOPY division director: Alberto Malesci Elisa Carlani Silvio Danese (*) Luigi Laghi (*) Paolo Dario Omodei (•) Paoletta Preatoni Beatrice Salvioli

division director: Luca Balzarini Cristiana Bonifacio Giorgia Farina Sara Galli Sara Imparato Romano Lutman (•) Paolo Malerba (•) Lorenzo Monti Federica Mrakic Sposta Silvana Muscarella Vittorio Pedicini Alessandra Pestalozza Dario Poretti Manuel Profili Elisa Rognone Felice Rognone (•) ECHOGRAPHY division director: Paola Magnoni Marina Canevini Caterina Comola Pasquale De Nittis Jean Claude Foteuh Cristiana Magnaghi Vascular & Interventional Radiology division director: Giorgio Brambilla Tito Livraghi (°) Vittorio Pedicini Dario Poretti

DIGESTIVE ENDOSCOPY service division director: Alessandro Repici Alessandra Carlino Nico Pagano Giacomo Rando Fabio Romeo Giuseppe Strangio Eva Maria Vitetta GENERAL AND MINIMALLY INVASIVE SURGERY division director: Riccardo Rosati Fabio Baticci (•) Martina Ceolin Matteo Donadon Ugo Elmore (•) Uberto Fumagalli Romario (•) Pietro Dante Muselli Alberto Peracchia (°) Matteo Porta GENERAL MEDICINE AND HEPATOLOGY division director: Maurizio Tommasini Roberto Ceriani (•) Luca Contu Giovanni Covini (•) Maria Gioia Lea Pich GENERAL SURGERY III division director: Marco Montorsi Stefano Bona (•) Florin Botea Daniele Del Fabbro Francesca Gavazzi Angela Palmisano Antonino Spinelli Guido Torzilli (liver surgery) (•) Alessandro Zerbi (pancreatic surgery) (•)

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

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Gynaecology Department director: Paolo E. Levi Setti GYNAECOLOGY division director: Domenico Vitobello Antonio Accardi Barbara Bianchini Gianluigi Bresciani Cinzia Bulletti Nicola Fattizzi Nicoletta Iedà Gabriele Siesto GYNAECOLOGY AND REPRODUCTIVE MEDICINE division director: Paolo Emanuele Levi Setti Elena Albani Veronica Arfuso (*) Annamaria Baggiani Renzo Benaglia Dorian Bosev Sonia Castelli (*) Raffaella De Cesare Alessia De Mita Alessandra Drovanti Valeria Liprandi Luciano Negri Maria Rosaria Parisen Toldin Laura Sacchi Cristian Specchia Elena Zannoni

Internal Medicine Department director: Mauro Podda division director: Marcello Monti Luca Livio Mancini Francesco Sacrini EMERGENCY DEPARTMENT division director: Salvatore Badalamenti Giuseppe Biancofiore Gianluigi Citterio Giuseppe Civitavecchia Carlo Fedeli Giovanni Giorgino Nicolaos Geroutis Elisabetta Lavezzi Alfonso Maiorino Silvia Oldani Stefano Ottolini Antonio Voza ENDOCRINOLOGY AND DIABETOLOGY division director: Andrea Lania Paolo Colombo Pietro Travaglini (°) GENERAL MEDICINE AND pneumology division director: Michele Ciccarelli Maria Francesca Barmina Massimo Crippa Alberto Grassi Alessandra Ibba Lucia Testoni

(*) Physician dealing with activity in the Research laboratories too (**) Research staff (***) Research nurse (•) Head of unit (°) Consultant

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■ Divisions that join in the Humanitas Cancer Center

INTERNAL MEDICINE division director: Mauro Podda Ilaria Bianchi (*) Ana Lleo De Nalda (*) Maria De Santis (*) Pietro Invernizzi (*) Francesca Meda (*) Carlo Francesco Selmi (*)

NEPHROLOGY AND DIALYSIS division director: Salvatore Badalamenti Claudio Angelini (•) Paola Arosio Cesare Berra (•) Albania Calvetta Silvia Finazzi Giorgio Graziani (°) Marco Mirani Rosa Pedale Claudio Ponticelli (°) Silvia Santostasi Rossella Valentino Simona Verdesca 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: Simona Marcheselli

BREAST UNIT division director: Corrado Tinterri

Beatrice Albano Manuel Corato Lara Fratticci Barbara Stival NEUROLOGY II division director: Eduardo Nobile Orazio Claudia Giannotta Francesca Gallia Elda Judica Fabrizia Terenghi NEUROSURGERY▲ division director: Maurizio Fornari Riccardo Rodriguez y Baena Giovanni Battista Lasio Lorenzo Bello (oncologic neurosurgery) Paolo Gaetani (•) Enrico Aimar Andrea Cardia Francesco Costa Enrica Maria Fava Alessandro Ortolina Federico Pessina

▲ from May 2011

director: Armando Santoro

Claudio Andreoli Marco Eboli Wolfgang Gatzemeier (•) Carlos Garcia Etienne (**) Sergio Orefice (°) Carlo Marco Rossetti Arianna Rubino Andrea Sagona GENERAL AND ONCOLOGIC SURGERY division director: Vittorio Lorenzo Quagliuolo Antonella Ardito Pietro Francesco Bagnoli Andrea Brocchi Luca Cozzaglio (•) Leandro Gennari (°) Chiara Erminia Mussi MEDICAL ONCOLOGY AND HAEMATOLOGY division director: Armando Santoro Margherita Autuori Antonella Anastasia Monica Balzarotti (*) Monica Bertossi (**) Alexia Bertuzzi Stefania Bramanti Carlo Carnaghi (*) Luca Castagna (•) Carolina Cauchi Raffaele Cavina (•) Elisa Crotti (**) Fabio De Vincenzo Barbara Ercoli (**) Giovanna Finocchiaro Rita Finotto (**) Isabella Garassino Laura Giordano (**) Adalberto Ibatici Natalia Locopo (**) Massimo Magagnoli Giovanna Masci Rita Mazza

Manuela Mencaglia Simona Naimo Andrea Nozza Nicola Personeni Tiziana Pressiani Lorenza Rimassa (•) Luca Rubino (*) Barbara Sarina Francesco Sclafani Matteo Simonelli Licia Vanessa Siracusano Elisabetta Todisco (**) Laura Toppo Rosalba Torrisi (•) Luca Toschi Mariachiara Tronconi Marialuisa Valente Laura Velutti Paolo Andrea Zucali (•) Monica Zuradelli PET AND NUCLEAR MEDICINE division director: Arturo Chiti Lidja Antunovic Giovanna Pepe Marcello Rodari Giovanni Tosi RADIOTHERAPY AND RADIOSURGERY division director: Marta Scorsetti Filippo Alongi Annamaria Ascolese Simona Castiglioni Erminia Infusino Paola Lattuada Pietro Mancosu Pierina Navarria Chiara Pellegrini Sara Pentimalli Antonella Roggio Angelo Tozzi THORACIC SURGERY division director: Marco Alloisio Umberto Cariboni Giorgio Maria Ferraroli Maurizio Valentino Infante Alberto Testori (•)

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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 Alessandra Martano Luciana Marzella Ilaria Papini Zorli Davide Smarrelli Angela Trabucco 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

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

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

knee ORTHOPAEDICS and sport traumatology division director: Piero Volpi co-head: Matteo G.M. Denti Corrado Bait Matteo Cervellin Emanuele Prospero

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

(•) Head of unit

(**) Research staff

■ Divisions that join in the Humanitas Cancer Center

(***) Research nurse

(°) Consultant

director: Stefano Respizzi Cardiac & Respiratory Rehabilitation division director: Stefano Aglieri Anna Beretta Alessandro Eusebio Ornella Riccardi Neurologic Rehabilitation division director: Bruno Bernardini Giovanna Cerina Carla Corsini Verusca Gasparroni Sara Ghirmai Marco Augusto Pagani Orthopaedic Rehabilitation division director: Stefano Respizzi Barbara Baroni Maria Cristina D’Agostino Gianluca Stefano Galimberti

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 Josè Luis Vallejo Garcia Pietro Paolo Vico

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 Erminia Casari Elisabetta Corsi Concetta De Luca Antonella Ferrario Rossana Mineri Marta Monari Carla Ripamonti Serenella Valaperta PATHOLOGY division director: Massimo Roncalli Silvia Armenia Andrea Bornati Paola Bossi Piergiuseppe Colombo (•) Annarita Destro Luca Di Tommaso Bethania Fernandes Barbara Fiamengo Sofia Manara Cornelia Navligu Daoud Rahal (•) Paola Spaggiari Gaia Spagnuolo SURGICAL DAY HOSPITAL division director: Roberta Monzani Marco Babbini Diego Beltrutti (°) Francesco Carrera Aljosa Ciarloni Laura Crozzoli Maria Del Carmen Rodriguez Michele De Ruvo Chiara Ferrari Fabio Intelligente (°) Annarita La Rocca Oreste Davide Montino Rossana Peretti Beatrice Rossi Claudio Sacchi Alessandro Scafella

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

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Departments and teams Scientific Research and Laboratories

Scientific superintendence

Updated to February 2011

Scientific Direction and Research Laboratories

director: Nicola Dioguardi Sonia Di Biccari Barbara Franceschini Carlo Russo Stefano Musardo

director: Alberto Mantovani Annunciata Vecchi

Clinical trials office director: Michele Tedeschi Clara Caccialanza Alessandra GiampĂ Francesco Minuti Emanuela Morenghi Megan Rosalind

Adaptive Immunity group leader: Antonella Viola Javier Cibella Marino Kallikourdis Cristina Mazzon Sara Morlacchi Adelaida Sarukhan Cristiana Soldani Anna Elisa Trovato Mary Wang Lucia Zanotti AUTOIMMUNITY AND METABOLISM group leader: Carlo Francesco Selmi (3) Francesca Cavaciocchi Maria De Santis (3) Francesca Meda (3) Cellular Immunology group leader: Paola Allavena Marco Erreni Giovanni Germano Federica Marchesi Samantha Pesce Imran Siddiqui Clinical and Experimental Immunology group leader: Domenico Mavilio (2)

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

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(*) staff

Stefania Bonaldo Enrico Brunetta (2) Kelly Lorraine Hudspeth Ivana Matera Irene Mattiola Joanna Mikulak Alessandra Roberto Marta Rusmini

Clinical Pharmacology group leader: Alfredo Gorio Stephana Carelli

Bedsheba Nachimuthu Benedetta Savino Nina Machado Torres Rafal Tusinski

Experimental Immunopathology group leader: Cecilia Garlanda

Leukocyte Migration group leader: Silvano Sozzani

Elisa Barbati Edoardo Bonavita Sebastien Jaillon Fabio Pasqualini Nadia Polentarutti Gastrointestinal Immunopathology group leader: Silvio Danese (1) Carmen Correale Gionata Fiorino Marco Genua Patrizia Naccarato Benjamin Nachimuthu Emanuela Sala Orsola Sociale (*) Hainalka Szabo Stefania Vetrano Hepatobiliary Immunopathology group leader: Pietro Invernizzi (3) Francesca Bernuzzi Ana Lleo De Nalda (3) Immunopharmacology group leader: Barbara Bottazzi Ivan Cuccovillo Antonio Inforzato Ilaria Laface Marina Sironi Sonia Valentino Leukocyte Biology group leader: Massimo Locati Raffaella Bonecchi Elena Borroni Cinzia Cancellieri Nicoletta Caronni Graziella Curtale Massimiliano Mirolo Laura Mori

Annalisa Del Prete Safyie Gonzalvo Feo Molecular Gastroenterology group leader: Luigi Laghi (1) Gianluca Basso Paolo Bianchi Giuseppe Celesti Giuseppe Di Caro Lucia Fini Valentina Giatti (*) Fabio Grizzi

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

Molecular Immunology group leader: Antonio Sica Stefania Banfi Chiara Porta Laura Strauss Maria Grazia Totaro National Research Council (CNR) Human Genome and Medical Biotechnologies group leaders: Paolo Vezzoni, Anna Villa Maria Elena Caldana Alessandra Castelli Laura Crisafulli Francesca Faggioli Francesca Ficara Maria Luisa Focarelli Michela Frascoli Nadia Lo Iacono Virginia Maina Veronica Marrella Cristina Panaroni Alessandra Pangrazio Marianna Paulis Cristina Sobacchi Dario Strina Lucia Susani

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Papers published 2010

Papers published 2010 At 31 January 2011 * = Corresponding author

P r e c l i n i c a l

R e s e a r c h Mantovani A.

RESEARCH LABORATORIES Cao R, Xue Y, Hedlund EM, Zhong Z, Tritsaris K, Tondelli B, Lucchini F, Zhu Z, Dissing S, Cao Y.

VEGFR1-mediated pericyte ablation links VEGF and PlGF to cancer-associated retinopathy.

La mala educación of Tumor-Associated Macrophages: Diverse Pathways and New Players.

Cancer Cell. 2010 Feb 17;17(2):111-112.

Raw IF (2009): 25.288

Normalized IF: 15

Proc Natl Acad Sci U S A. 2010 Jan 12;107(2):856-61. Epub 2009 Dec 22.

Raw IF (2009): 9.432 Normalized IF: 4

Chouery E, Pangrazio A, Frattini A, Villa A, Van Wesenbeeck L, Piters E, Van Hul W, Coxon FP, Schouten T, Helfrich M, Lefranc G, Mégarbané A.

Danese S, Gao B.

J Bone Miner Res. 2010 Mar;25(3):676-80.

Raw IF (2009): 6.043 Normalized IF: 6

Interleukin-6: a therapeutic Jekyll and Hyde in gastrointestinal and hepatic diseases.

Gut. 2010 Feb;59(2):149-51.

Raw IF (2009): 9.357

Normalized IF: 8

Danese S.

Anti TNF-alpha Treatment For Crohn’ Disease: “Ménage A Trois”.

Curr Drug Targets. 2010 Feb;11(2):136-7.

Raw IF (2009): 3.932

Normalized IF: 6

Di Pucchio T, Danese S, De Cristofaro R, Rutella S.

Inhibitors of indoleamine 2,3-dioxygenase: a review of novel patented lead compounds.

Expert Opin Ther Pat. 2010 Feb;20(2):229-50.

Raw IF (2009): 1.280 Normalized IF: 2 Marchesi F, Piemonti L, Mantovani A, Allavena P.

Molecular mechanisms of perineural invasion, a forgotten pathway of dissemination and metastasis.

Cytokine Growth Factor Rev. 2010 Feb;21(1):77-82. Epub 2010 Jan 8.

Raw IF (2009): 6.489 Normalized IF: 6 Rutella S, Vetrano S, Correale C, Graziani C, Sturm A, Spinelli A, De Cristofaro R, Repici A, Malesci A, Danese S.

Enhanced platelet adhesion induces angiogenesis in intestinal inflammation and inflammatory bowel disease microvasculature.

J Cell Mol Med. 2010 Feb 16. [Epub ahead of print] Raw IF (2009): 5.228 Normalized IF: 6

A new familial sclerosing bone dysplasia.

Darling TN, Pacheco-Rodriguez G, Gorio A, Lesma E, Walker C, Moss J.

Lymphangioleiomyomatosis and TSC2-/- cells.

Lymphat Res Biol. 2010 Mar;8(1):59-69.

Raw IF (2009): 0 Normalized IF: 0.1 Fava F, Danese S.

Crohn’s disease: Bacterial clearance in Crohn’s disease pathogenesis.

News - Nat Rev Gastroenterol Hepatol. 2010 Mar;7(3):126-8.

Raw IF (2009): 0 Normalized IF: 0.1 Germano G, Frapolli R, Simone M, Tavecchio M, Erba E, Pesce S, Pasqualini F, Grosso F, Sanfilippo R, Casali PG, Gronchi A, Virdis E, Tarantino E, Pilotti S, Greco A, Nebuloni M, Galmarini CM, Tercero JC, Mantovani A, D’Incalci M, Allavena P.

Antitumor and Anti-inflammatory Effects of Trabectedin on Human Myxoid Liposarcoma Cells.

Cancer Res. 2010 Mar 15;70(6):2235-44. Epub 2010 Mar 9.

Raw IF (2009): 7.543 Normalized IF: 8 Murakami M, Francavilla C, Torselli I, Corada M, Maddaluno L, Sica A, Matteoli G, Iliev ID, Mantovani A, Rescigno M, Cavallaro U, Dejana E.

Inactivation of Junctional Adhesion Molecule-A Enhances Antitumoral Immune Response by Promoting Dendritic Cell and T Lymphocyte Infiltration.

Cancer Res. 2010 Mar 1;70(5):1759-65. Epub 2010 Feb 16.

Raw IF (2009): 7.543 Normalized IF: 4 Sica A.

Macrophages give Gas(6) to cancer.

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Blood. 2010 Mar 18;115(11):2122-3.

Raw IF (2009): 10.555

Normalized IF: 8

Deban L, Russo RC, Sironi M, Moalli F, Scanziani M, Zambelli V, Cuccovillo I, Bastone A, Gobbi M, Valentino S, Doni A, Garlanda C, Danese S, Salvatori G, Sassano M, Evangelista V, Rossi B, Zenaro E, Constantin G, Laudanna C, Bottazzi B, Mantovani A.

Regulation of leukocyte recruitment by the long pentraxin PTX3.

Nat Immunol. 2010 Apr;11(4):328-34. Epub 2010 Mar 7.

Raw IF (2009): 26.000 Normalized IF: 15 Mantovani A, Garlanda C, Allavena P.

Molecular pathways and targets in cancer-related inflammation.

Ann Med. 2010 Apr;42(3):161-70.

Raw IF (2009): 4.246

Normalized IF: 6

Mantovani A, Sica A.

Macrophages, innate immunity and cancer: balance, tolerance, and diversity.

Curr Opin Immunol. 2010 Apr;22(2):231-7. Epub 2010 Feb 9.

Raw IF (2009): 10.881 Normalized IF: 8 Martinez de la Torre Y, Fabbri M, Jaillon S, Bastone A, Nebuloni M, Vecchi A, Mantovani A, Garlanda C.

PLoS One. 2010 Jun 10;5(6):e11052.

Raw IF (2009): 4.351

Normalized IF: 3

Inforzato A, Baldock C, Jowitt TA, Holmes DF, Lindstedt R, Marcellini M, Rivieccio V, Briggs DC, Kadler KE, Verdoliva A, Bottazzi B, Mantovani A, Salvatori G, Day AJ.

The angiogenic inhibitor long pentraxin PTX3 forms an asymmetric octamer with two binding sites for FGF2.

J Biol Chem. 2010 Jun 4;285(23):17681-92. Epub 2010 Apr 2.

Raw IF (2009): 5.328 Normalized IF: 3 Mantovani A.

Molecular Pathways Linking Inflammation and Cancer.

Curr Mol Med. 2010 Jun;10(4):369-73.

Raw IF (2009): 5.096

Normalized IF: 6

Mantovani A.

Role of inflammatory cells and mediators in tumor invasion and metastasis.

Cancer Metastasis Rev. 2010 Jun;29(2):241.

Raw IF (2009): 9.345 Normalized IF: 8

Evolution of the Pentraxin Family: The New Entry PTX4.

Nika K, Soldani C, Salek M, Paster W, Gray A, Etzensperger R, Fugger L, Polzella P, Cerundolo V, Dushek O, Hรถfer T, Viola A, Acuto O.

J Immunol. 2010 May 1;184(9):5055-64. Epub 2010 Mar 31.

Raw IF (2009): 5.646 Normalized IF: 6

Constitutively Active Lck Kinase in T Cells Drives Antigen Receptor Signal Transduction.

Bottai D, Cigognini D, Madaschi L, Adami R, Nicora E, Menarini M, Di Giulio A, Gorio A.

Immunity. 2010 Jun 25;32(6):766-77. Epub 2010 Jun 11.

Raw IF (2009): 20.589 Normalized IF: 15

Embryonic Stem Cells Promote Motor Recovery and Affect Inflammatory Cell Infiltration in Spinal Cord Injured Mice.

Solinas G, Marchesi F, Garlanda C, Mantovani A, Allavena P.

Exp Neurol. 2010 Jun;223(2):452-63. Epub 2010 Jan 25.

Raw IF (2009): 3.914 Normalized IF: 6

Cancer Metastasis Rev. 2010 Jun;29(2):243-8.

Raw IF (2009): 9.345 Normalized IF: 8

Drexler SK, Wales J, Andreakos E, Kong P, Davis A, Garlanda C, Mantovani A, Hussell T, Feldmann M, Foxwell BM.

Evidence for a DC-specific inhibitory mechanism that depends on MyD88 and SIGIRR. Scand J Immunol. 2010 Jun;71(6):393-402.

Raw IF (2009): 2.108 Raw IF: 1

Inflammation-mediated promotion of invasion and metastasis.

Barbon A, Fumagalli F, Caracciolo L, Madaschi L, Lesma E, Mora C, Carelli S, Slotkin TA, Racagni G, Di Giulio AM, Gorio A, Barlati S.

Acute spinal cord injury persistently reduces R/G RNA editing of AMPA receptors.

J Neurochem. 2010 Jul;114(2):397-407. Epub 2010 Apr 23.

Raw IF (2009): 3.999 Normalized IF: 3

Giardino Torchia ML, Ciaglia E, Masci AM, Vitiello L, Fogli M, la Sala A, Mavilio D, Racioppi L.

Borroni EM, Mantovani A, Locati M, Bonecchi R.

Dendritic cells/natural killer cross-talk: a novel target for human immunodeficiency virus type-1 protease inhibitors.

Pharmacol Ther. 2010 Jul;127(1):1-8. Epub 2010 May 6 Raw IF (2009): 8.897 Normalized IF: 8

Chemokine receptors intracellular trafficking.

87

Papers published 2010

Cassani B, Poliani PL, Marrella V, Schena F, Sauer AV, Ravanini M, Strina D, Busse CE, Regenass S, Wardemann H, Martini A, Facchetti F, van der Burg M, Rolink AG, Vezzoni P, Grassi F, Traggiai E, Villa A.

Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the Rag2 mouse model of Omenn syndrome.

J Exp Med. 2010 Jul 5;207(7):1525-40. Epub 2010 Jun 14.

Raw IF (2009): 14.505 Normalized IF: 10 Marchesi F, Locatelli M, Solinas G, Erreni M, Allavena P, Mantovani A.

Role of CX3CR1/CX3CL1 axis in primary and secondary involvement of the nervous system by cancer.

J Neuroimmunol. 2010 Jul 27;224(1-2):39-44. Epub 2010 Jul 13.

Raw IF (2009): 2.841 Normalized IF: 4 Solinas G, Schiarea S, Liguori M, Fabbri M, Pesce S, Zammataro L, Pasqualini F, Nebuloni M, Chiabrando C, Mantovani A, Allavena P.

Tumor-Conditioned Macrophages Secrete MigrationStimulating Factor: A New Marker for M2-Polarization, Influencing Tumor Cell Motility.

J Proteome Res. 2010 Sep 3;9(9):4376-92.

Raw IF (2009): 5.132 Normalized IF: 6

Sivori S, Falco M, Carlomagno S, Romeo E, Soldani C, Bensussan A, Viola A, Moretta L, Moretta A.

A novel KIR-associated function: evidence that CpG DNA uptake and shuttling to early endosomes is mediated by KIR3DL2.

Blood. 2010 Sep 9;116(10):1637-47. Epub 2010 Feb 10.

Raw IF (2009): 10.555 Normalized IF: 4 Agostinis C, Bulla R, Tripodo C, Gismondi A, Stabile H, Bossi F, Guarnotta C, Garlanda C, De Seta F, Spessotto P, Santoni A, Ghebrehiwet B, Girardi G, Tedesco F.

An alternative role of C1q in cell migration and tissue remodeling: contribution to trophoblast invasion and placental development.

J Immunol. 2010 Oct 1;185(7):4420-9. Epub 2010 Sep 1.

Raw IF (2009): 5.646 Normalized IF: 3

J Immunol. 2010 Jul 1;185(1):642-52. Epub 2010 Jun 7.

Raw IF (2009): 5.646 Normalized IF: 6

Biswas SK, Mantovani A.

Sozzani S, Vermi W, Del Prete A, Facchetti F.

Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm.

Trafficking properties of plasmacytoid dendritic cells in health and disease.

Trends Immunol. 2010 Jul;31(7):270-7. Epub 2010 Jun 25.

Raw IF (2009): 8.768 Normalized IF: 4 Drexler SK, Kong P, Inglis J, Williams RO, Garlanda C, Mantovani A, Yazdi AS, Brennan F, Feldmann M, Foxwell BM.

SIGIRR/TIR8 is an inhibitor of TLR signalling in primary human cells and regulates inflammation in models of rheumatoid arthritis.

Arthritis Rheum. 2010 Aug;62(8):2249-61.

Raw IF (2009): 7.332 Normalized IF: 4

Convergent pathways of macrophage polarization: The role of B cells.

Eur J Immunol. 2010 Aug;40(8):2131-3.

Raw IF (2009): 5.179

Nat Immunol. 2010 Oct;11(10):889-96. Epub 2010 Sep 20.

Raw IF (2009): 26.00 Normalized IF: 15

Dhirapong A, Lleo A, Yang GX, Tsuneyama K, Dunn R, Kehry M, Packard TA, Cambier JC, Liu FT, Lindor K, Coppel RL, Ansari AA, Gershwin ME.

B cell depletion therapy exacerbates murine primary biliary cirrhosis.

Hepatology. 2010 Oct 18. [Epub ahead of print] Raw IF (2009): 10.84 Normalized IF: 8

Job ER, Deng YM, Tate MD, Bottazzi B, Crouch EC, Dean MM, Mantovani A, Brooks AG, Reading PC.

Sica A, Porta C, Riboldi E, Locati M.

88

Cell Lines Reveals Perturbations of Key Functional Networks.

Normalized IF: 6

Schiarea S, Solinas G, Allavena P, Scigliuolo GM, Bagnati R, Fanelli R, Chiabrando C.

Secretome Analysis of Multiple Pancreatic Cancer

Pandemic H1N1 Influenza A Viruses Are Resistant to the Antiviral Activities of Innate Immune Proteins of the Collectin and Pentraxin Superfamilies.

J Immunol. 2010 Oct 1;185(7):4284-91. Epub 2010 Sep 3.

Raw IF (2009): 5.646 Normalized IF: 3

Otero K, Vecchi A, Hirsch E, Kearley J, Vermi W, Del Prete A, Gonzalvo-Feo S, Garlanda C, Azzolino O, Salogni L, Lloyd

CM, Facchetti F, Mantovani A*, Sozzani S.*

Gaetano C, Locati M, Mantovani A.

Non-redundant role of CCRL2 in lung dendritic cell trafficking.

Control of iron homeostasis as a key component of macrophage polarization.

*This project was coordinated by AM and SS Blood. 2010 Oct 21;116(16):2942-9. Epub 2010 Jul 6.

Raw IF (2009): 10.555 Normalized IF: 8

Haematologica. 2010 Nov;95(11):1801-3.

Raw IF (2009): 6.416

Pauwels NS, Bracke KR, Maes T, Van Pottelberge GR, Garlanda C, Mantovani A, Joos GF, Brusselle GG.

Cigarette smoke induces PTX3 expression in pulmonary veins of mice in an IL-1 dependent manner.

Respir Res. 2010 Oct 4;11:134.

Raw IF (2009): 3.127

Normalized IF: 3

Sozzani S, Locati M, Vacca A, Adorini L, Semenzato G.

The Italian Society of Immunology: past, present and future.

Eur J Immunol. 2010 Oct;40(10):2664-6.

Commentary Raw IF (2009): 5.179 Normalized IF: 1.2 Bellora F, Castriconi R, Dondero A, Reggiardo G, Moretta L, Mantovani A, Moretta A, Bottino C.

The interaction of human natural killer cells with either unpolarized or polarized macrophages results in different functional outcomes.

Proc Natl Acad Sci U S A. 2010 Nov 30. [Epub ahead of print] Raw IF (2009): 9.432 Normalized IF: 4 Cammarota R, Bertolini V, Pennesi G, Bucci EO, Gottardi O, Garlanda C, Laghi L, Barberis MC, Sessa F, Noonan DM, Albini A.

The tumor microenviroment of colo-rectal cancer; stromal TLR-4 expression as a potential prognostic marker.

J Transl Med. 2010 Nov 8;8:112.

Raw IF (2009): 3.407

Normalized IF: 3

Dinarello C, Arend W, Sims J, Smith D, Blumberg H, O’Neill L, Goldbach-Mansky R, Pizarro T, Hoffman H, Bufler P, Nold M, Ghezzi P, Mantovani A, Garlanda C, Boraschi D, Rubartelli A, Netea M, van der Meer J, Joosten L, Mandrup-Poulsen T, Donath M, Lewis E, Pfeilschifter J, Martin M, Kracht M, Muehl H, Novick D, Lukic M, Conti B, Solinger A, Peyman K, van de Veerdonk F, Gabel C.

Normalized IF: 6

Gorini S, Callegari G, Romagnoli G, Mammi C, Mavilio D, Rosano G, Fini M, Di Virgilio F, Gulinelli S, Falzoni S, Cavani A, Ferrari D, la Sala A.

ATP secreted by endothelial cells blocks CX3CL1-elicited natural killer cell chemotaxis and cytotoxicity via P2Y11 receptor activation.

Blood. 2010 Nov 25;116(22):4492-500. Epub 2010 Jul 28.

Raw IF (2009): 10.555 Normalized IF: 4 Ma YJ, Doni A, Skjoedt MO, Honore C, Arendrup M, Mantovani A, Garred P.

Heterocomplexes of mannose-binding lectin and the pentraxins PTX3 or SAP trigger cross-activation of the complement system.

J Biol Chem. 2010 Nov 24. [Epub ahead of print] Raw IF (2009): 5.328 Normalized IF: 6 Porta C, Riboldi E, Sica A.

Mechanisms linking pathogens-associated inflammation and cancer.

Cancer Lett. 2010 Nov 17. [Epub ahead of print] Raw IF (2009): 3.741 Normalized IF: 4 Russo RC, Garcia CC, Barcelos LS, Rachid MA, Guabiraba R, Roffê E, Souza AL, Sousa LP, Mirolo M, Doni A, Cassali GD, Pinho V, Locati M, Teixeira MM.

Phosphoinositide 3-kinase {gamma} plays a critical role in bleomycin-induced pulmonary inflammation and fibrosis in mice.

J Leukoc Biol. 2010 Nov 2. [Epub ahead of print] Raw IF (2009): 4.403 Normalized IF: 6 Zanier ER, Brandi G, Peri G, Longhi L, Zoerle T, Tettamanti M, Garlanda C, Sigurtà A, Valaperta S, Mantovani A, De Simoni MG, Stocchetti N.

Cerebrospinal fluid pentraxin 3 early after subarachnoid hemorrhage is associated with vasospasm.

Intensive Care Med. 2010 Nov 12. [Epub ahead of print] Raw IF (2009): 5.168 Normalized IF: 6

IL-1 family nomenclature.

Nat Immunol. 2010 Nov;11(11):973.

Raw IF (2009): 26.00

Normalized IF: 7.5

Acquati F, Bertilaccio S, Grimaldi A, Monti L, Cinquetti R, Bonetti P, Lualdi M, Vidalino L, Fabbri M, Sacco MG, Rooijen

89

Papers published 2010

NV, Campomenosi P, Vigetti D, Passi A, Riva C, Capella C, Sanvito F, Doglioni C, Gribaldo L, Macchi P, Sica A, Noonan DM, Ghia P, Taramelli R.

Microenvironmental control of malignancy exerted by RNASET2. a widely conserved extracellular RNase.

Proc Natl Acad Sci U S A. 2010 Dec 28. [Epub ahead of print] Raw IF (2009): 9.432 Normalized IF: 4 Allavena P, Germano G, Marchesi F, Mantovani A.

Chemokines in cancer related inflammation.

Exp Cell Res. 2010 Dec 3. [Epub ahead of print] Raw IF (2009): 3.589 Normalized IF: 4 Brunetta E, Hudspeth KL, Mavilio D.

Pathologic natural killer cell subset redistribution in HIV-1 infection: new insights in pathophysiology and clinical outcomes.

J Leukoc Biol. 2010 Dec;88(6):1119-30. Epub 2010 Jul 22.

Raw IF (2009): 4.403 Normalized IF: 6

Cancer Immunol Immunother. 2010 Dec;59(12):1895-901.

Epub 2010 Mar 5.

Meeting report Raw IF (2009): 3.791 Normalized IF: 1.2 Mantovani A.

The growing diversity and spectrum of action of myeloid-derived suppressor cells.

Eur J Immunol. 2010 Dec;40(12):3317-3320.

Raw IF (2009): 5.179 Normalized IF: 6

Moalli F, Doni A, Deban L, Zelante T, Zagarella S, Bottazzi B, Romani L, Mantovani A, Garlanda C.

Role of complement and Fc{gamma} receptors in the protective activity of the long pentraxin PTX3 against Aspergillus fumigatus.

Blood. 2010 Dec 9;116(24):5170-80. Epub 2010 Sep 9.

Raw IF (2009): 10.555 Normalized IF: 8

Chiarini M, Sabelli C, Melotti P, Garlanda C, Savoldi G, Mazza C, Padoan R, Plebani A, Mantovani A, Notarangelo LD, Assael BM, Badolato R.

Viola A, Contento RL, Molon B.

PTX3 genetic variations affect the risk of Pseudomonas aeruginosa airway colonization in cystic fibrosis patients.

Curr Top Microbiol Immunol. 2010;340:109-22.

Raw IF (2009): 4.160 Normalized IF: 6

Genes Immun. 2010 Dec;11(8):665-70. Epub 2010 Oct 7.

Raw IF (2009): 4.222 Normalized IF: 3

Bonecchi R, Savino B, Borroni EM, Mantovani A, Locati M.

Clemens J, Holmgren J, Kaufmann SH, Mantovani A.

Ten years of the Global Alliance for Vaccines and Immunization: challenges and progress.

Nat Immunol. 2010 Dec;11(12):1069-72.

Raw IF (2009): 26.00

Normalized IF: 15

Contento RL, Campello S, Trovato AE, Magrini E, Anselmi F, Viola A.

Adhesion shapes T cells for prompt and sustained T-cell receptor signalling.

EMBO J. 2010 Dec 1;29(23):4035-47. Epub 2010 Oct 15.

Raw IF (2009): 8.993 Normalized IF: 8

90

Tumor Biotherapy (NIBIT), Siena, 1-3 October 2009.

Maio M, Nicolay HJ, Ascierto PA, Belardelli F, Camerini R, Colombo MP, Queirolo P, Ridolfi R, Russo V, Fonsatti E, Parmiani G; NIBIT (Allavena P collaborator).

Seventh annual meeting of the Italian Network for

Signaling amplification at the immunological synapse.

Chemokine Decoy Receptors: Structure-Function and Biological Properties.

Curr Top Microbiol Immunol. 2010;341:15-36.

Raw IF (2009): 4.160 Normalized IF: 6 Meroni PL, Tedesco F, Locati M, Vecchi A, Di Simone N, Acaia B, Pierangeli SS, Borghi MO.

Anti-phospholipid antibody mediated fetal loss: still an open question from a pathogenic point of view.

Lupus. 2010;19(4):453-6.

Raw IF (2009): 2.586

Normalized IF: 2

Benfante R, Antonini RA, De Pizzol M, Gotti C, Clementi F, Locati M, Fornasari D.

Expression of the Îą7 nAChR subunit duplicate form (CHRFAM7A) is down-regulated in the monocytic cell line THP-1 on treatment with LPS. J Neuroimmunol. 2011 Jan;230(1-2):74-84. Epub 2010 Oct 4.

Raw IF (2009): 2.841 Normalized IF: 2

Deban L, Jaillon S, Garlanda C, Bottazzi B, Mantovani A.

Pentraxins in innate immunity: lessons from PTX3.

Cell Tissue Res. 2011 Jan;343(1):237-49. Epub 2010 Aug 4.

Raw IF (2009): 2.308 Normalized IF: 2

laboratory tests Cosentino S, Donida BM, Marasco E, Del Favero E, Cant첫 L, Lombardi G, Colombini A, Iametti S, Valaperta S, Fiorilli A, Tettamanti G, Ferraretto A.

Calcium ions enclosed in casein phosphopeptide aggregates are directly involved in the mineral uptake by differentiated HT-29 cells.

International Dairy Journal 20 (2010) 770-776.

Raw IF (2009): 2.409 Normalized IF: 3

91

Papers published 2010

T r a s l a t i o n a l Cardiovascular Diseases Department

R e s e a r c h Scaldaferri F, Correale C, Gasbarrini A, Danese S.

Mucosal biomarkers in inflammatory bowel disease: Key pathogenic players or disease predictors?

World J Gastroenterol. 2010 Jun 7;16(21):2616-25.

Raw IF (2009): 2.092 Normalized IF: 4

HAEMODYNAMICS AND INVASIVE CARDIOLOGY Predazzi IM, Martínez-Labarga C, Vecchione L, Mango R, Ciccacci C, Amati F, Ottoni C, Crawford MH, Rickards O, Romeo F, Novelli G.

Fiorino G, Correale C, Fries W, Repici A, Malesci A, Danese S.

Population differences in allele frequencies at the OLR1 locus may suggest geographic disparities in cardiovascular risk events.

Expert Rev Clin Immunol. 2010 Jul;6(4):567-572.

Raw IF (2009): 0 Normalized IF: 0.1

Ann Hum Biol. 2010 Apr;37(2):136-48.

Raw IF (2009): 1.064

Normalized IF: 1

Leukocyte traffic control: a novel therapeutic strategy for inflammatory bowel disease.

Iborra M, Bernuzzi F, Invernizzi P, Danese S.

MicroRNAs in autoimmunity and inflammatory bowel disease: Crucial regulators in immune response.

Gastroenterology Department GASTROENTEROLOGY AND DIGESTIVE ENDOSCOPY Danese S, Laghi L, Repici A, Malesci A. Colorectal cancer screening: Dying en route?

Dig Liver Dis. 2010 May;42(5):350-1. Epub 2010 Mar 19.

Raw IF (2009): 2.972 Normalized IF: 6

Danese S, Mantovani A.

Inflammatory bowel disease and intestinal cancer: a paradigm of the Yin-Yang interplay between inflammation and cancer.

Oncogene. 2010 Jun 10;29(23):3313-23. Epub 2010 Apr 19.

Raw IF (2009): 7.135 Normalized IF: 8 Laverny G, Penna G, Vetrano S, Correale C, Nebuloni M, Danese S*, Adorini L*.

Efficacy of a potent and safe vitamin D receptor agonist for the treatment of inflammatory bowel disease. *Adorini L and Danese Silvio contributed equally to this study Immunol Lett. 2010 Jun 15;131(1):49-58. Epub 2010 Mar 27.

Raw IF (2009): 2.906 Normalized IF: 4

92

Pietro Invernizzi and Danese Silvio contributed equally to this study Autoimmun Rev. 2010 Jul 11. [Epub ahead of print] Raw IF (2009): 6.368 Normalized IF: 6 Bonanno G, Procoli A, Mariotti A, Corallo M, Perillo A, Danese S, De Cristofaro R, Scambia G, Rutella S.

Effects of pegylated G-CSF on immune cell number and function in patients with gynecological malignancies.

J Transl Med. 2010 Nov 9;8(1):114. [Epub ahead of print] Raw IF (2009): 3.407 Normalized IF: 3

Di Sabatino A, Rovedatti L*, Vetrano S*, Vidali F, Biancheri P, Rescigno M, Danese S, Macdonald TT, Corazza GR.

Involvement of CD40-CD40 Ligand in Uncomplicated and Refractory Celiac Disease. *These authors contributed equally to this manuscript and should be considered as joint second authors Am J Gastroenterol. 2010 Dec 7. [Epub ahead of print] Raw IF (2009): 6.012 Normalized IF: 6

Szabò H., Fiorino G., Danese S.

Heat shock protein 47 is a new candidate molecule as anti-fibrotic treatment of Crohn’s disease: authors’ reply.

Aliment Pharmacol Ther 2010 (31), 922–928.

Letter to the Editor (comments) Raw IF (2009): 4.357 Normalized IF: 1.2

Ginaecology Department REPRODUCTIVE MEDICINE Borini A, Levi Setti PE, Anserini P, Luca RD, Santis LD, Porcu E, La Sala GB, Ferraretti A, Bartolotti T, Coticchio G, Scaravelli G.

Multicenter observational study on slow-cooling oocyte cryopreservation: clinical outcome.

Fertil Steril. 2010 Oct;94(5):1662-8. Epub 2010 Jan 4.

Raw IF (2009): 3.970 Normalized IF: 6 Criado E, Albani E, Novara PV, Smeraldi A, Cesana A, Parini V, Levi-Setti PE.

Ponticelli C, Scolari MP.

Calcineurin inhibitors in renal transplantation still needed but in reduced doses: a review.

Transplant Proc. 2010 Jul-Aug;42(6):2205-8.

Raw IF (2009): 0.994 Normalized IF: 2 Ponticelli C, Locatelli F.

Autosomal dominant polycystic kidney disease and mTOR inhibitors: the narrow road between hope and disappointment.

Nephrol Dial Transplant. 2010 Dec;25(12):3809-12. Epub 2010 Aug 26.

Raw IF (2009): 3.306 Normalized IF: 6

Human oocyte ultravitrification with a low concentration of cryoprotectants by ultrafast cooling: a new protocol.

Ponticelli C, Coppo R, Salvadori M.

Fertil Steril. 2010 Dec 2. [Epub ahead of print] Raw IF (2009): 3.970 Normalized IF: 6

Nephrol Dial Transplant. 2011 Jan;26(1):35-41. Epub 2010 Sep 15.

Raw IF (2009): 3.306 Normalized IF: 6

Internal Medicine Department

Glomerular diseases and transplantation: similarities in pathogenetic mechanisms and treatment options.

INTERNAL MEDICINE Selmi C, Torok NJ, Affronti A, Gershwin ME.

Genomic variants associated with primary biliary cirrhosis.

ENDOCRINOLOGY AND DIABETOLOGY Bucciarelli LG, Pollreisz A, Kebschull M, Ganda A, Kalea AZ, Hudson BI, Zou YS, Lalla E, Ramasamy R, Colombo PC, Schmidt AM, Yan SF.

Inflammatory stress in primary venous and aortic endothelial cells of type 1 diabetic mice.

Diab Vasc Dis Res. 2009 Oct;6(4):249-61.

Raw IF (2009): 0 Normalized IF: 0.1

Genome Med. 2010 Jan 26;2(1):5.

Raw IF (2009): 0

Normalized IF: 0.1

Selmi C.

The worldwide gradient of autoimmune conditions.

Autoimmun Rev. 2010 Mar;9(5):A247-50. Epub 2010 Feb 9.

Raw IF (2009): 6.368 Normalized IF: 6

Deane S, Selmi C, Teuber SS, Gershwin ME.

GENERAL MEDICINE AND NEPHROLOGY Ponticelli C.

Humoral Antibodies in Organ Transplantation: Angels or Demons?

Am J Transplant. 2010 May;10(5):1332; author reply 1333.

Epub 2010 Jan 29. Letter to the Editor (comments) Raw IF (2009): 6.433 Normalized IF: 1.2

Macrophage Activation Syndrome in Autoimmune Disease.

Int Arch Allergy Immunol. 2010 Apr 21;153(2):109-120.

Raw IF (2009): 2.542 Normalized IF: 4

Hov JR, Lleo A, Selmi C, Woldseth B, Fabris L, Strazzabosco M, Karlsen TH, Invernizzi P.

Genetic associations in Italian primary sclerosing

93

Papers published 2010

cholangitis: Heterogeneity across Europe defines a critical role for HLA-C. J Hepatol. 2010 May;52(5):712-7. Epub 2010 Mar 4.

Raw IF (2009): 7.818 Normalized IF: 8

Selmi C, Gershwin ME.

Functional autoantibodies in primary biliary cirrhosis: a reply to Peter A. Berg.

Trends Immunol. 2010 Vol.31 No.3: 89-90. Epub 2010 Feb 9.

Letter to the Editor (comments) Raw IF (2009): 8.768 Normalized IF: 1.6

Invernizzi P, Selmi C, Gershwin ME.

Update on primary biliary cirrhosis.

Dig Liver Dis. 2010 Jun;42(6):401-8. Epub 2010 Mar 31.

Raw IF (2009): 2.972 Normalized IF: 6

Selmi C, Gershwin ME.

Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis.

Nat Genet. 2010 Aug;42(8):658-60. Epub 2010 Jul 18.

Raw IF (2009): 34.284 Normalized IF: 15

Lleo A, Bowlus CL, Yang GX, Invernizzi P, Podda M, Van de Water J, Ansari AA, Coppel RL, Worman HJ, Gores GJ, Gershwin ME.

Biliary apotopes and anti-mitochondrial antibodies activate innate immune responses in primary biliary cirrhosis.

Hepatology. 2010 Sep;52(3):987-98.

Raw IF (2009): 10.840

Normalized IF: 4

Autoantibodies in autoimmune liver disease: biomarkers versus epiphenomena.

Selmi C.

Gut. 2010 Jun;59(6):712-3.

Raw IF (2009): 9.357

Autoimmun Rev. 2010 Oct;9(12):795-800. Epub 2010 Aug 15.

Raw IF (2009): 6.368 Normalized IF: 6

Normalized IF: 8

Lu Q, Renaudineau Y, Cha S, Ilei G, Brooks WH, Selmi C, Tzioufas A, Pers JO, Bombardieri S, Gershwin ME, Gay S, Youinou P.

Epigenetics in autoimmune disorders: Highlights of the 10th SjĂśgrenâ&#x20AC;&#x2122;s Syndrome Symposium.

Autoimmun Rev. 2010 Jul;9(9):627-30. Epub 2010 May 7.

Raw IF (2009): 6.368 Normalized IF: 3

Autoimmunity in 2009.

Bernuzzi F, Fenoglio D, Battaglia F, Fravega M, Gershwin ME, Indiveri F, Ansari AA, Podda M, Invernizzi P, Filaci G.

Phenotypical and functional alterations of CD8 regulatory T cells in primary biliary cirrhosis.

Pietro Invernizzi and Gilberto Filaci contributed equally to this study J Autoimmun. 2010 Nov;35(3):176-80. Epub 2010 Jul 16.

Raw IF (2009): 7.231 Normalized IF: 8

Cerri G, Cocchi CA, Montagna M, Zuin M, Podda M, Cavallari P, Selmi C.

Bowlus CL, Li CS, Karlsen TH, Lie BA, Selmi C.

Patients with primary biliary cirrhosis do not show postexercise depression of cortical excitability.

Primary sclerosing cholangitis in genetically diverse populations listed for liver transplantation: unique clinical and human leukocyte antigen associations.

Clin Neurophysiol. 2010 Aug;121(8):1321-8. Epub 2010 Apr 2.

Raw IF (2009): 3.122 Normalized IF: 6

94

Marzioni M, Benedetti A, Fabris L, Strazzabosco M, Portincasa P, Palmieri VO, Tiribelli C, Croce L, Bruno S, Rossi S, Vinci M, Prisco C, Mattalia A, Toniutto P, Picciotto A, Galli A, Ferrari C, Colombo S, Casella G, Morini L, Caporaso N, Colli A, Spinzi G, Montanari R, Gregersen PK, Heathcote EJ, Hirschfield GM, Siminovitch KA, Amos CI, Gershwin ME, Seldin MF.

Liu X, Invernizzi P, Lu Y, Kosoy R, Lu Y, Bianchi I, Podda M, Xu C, Xie G, Macciardi F, Selmi C, Lupoli S, Shigeta R, Ransom M, Lleo A, Lee AT, Mason AL, Myers RP, Peltekian KM, Ghent CN, Bernuzzi F, Zuin M, Rosina F, Borghesio E, Floreani A, Lazzari R, Niro G, Andriulli A, Muratori L, Muratori P, Almasio PL, Andreone P, Margotti M, Brunetto M, Coco B, Alvaro D, Bragazzi MC, Marra F, Pisano A, Rigamonti C, Colombo M,

Liver Transpl. 2010 Nov;16(11):1324-30.

Raw IF (2009): 3.724

Normalized IF: 6

Denk GU, Maitz S, Wimmer R, Rust C, Invernizzi P, Ferdinandusse S, Kulik W, Fuchsbichler A, Fickert P, Trauner M, Hofmann AF, Beuers U.

Conjugation is essential for the anticholestatic effect of NorUrsodeoxycholic acid in taurolithocholic acidinduced cholestasis in rat liver.

Hepatology. 2010 Nov;52(5):1758-68.

Raw IF (2009): 10.840

primary biliary cirrhosis.

Normalized IF: 4

J Hepatol. 2010 Dec 9. [Epub ahead of print] Raw IF (2009): 7.818 Normalized IF: 8

Selmi C, Vergani D, Mieli-Vergani G, Mieli-Vergani G.

Viruses and Autoantibodies in Biliary Atresia.

Selmi C, Mackay IR, Gershwin ME.

Gastroenterology. 2010 Nov;139(5):1461-4. Epub 2010 Sep 25.

Raw IF (2009): 12.899 Normalized IF: 10

The autoimmunity of primary biliary cirrhosis and the clonal selection theory.

Tsuda M, Torgerson TR, Selmi C, Gambineri E, Carneiro-Sampaio M, Mannurita SC, Leung PS, Norman GL, Gershwin ME.

The spectrum of autoantibodies in IPEX syndrome is broad and includes anti-mitochondrial autoantibodies.

J Autoimmun. 2010 Nov;35(3):265-8. Epub 2010 Jul 22.

Raw IF (2009): 7.231 Normalized IF: 4 Bizzaro N, Covini G, Rosina F, Muratori P, Tonutti E, Villalta D, Pesente F, Alessio MG, Tampoia M, Antico A, Platzgummer S, Porcelli B, Terzuoli L, Liguori M, Bassetti D, Brusca I, Almasio PL, Tarantino G, Bonaguri C, Agostinis P, Bredi E, Tozzoli R, Invernizzi P, Selmi C.

Overcoming a â&#x20AC;&#x153;Probableâ&#x20AC;? Diagnosis in Antimitochondrial Antibody Negative Primary Biliary Cirrhosis: Study of 100 Sera and Review of the Literature.

Clin Rev Allergy Immunol. 2010 Dec 29. [Epub ahead of print] Raw IF (2009): 2.597 Normalized IF: 4

Immunol Cell Biol. 2011 Jan;89(1):70-80. Epub 2010 Oct 26.

Raw IF (2009): 4.2 Normalized IF: 6

Invernizzi P.

Hunting for fibrosis progression genes in hepatitis C patients.

Clin Sci (Lond). 2011 Apr;120(7):285-6. Epub 2010 Nov 18.

Raw IF (2009): 3.982 Normalized IF: 6

RHEUMATOLOGY Belloli L, Ughi N, Massarotti M, Marasini B, Biondi ML, Brambilla G.

Role of fetuin-A in systemic sclerosis-associated calcinosis.

J Rheumatol. 2010 Dec;37(12):2638-9.

Letter to the Editor (comment) Raw IF (2009): 3.854

Normalized IF: 0.8

Invernizzi P.

Drug-induced liver injury: Is it time for genetics to change our clinical practice?

J Hepatol. 2010 Dec;53(6):993-4. Epub 2010 Aug 19.

Raw IF (2009): 7.818 Normalized IF: 8 Liu H, Norman GL, Shums Z, Worman HJ, Krawitt EL, Bizzaro N, Vergani D, Bogdanos DP, Dalekos GN, Milkiewicz P, Czaja AJ, Heathcote EJ, Hirschfield GM, Tan EM, Miyachi K, Bignotto M, Battezzati PM, Lleo A, Leung PS, Podda M, Gershwin ME, Invernizzi P.

PBC Screen: An IgG/IgA dual isotype ELISA detecting multiple mitochondrial and nuclear autoantibodies specific for primary biliary cirrhosis.

J Autoimmun. 2010 Dec;35(4):436-42. Epub 2010 Oct 6.

Raw IF (2009): 7.231 Normalized IF: 8 Selmi C.

The evidence does not support a viral etiology for

THROMBOSIS CENTRE Mendolicchio GL, Zavalloni D, Bacci M, Corrada E, Marconi M, Lodigiani C, Presbitero P, Rota L, Ruggeri ZM.

Variable effect of P2Y12 inhibition on platelet thrombus volume in flowing blood.

J Thromb Haemost. 2010 Nov 16. doi: 10.1111/j.15387836.2010.04144.x. [Epub ahead of print] Raw IF (2009): 6.069 Normalized IF: 6 Pignatelli P, Carnevale R, Di Santo S, Bartimoccia S, Sanguigni V, Lenti L, Finocchi A, Mendolicchio L, Soresina AR, Plebani A, Violi F.

Inherited Human gp91phox Deficiency Is Associated With Impaired Isoprostane Formation and Platelet Dysfunction.

Arterioscler Thromb Vasc Biol. 2010 Nov 11. [Epub ahead of print] Raw IF (2009): 7.235 Normalized IF: 4

95

Papers published 2010

Ruggeri ZM, Zarpellon A, Roberts JR, Mc Clintock RA, Jing H, Mendolicchio GL.

Unravelling the mechanism and significance of thrombin binding to platelet glycoprotein Ib.

Fraction from Adipose Tissues.

Tissue Eng Part C Methods. 2010 Dec;16(6):1515-21. Epub 2010 Sep 6.

Raw IF (2009): 4.582 Normalized IF: 3

Thromb Haemost. 2010 Nov 3;104(5):894-902. Epub 2010 Oct 12.

Raw IF (2009): 4.451 Normalized IF: 6 Pezzini A, Grassi M, Lodigiani C, Patella R, Gandolfo C, Casoni F, Musolino R, Calabrò RS, Bovi P, Adami A, Delodovici ML, Del Zotto E, Rota LL, Rasura M, Del Sette M, Giossi A, Volonghi I, Zini A, Cerrato P, Costa P, Magoni M, Iacoviello L, Padovani A; on behalf of the Italian Project on Stroke in Young Adults Investigators.

Predictors of Migraine Subtypes in Young Adults With Ischemic Stroke. The Italian Project on Stroke in Young Adults.

Stroke. 2011 Jan;42(1):17-21. Epub 2010 Nov 24.

Raw IF (2009): 7.041 Normalized IF: 8

Giovannetti E, Zucali PA, Peters GJ, Cortesi F, Dâ&#x20AC;&#x2122;Incecco A, Smit EF, Falcone A, Burgers JA, Santoro A, Danesi R, Giaccone G, Tibaldi C.

Association of Polymorphisms in AKT1 and EGFR with Clinical Outcome and Toxicity in Non-Small Cell Lung Cancer Patients Treated with Gefitinib.

Zucali PA, Giovannetti E, Assaraf YG, Ceresoli GL, Peters GJ, Santoro A.

NEUROSURGERY Gaetani P, Hulleman E, Levi D, Quarto M, Scorsetti M, Helins K, Simonelli M, Colombo P, Baena y Rodriguez R.

Expression of the transcription factor HEY1 in glioblastoma: a preliminary clinical study.

New tricks for old biomarkers: thymidylate synthase expression as a predictor of pemetrexed activity in malignant mesothelioma.

Ann Oncol. 2010 Jul;21(7):1560-1. Epub 2010 May 5.

Letter Raw IF (2009): 5.647 Normalized IF: 1.2

Normalized IF: 1

Di Ieva A, Grizzi F, Tschabitscher M, Colombo P, Casali M, Simonelli M, Widhalm G, Muzzio PC, Matula C, Chiti A, Rodriguez Y Baena R.

Correlation of microvascular fractal dimension with positron emission tomography [(11)C]-methionine uptake in glioblastoma multiforme: Preliminary findings.

Microvasc Res. 2010 Sep;80(2):267-73. Epub 2010 Apr 13.

Raw IF (2009): 3.075 Normalized IF: 6 Faustini M, Bucco M, Chlapanidas T, Lucconi G, Marazzi M, Tosca MC, Gaetani P, Klinger M, Villani S, Ferretti VV, Vigo D, Torre ML.

96

MEDICAL ONCOLOGY AND HAEMATOLOGY

Mol Cancer Ther. 2010 Mar;9(3):581-93. Epub 2010 Feb 16.

Raw IF (2009): 4.953 Normalized IF: 6

Neuroscience Area

Tumori. 2010 Jan-Feb;96(1):97-102.

Raw IF (2009): 0.863

Oncology Department

Nonexpanded Mesenchymal Stem Cells for Regenerative Medicine: Yield in Stromal Vascular

Petrini I, Zucali PA, Lee HS, Pineda MA, Meltzer PS, WalterRodriguez B, Roncalli M, Santoro A, Wang Y, Giaccone G.

Expression and Mutational Status of c-kit in Thymic Epithelial Tumors.

J Thorac Oncol. 2010 Sep;5(9):1447-53.

Raw IF (2009): 4.547

Normalized IF: 6

Zucali PA, Petrini I, Lorenzi E, Merino M, Cao L, Di Tommaso L, Lee HS, Incarbone M, Walter BA, Simonelli M, Roncalli M, Santoro A, Giaccone G.

Insulin-like growth factor-1 receptor and phosphorylated AKT-serine 473 expression in 132 resected thymomas and thymic carcinomas.

Cancer. 2010 Oct 15;116(20):4686-95.

Raw IF (2009): 5.418

Normalized IF: 6

Santoro A, Gullo G.

Norata GD, Garlanda C, Catapano AL.

Trastuzumab beyond progression: a challenge to translational oncology?

The Long Pentraxin PTX3: A Modulator of the Immunoinflammatory Response in Atherosclerosis and Cardiovascular Diseases.

Ann Oncol. 2010 Nov;21(11):2131-4. Epub 2010 Aug 23.

Raw IF (2009): 5.647 Normalized IF: 6 Zuradelli M, Peissel B, Manoukian S, Zaffaroni D, Barile M, Pensotti V, Cavallari U, Masci G, Mariette F, Benski AC, Santoro A, Radice P.

Four new cases of double heterozygosity for BRCA1 and BRCA2 gene mutations: clinical, pathological, and family characteristics.

Breast Cancer Res Treat. 2010 Nov;124(1):251-8. Epub 2010 Apr 7.

Raw IF (2009): 4.696 Normalized IF: 6

Trends Cardiovasc Med. 2010 Feb;20(2):35-40.

Raw IF (2009): 4.367 Normalized IF: 6 Hollan I, Bottazzi B, Cuccovillo I, Førre ØT, Mikkelsen K, Saatvedt K, Almdahl SM, Mantovani A, Meroni PL; Feiring Heart Biopsy Study Group.

Increased levels of serum pentraxin 3. a novel cardiovascular biomarker, in patients with inflammatory rheumatic disease.

Arthritis Care Res (Hoboken). 2010 Mar;62(3):378-85.

Raw IF (2009): 4.152 Normalized IF: 4 Locatelli M, Boiocchi L, Ferrero S, Martinelli Boneschi F, Zavanone M, Pesce S, Allavena P, Maria Gaini S, Bello L, Mantovani A.

Orthopaedic Area hip surgery Roato I, Caldo D, D’Amico L, D’Amelio P, Godio L, Patanè S, Astore F, Grappiolo G, Boggio M, Scagnelli R, Molfetta L, Ferracini R.

Osteoclastogenesis in peripheral blood mononuclear cell cultures of periprosthetic osteolysis patients and the phenotype of T cells localized in periprosthetic tissues.

Biomaterials. 2010 Oct;31(29):7519-25. Epub 2010 Jul 17.

Raw IF (2009): 7.365 Normalized IF: 4

Human glioma tumors express high levels of the chemokine receptor CX3CR1.

Eur Cytokine Netw. 2010 Mar 1;21(1):27-33.

Raw IF (2009): 1.436 Normalized IF: 2 Poliani PL, Kisand K, Marrella V, Ravanini M, Notarangelo LD, Villa A, Peterson P, Facchetti F.

Human Peripheral Lymphoid Tissues Contain Autoimmune Regulator-Expressing Dendritic Cells.

Am J Pathol. 2010 Mar;176(3):1104-12. Epub 2010 Jan 21.

Raw IF (2009): 5.673 Normalized IF: 3 Couëdel C, Roman C, Jones A, Vezzoni P, Villa A, Cortes P.

Analysis of mutations from SCID and Omenn syndrome patients reveals the central role of the Rag2 PHD domain in regulating V(D)J recombination.

Scientific Direction Research Laboratories Cassani B, Poliani PL, Moratto D, Sobacchi C, Marrella V, Imperatori L, Vairo D, Plebani A, Giliani S, Vezzoni P, Facchetti F, Porta F, Notarangelo LD, Villa A, Badolato R.

J Clin Invest. 2010 Apr;120(4):1337-44. doi: 10.1172/JCI41305.

Epub 2010 Mar 15.

Raw IF (2009): 15.387 Normalized IF: 7.5 Mauri T, Bellani G, Patroniti N, Coppadoro A, Peri G, Cuccovillo I, Cugno M, Iapichino G, Gattinoni L, Pesenti A, Mantovani A.

Defect of regulatory T cells in patients with Omenn syndrome.

Persisting high levels of plasma pentraxin 3 over the first days after severe sepsis and septic shock onset are associated with mortality.

J Allergy Clin Immunol. 2010 Jan;125(1):209-16.

Raw IF (2009): 9.165 Normalized IF: 8

Intensive Care Med. 2010 Apr;36(4):621-9. Epub 2010 Jan 30.

Raw IF (2009): 5.168 Normalized IF: 6

97

Papers published 2010

De Filippo C, Pini-Prato A, Mattioli G, Avanzini S, Rapuzzi G, Cavalieri D, Di Paola M, Stefanini I, Ceccherini I, Mavilio D, Lionetti P, Jasonni V.

Mauri T, Masson S, Pradella A, Bellani G, Coppadoro A, Bombino M, Valentino S, Patroniti N, Mantovani A, Pesenti A, Latini R.

Genomics approach to the analysis of bacterial communities dynamics in Hirschsprungâ&#x20AC;&#x2122;s diseaseassociated enterocolitis: a pilot study.

Elevated plasma and alveolar levels of soluble receptor for advanced glycation endproducts are associated with severity of lung dysfunction in ARDS patients.

Pediatr Surg Int. 2010 May;26(5):465-71. Epub 2010 Mar 20.

Raw IF (2009): 0.945 Normalized IF: 1

Tohoku J Exp Med. 2010;222(2):105-12.

Raw IF (2009): 1.347

Pulsatelli L, Peri G, Macchioni P, Boiardi L, Salvarani C, Cantini F, Mantovani A, Meliconi R.

Nebuloni M, Pasqualini F, Zerbi P, Lauri E, Mantovani A, Vago L, Garlanda C.

Serum levels of long pentraxin PTX3 in patients with polymyalgia rheumatica.

Normalized IF: 2

PTX3 expression in the heart tissues of patients with myocardial infarction and infectious myocarditis.

Clin Exp Rheumatol. 2010 Sep-Oct;28(5):756-8. Epub 2010 Oct 22.

Raw IF (2009): 2.396 Normalized IF: 1

Cardiovasc Pathol. 2011 Jan-Feb;20(1):e27-35. Epub 2010 Mar 30.

Raw IF (2009): 1.626 Normalized IF: 2

Barbui T, Carobbio A, Finazzi G, Vannucchi AM, Barosi G, Antonioli E, Guglielmelli P, Pancrazzi A, Salmoiraghi S, Zilio P, Ottomano C, Marchioli R, Cuccovillo I, Bottazzi B, Mantovani A, Rambaldi A.

Gagliano N, Costa F, Tartaglia GM, Pettinari L, Grizzi F, Sforza C, Portinaro N, Gioia M, Annoni G.

Inflammation and thrombosis in essential thrombocythemia and polycythemia vera: different role of C-reactive protein and Pentraxin 3.

Haematologica. 2010 Dec 20. [Epub ahead of print] Raw IF (2009): 6.416 Normalized IF: 3

Effects of aging and cyclosporin a on collagen turnover in human gingiva.

Open Dent J. 2009 Nov 5;3:219-26.

Raw IF (2009): 0

Normalized IF: 0.1

Di Ieva A, Grizzi F.

Microvessel density.

Erreni M, Solinas G, Brescia P, Osti D, Zunino F, Colombo P, Destro A, Roncalli M, Mantovani A, Draghi R, Levi D, Rodriguez Y Baena R, Gaetani P, Pelicci G, Allavena P.

Human glioblastoma tumours and neural cancer stem cells express the chemokine CX3CL1 and its receptor CX3CR1.

Eur J Cancer. 2010 Dec;46(18):3383-92. Epub 2010 Aug 19.

Raw IF (2009): 4.121 Normalized IF: 6

Masson S, Aleksova A, Favero C, Staszewsky L, Bernardinangeli M, Belvito C, Cioffi G, Sinagra G, Mazzone C, Bertocchi F, Vago T, Peri G, Cuccovillo I, Masuda N, Barlera S, Mantovani A, Maggioni AP, Franzosi MG, Disertori M, Latini R; on behalf of the GISSI-AF investigators.

Predicting atrial fibrillation recurrence with circulating inflammatory markers in patients in sinus rhythm at high risk for atrial fibrillation: data from the GISSI atrial fibrillation trial.

98

Heart. 2010 Dec;96(23):1909-14. Epub 2010 Oct 21.

Raw IF (2009): 5.385 Normalized IF: 3

J Neurosurg Pediatr. 2010 Sep;6(3):304-6; author reply 306.

Letter To The Editor (comments) Raw IF (2009): 0.171 Normalized IF: 0.2

Di Ieva A, Grizzi F, Sherif C, Matula C, Tschabitscher M.

Angioarchitectural heterogeneity in human glioblastoma multiforme: A fractal-based histopathological assessment.

Microvasc Res. 2010 Dec 28. [Epub ahead of print] Raw IF (2009): 3.075 Normalized IF: 6

Special Diagnostic and Treatment Services LABORATORY TESTS Bettio D, Venci A, Cariboni U, Di Rocco M, Infante M.

Fluorescent in situ hybridization (FISH) in the differential diagnosis of ground-glass opacities in the lung.

Lung Cancer. 2010 Jul 29. [Epub ahead of print] Raw IF (2009): 3.14 Normalized IF: 6 Monari M, Valaperta S, Assandri R, Montanelli A.

Diagnostic accuracy of a new commercially available HCV-antigen test.

Microbiologia Medica, Vol. 25 (1), 2010.

Raw IF (2009): 0

Normalized IF: 0.1

dynamic contrast imaging: The importance of tumor cell differentiation.

Hepatology. 2010 Nov;52(5):1723-30.

Raw IF (2009): 10.840

Normalized IF: 4

Colombo P, Ceresoli GL, Boiocchi L, Taverna G, Grizzi F, Bertuzzi A, Santoro A, Roncalli M.

Prostatic stromal tumor with fatal outcome in a young man: histopathological and immunohistochemical case presentation.

Rare Tumors. 2010 Dec 31;2(4):e57.

Raw IF (2009): 0

Normalized IF: 0.1

Di Tommaso L, Battista S, Annarita D, Sciarra A, Morenghi E, Roncalli M.

Cracking Spaces in Hashimoto Thyroiditis Are Lymphatic and Prelymphatic Vessels: A Gift of Immunohistochemistry for the Centenary of Hashimotoâ&#x20AC;&#x2122;s Description.

Am J Surg Pathol. 2010 Dec;34(12):1857-61.

Raw IF (2009): 4.062 Normalized IF: 6

PATHOLOGY Spano D, Russo R, Di Maso V, Rosso N, Terracciano LM, Roncalli M, Tornillo L, Capasso M, Tiribelli C, Iolascon A.

Galectin-1 and its involvement in hepatocellular carcinoma aggressiveness.

Mol Med. 2010 Mar;16(3-4):102-15. Epub 2009 Dec 21.

Raw IF (2009): 5.020 Normalized IF: 3 Di Tommaso L, Tresoldi D, Navligu CI, Destro A, Comi P, Morbiducci U, Roncalli M, Rizzo G.

A 3-D study of capsular invasion in follicular thyroid tumors. A novel approach to an old dilemma.

Pathologica. 2010 Jun;102(3):93-5.

Raw IF (2009): 0

Normalized IF: 0.1

Roncalli M, Park YN, Di Tommaso L.

Histopathological classification of hepatocellular carcinoma.

Dig Liver Dis. 2010 Jul;42 Suppl 3:S228-34.

Raw IF (2009): 2.972 Normalized IF: 6

Iavarone M, Sangiovanni A, Forzenigo LV, Massironi S, Fraquelli M, Aghemo A, Ronchi G, Biondetti P, Roncalli M, Colombo M.

Diagnosis of hepatocellular carcinoma in cirrhosis by

Specialised Divisions of Surgery UROLOGY Taverna GL, Grizzi F, Minuti F, Seveso M, Piccinelli A, Giusti G, Benetti A, Maugeri O, Pasini L, Zandegiacomo S, Colombo PG, Di Biccari S, Graziotti P.

PSA repeatedly fluctuating levels are reassuring enough to avoid biopsy?

Arch Ital Urol Androl. 2009 Dec;81(4):203-8.

Raw IF (2009): 0 Normalized IF: 0.1 Taverna G, Grizzi F, Colombo P, Graziotti PP.

Microvessel density estimate: friend or foe in the light of prostate vascular system complexity?

World J Urol. 2010 Jun;28(3):405-6. Epub 2010 Jan 21.

Letter To The Editor (comments) Raw IF (2009): 2.629 Normalized IF: 0.8

99

Papers published 2010

C l i n i c a l

R e s e a r c h

Cardiovascular Department

O’Connell J, Rogers J, Ross H, Russell S, Vanhaecke J.

The International Society of Heart and Lung Transplantation guidelines for the care of heart transplant recipients.

J Heart Lung Transplant. 2010 Aug;29(8):914-56.

Raw IF (2009): 3.541 Normalized IF: 3

CARDIAC SURGERY Malvindi PG, van Putte BP, Heijmen RH, Schepens MA, Morshuis WJ.

Reoperations for aortic false aneurysms after cardiac surgery.

Ann Thorac Surg. 2010 Nov;90(5):1437-43.

Raw IF (2009): 3.644 Normalized IF: 6 Raffa GM, Jackson V, Liska J, Eriksson MJ, Caidahl K, Eriksson P, Franco-Cereceda A.

Endothelin-1 and brain natriuretic peptide plasma levels decrease after aortic surgery.

J Heart Valve Dis. 2010 Nov;19(6):724-30.

Raw IF (2009): 1.033

Domino heart transplantation: long-term outcome of recipients and their living donors: single center experience.

Normalized IF: 2

CLINICAL CARDIOLOGY II Gronda E, Aronica A, Visconti M, Di Malta A, Pini D, Mangiavacchi M, Andreuzzi B, Municinò A, Genovese S, Morenghi E.

[Gender differences of at risk patients with overt heart failure in the real world of general practice. Data from the GIPSI (Gestione Integrata Progetto Scompenso in Italia) registry] G Ital Cardiol (Rome). 2010 Mar;11(3):233-8. Italian.

Raw IF (2009): 0 Normalized IF: 0.1

100

Gasparini M, Cappelleri A.

Atrial arrhythmias after cardiac resynchronization therapy: an inverse correlation with achieving 100% biventricular pacing and cardiac resynchronization therapy effectiveness.

Europace. 2010 Jan;12(1):9-10.

Raw IF (2009): 1.871

Normalized IF: 2

Normalized IF: 1

Raffa GM, Pellegrini C, Viganò M.

Transplant Proc. 2010 Nov;42(9):3688-93.

Raw IF (2009): 0.994

ELECTROPHYSIOLOGY AND ELECTROSTIMULATION

Costanzo MR, Costanzo MR, Dipchand A, Starling R, Anderson A, Chan M, Desai S, Fedson S, Fisher P, Gonzales-Stawinski G, Martinelli L, McGiffin D, Smith J, Taylor D, Meiser B, Webber S, Baran D, Carboni M, Dengler T, Feldman D, Frigerio M, Kfoury A, Kim D, Kobashigawa J, Shullo M, Stehlik J, Teuteberg J, Uber P, Zuckermann A, Hunt S, Burch M, Bhat G, Canter C, Chinnock R, Crespo-Leiro M, Delgado R, Dobbels F, Grady K, W K, Lamour J, Parry G, Patel J, Pini D, Towbin J, Wolfel G, Delgado D, Eisen H, Goldberg L, Hosenpud J, Johnson M, Keogh A, Lewis C,

Maines M, Landolina M, Lunati M, Lonardi G, Pappone A, Proclemer A, Zanotto G, Santini M, Varbaro A, Vimercati M, Valsecchi S; Italian Clinical Service Optivol-CRT Group: (Gasparini M, Ceriotti C, Regoli F).

Intrathoracic and ventricular impedances are associated with changes in ventricular volume in patients receiving defibrillators for CRT. Pacing Clin Electrophysiol. 2010 Jan;33(1):64-73. Epub 2009 Oct 10.

Raw IF (2009): 1.578 Normalized IF: 0.4 Gasparini M, Steinberg JS, Arshad A, Regoli F, Galimberti P, Rosier A, Daubert JC, Klersy C, Kamath G, Leclercq C.

Resumption of sinus rhythm in patients with heart failure and permanent atrial fibrillation undergoing cardiac resynchronization therapy: a longitudinal observational study.

Eur Heart J. 2010 Apr;31(8):976-83. Epub 2010 Jan 12.

Raw IF (2009): 9.800 Normalized IF: 8 Iacopino S, Gasparini M, Zanon F, Dicandia C, Distefano G, Curnis A, Donati R, Neja CP, Calvi V, Davinelli M, Novelli V, Muto C.

Low-dose dobutamine stress echocardiography to assess left ventricular contractile reserve for cardiac resynchronization therapy: data from the Low-Dose Dobutamine Stress Echocardiography to Predict Cardiac Resynchronization Therapy Response (LODOCRT) trial.

Congest Heart Fail. 2010 May;16(3):104-10.

Raw IF (2009): 0 Normalized IF: 0.1

Gasparini M, Anselme F, Clementy J, Santini M, MartĂ­nezFerrer J, De Santo T, Santi E, Schwab JO; ADVANCE CRT-D Investigators.

BIVentricular versus right ventricular antitachycardia pacing to terminate ventricular tachyarrhythmias in patients receiving cardiac resynchronization therapy: the ADVANCE CRT-D Trial.

Am Heart J. 2010 Jun;159(6):1116-1123.e2.

Raw IF (2009): 4.357 Normalized IF: 6 Schwartz PJ, Spazzolini C, Priori SG, Crotti L, Vicentini A, Landolina M, Gasparini M, Wilde AA, Knops RE, Denjoy I, Toivonen L, MĂśnnig G, Al-Fayyadh M, Jordaens L, Borggrefe M, Holmgren C, Brugada P, De Roy L, Hohnloser SH, Brink PA.

Who are the long-QT syndrome patients who receive an implantable cardioverter-defibrillator and what happens to them?: data from the European Long-QT Syndrome Implantable Cardioverter-Defibrillator (LQTS ICD) Registry.

Circulation. 2010 Sep 28;122(13):1272-82. Epub 2010 Sep 13.

Raw IF (2009): 14.816 Normalized IF: 5 Authors/Task Force Members, Dickstein K, Vardas PE, Auricchio A, Daubert JC, Linde C, McMurray J, Ponikowski P, Priori SG, Sutton R, van Veldhuisen DJ; ESC Committee for Practice Guidelines (CPG), Vahanian A, Auricchio A, Bax J, Ceconi C, Dean V, Filippatos G, Funck-Brentano C, Hobbs R, Kearney P, McDonagh T, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Vardas P, Widimsky P; Document Reviewers, Tendera M, Anker SD, Blanc JJ, Gasparini M, Hoes AW, Israel CW, Kalarus Z, Merkely B, Swedberg K, Camm AJ.

2010 Focused Update of ESC Guidelines on device therapy in heart failure: An update of the 2008 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure and the 2007 ESC Guidelines for cardiac and resynchronization therapy* * Developed with the special contribution of the Heart Failure Association and the European Heart Rhythm Association.

Guidelines for the diagnosis and treatment of acute and chronic heart failure and the 2007 ESC Guidelines for cardiac and resynchronization therapy * Developed with the special contribution of the Heart Failure Association and the European Heart Rhythm Association.

Europace. 2010 Nov;12(11):1526-36.

Raw IF (2009): 1.871

Normalized IF: 0.4

Authors/Task Force Members, Dickstein K, Vardas PE, Auricchio A, Daubert JC, Linde C, McMurray J, Ponikowski P, Priori SG, Sutton R, van Veldhuisen DJ; ESC Committee for Practice Guidelines (CPG), Vahanian A, Auricchio A, Bax J, Ceconi C, Dean V, Filippatos G, Funck-Brentano C, Hobbs R, Kearney P, McDonagh T, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Vardas P, Widimsky P; Document Reviewers, Tendera M, Anker SD, Blanc JJ, Gasparini M, Hoes AW, Israel CW, Kalarus Z, Merkely B, Swedberg K, Camm AJ.

2010 Focused Update of ESC guidelines on device therapy in heart failure: An update of the 2008 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure and the 2007 ESC guidelines for cardiac and resynchronization therapy* * Developed with the special contribution of the Heart Failure Association and the European Heart Rhythm Association.

Eur Heart J. 2010 Nov;31(21):2677-87. Epub 2010 Aug 27.

Raw IF (2009): 9.8 Normalized IF: 1.6 Muto C, Gasparini M, Neja CP, Iacopino S, Davinelli M, Zanon F, Dicandia C, Distefano G, Donati R, Calvi V, Denaro A, Tuccillo B.

Presence of left ventricular contractile reserve predicts midterm response to cardiac resynchronization therapy-results from the LOw dose DObutamine StressEcho in Cardiac Resynchronization Therapy (LODOCRT) Trial.

Heart Rhythm. 2010 Nov;7(11):1600-5. Epub 2010 Aug 3.

Raw IF (2009): 4.559 Normalized IF: 6

Eur J Heart Fail. 2010 Nov;12(11):1143-53.

Raw IF (2009): 3.706 Normalized IF: 1.2 Authors/Task Force Members, Dickstein K, Vardas PE, Auricchio A, Daubert JC, Linde C, McMurray J, Ponikowski P, Priori SG, Sutton R, van Veldhuisen DJ; ESC Committee for Practice Guidelines (CPG), Vahanian A, Auricchio A, Bax J, Ceconi C, Dean V, Filippatos G, Funck-Brentano C, Hobbs R, Kearney P, McDonagh T, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Vardas P, Widimsky P; Document Reviewers, Tendera M, Anker SD, Blanc JJ, Gasparini M, Hoes AW, Israel CW, Kalarus Z, Merkely B, Swedberg K, Camm AJ.

2010 Focused Update of ESC Guidelines on device therapy in heart failure: An update of the 2008 ESC

HAEMODYNAMICS AND INVASIVE CARDIOLOGY Chieffo A, Hoye A, Mauri F, Mikhail GW, Ammerer M, Grines C, Grinfeld L, Madan M, Presbitero P, Skelding KA, Weiner BH, Mehran R; on behalf of the WIN Group.

Gender-based issues in interventional cardiology: A consensus statement from the Women in Innovations (WIN) Initiative.

Catheter Cardiovasc Interv. 2010 Feb 1;75(2):145-152.

Raw IF (2009): 2.363 Normalized IF: 4

101

Papers published 2010

Chieffo A, Hoye A, Mauri F, Mikhail GW, Ammerer M, Grines C, Grinfeld L, Madan M, Presbitero P, Skelding KA, Weiner BH, Mehran R.

Gender-based issues in interventional cardiology: a consensus statement from the Women in Innovations (WIN) initiative.

EuroIntervention. 2010 Feb;5(7):773-9.

Raw IF (2009): 0

Normalized IF: 0.1

Chieffo A, Hoye A, Mauri F, Mikhail G, Ammerer M, Grines C, Grinfeld L, Madan M, Presbitero P, Skelding KA, Weiner BH, Mehran R.

Gender-Based Issues in Interventional Cardiology: a Consensus Statement from the Women in Innovations (WIN) Initiative.

Rev Esp Cardiol. 2010 Feb;63(2):200-208. English, Spanish.

Raw IF (2009): 2.746 Normalized IF: 2 Chieffo A, Hoye A, Mauri F, Mikhail G, Ammerer M, Grines C, Grinfeld L, Madan M, Presbitero P, Skelding KA, Weiner BH, Mehran R.

Cuestiones relativas al sexo en cardiología intervencionista: declaración de consenso de la iniciativa Women in Innovations (WIN).

Rev Esp Cardiol. 2010 Feb;63(2):200-208. English, Spanish.

Raw IF (2009): 2.746 Normalized IF: 2

Percutaneous aortic valve in severe valvular regurgitation caused by infective endocarditis.

Int J Cardiol. 2010 Mar 18. [Epub ahead of print] Raw IF (2009): 3.469 Normalized IF: 6 Topol EJ, Bousser MG, Fox KA, Creager MA, Despres JP, Easton JD, Hamm CW, Montalescot G, Steg PG, Pearson TA, Cohen E, Gaudin C, Job B, Murphy JH, Bhatt DL; CRESCENDO Investigators (Marco Rossi).

Rimonabant for prevention of cardiovascular events (CRESCENDO): a randomised, multicentre, placebocontrolled trial.

Lancet. 2010 Aug 14;376(9740):517-23.

Raw IF (2009): 30.758

Normalized IF: 3

CURRENT-OASIS 7 Investigators, Mehta SR, Bassand JP, Chrolavicius S, Diaz R, Eikelboom JW, Fox KA, Granger CB, Jolly S, Joyner CD, Rupprecht HJ, Widimsky P, Afzal R, Pogue J, Yusuf S.(Marco Rossi Collaborator).

Dose comparisons of clopidogrel and aspirin in acute coronary syndromes.

N Engl J Med. 2010 Sep 2;363(10):930-42. Erratum in: N Engl J Med. 2010 Oct 14;363(16):1585.

Raw IF (2009): 47.050 Normalized IF: 3

Gerstein HC, Ratner RE, Cannon CP, Serruys PW, GarcíaGarcía HM, van Es GA, Kolatkar NS, Kravitz BG, Miller DM, Huang C, Fitzgerald PJ, Nesto RW; APPROACH Study Group (Presbitero P, Genovese S).

Pagnotta P, Briguori C, Mango R, Visconti G, Focaccio A, Belli G, Presbitero P.

Effect of rosiglitazone on progression of coronary atherosclerosis in patients with type 2 diabetes mellitus and coronary artery disease: the assessment on the prevention of progression by rosiglitazone on atherosclerosis in diabetes patients with cardiovascular history trial.

Catheter Cardiovasc Interv. 2010 Sep 1;76(3):366-371.

Raw IF (2009): 2.363 Normalized IF: 4

Circulation. 2010 Mar 16;121(10):1176-87. Epub 2010 Mar 1.

Raw IF (2009): 14.816 Normalized IF: 2 Lablanche JM, Leone A, Merkely B, Morais J, Alonso J, Santini M, Eha J, Demil N, Licour M, Tardif JC; CENTAURUS investigators (Presbitero P).

Comparison of the efficacy of rosuvastatin versus atorvastatin in reducing apolipoprotein B/ apolipoprotein A-1 ratio in patients with acute coronary syndrome: results of the CENTAURUS study.

102

Presbitero P, Mennuni MG, Pagnotta P, Gasparini GL, Ramondo A.

Arch Cardiovasc Dis. 2010 Mar;103(3):160-9. Epub 2010 Apr 8.

Raw IF (2009): 0.663 Normalized IF: 0.2

Rotational atherectomy in resistant chronic total occlusions.

Romagnoli E, De Servi S, Tamburino C, Colombo A, Burzotta F, Presbitero P, Bolognese L, Paloscia L, Rubino P, Sardella G, Briguori C, Ettori F, Franco G, Di Girolamo D, Sheiban I, Piatti L, Greco C, Petronio S, Loi B, Lioy E, Benassi A, Patti A, Gaspardone A, Capodanno D, Biondi-Zoccai GG, Sangiorgi G; I-BIGIS Study Group Milan, Italy.

Real-world outcome of coronary bifurcation lesions in the drug-eluting stent era: Results from the 4.314patient Italian Society of Invasive Cardiology (SICI-GISE) Italian Multicenter Registry on Bifurcations (I-BIGIS).

Am Heart J. 2010 Sep;160(3):535-542.e1.

Raw IF (2009): 4.357 Normalized IF: 1.2 Politi A, Martinoni A, Klugmann S, Zanini R, Onofri M, Guagliumi G, Fiorentini C, Lettieri C, Belli G, Piccaluga E,

De Cesare N, D’urbano M, Ettori F, Repetto A, Musumeci G, Castiglioni B, Colombo P, Passamonti E, Bramucci E, Cattaneo L, Ferrari G, Repetto S, Bartorelli A, Pirelli S, De Servi S; on behalf of the LombardIMA Study Group.

LombardIMA: a regional registry for coronary angioplasty in ST-elevation myocardial infarction.

J Cardiovasc Med (Hagerstown). 2010 Oct 7. [Epub ahead of print] Raw IF (2009): 0 Normalized IF: 0.1 Ferrante G, Zavalloni D, Corrada E, Presbitero P.

Rosiglitazone plus metformin to prevent type 2 diabetes mellitus.

Lancet. 2010 Oct 23;376(9750):1387-8. Letter To The Editor (comments) Raw IF (2009): 30.758 Normalized IF: 3

VASCULAR SURGERY Capsoni F, Poletto G, Giorgetti PL.

Fibromuscular dysplasia: a rare disease that can mimic vasculitis.

Rheumatol Int. 2010 May 19. [Epub ahead of print] Raw IF (2009): 1.493 Normalized IF: 2

Diagnostic Imaging Department RADIOLOGY AND DIAGNOSTIC IMAGING Livraghi T, Ceriani R, Palmisano A, Pedicini V, Pich MG, Tommasini MA, Torzilli G.

Complete Response in 5 Out of 38 Patients with Advanced Hepatocellular Carcinoma Treated with Stem Cell Differentiation Stage Factors: Case Reports from a Single Centre.

Curr Pharm Biotechnol. 2010 Nov 2. [Epub ahead of print] Raw IF (2009): 3.404 Normalized IF: 6 Livraghi T, Brambilla G, Carnaghi C, Tommasini MA, Torzilli G.

Is it time to reconsider the BCLC/AASLD therapeutic flow-chart?

J Surg Oncol. 2010 Dec 1;102(7):868-76.

Raw IF (2009): 2.502

Normalized IF: 6

Gastroenterology Department Sorrentino D, Paviotti A, Fiorino G.

Anti-TNF’s for Postoperative Recurrence in Crohn’s Disease: The If’s and How’s.

Curr Drug Targets. 2010 Feb 1;11(2):219-26. Epub 2009 Nov 17.

Raw IF (2009): 3.932 Normalized IF: 6

Fiorino G, Fries W, De La Rue SA, Malesci AC, Repici A, Danese S.

New Drug Delivery Systems in Inflammatory Bowel Disease: MMX() and Tailored Delivery to the Gut. Curr Med Chem. 2010;17(17):1851-7.

Raw IF (2009): 4.708

Normalized IF: 6

Dignass A, Van Assche G, Lindsay JO, Lémann M, Söderholm J, Colombel JF, Danese S, D’Hoore A, Gassull M, Gomollón F, Hommes DW, Michetti P, O’Morain C, Öresland T, Windsor A, Stange EF, Travis SPL for the European Crohn’s and Colitis Organisation (ECCO).

The second European evidence-based consensus on the diagnosis and management of Crohn’s disease: Current management Journal of Crohn’s and Colitis (2010) 4. 28–62 Raw IF (2009): 1.729 Normalized IF: 1

Fries W, La Malfa G, Costantino G, Repici A, Mazziotti S, Navarra G.

Combined approach with biologics and surgery for enterocutaneous fistulas in Crohn’s disease.

Inflamm Bowel Dis. 2010 Apr 9. [Epub ahead of print] Raw IF (2009): 4.643 Normalized IF: 3

Repici A, Hassan C, Carlino A, Pagano N, Zullo A, Rando G, Strangio G, Romeo F, Nicita R, Rosati R, Malesci A.

Endoscopic submucosal dissection in patients with early esophageal squamous cell carcinoma: results from a prospective Western series.

Gastrointest Endosc. 2010 Apr;71(4):715-21.

Raw IF (2009): 6.713 Normalized IF: 6

Repici A, Presbitero P, Carlino A, Strangio G, Rando G, Pagano N, Romeo F, Rosati R.

First human case of esophagus-tracheal fistula closure

103

Papers published 2010

by using a cardiac septal occluder (with video).

Gastrointest Endosc. 2010 Apr;71(4):867-9. Epub 2010 Feb 24.

Raw IF (2009): 6.713 Normalized IF: 6 Danese S, Fiorino G, Angelucci E, Vetrano S, Pagano N, Rando G, Spinelli A, Malesci A, Repici A.

Narrow-band imaging endoscopy to assess mucosal angiogenesis in inflammatory bowel disease: A pilot study.

Current practice with endoscopic submucosal dissection in Europe: position statement from a panel of experts.

Endoscopy. 2010 Jul 9. [Epub ahead of print] Raw IF (2009): 5.545 Normalized IF: 3

World J Gastroenterol. 2010 May 21;16(19):2396-400.

Raw IF (2009): 2.092 Normalized IF: 4

Fuccio L, Repici A, Cennamo V.

Conio M, Blanchi S, Repici A, Bastardini R, Marinari GM.

Am J Gastroenterol. 2010 Jul;105(7):1670; author reply 1670-1.

Letter (comment) Raw IF (2009): 6.012 Normalized IF: 1.2

Use of an over-the-scope clip for endoscopic sealing of a gastric fistula after sleeve gastrectomy.

Endoscopy. 2010;42 Suppl 2:E71-2. Epub 2010 Mar 1.

Raw IF (2009): 5.545 Normalized IF: 3

Concerns on the very high complication rates reported after self-expanding metal stent (SEMS) placement for colorectal cancer in a Catalan retrospective study.

Peyrin-Biroulet L, Danese S.

Conio M, Blanchi S, Repici A, Ruggeri C, Fisher DA, Filiberti R.

Infliximab and azathioprine for crohn’s disease: a supersonic combination?

Cap-assisted endoscopic mucosal resection for colorectal polyps.

Gastroenterology. 2010 Jul 23. [Epub ahead of print] Raw IF (2009): 12.899 Normalized IF: 10

Dis Colon Rectum. 2010 Jun;53(6):919-27.

Raw IF (2009): 2.536

Normalized IF: 3

Parodi A, Repici A, Pedroni A, Blanchi S, Conio M.

Endoscopic management of GI perforations with a new over-the-scope clip device (with videos ).

Gastrointest Endosc. 2010 Jun 18. [Epub ahead of print] Raw IF (2009): 6.713 Normalized IF: 6 Repici A, Hassan C, Sharma P, Conio M, Siersema P.

Systematic review: self-expanding plastic stent for benign oesophageal strictures.

Aliment Pharmacol Ther. 2010 Jun;31(12):1268-75. Epub 2010 Mar 17.

Raw IF (2009): 4.357 Normalized IF: 6

104

Deprez PH, Bergman JJ, Meisner S, Ponchon T, Repici A, Ribeiro MD, Haringsma J.

Repici A, Pagano N, Romeo F, Danese S, Arosio M, Rando G, Strangio G, Carlino A, Malesci A.

Endoscopic flexible treatment of Zenker’s diverticulum: a modification of the needle-knife technique.

Endoscopy. 2010 Jul;42(7):532-535. Epub 2010 Jun 30.

Raw IF (2009): 5.545 Normalized IF: 6 Jackson CS, Fryer J, Danese S, Vanagunas A, Polensky S, Buchman AL.

Mesenteric Vascular Thromboembolism in Inflammatory Bowel Disease: A Single Center Experience.

J Gastrointest Surg. 2010 Sep 8. [Epub ahead of print] Raw IF (2009): 2.402 Normalized IF: 3

Tursi A, Brandimarte G, Papa A, Giglio A, Elisei W, Giorgetti GM, Forti G, Morini S, Hassan C, Pistoia MA, Modeo ME, Rodino’ S, D’Amico T, Sebkova L, Sacca’ N, Di Giulio E, Luzza F, Imeneo M, Larussa T, Di Rosa S, Annese V, Danese S, Gasbarrini A.

Matthieu Allez, Konstantinos Karmiris, Edouard Louis, Gert Van Assche, Shomron Ben-Horin, Amir Klein, Janneke Van der Woude, Filip Baert, Rami Eliakim, Konstantinos Katsanos, Jørn Brynskov, Flavio Steinwurz, Silvio Danese, Severine Vermeire, Jean-Luc Teillaud, Marc Lémann, Yehuda Chowers

Treatment of Relapsing Mild-to-Moderate Ulcerative Colitis With the Probiotic VSL#3 as Adjunctive to a Standard Pharmaceutical Treatment: A Double-Blind, Randomized, Placebo-Controlled Study.

Report of the ECCO pathogenesis workshop on antiTNF therapy failures in inflammatory bowel diseases: Definitions, frequency and pharmacological aspects.

Am J Gastroenterol. 2010 Jun 1. [Epub ahead of print] Raw IF (2009): 6.012 Normalized IF: 3

Journal of Crohn’s and Colitis 2010 October (Vol. 4. Issue 4.

Pages 355-366) Raw IF (2009): 1.729 Normalized IF: 1

Repici A.

Endoscopic treatment of zenker diverticulum.

Gastroenterol Hepatol (N Y). 2010 Oct;6(10):628-30.

Raw IF (2009): 0 Normalized IF: 0.1 Fiorino G, Bonifacio C, Peyrin-Biroulet L, Minuti F, Repici A, Spinelli A, Fries W, Balzarini L, Montorsi M, Malesci A, Danese S.

Prospective comparison of computed tomography enterography and magnetic resonance enterography for assessment of disease activity and complications in ileocolonic Crohn’s disease.

Inflamm Bowel Dis. 2010 Nov 8. [Epub ahead of print] Raw IF (2009): 4.643 Normalized IF: 6 Frulloni L, Falconi M, Gabbrielli A, Gaia E, Graziani R, Pezzilli R, Uomo G, Andriulli A, Balzano G, Benini L, Calculli L, Campra D, Capurso G, Cavestro GM, De Angelis C, Ghezzo L, Manfredi R, Malesci A, Mariani A, Mutignani M, Ventrucci M, Zamboni G, Amodio A, Vantini I; Italian Association for the Study of the Pancreas (AISP), Bassi C, Delle Fave G, Frulloni L, Vantini I, Falconi M, Frulloni L, Gabbrielli A, Graziani R, Pezzilli R, Capurso IV, Cavestro GM, De Angelis C, Falconi M, Gaia E, Ghezzo L, Gabbrielli A, Graziani R, Manfredi R, Malesci A, Mariani A, Mutignani M, Pezzilli R, Uomo G, Ventrucci M, Zamboni G, Vantini I, Magarini F, Albarello L, Alfieri S, Amodio A, Andriulli A, Anti M, Arcidiacono P, Baiocchi L, Balzano G, Benini L, Berretti D, Boraschi P, Buscarini E, Calculli L, Carroccio A, Campra D, Celebrano MR, Capurso G, Casadei R, Cavestro GM, Chilovi F, Conigliaro R, Dall’Oglio L, De Angelis C, De Boni M, De Pretis G, Di Priolo S, Di Sebastiano PL, Doglietto GB, Falconi M, Filauro M, Frieri G, Frulloni L, Fuini A, Gaia E, Ghezzo L, Gabbrielli A, Graziani R, Loriga P, Macarri G, Manes G, Manfredi R, Malesci A, Mariani A, Massucco P, Milani S, Mutignani M, Pasquali C, Pederzoli P, Pezzilli R, Pietrangeli M, Rocca R, Russello D, Siquini W, Traina M, Uomo G, Veneroni L, Ventrucci M, Zilli M, Zamboni G.

Pariente B, Cosnes J, Danese S, Sandborn WJ, Lewin M, Fletcher JG, Chowers Y, D’Haens G, Feagan BG, Hibi T, Hommes DW, Irvine EJ, Kamm MA, Loftus EV Jr, Louis E, Michetti P, Munkholm P, Oresland T, Panés J, Peyrin-Biroulet L, Reinisch W, Sands BE, Schoelmerich J, Schreiber S, Tilg H, Travis S, van Assche G, Vecchi M, Mary JY, Colombel JF, Lémann M.

Development of the crohn’s disease digestive damage score, the Lémann score.

Inflamm Bowel Dis. 2010 Nov 28. [Epub ahead of print] Raw IF (2009): 4.643 Normalized IF: 3 Repici A, Vleggaar FP, Hassan C, van Boeckel PG, Romeo F, Pagano N, Malesci A, Siersema PD.

Efficacy and safety of biodegradable stents for refractory benign esophageal strictures: the BEST (Biodegradable Esophageal Stent) study.

Gastrointest Endosc. 2010 Nov;72(5):927-34.

Raw IF (2009): 6.713 Normalized IF: 6 Spada C, Hassan C, Ingrosso M, Repici A, Riccioni ME, Pennazio M, Pirozzi GA, Pagano N, Cesaro P, Spera G, Petruzziello L, Costamagna G.

A new regimen of bowel preparation for PillCam colon capsule endoscopy: A pilot study.

Dig Liver Dis. 2010 Nov 17. [Epub ahead of print] Raw IF (2009): 2.972 Normalized IF: 3 Ansaloni L, Andersson RE, Bazzoli F, Catena F, Cennamo V, Di Saverio S, Fuccio L, Jeekel H, Leppaniemi A, Moore E, Pinna AD, Pisano M, Repici A, Sugarbaker PH, Tuech JJ.

Italian consensus guidelines for chronic pancreatitis.

Guidelines in the Management of Obstructing Cancer of the Left Colon: Consensus Conference of the World Society of Emergency Surgery (WSES) and Peritoneum and Surgery (PnS) Society.

Dig Liver Dis. 2010 Nov;42 Suppl 6:S381-406.

Raw IF (2009): 2.972 Normalized IF: 6

World J Emerg Surg. 2010 Dec 28;5(1):29. [Epub ahead of print] Raw IF (2009): 0 Normalized IF: 0.1

Leufkens AM, Demarco DC, Rastogi A, Akerman PA, Azzouzi K, Rothstein RI, Vleggaar FP, Repici A, Rando G, Okolo PI, Dewit O, Ignjatovic A, Odstrcil E, East J, Deprez PH, Saunders BP, Kalloo AN, Creel B, Singh V, Lennon AM, Siersema PD; (The Third Eye Retroscope Randomized Clinical Evaluation (TERRACE) Study Group).

Effect of a retrograde-viewing device on adenoma detection rate during colonoscopy: the TERRACE study.

Gastrointest Endosc. 2010 Nov 8. [Epub ahead of print] Raw IF (2009): 6.713 Normalized IF: 6

Kopylov U, Mantzaris GJ, Katsanos KH, Reenaers C, Ellul P, Rahier JF, Israeli E, Lakatos PL, Fiorino G, Cesarini M, Tsianos EV, Louis E, Ben-Horin S.

The efficacy of shortening the dosing interval to once every six weeks in Crohn’s patients losing response to maintenance dose of infliximab.

Aliment Pharmacol Ther. 2010 Dec 1. doi: 10.1111/j.13652036.2010.04523.x. [Epub ahead of print] Raw IF (2009): 4.357 Normalized IF: 3

105

Repici A, Pagano N, Fumagalli U, Peracchia A, Narne S, Malesci A, Rosati R.

Transoral treatment of Zenker diverticulum: flexible endoscopy versus endoscopic stapling. A retrospective comparison of outcomes.

Dis Esophagus. 2010 Dec 10. doi: 10.1111/j.14422050.2010.01143.x. [Epub ahead of print] Raw IF (2009): 1.493 Normalized IF: 2 Cottone M, Kohn A, Daperno M, Armuzzi A, Guidi L, D’Inca R, Bossa F, Angelucci E, Biancone L, Gionchetti P, Ardizzone S, Papi C, Fries W, Danese S, Rigler G, Cappello M, Castiglione F, Annese V, Orlando A.

Advanced age is an independent risk factor for severe infections and mortality in patients given anti-tumor necrosis factor therapy for inflammatory bowel disease.

Clin Gastroenterol Hepatol. 2011 Jan;9(1):30-5. Epub 2010 Oct 15.

Raw IF (2009): 5.642 Normalized IF: 3

World J Gastroenterol. 2010 Aug 14;16(30):3857-8.

Letter to the Editor (comments) Raw IF (2009): 2.092 Normalized IF: 0.8 Zerbi A, Pecorelli N.

Pancreatic metastases: An increasing clinical entity.

World J Gastrointest Surg. 2010 Aug 27;2(8):255-9.

Raw IF (2009): 0 Normalized IF: 0.1 Del Chiaro M, Zerbi A, Capurso G, Zamboni G, Maisonneuve P, Presciuttini S, Arcidiacono PG, Calculli L, Falconi M.

Familial pancreatic cancer in Italy. Risk assessment, screening programs and clinical approach: A position paper from the Italian Registry.

Dig Liver Dis. 2010 Sep;42(9):597-605. Epub 2010 Jun 2.

Raw IF (2009): 2.972 Normalized IF: 6 Gabbrielli A, Pezzilli R, Uomo G, Zerbi A, Frulloni L, Rai PD, Castoldi L, Costamagna G, Bassi C, Carlo VD.

ERCP in acute pancreatitis: What takes place in routine clinical practice?

GENERAL SURGERY III Donadon M, Bona S, Montorsi M, Torzilli G.

FDG-PET positive granuloma of the liver mimicking local recurrence after hepatic resection of colorectal liver metastasis.

Hepatogastroenterology. 2010 Jan-Feb;57(97):138-9.

Raw IF (2009): 0.669 Normalized IF: 2 Torzilli G, Donadon M, Montorsi M, Makuuchi M.

Concerns About Ultrasound-Guided RadiofrequencyAssisted Segmental Liver Resection.

Ann Surg. 2010 Jun;251(6):1191-2; author reply 1192-3. Letter to the Editor (comments) Raw IF (2009): 7.9 Normalized IF: 1.6 Botea F, Marconi M, Lutman F, Balzarini L, Roncalli M, Montorsi M, Torzilli G.

Radiological estimation of size in colorectal liver metastases: is it reliable? Comparison with postresectional measurements.

Updates Surg. 2010 Aug;62(1):21-6.

Raw IF (2009): 0

Normalized IF: 0.1

Donadon M, Torzilli G.

106

Reply to “Application of contrast-enhanced intraoperative ultrasonography in the decision-making about hepatocellular carcinoma operation”.

World J Gastrointest Endosc. 2010 Sep 16;2(9):308-13.

Raw IF (2009): 0 Normalized IF: 0.1 Zerbi A, Capitanio V, Boninsegna L, Pasquali C, Rindi G, Delle Fave G, Del Chiaro M, Casadei R, Falconi M; AISP Network Study Group.

Surgical treatment of pancreatic endocrine tumours in Italy: results of a prospective multicentre study of 262 cases.

Langenbecks Arch Surg. 2010 Sep 21. [Epub ahead of print] Commentary Raw IF (2009): 1.572 Normalized IF: 0.8 Dapri G, Carnevali P, Himpens J, Bianchi P, Opocher E, Montorsi M, Cadière GB.

Single-Access Transumbilical Diagnostic Laparoscopy for Pancreatic Tumor Using Curved and Reusable Instruments.

Ann Surg Oncol. 2010 Nov 16. [Epub ahead of print] Raw IF (2009): 4.130 Normalized IF: 3 De Rai P, Zerbi A, Castoldi L, Bassi C, Frulloni L, Uomo G, Gabbrielli A, Pezzilli R, Cavallini G, Di Carlo V; the ProInf-AISP (Progetto Informatizzato Pancreatite Acuta, Associazione Italiana per lo Studio del Pancreas [Computerized Project on Acute Pancreatitis, Italian Association for the Study of the Pancreas]) Study Group.

Surgical management of acute pancreatitis in Italy:

lessons from a prospective multicentre study.

HPB (Oxford). 2010 Nov;12(9):597-604. doi: 10.1111/j.14772574.2010.00201.x. Epub 2010 Sep 2.

Raw IF (2009): 0 Normalized IF: 0.1 Torzilli G, Garancini M, Donadon M, Cimino M, Procopio F, Montorsi M.

Intraoperative ultrasonographic detection of communicating veins between adjacent hepatic veins during hepatectomy for tumours at the hepatocaval confluence.

Br J Surg. 2010 Dec;97(12):1867-73. doi: 10.1002/bjs.7230. Epub 2010 Aug 26.

Raw IF (2009): 4.077 Normalized IF: 6 Pezzilli R, Zerbi A, Di Carlo V, Bassi C, Delle Fave GF.

Fiocca R, Mastracci L, Engstrรถm C, Attwood S, Ell C, Galmiche JP, Hatlebakk J, Junghard O, Lind T, Lundell L; LOTUS trial collaborators (Rosati R).

Long-term outcome of microscopic esophagitis in chronic GERD patients treated with esomeprazole or laparoscopic antireflux surgery in the LOTUS trial.

Am J Gastroenterol. 2010 May;105(5):1015-23. Epub 2009 Nov 10.

Raw IF (2009): 6.012 Normalized IF: 1.2 Fumagalli U, de Carli S, de Pascale S, Rimassa L, Bignardi M, Rosati R.

Adrenal metastases from adenocarcinoma of the esophagogastric junction: adrenalectomy and longterm survival.

Updates Surg. 2010 Aug;62(1):63-7.

Raw IF (2009): 0

Normalized IF: 0.1

Practical guidelines for acute pancreatitis.

Pancreatology. 2010;10(5):523-35. Epub 2010 Oct 23.

Raw IF (2009): 2.195 Normalized IF: 4

Fumagalli U, Verrusio C, Elmore U, Massaron S, Rosati R.

Barabino M, Santambrogio R, Pisani Ceretti A, Scalzone R, Montorsi M, Opocher E.

Updates Surg. 2010 Oct;62(2):105-9. Epub 2010 Sep 22.

Raw IF (2009): 0 Normalized IF: 0.1

Is there still a role for laparoscopy combined with laparoscopic ultrasonography in the staging of pancreatic cancer?

Surg Endosc. 2011 Jan;25(1):160-5. Epub 2010 Jun 22.

Raw IF (2009): 3.307 Normalized IF: 3

Preliminary results of transumbilical single-port laparoscopic cholecystectomy.

General Anaesthesia and Intensive Care Department

MINIMALLY INVASIVE SURGERY Casaccia M, Torelli P, Pasa A, Sormani MP, Rossi E; IRLSS Centers.

Collaborators: Casaccia M, Valente U, Spinoglio G, Prete F, Logrieco G, Buccoliero F, Berta R, Donini I, Donini A, Valeri A, Prosperi P, Saviano M, Gelmini R, Uggeri F, Caprotti R, Romano F, Colecchia G, Monteferrante E, Pedrazzoli C, Bigi L, Barbieri IM, Moraldi A, Dallatorre A, Basso N, Silecchia G, Rosati R, Bona S, Cavaliere P, Bresadola F, Terrosu G, Mosca F, Pietrabissa A, Memeo V, Puglisi F, Dionigi R, Benevento A, Boni L, Liboni A, Feo C, Borghi F, Geretto P, Torelli P, Moroni R, Sorrentino M, di Sebastiano P, Ambrosio A, Verdecchia GM, Cavaliere D.

GENERAL ANAESTHESIA AND INTENSIVE CARE Bellato V, Ferraroli GM, De Caria D, Infante MV, Cariboni U, Spoto MR, Alloisio M, Bordone G.

Management of postoperative bronchopleural fistula with a tracheobronchial stent in a patient requiring mechanical ventilation.

Intensive Care Med. 2010 Apr;36(4):721-2. Epub 2010 Jan 27.

Raw IF (2009): 5.168 Normalized IF: 3

Putative predictive parameters for the outcome of laparoscopic splenectomy: a multicenter analysis performed on the Italian Registry of Laparoscopic Surgery of the Spleen.

Giustiniano E, Alfano A, Battistini GM, Gavazzeni V, Spoto MR, Cancellieri F.

Ann Surg. 2010 Feb;251(2):287-91.

Raw IF (2009): 7.9

J Cardiovasc Med (Hagerstown). 2010 Jul;11(7):522-8.

Raw IF (2009): 0.712 Normalized IF: 1

Normalized IF: 1.6

Cerebral oximetry during carotid clamping: is blood pressure raising necessary?

107

Papers published 2010

Gynaecology Department REPRODUCTIVE MEDICINE Levi Setti PE, Albani E, Cesana A, Novara PV, Zannoni E, Baggiani AM, Morenghi E, Arfuso V, Scaravelli G.

Italian Constitutional Court modifications of a restrictive assisted reproduction technology law significantly improve pregnancy rate.

Hum Reprod. 2010 Dec 9. [Epub ahead of print] Raw IF (2009): 3.859 Normalized IF: 6

Graziani G, Finazzi S, Mangiarotti R, Como G, Fedeli C, Oldani S, Morganti A, Badalamenti S.

Different cardiovascular responses to hemodialysisinduced fluid depletion and blood pressure compliance.

J Nephrol. 2010 Jan-Feb;23(1):55-61.

Raw IF (2009): 1.252

Normalized IF: 2

Ponticelli C, Glassock RJ, Moroni G.

Induction and maintenance therapy in proliferative lupus nephritis.

J Nephrol. 2010 Jan-Feb;23(1):9-16.

Raw IF (2009): 1.252

Normalized IF: 2

Negri L, Levi-Setti PE.

Pregnancy Rate after Varicocele Repair: How Many Miscarriages?

J Androl. 2011 Jan-Feb;32(1):1. Epub 2010 Aug 26.

Letter To The Editor (comments) Raw IF (2009): 2.344 Normalized IF: 0.8

Ponticelli CE, Glassock RJ. Treatment of focal segmental glomerulosclerosis.

Kidney Int. 2010 Feb;77(3):259; author reply 259.

Letter to the Editor (comments) Raw IF (2009): 6.193

Normalized IF: 1.2

Ponticelli C, Passerini P.

Internal Medicine Department

Can prognostic factors assist therapeutic decisions in idiopathic membranous nephropathy?

J Nephrol. 2010 Mar-Apr;23(2):156-63.

Raw IF (2009): 1.252

Normalized IF: 2

EMERGENCY DEPARTMENT Mirani M, Berra C, Finazzi S, Calvetta A, Radaelli MG, Favareto F, Graziani G, Badalamenti S.

Inter-Day Glycemic Variability Assessed by Continuous Glucose Monitoring in Insulin-Treated Type 2 Diabetes Patients on Hemodialysis.

Diabetes Technol Ther. 2010 Oct;12(10):749-53.

Raw IF (2009): 2.62 Normalized IF: 4

GENERAL MEDICINE AND NEPHROLOGY Potena L, Bianchi IG, Magnani G, Masetti M, Coccolo F, Fallani F, Russo A, Grigioni F, Branzi A, Ponticelli C.

108

Graziani G, Moroni L, Ponticelli C.

Should we look after the brain to protect kidney function in deceased donor renal transplant?

Crit Care Med. 2010 Apr;38(4):1222-3.

Raw IF (2009): 6.373

Normalized IF: 6

Corbetta G, Ponticelli C.

Once-a-day administration of everolimus, cyclosporine, and steroid after renal transplantation: a review of the rationale.

Transplant Proc. 2010 May;42(4):1303-7.

Raw IF (2009): 0.994

Cyclosporine lowering with everolimus or mycophenolate to preserve renal function in heart recipients: a randomized study.

Ponticelli C, Graziani G.

Transplantation. 2010 Jan 27;89(2):263-5. Letter to the Editor (results) Raw IF (2009): 3.498 Normalized IF: 3

Nat Rev Nephrol. 2010 Jun;6(6):317-8.

Commento editoriale Raw IF (2009): 0

Normalized IF: 2

Management of drug toxicity in patients with renal insufficiency.

Normalized IF: 0.1

Ponticelli C, Passerini P.

Management of idiopathic membranous nephropathy.

Expert Opin Pharmacother. 2010 Sep;11(13):2163-75.

Raw IF (2009): 2.018 Normalized IF: 2 Graziani G, Fedeli C, Moroni L, Cosmai L, Badalamenti S, Ponticelli C.

Gitelman syndrome: pathophysiological and clinical aspects.

QJM. 2010 Oct;103(10):741-8. Epub 2010 Jul 22.

Raw IF (2009): 2.627 Normalized IF: 6

Ann N Y Acad Sci. 2010 Mar;1190(1):97-103.

Raw IF (2009): 2.670 Normalized IF: 3 Fujimoto M, Tsuneyama K, Kinoshita H, Goto H, Takano Y, Selmi C, Keen CL, Gershwin ME, Shimada Y.

The traditional Japanese formula keishibukuryogan reduces liver injury and inflammation in patients with nonalcoholic fatty liver disease.

Ann N Y Acad Sci. 2010 Mar;1190(1):151-8.

Raw IF (2009): 2.670 Normalized IF: 3 Pettigrew HD, Selmi C, Teuber SS, Gershwin ME.

Ponticelli C, Colombo D, Novara M, Basilisco G; on behalf of the CETRA Study Group.

Mold and human health: separating the wheat from the chaff.

Gastrointestinal symptoms impair quality of life in Italian renal transplant recipients but are underrecognized by physicians.

Clin Rev Allergy Immunol. 2010 Apr;38(2-3):148-55.

Raw IF (2009): 2.597 Normalized IF: 4

Transpl Int. 2010 Nov;23(11):1126-34. doi: 10.1111/j.14322277.2010.01115.x. Epub 2010 Aug 19.

Raw IF (2009): 3.254 Normalized IF: 6 Ponticelli C, Musallam KM, Cianciulli P, Cappellini MD.

Renal complications in transfusion-dependent beta thalassaemia.

Blood Rev. 2010 Nov;24(6):239-44. Epub 2010 Sep 20.

Raw IF (2009): 7.185 Normalized IF: 8 Ponticelli C, Glassock RJ.

Posttransplant Recurrence of Primary Glomerulonephritis.

Clin J Am Soc Nephrol. 2010 Dec;5(12):2363-72. Epub 2010 Oct 28.

Raw IF (2009): 4.844 Normalized IF: 6

Oertelt-Prigione S, Crosignani A, Gallieni M, Vassallo E, Podda M, Zuin M.

Severe hepatic encephalopathy in a patient with liver cirrhosis after administration of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker combination therapy: a case report.

J Med Case Reports. 2010 May 19;4:141.

Raw IF (2009): 0

Normalized IF: 0.1

Alvaro D, Crocetti E, Ferretti S, Bragazzi MC, Capocaccia R; AISF Cholangiocarcinoma committee: Collaborators: Alvaro D, Benedetti A, Bragazzi MC, Capocaccia R, Crocetti E, Fabris L, Gianmarco F, Ferretti S, Floreani A, Grazi G, Invernizzi P, Laghi A, Mancino M, Marzioni M, Mutignani M, Paolantonio P, Sonzogni A, Strazzabosco M, Stroffolini T.

Descriptive epidemiology of cholangiocarcinoma in Italy.

Graziani G, Calvetta A, Cucchiari D, Valaperta S, Montanelli A.

Dig Liver Dis. 2010 Jul;42(7):490-5. Epub 2009 Dec 22.

Raw IF (2009): 2.972 Normalized IF: 1.2

Life-threatening hypercalcemia in patients with rhabdomyolysis-induced oliguric acute renal failure.

Selmi C, Gershwin ME.

J Nephrol. 2011 Jan-Feb;24(1):128-31. Epub 2010 Oct 4.

Raw IF (2009): 1.252 Normalized IF: 2

INTERNAL MEDICINE Freeman SL, Fisher L, German JB, Leung PS, Prince H, Selmi C, Naguwa SM, Gershwin ME.

Dairy proteins and the response to pneumovax in senior citizens: a randomized, double-blind, placebocontrolled pilot study.

The etiology mystery in primary biliary cirrhosis.

Dig Dis. 2010;28(1):105-15. Epub 2010 May 7.

Raw IF (2009): 1.487 Normalized IF: 2 Liu H, Liu Y, Wang L, Xu D, Lin B, Zhong R, Gong S, Podda M, Invernizzi P.

Prevalence of primary biliary cirrhosis in adults referring hospital for annual health check-up in Southern China.

BMC Gastroenterol. 2010 Sep 3;10:100.

Raw IF (2009): 1.886

Normalized IF: 2

109

Papers published 2010

Montali L, Tanaka A, Riva P, Takahashi H, Cocchi C, Ueno Y, Miglioretti M, Takikawa H, Vecchio L, Frigerio A, Bianchi I, Jorgensen R, Lindor KD, Podda M, Invernizzi P; the ItalianJapanese PBC Study Group.

A short version of a HRQoL questionnaire for Italian and Japanese patients with PBC. Dig Liver Dis. 2010 Oct;42(10):718-23. Epub 2010 Feb 16.

Raw IF (2009): 2.972 Normalized IF: 6 Selmi C, Podda M.

Methotrexate for Primary Biliary Cirrhosis: Who Is to Be Trusted?

Dig Dis Sci. 2010 Nov;55(11):3013-5.

Raw IF (2009): 1.838

Normalized IF: 2

Costantino G, Dipaola F, Selmi C, Furlan R.

Orthostatic intolerance and coronary reserve: a matter of a certain gravity.

Intern Emerg Med. 2010 Dec 7. [Epub ahead of print] Letter to the Editor (results) Raw IF (2009): 2.371 Normalized IF: 3 Alvaro D, Bragazzi MC, Benedetti A, Fabris L, Fava G, Invernizzi P, Marzioni M, Nuzzo G, Strazzabosco M, Stroffolini T; from and the AISF “Cholangiocarcinoma” committee.

Cholangiocarcinoma in Italy: A national survey on clinical characteristics, diagnostic modalities and treatment. Results from the “Cholangiocarcinoma” committee of the Italian Association for the Study of Liver disease.

Dig Liver Dis. 2011 Jan;43(1):60-5. Epub 2010 Jun 26.

Raw IF (2009): 2.972 Normalized IF: 3

RHEUMATOLOGY Scarpato S, Antivalle M, Favalli EG, Nacci F, Frigelli S, Bartoli F, Bazzichi L, Minisola G, Matucci Cerinic M; RIVIERA coauthors (Salvarani C, Altucci P, Bombardieri S, Battaglia E, Ferri C, Pozzi MR, Afeltra A, Bersi M, Tartarelli G, Montecucco CM, Altomare E, Bambara LM, Bucci R, Colombelli PL, Corsaro S, Rinaldi F, Sinigaglia L, Trotta F, Carrabba M, Migliore A, Bianchi G, Grassi W, Rocchetta PA, Altomonte L, Coaccioli S, Danieli-Armando G, Perpignano G, Broggini M, Morassi P, Peronato G, Canesi B, Delsante G, Di Giuseppe P, Di Rosa SO, Gorla R, Malavolta N, Solinas F, Todesco S, Varcasia G, Versace F, Sabadini L, Del Giacco S, Marasini B, Bagnato G, Gerli R, Modena V, Di Piazza V).

110

Patient preferences in the choice of anti-TNF therapies

in rheumatoid arthritis. Results from a questionnaire survey (RIVIERA study).

Rheumatology (Oxford). 2010 Feb;49(2):289-94. Epub 2009 Nov 17.

Raw IF (2009): 4.236 Normalized IF: 1.2 Massarotti M, Uboldi F, Fabbriciani G, Marasini B.

Polyostotic Paget Disease Involving Bones of the Upper Extremity.

South Med J. 2010 Dec;103(12):1253-5.

Raw IF (2009): 0.924

Normalized IF: 2

Belloli L, Ughi N, Marasini B.

Vitamin D in systemic sclerosis.

Clin Rheumatol. 2011 Jan;30(1):145-6. Epub 2010 Sep 28.

Letter to the Editor (comment) Raw IF (2009): 1.668 Normalized IF: 0.4

THROMBOSIS CENTRE Blanco-Molina A, Rota LL, Di Micco P, Brenner B, TrujilloSantos J, Ruiz-Gamietea A, Monreal M; RIETE Investigators.

Venous thromboembolism during pregnancy, postpartum or during contraceptive use.

Thromb Haemost. 2010 Feb 1;103(2):306-11. Epub 2009 Nov 13.

Raw IF (2009): 4.451 Normalized IF: 6

Neuroscience Area NEUROLOGY II Joint Task Force of the EFNS and the PNS: Van den Bergh PY, Hadden RD, Bouche P, Cornblath DR, Hahn A, Illa I, Koski CL, Léger JM, Nobile-Orazio E, Pollard J, Sommer C, van Doorn PA, van Schaik IN.

European Federation of Neurological Societies/ Peripheral Nerve Society Guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society--First Revision.

J Peripher Nerv Syst. 2010 Mar;15(1):1-9.

Raw IF (2009): 3.623

Normalized IF: 6

Van den Bergh PY, Hadden RD, Bouche P, Cornblath DR, Hahn A, Illa I, Koski CL, LĂŠger JM, Nobile-Orazio E, Pollard J, Sommer C, van Doorn PA, van Schaik IN.

European Federation of Neurological Societies/ Peripheral Nerve Society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society - first revision.

Eur J Neurol. 2010 Mar;17(3):356-63.

Raw IF (2009): 2.510

Normalized IF: 4

Benedetti L, Briani C, Franciotta D, Fazio R, Paolasso I, Comi C, Luigetti M, Sabatelli M, Giannini F, Mancardi GL, Schenone A, Nobile-Orazio E, Cocito D.

Rituximab in patients with chronic inflammatory demyelinating polyradiculoneuropathy: a report of 13 cases and review of the literature.

J Neurol Neurosurg Psychiatry. 2010 Jul 16. [Epub ahead of print] Raw IF (2009): 4.869 Normalized IF: 3 Joint Task Force of the EFNS and the PNS: Hadden RD, Nobile-Orazio E, Sommer CL, Hahn AF, Illa I, Morra E, Pollard JD, Lunn MP, Bouche P, Cornblath DR, Evers E, Koski CL, LĂŠger JM, Van den Bergh P, van Doorn PA, van Schaik IN.

European Federation of Neurological Societies/ Peripheral Nerve Society Guideline on management of paraproteinemic demyelinating neuropathies. Report of a Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society--first revision.

J Peripher Nerv Syst. 2010 Sep;15(3):185-95. doi: 10.1111/ j.1529-8027.2010.00278.x.

Raw IF (2009): 3.623 Normalized IF: 6 Nobile-Orazio E, Gallia F, Tuccillo F, Terenghi F.

Chronic inflammatory demyelinating polyradiculoneuropathy and multifocal motor neuropathy: treatment update.

Curr Opin Neurol. 2010 Oct;23(5):519-23.

Raw IF (2009): 5.430 Normalized IF: 6 Riva N, Iannaccone S, Corbo M, Casellato C, Sferrazza B, Lazzerini A, Scarlato M, Cerri F, Previtali SC, Nobile-Orazio E, Comi G, Quattrini A.

Motor nerve biopsy: Clinical usefulness and histopathological criteria.

Ann Neurol. 2010 Nov 12. [Epub ahead of print] Raw IF (2009): 9.317 Normalized IF: 4

Nobile-Orazio E.

Update on neuropathies associated with monoclonal gammopathy of undetermined significance (20082010).

J Peripher Nerv Syst. 2010 Dec;15(4):302-6. doi: 10.1111/ j.1529-8027.2010.00283.x.

Raw IF (2009): 3.623 Normalized IF: 6 Pazzaglia C, Briani C, Nobile-Orazio E, Caliandro P, Granata G, Tonali PA, Padua L.

Occurrence and characterization of Pain in immunemediated neuropathies: a multicentre prospective study.

Eur J Neurol. 2011 Jan;18(1):177-83. doi: 10.1111/j.14681331.2010.03108.x. Epub 2010 Jun 12.

Raw IF (2009): 2.51 Normalized IF: 2

NEUROSURGERY Di Ieva A, Grizzi F, Rognone E, Tse ZT, Parittotokkaporn T, Rodriguez Y Baena F, Tschabitscher M, Matula C, Trattnig S, Rodriguez Y Baena R.

Magnetic resonance elastography: a general overview of its current and future applications in brain imaging.

Neurosurg Rev. 2010 Apr;33(2):137-45; discussion 145. Epub 2010 Feb 27.

Raw IF (2009): 1.897 Normalized IF: 4 Tancioni F, Lorenzetti M, Navarria P, Nozza A, Castagna L, Gaetani P, Aimar E, Levi D, Di Ieva A, Pisano P, Santoro A, Scorsetti M, Rodriguez Y Baena R.

Vertebroplasty for pain relief and spinal stabilization in multiple myeloma.

Neurol Sci. 2010 Apr;31(2):151-7.

Raw IF (2009): 1.120

Normalized IF: 1

Tancioni F, Navarria P, Lorenzetti MA, Pedrazzoli P, Masci G, Mancosu P, Alloisio M, Morenghi E, Santoro A, Rodriguez Y Baena R, Scorsetti M.

Multimodal Approach to the Management of Metastatic Epidural Spinal Cord Compression (MESCC) due to Solid Tumors.

Int J Radiat Oncol Biol Phys. 2010 Dec 1;78(5):1467-73. Epub 2010 Mar 16.

Raw IF (2009): 4.592 Normalized IF: 6

111

Papers published 2010

Di Ieva A.

Microtechnologies in neurosurgery.

Proc Inst Mech Eng H. 2010;224(6):797-800.

Raw IF (2009): 0.951 Normalized IF: 1

J Gastrointest Surg. 2010 May;14(5):805-11. Epub 2010 Feb 9.

Raw IF (2009): 2.402 Normalized IF: 6 Colavelli C, Pastore M, Morenghi E, Coladonato M, Tronconi C, Rimassa L, Fumagalli U, Rosati R, Doci R, Cozzaglio L.

Di Ieva A, Gaetani P, Matula C, Sherif C, Skopec M, Tschabitscher M.

Nutritional and digestive effects of gastrectomy for gastric cancer

Berengario da Carpi: a pioneer in neurotraumatology.

Nutritional Therapy & Metabolism 2010; 28 (3): 129-136.

Raw IF (2009): 0 Normalized IF: 0.1

J Neurosurg. 2010 Dec 3. [Epub ahead of print] Commentary Raw IF (2009): 2.594 Normalized IF: 1.2

Gianotti L, Braga M, R, Bozzetti F, Mariani L; on behalf the GlutamItaly Research Group of SINPE (L. Cozzaglio, M. Coladonato).

Oncology Department BREAST UNIT Pavlidis N, Gatzemeier W, Popescu R, Stahel R, Pinedo H, Cavalli F, Costa A.

The Masterclass of the European School of Oncology: The ‘key educational event’ of the school.

Eur J Cancer. 2010 Aug;46(12):2159-65. Epub 2010 Jul 6.

Raw IF (2009): 4.121 Normalized IF: 6 Rubino A, Doci R, Foteuh JC, Morenghi E, Fissi S, Giorgetta C, Abumalouh I, Tommaso LD, Gennari L.

Hepatic metastases from breast cancer.

Updates Surg. 2010 Nov 3. [Epub ahead of print] Raw IF (2009): 0 Normalized IF: 0.1 Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Correa C, McGale P, Taylor C, Wang Y, Clarke M, Davies C, Peto R, Bijker N, Solin L, Darby S.Collaborator (Tinterri C et al.).

Overview of the randomized trials of radiotherapy in ductal carcinoma in situ of the breast.

J Natl Cancer Inst Monogr. 2010;2010(41):162-77.

Raw IF (2009): 14.069 Normalized IF: 2

GENERAL AND ONCOLOGIC SURGERY Cozzaglio L, Coladonato M, Biffi R, Coniglio A, Corso V, Dionigi P, Gianotti L, Mazzaferro V, Morgagni P, Rosa F, Rosati R, Roviello F, Doci R.

112

Duodenal Fistula after Elective Gastrectomy for Malignant Disease: an Italian Retrospective Multicenter Study.

Metabolic and clinical effects of parenteral L-alanine-Lglutamine in surgical oncology.

Nutritional Therapy & Metabolism 2010; 28 (2): 77-85.

Raw IF (2009): 0 Normalized IF: 0.1 Cozzaglio L, Bottura R, Di Rocco M, Gennari L, Doci R.

Sentinel lymph node biopsy in gastric cancer: Possible applications and limits.

Eur J Surg Oncol. 2011 Jan;37(1):55-9. Epub 2010 Nov 27.

Raw IF (2009): 2.564 Normalized IF: 4

MEDICAL ONCOLOGY AND HAEMATOLOGY Reni M, Sartori N, Mambrini A, Berardi R, Passardi A, Milella M, Cereda S, Tronconi MC, Aprile G, Cordio S, Pasetto LM, Rognone A, Pederzoli P, Massimo F.

An Italian study on treatment trends and outcomes of patients with stage III pancreatic adenocarcinoma in the gemcitabine era: is it time to change?

Anticancer Drugs. 2010 Apr;21(4):459-64.

Raw IF (2009): 2.230

Normalized IF: 2

Gregorc V, Zucali PA, Santoro A, Ceresoli GL, Citterio G, De Pas TM, Zilembo N, De Vincenzo F, Simonelli M, Rossoni G, Spreafico A, Viganò MG, Fontana F, De Braud FG, Bajetta E, Caligaris-Cappio F, Bruzzi P, Lambiase A, Bordignon C.

Phase II Study of Asparagine-Glycine-Arginine-Human Tumor Necrosis Factor {alpha}, a Selective Vascular Targeting Agent, in Previously Treated Patients With Malignant Pleural Mesothelioma.

J Clin Oncol. 2010 May 20;28(15):2604-11. Epub 2010 Apr 20.

Raw IF (2009): 17.793 Normalized IF: 15 Krzakowski M, Ramlau R, Jassem J, Szczesna A, Zatloukal

P, Von Pawel J, Sun X, Bennouna J, Santoro A, Biesma B, Delgado FM, Salhi Y, Vaissiere N, Hansen O, Tan EH, Quoix E, Garrido P, Douillard JY.

Phase III Trial Comparing Vinflunine With Docetaxel in Second-Line Advanced Non-Small-Cell Lung Cancer Previously Treated With Platinum-Containing Chemotherapy.

J Clin Oncol. 2010 May 1;28(13):2167-73. Epub 2010 Mar 29.

Raw IF (2009): 17.793 Normalized IF: 7.5 Sarina B, Castagna L, Farina L, Patriarca F, Benedetti F, Carella AM, Falda M, Guidi S, Ciceri F, Bonini A, Ferrari S, Malagola M, Morello E, Milone G, Bruno B, Mordini N, Viviani S, Levis A, Giordano L, Santoro A, Corradini P.

Allogeneic transplantation improves the overall and progression-free survival of Hodgkin’s lymphoma patients relapsing after autologous transplantation: a retrospective study based on the time of HLA typing and donor availability.

Blood. 2010 May 6;115(18):3671-7. Epub 2010 Mar 10.

Raw IF (2009): 10.555 Normalized IF: 8 Rimassa L, Santoro A.

The present and the future landscape of treatment of advanced hepatocellular carcinoma.

Dig Liver Dis. 2010 Jul;42 Suppl 3:S273-80.

Raw IF (2009): 2.972 Normalized IF: 6 Santoro A, Pressiani T, Citterio G, Rossoni G, Donadoni G, Pozzi F, Rimassa L, Personeni N, Bozzarelli S, Rossoni G, Colombi S, De Braud FG, Caligaris-Cappio F, Lambiase A, Bordignon C.

Activity and safety of NGR-hTNF, a selective vasculartargeting agent, in previously treated patients with advanced hepatocellular carcinoma.

Br J Cancer. 2010 Sep 7;103(6):837-44. Epub 2010 Aug 17.

Raw IF (2009): 4.346 Normalized IF: 6 Sclafani F, Carnaghi C, Colombo P, Bozzarelli S, De Vincenzo F, Rimassa L, Giorgetti PL, Santoro A.

Case Report of Acute Aortic Dissection during Treatment with Capecitabine for a Late Recurrence of Breast Cancer.

Chemotherapy. 2010;56(3):203-7. Epub 2010 Jun 11.

Raw IF (2009): 2.028 Normalized IF: 2 Saber W, Moua T, Williams EC, Verso M, Agnelli G, Couban S, Young A, De Cicco M, Biffi R, Van Rooden CJ, Huisman MV, Fagnani D, Cimminiello C, Moia M, Magagnoli M, Povoski SP,

Malak SF, Lee AY.

Risk factors of catheter-related thrombosis (CRT) in cancer patients: a patient-level data (IPD) meta-analysis of clinical trials and prospective studies.

J Thromb Haemost. 2010 Oct 29. doi: 10.1111/j.15387836.2010.04126.x. [Epub ahead of print] Raw IF (2009): 6.069 Normalized IF: 3 Santoro A, Rimassa L, Sobrero AF, Citterio G, Sclafani F, Carnaghi C, Pessino A, Caprioni F, Andretta V, Tronconi MC, Finocchiaro G, Rossoni G, Zanoni A, Miggiano C, Rizzardi GP, Traversari C, Caligaris-Cappio F, Lambiase A, Bordignon C.

Phase II study of NGR-hTNF, a selective vascular targeting agent, in patients with metastatic colorectal cancer after failure of standard therapy.

Eur J Cancer. 2010 Oct;46(15):2746-52. Epub 2010 Aug 12.

Raw IF (2009): 4.121 Normalized IF: 6 Sclafani F, Gullo G, Santoro A.

Postoperative Chemoradiotherapy or Surgery Alone for Gastric Cancer: The Plausibility of the Question and Pertinence of the Answer.

J Clin Oncol. 2010 Oct 20;28(30):e615-6; author reply e617-8.

Epub 2010 Aug 23. Letter to the Editor (comments) Raw IF (2009): 17.793 Normalized IF: 3 International Prognostic Factors Study Group, Lorch A, Beyer J, Bascoul-Mollevi C, Kramar A, Einhorn LH, Necchi A, Massard C, De Giorgi U, Fléchon A, Margolin KA, Lotz JP, Germa Lluch JR, Powles T, Kollmannsberger CK. Collaborators (107): Lorch A, Neubauer A, Beyer J, Rick O, Einhorn LH, Necchi A, Nicolai N, Salvioni R, Fizazi K, Massard C, De Giorgi U, Aieta M, Chioni A, De Vivo R, Fornarini G, Palmieri G, Banna GL, Scandurra G, Berretta M, Pessa S, Messina C, Valcamonico F, Pedrazzoli P, Schiavetto I, Ortega C, Vormola R, Lo Re G, Tumolo S, Basso U, Sava T, Morelli F, Tedeschi L, Simonelli M, Zucali P, Pizzocaro G, Boyle H, Droz JP, Fléchon A, Margolin KA, Baron A, Lotz JP, Fernández A, Germà JR, Maroto P, Mellado B, Martínez del Prado P, Vázquez S, Arranz JA, Castellanos D, Sastre J, Terrasa J, González E, Lainez N, Sánchez M, Gumà J, Dorta FJ, Almenar D, Aparicio J, Climent MA, Gironés R, Saenz A, Powles T, Shamash J, Kollmannsberger CK, Hartmann JT, Mayer F, Kirby J, Mead B, Simmonds P, Bokemeyer C, Honecker F, Oechsle K, Fossa S, Oldenburg J, Rodenhuis S, Fenner M, Papiani G, Rosti G, Bosl G, Feldman D, Motzer R, Turkula S, Savage P, Gauler T, HayesLattin B, Moore C, Nichols C, Rehmsmeier C, Berdel WE, DeSantis M, Jahn-Kuch D, Cavallin-Stahl E, Cohn-Cedermark G, Dahl O, Higano C, Daugaard G, Hentrich M, Dieing A, Sammler C, Wandt H, Metzner B, Schöffski P, Binh B, Houede N, Gerl A, Gillessen S, Cathomas R.

Prognostic factors in patients with metastatic germ cell tumors who experienced treatment failure with

113

Papers published 2010

cisplatin-based first-line chemotherapy.

J Clin Oncol. 2010 Nov 20;28(33):4906-11. Epub 2010 Oct 18.

Raw IF (2009): 17.793 Normalized IF: 3 Banna GL, Di Maio M, Follador A, Collovà E, Menis J, Novello S, Bria E; on behalf of ISA Co-Authors (Garassino I).

Italian Survey on Adjuvant treatment of non-small cell lung cancer (ISA).

Lung Cancer. 2010 Dec 6. [Epub ahead of print] Raw IF (2009): 3.14 Normalized IF: 1.2 Tronconi MC, Carnaghi C, Bignardi M, Doci R, Rimassa L, Di Rocco M, Scorsetti M, Santoro A.

Rectal squamous cell carcinoma treated with chemoradiotherapy: report of six cases.

Int J Colorectal Dis. 2010 Dec;25(12):1435-9. Epub 2010 Jun 15.

Raw IF (2009): 2.102 Normalized IF: 4 Corradini P, Sarina B, Farina L.

Allogeneic transplantation for Hodgkin’s lymphoma.

Br J Haematol. 2011 Feb;152(3):261-72. doi: 10.1111/j.13652141.2010.08492.x. Epub 2010 Dec 13.

Raw IF (2009): 4.597 Normalized IF: 6

NUCLEAR MEDICINE Boellaard R, O’Doherty MJ, Weber WA, Mottaghy FM, Lonsdale MN, Stroobants SG, Oyen WJ, Kotzerke J, Hoekstra OS, Pruim J, Marsden PK, Tatsch K, Hoekstra CJ, Visser EP, Arends B, Verzijlbergen FJ, Zijlstra JM, Comans EF, Lammertsma AA, Paans AM, Willemsen AT, Beyer T, Bockisch A, Schaefer-Prokop C, Delbeke D, Baum RP, Chiti A, Krause BJ.

FDG PET and PET/CT: EANM procedure guidelines for tumour PET imaging: version 1.0.

Eur J Nucl Med Mol Imaging. 2010 Jan;37(1):181-200.

Raw IF (2008): 4.531 Normalized IF: 3 Bombardieri E, Coliva A, Maccauro M, Seregni E, Orunesu E, Chiti A, Lucignani G.

Imaging of neuroendocrine tumours with gammaemitting radiopharmaceuticals.

Q J Nucl Med Mol Imaging. 2010 Feb;54(1):3-15.

Raw IF (2009): 2.877 Normalized IF: 3

114

Bombardieri E, Ambrosini V, Aktolun C, Baum RP, BishofDelaloye A, Del Vecchio S, Maffioli L, Mortelmans L, Oyen W, Pepe G, Chiti A; Oncology Committee of the EANM.

111In-pentetreotide scintigraphy: procedure guidelines for tumour imaging.

Eur J Nucl Med Mol Imaging. 2010 Jul;37(7):1441-8.

Raw IF (2009): 4.531 Normalized IF: 6 Chiti A, Kirienko M, Grégoire V.

Clinical use of PET-CT data for radiotherapy planning: What are we looking for?

Radiother Oncol. 2010 Sep;96(3):277-9. Epub 2010 Aug 18.

Raw IF (2009): 4.343 Normalized IF: 6 Gregoire V, Chiti A.

PET in radiotherapy planning: particularly exquisite test or pending and experimental tool?

Radiother Oncol. 2010 Sep;96(3):275-6. Epub 2010 Aug 12.

Introductory Journal Article Raw IF (2009): 4.343 Normalized IF: 1.2 Virgolini I, Ambrosini V, Bomanji JB, Baum RP, Fanti S, Gabriel M, Papathanasiou ND, Pepe G, Oyen W, De Cristoforo C, Chiti A.

Procedure guidelines for PET/CT tumour imaging with (68)Ga-DOTA-conjugated peptides: (68)Ga-DOTA-TOC, (68)Ga-DOTA-NOC, (68)Ga-DOTA-TATE. Eur J Nucl Med Mol Imaging. 2010 Oct;37(10):2004-10.

Raw IF (2009): 4.531 Normalized IF: 6 Bombardieri E, Giammarile F, Aktolun C, Baum RP, Bischof Delaloye A, Maffioli L, Moncayo R, Mortelmans L, Pepe G, Reske SN, Castellani MR, Chiti A.

(131)I/ (123)I-Metaiodobenzylguanidine (mIBG) scintigraphy: procedure guidelines for tumour imaging.

Eur J Nucl Med Mol Imaging. 2010 Dec;37(12):2436-46.

Raw IF (2009): 4.531 Normalized IF: 6 Chiti A, Picchio M.

The rising PET: the increasing use of choline PET/CT in prostate cancer.

Eur J Nucl Med Mol Imaging. 2011 Jan;38(1):53-4. Epub 2010 Nov 20.

Editorial Commentary Raw IF (2009): 4.531 Normalized IF: 1.2

RADIOTHERAPY AND RADIOSURGERY Scorsetti M, Signori C, Lattuada P, Urso G, Bignardi M, Navarria P, Castiglioni S, Mancosu P, Trucco P.

Applying failure mode effects and criticality analysis in radiotherapy: Lessons learned and perspectives of enhancement.

Radiother Oncol. 2010 Mar;94(3):367-374. Epub 2010 Jan 29.

Raw IF (2009): 4.343 Normalized IF: 6 Scorsetti M, Bignardi M, Clivio A, Cozzi L, Fogliata A, Lattuada P, Mancosu P, Navarria P, Nicolini G, Urso G, Vanetti E, Vigorito S, Santoro A.

Volumetric Modulation Arc Radiotherapy Compared with Static Gantry Intensity-Modulated Radiotherapy for Malignant Pleural Mesothelioma Tumor: A Feasibility Study.

Int J Radiat Oncol Biol Phys. 2010 Jul 1;77(3):942-9. Epub 2010 Apr 8.

Raw IF (2009): 4.592 Normalized IF: 6 Bignardi M, Navarria P, Mancosu P, Cozzi L, Fogliata A, Tozzi A, Castiglioni S, Carnaghi C, Tronconi MC, Santoro A, Scorsetti M.

Clinical Outcome of Hypofractionated Stereotactic Radiotherapy for Abdominal Lymph Node Metastases.

Int J Radiat Oncol Biol Phys. 2010 Aug 26. [Epub ahead of print] Raw IF (2009): 4.592 Normalized IF: 6 Mancosu P, Cozzi L, Fogliata A, Lattuada P, Reggiori G, Cantone MC, Navarria P, Scorsetti M.

Collimator angle influence on dose distribution optimization for vertebral metastases using volumetric modulated arc therapy.

Med Phys. 2010 Aug;37(8):4133-7.

Raw IF (2009): 2.704

Radiat Oncol. 2010 Oct 15;5:93.

Raw IF (2009): 2.529

Normalized IF: 4

Scorsetti M, Navarria P, Mancosu P, Alongi F, Castiglioni S, Cavina R, Cozzi L, Fogliata A, Pentimalli S, Tozzi A, Santoro A.

Large volume unresectable locally advanced non-small cell lung cancer: acute toxicity and initial outcome results with Rapid Arc. Radiat Oncol. 2010 Oct 15;5:94.

Raw IF (2009): 2.529

Normalized IF: 4

THORACIC SURGERY Infante MV, Pedersen JH.

Screening for lung cancer: are we there yet?

Curr Opin Pulm Med. 2010 Jul;16(4):301-6.

Raw IF (2009): 2.697 Normalized IF: 4 Infante M, Chiesa G, Solomon D, Morenghi E, Passera E, Lutman FR, Bottoni E, Cariboni U, Errico V, Voulaz E, Ferraroli G, Testori A, Inzirillo F, Chiarenza M, Roncalli M, Cavuto S, Chiti A, Alloisio M, Ravasi G; for the DANTE Study Group.

Surgical Procedures in the DANTE Trial, A Randomized Study of Lung Cancer Early Detection with Spiral Computed Tomography: Comparative Analysis in the Screening and Control Arm. J Thorac Oncol. 2010 Dec 21. [Epub ahead of print] Raw IF (2009): 4.547 Normalized IF: 6

Normalized IF: 4

Mancosu P, Sghedoni R, Bettinardi V, Aquilina MA, Navarria P, Cattaneo GM, Di Muzio N, Cozzi L, Scorsetti M.

Semiautomatic technique for defining the internal gross tumor volume of lung tumors close to liver/ spleen cupola by 4D-CT. Med Phys. 2010 Sep;37(9):4572-6.

Raw IF (2009): 2.704

Arc Therapy in head and neck cancer patients.

Normalized IF: 4

Scorsetti M, Fogliata A, Castiglioni S, Bressi C, Bignardi M, Navarria P, Mancosu P, Cozzi L, Pentimalli S, Alongi F, Santoro A.

Early clinical experience with Volumetric Modulated

Orthopaedic Department SHOULDER ARTHROSCOPIC SURGERY Padua R, Castagna A, Ceccarelli E, BondĂŹ R, Alviti F, Padua L.

Intracapsular osteochondroma of the humeral head in an adult causing restriction of motion: a case report.

J Shoulder Elbow Surg. 2009 Jul-Aug;18(4):e30-1. Epub 2009 Jan 7.

Raw IF (2009): 1.934 Normalized IF: 4

115

Papers published 2010

De Filippo M, Araoz PA, Pogliacomi F, Castagna A, Petriccioli D, Sverzellati N, Zompatori M.

Garofalo R, Conti M, Notarnicola A, Maradei L, Giardella A, Castagna A.

Recurrent superior labral anterior-to-posterior tears after surgery: detection and grading with CT arthrography.

Effects of one-month continuous passive motion after arthroscopic rotator cuff repair: results at 1-year followup of a prospective randomized study.

Radiology. 2009 Sep;252(3):781-8. Epub 2009 Jul 31.

Raw IF (2009): 6.341 Normalized IF: 3

Musculoskelet Surg. 2010 May;94 Suppl 1:S79-83.

Raw IF (2009): 0 Normalized IF: 0.1

Padua R, Castagna A, Alviti F, Padua L.

Measuring shoulder function: A systematic review of four questionnaires.

Arthritis Care Res (Hoboken). 2010 Jan 29. [Epub ahead of print] Letter to the Editor (comment) Raw IF (2009): 4.152 Normalized IF: 0.8 Randelli P, Castagna A, Cabitza F, Cabitza P, Arrigoni P, Denti M.

Infectious and thromboembolic complications of arthroscopic shoulder surgery.

J Shoulder Elbow Surg. 2010 Jan-Feb;19(1):97-101.

Raw IF (2009): 1.934 Normalized IF: 4 Bak K, Wiesler ER, Poehling GG; ISAKOS Upper Extremity Committee: Wiesler ER, Poehling GG, Enjismann B, Larrain M, Arce G, Gutierrez V, Taverna E, Hardy P, Etoi E, Kibler B, GutiĂŠrrez M, Provencher MT, Plancher K, Lintner D, Castagna A, Bak K.

Consensus statement on shoulder instability.

Arthroscopy. 2010 Feb;26(2):249-55. Epub 2009 Dec 16.

Raw IF (2009): 2.608 Normalized IF: 1.2 Castagna A, Garofalo R, Cesari E, Marcopoulos N, Borroni M, Conti M.

Anterior and posterior internal impingement: an evidence-based review.

Br J Sports Med. 2010 Apr;44(5):382-8.

Raw IF (2009): 2.547

Normalized IF: 6

Garofalo R, Notarnicola A, Moretti L, Moretti B, Marini S, Castagna A.

Deep vein thromboembolism after arthroscopy of the shoulder: two case reports and a review of the literature.

BMC Musculoskelet Disord. 2010 Apr 8;11:65.

Raw IF (2009): 1.880 Normalized IF: 4

Padua R, Padua L, Ceccarelli E, Bondi R, Alviti F, Castagna A.

Italian version of ASES questionnaire for shoulder assessment: cross-cultural adaptation and validation.

Musculoskelet Surg. 2010 May;94 Suppl 1:S85-90.

Raw IF (2009): 0 Normalized IF: 0.1 Padua R, Castagna A, Alviti F, Padua L.

Systematic review of shoulder function questionnaires: comment on the article by Roy et al.

Arthritis Care Res (Hoboken). 2010 Jun;62(6):900-1; author reply 901. Letter to the Editor (comment) Raw IF (2009): 4.152 Normalized IF: 0.8 Parsons BO, Boileau P, Rhee YG, Sonnabend DA, Checchia SL, Castagna A, Flatow EL.

Surgical management of traumatic anterior glenohumeral instability: an international perspective.

Instr Course Lect. 2010;59:245-53.

Raw IF (2009): 0

Normalized IF: 0.1

Castagna A, Markopoulos N, Conti M, Delle Rose G, Papadakou E, Garofalo R.

Arthroscopic Bankart Suture-Anchor Repair: Radiological and Clinical Outcome at Minimum 10 Years of Follow-up.

Am J Sports Med. 2010 Oct;38(10):2012-6. Epub 2010 Jul 1.

Raw IF (2009): 3.605 Normalized IF: 6 Castagna A, Randelli M, Garofalo R, Maradei L, Giardella A, Borroni M.

Mid-term results of a metal-backed glenoid component in total shoulder replacement.

J Bone Joint Surg Br. 2010 Oct;92(10):1410-5.

Raw IF (2009): 2.655 Normalized IF: 6

Castagna A, Garofalo R, Melito G, Markopoulos N, De Giorgi S.

The role of arthroscopy in the revision of failed Latarjet procedures.

116

Musculoskelet Surg. 2010 May;94 Suppl 1:S47-55.

Raw IF (2009): 0 Normalized IF: 0.1

Padua R, Alviti F, Padua L, Castagna A.

Therapeutic effects of hyaluronate injections in patients with chronic painful shoulder: A meta-analysis of randomized controlled trials.

Arthritis Care Res (Hoboken). 2010 Nov;62(11):1673; author reply 1673-4. doi: 10.1002/acr.20286. Epub 2010 Jul 8.

Letter to the Editor (results) Raw IF (2009): 4.152 Normalized IF: 2 Padua R, Alviti F, Padua L, Castagna A.

Meta-analysis of hyaluronate injections for shoulder pain: Comment on the article by Saito et al.

Arthritis Care Res (Hoboken). 2010 Nov;62(11):1673. doi: 10.1002/acr.20286. Epub 2010 Jul 8.

Letter to the Editor (comment) Raw IF (2009): 4.152 Normalized IF: 0.8 Garofalo R, Karlsson J, Nordenson U, Cesari E, Conti M, Castagna A.

Anterior-superior internal impingement of the shoulder: an evidence-based review.

Knee Surg Sports Traumatol Arthrosc. 2010 Dec;18(12):168893. Epub 2010 Aug 11.

Raw IF (2009): 1.674 Normalized IF: 4 Garofalo R, Pouliart N, Vinci E, Franceschi G, Aldegheri R, Castagna A.

Anterosuperior Labral Tear Without Biceps Anchor Involvement: A Subtle Isolated Cause of a Painful Shoulder.

Arthroscopy. 2011 Jan;27(1):17-23. Epub 2010 Oct 15.

Raw IF (2009): 2.608 Normalized IF: 6

Prevention, Rehabilitation, and Prevention: (Aglieri S.).

Cardiac rehabilitation in very old patients: data from the Italian Survey on Cardiac Rehabilitation-2008 (ISYDE-2008)--official report of the Italian Association for Cardiovascular Prevention, Rehabilitation, and Epidemiology.

J Gerontol A Biol Sci Med Sci. 2010 Dec;65(12):1353-61. Epub 2010 Jul 28.

Raw IF (2009): 3.083 Normalized IF: 0.8

Special Diagnostic and Treatment Services LABORATORY TESTS Casari E, Ferrario A, Morenghi E, Montanelli A.

Gardnerella, Trichomonas vaginalis, Candida, Chlamydia trachomatis, Mycoplasma hominis and Ureaplasma urealyticum in the genital discharge of symptomatic fertile and asymptomatic infertile women.

New Microbiol. 2010 Jan;33(1):69-76.

Raw IF (2009): 0.947

Normalized IF: 1

OTHERS Nicoli E.

[Norms and responsibilities of the occupational physician in psychosocial risks management].

Rehabilitation Department NEUROLOGIC REHABILITATION Bellelli G, Buccino G, Bernardini B, Padovani A, Trabucchi M.

Action observation treatment improves recovery of postsurgical orthopedic patients: evidence for a topdown effect?

G Ital Med Lav Ergon. 2010 Jul-Sep;32(3):368-71. Italian.

Raw IF (2009): 0 Normalized IF: 0.1

Specialised Divisions of Surgery OPHTHALMOLOGY

Arch Phys Med Rehabil. 2010 Oct;91(10):1489-94.

Raw IF (2009): 2.184 Normalized IF: 3

di Lauro R, De Ruggiero P, di Lauro R, di Lauro MT, Romano MR.

Giallauria F, Vigorito C, Tramarin R, Fattirolli F, Ambrosetti M, De Feo S, Griffo R, Riccio C, Piepoli M; ISYDE-2008 Investigators of the Italian Association for Cardiovascular

Graefes Arch Clin Exp Ophthalmol. 2010 Jun;248(6):785-91.

Epub 2010 Feb 5.

Raw IF (2009): 2.102 Normalized IF: 4

Intravitreal bevacizumab for surgical treatment of severe proliferative diabetic retinopathy.

117

Papers published 2010

Valldeperas X, Angi M, Romano V, Romano MR.

Bilateral Keratectasia 34 Years after Corneal Transplant.

Curr Drug Targets. 2011 Feb 1;12(2):190-8. Epub 2010 Oct 1.

Raw IF (2009): 3.932 Normalized IF: 3

Case Report Ophthalmol. 2010 Jul 2;1(1):24-29.

Raw IF (2009): 0 Normalized IF: 0.1 Valldeperas X, Arango A, Blazquez A, Romano M.

PLASTIC SURGERY II

Tonic Pupil and Corneal Anesthesia after Vitrectomy and Encircling Band for Retinal Detachment in an ExPremature Child.

Klinger M, Caviggioli F, Klinger F, Villani F, Montorsi M.

Case Report Ophthalmol. 2010 Sep 29;1(2):66-70.

Raw IF (2009): 0 Normalized IF: 0.1

Int Surg. 2009 Oct-Dec;94(4):289-91.

Raw IF (2009): 0.297

Vinciguerra P, Albè E, Mahmoud AM, Trazza S, Hafezi F, Roberts CJ.

Villani F, Caviggioli F, Giannasi S, Klinger M, Klinger F.

Intra- and Postoperative Variation in Ocular Response Analyzer Parameters in Keratoconic Eyes After Corneal Cross-Linking.

J Refract Surg. 2010 Sep;26(9):669-76. doi: 10.3928/1081597X20100331-01. Epub 2010 Apr 15.

Raw IF (2009): 2.320 Normalized IF: 4

Squamous cell deep carcinoma after abdominal dermolipectomy: a case report.

Normalized IF: 1

Current Applications and Safety of Autologous Fat Grafts: A Report of the ASPS Fat Graft Task Force.

Plast Reconstr Surg. 2010 Feb;125(2):758-9; author reply 759.

Letter to the Editor (comment) Raw IF (2009): 2.743 Normalized IF: 1.2 Caviggioli F, Villani F, Forcellini D, Vinci V, Klinger F.

Hafezi F, Koller T, Vinciguerra P, Seiler T.

Marked remodelling of the anterior corneal surface following collagen cross-linking with riboflavin and UVA. Br J Ophthalmol. 2010 Oct 8. [Epub ahead of print] Letter To The Editor (results) Raw IF (2009): 2.917 Normalized IF: 3 Romano MR, Vinciguerra P, Valldeperas X, Romano V, Angi M, Furgiuele D, Costagliola C.

Inferior pseudophakic retinal detachment.

Ophthalmology. 2010 Nov;117(11):2233.e3-4. Letter To The Editor (comments) Raw IF (2009): 5.491 Normalized IF: 1.2

Plast Reconstr Surg. 2010 Apr;125(4):174e-6e.

Raw IF (2009): 2.743 Normalized IF: 6 Caviggioli F, Maione L, Vinci V, Klinger M.

The most current algorithms for the treatment and prevention of hypertrophic scars and keloids.

Plast Reconstr Surg. 2010 Sep;126(3):1130-1.

Letter to the Editor (comment) Raw IF (2009): 2.743 Normalized IF: 1.2 Klinger M, Caviggioli F, Vinci V, Salval A, Villani F.

Romano MR, Quaranta G, Bregu M, Albe E, Vinciguerra P.

Treatment of chronic posttraumatic ulcers using autologous fat graft.

No retinal morphology changes after use of riboflavin and long-wavelength ultraviolet light for treatment of keratoconus.

Plast Reconstr Surg. 2010 Sep;126(3):154e-5e.

Raw IF (2009): 2.743 Normalized IF: 6

Acta Ophthalmol. 2010 Dec 14. doi: 10.1111/j.17553768.2010.02067.x. [Epub ahead of print] Letter To The Editor (results) Raw IF (2009): 2.441 Normalized IF: 2 Romano MR, Valldeperas X, Vinciguerra P, Wong D.

118

Nipple resuscitation by lipostructure in burn sequelae and scar retraction.

Sub-macular Surgery: is still an option for Age-related Macular Degeneration?

Villani F, Caviggioli F, Klinger F, Maione L, Klinger M.

Fat Graft before breast reconstruction by latissimus dorsi.

Plast Reconstr Surg. 2010 Oct;126(4):190e-192e.

Raw IF (2009): 2.743 Normalized IF: 6

UROLOGY Taverna G, Corinti M, Colombo P, Grizzi F, Seveso M, Piccinelli A, Giusti G, Benetti A, Zucali PA, Graziotti P.

Bladder metastases of appendiceal mucinous adenocarcinoma: a case presentation.

BMC Cancer. 2010 Feb 23;10:62.

Raw IF (2009): 2.736

Normalized IF: 4

Giusti G, Maugeri O, Taverna G, Benetti A, Zandegiacomo S, Peschechera R, Graziotti P.

Tubeless percutaneous nephrolithotomy: Our experience.

Arch Ital Urol Androl. 2010 Mar;82(1):34-6.

Raw IF (2009): 0 Normalized IF: 0.1 Seveso M, Taverna G, Giusti G, Benetti A, Maugeri O, Piccinelli A, Graziotti P.

Corporoplasty by plication: out patient surgery for the correction of penile curvature.

Arch Ital Urol Androl. 2010 Sep;82(3):164-6.

Raw IF (2009): 0 Normalized IF: 0.1

119

Scientific Report Š Istituto Clinico Humanitas May 2011 Scientific Direction: Alberto Mantovani Communication Manager: Walter Bruno Editorial Coordination: Humanitas: Monica Florianello in collaboration with: Michele Tedeschi and Clara Caccialanza (Clinical Trials Office) Annalisa Franceschetti and Elena Pisano (Human Resources Office) Zadig, Milano: Giulia Candiani in collaboration with: Maria Rosa Valetto and Laura Ferroglio Graphic design: Luisa Goglio, Brescia Photographs: Marco Capovilla, Milano Paolo Carlini, MIlano Renzo Chiesa, Milano Humanitas Press Office

Printed in May 2011

by Tipografia F.lli Verderio, Milano

Scientific Report 2010 ›2011 Results and Perspectives Scientific Report 2010 ›2011

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