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Volume 02, Issue 02

April-June 2010

MediNEWS.Direct! Peer Reviewed Medicine, Pharma, and Biotech News Research and Intelligence

INDIAN EDITION

FEATURED ARTICLE

MINI REVIEWS

Cervical Cancer: A Comparison of International Screening Guidelines, Techniques Used, and the Screening Programs in Developing Countries

INTERVIEW

Cervical Cancer: Current Scenario, Screening, and Intervention Strategies Dr. Gagan Saini

Dramatic Rise in Nonmelanoma Skin Cancer in the US A Simple Blood Test to Monitor Heart Transplant Rejection Regular Multivitamin Consumption Linked to Breast Cancer Risk Is Prophylactic Mastectomy Beneficial for BRCA1/2 Mutation Carriers? Hand-assisted Subtotal and Total Colectomies for Extensive Crohnâ&#x20AC;&#x2122;s Colitis

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CONTENTS FEATURED ARTICLE

Editorial Advisory Board Milena Braga-Basaria, MD Terry Ann Glauser, MD, MPH Karen Harrop, MPH B M Hegde, MD, FRCP Pratap Kumar, MD

Cervical Cancer: A Comparison of International Screening Guidelines, Techniques Used, and the Screening Programs in Developing Countries

INTERVIEW

Cervical Cancer: Current Scenario, Screening, and Intervention Strategies Dr Gagan Saini

MINI REVIEWS NEUROLOGY

Editorial Team Managing Editor Dr B M John

PD Patients have Enhanced Risk of Developing Melanoma

Assistant Content Editor Dhanya Mohan

Herpes Zoster Ophthalmicus Diagnosis, an Indicator for Increased Stroke Risk

Assistant Copy Editor Amoolya Moses Research Analysts Dr Raghavendra Rao Dr Shylaja B Dr Naina G Shruthi V B Design Balamurugan M

CARDIOLOGY

Atorvastatin Reduces Ischemic Recurrences after Non-ST-elevation Acute MI in Non-revascularizable CAD Patients

Simple Blood Test could Aid in Heart Transplant Rejection Surveillance

RECORD Trial Confirms Increased Risk of Heart Failure Events with Rosiglitazone in Type 2 DM Patients ONCOLOGY

Study Substantiates Effectiveness of Prophylactic Mastectomy in BRCA1/2 Mutation Carriers

Dramatic Rise in Nonmelanoma Skin Cancer Prevalence Seen Across the US

Swedish Research Says Regular Multivitamin Use can Enhance Risk of Breast Cancer

GASTROENTEROLOGY

20 Designed and Published on behalf of MediNEWS.Direct! by iLogy Healthcare Solutions

NEPHROLOGY

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CAV1 Gene Variant Linked to Increased Risk of Renal Allograft Failure NEWS

Study Recommends Hand-assisted Subtotal and Total Colectomies for Extensive Crohnâ&#x20AC;&#x2122;s Colitis

Dopamine-based MRI Sensor could Revolutionize Conventional Brain Imaging

Disrupted CSF Levels of Tau Protein could Help in Early Detection of Alzheimer Disease

Potential Marker for Amyotrophic Lateral Sclerosis Progression Identified

Beta-blockers could Improve Breast Cancer Survival Rates

Cleveland Clinic Researchers Design Prophylactic Vaccine against Breast Cancer

PROVENGE Receives FDA Approval for Advanced Prostate Cancer Treatment

Injectable Asclera Receives FDA Nod for Treating Small Varicose Veins

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FEATURED ARTICLE Cervical Cancer: A Comparison of International Screening Guidelines, Techniques Used, and the Screening Programs in Developing Countries Dhanya Mohan, Assistant Editor, MediNEWS.Direct!

Abstract: Cervical cancer is one of the most common malignant neoplasms occurring worldwide. Implementation of effective screening strategies has contributed to substantial reduction in the disease burden in developed countries. Despite the significant advancements in early detection and prevention strategies, the mortality rate due to the cancer is substantially high in developing countries including India. The review provides a comparison of various international policies followed for cervical cancer screening. The article also performs an extensive analysis of barriers impeding the successful implementation of screening programs in developing countries, diverse screening techniques currently used, and alternative screening tools. The review also discusses the ways of improving the accessibility of such screening programs in low-resource settings. Cervical cancer, the second most prevalent cancer among women, globally, is associated with substantial disease burden. The following key facts released by the National Cervical Cancer Coalition (NCCC) reiterate the need for effective cancer screening policies and therapeutic intervention to reduce the prevalence:1 • In the US, the annual incidence and deaths related to cervical cancer is around 10,000 and 3,700, respectively. • Although most of the human papillomavirus (HPV) infections are directly associated with cervical cancer, many women are ignorant about the infection or the association. • Women missing the recommended regular Pap and HPV tests as well as three shot prevention vaccine are at enhanced risk for contracting cervical cancer. • Main cause for cancer-related deaths among women in developing countries is cervical cancer. • 85% of the annual incidence of new cases and deaths reported worldwide is attributed to occur among women in developing countries.

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The data released by the International Agency for Research on Cancer (IARC) based on Globocan 2008 database also substantiates an increased incidence of cervical cancer in developing countries when compared to global statistics. Regions Evaluated

Crude AgeAnnual Cumulative incidence adjusted incidence risk in % rate incidence of new (0-74 rate cases years)

India

23.5

27.0

134420

2.8

South Asia

21.0

25.0

169854

2.7

Worldwide

15.8

15.2

529409

1.6

India

Cervical cancer is reported to be the most frequent malignancy occurring among Indian women aged between 15 to 44 years. According to a 2010 summary report released by WHO/ICO (Institut Català d’Oncologia) Information Centre on HPV and Cervical Cancer, cervical HPV infection occurs in 7.9% of women in the general population at a given time, with the HPV 16 or 18 viruses being the underlying cause for 82.5% of the invasive cervical cancers. Other key statistics related to cervical cancer published in the report are provided in the table given below.2 Annual incidence of new cases

134,420

Annual number of deaths

72,825

Estimated number of new cases in 2025

203,757

Estimated number of deaths in 2025

115,171

Number of women with enhanced cancer risk (aged ≥15 years)

366.58 milion

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International Policies for Screening

A wide variation has been observed in the screening policies adopted across countries with regard to the targeted age range, testing intervals, and the total number of scheduled screening. A comparison of different screening polices conducted by Elske van den Akkervan Marle et al concluded that the recommendation of an average screening age of around 50 years can be considered as a key characteristic for efficient screening policies. The researchers compared different international screening policies for which various parameters, such as epidemiologic, demographic, screening, and treatment

characteristics, were presumed to be similar to those in the Netherlands. Such screening policies were found to be very close to efficient frontier. However, there was a need for alternative polices to make them cost-effective by reducing the number of scheduled screenings, advancing the age of first screening, or increasing the screening interval.3 The following table shows the different guidelines put forth by various international organizations for the screening of cervical cancer.4, 5, 6

Organizations

American Cancer Society (ACS)

U. S. Preventive Services Task Force (USPSTF)

American College of Obstetricians and Gynecologists (ACOG)

Last updated

2002

2003

2009

Starting of screening

Around 3 years after the first vaginal coitus, but not later than age 21

Within 3 years after first sexual intercourse or age 21, whichever comes early

• 21 years • The screening should be avoided in younger age groups

Screening intervals

Conventional Pap smear

• Yearly • Every 2-3 years for women ≥ 30 years with 3 negative cytology tests

At least every 3 years

• Every 2 years for women between 21 to 29 years of age • Every 3 years for women ≥30 years with 3 consecutive negative cytology tests

Liquid-based cytology

• Biennially • Every 2-3 years, for women ≥ 30 years with 3 negative cytology tests

Inadequate evidence

• Every 2 years for women between 21 to 29 years • Every 3 years for women ≥30 years with 3 negative cytology tests • Cytology combined with HPV DNA testing is appropriate for women > 30 years • If both the tests are negative rescreening should be done at 3-year interval in low-risk women ≥ 30 years of age

HPV testing

Every 3 years in conjunction with conventional or liquid-based cytology

Inadequate evidence

Termination of screening

Women ≥70 years with ≥3 recent, successive negative results and no abnormal tests in the previous 10 years

Women >65 years with negative results and not at high risk for cervical cancer

Women between the ages of 65 and 70 with ≥3 recent, successive negative tests and no abnormal results in the last 10 years

Screening discontinuation post total hysterectomy

Women who had undergone the procedure for benign indications having no previous history of high-grade cervical intra-epithelial neoplasia (CIN)

Women who had undergone the procedure for benign indications

Women who had undergone the procedure for benign indications and no previous history of high-grade CIN

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According to the National Health Service (NHS) screening program, every woman in the targeted age range of 25-64 years is invited to undergo free screening every 3 to 5 years. The screening intervals recommended by NHS are as follows:7 Age group (years)

Screening frequencies

First Invitation

25-49

Every 3 years

50-64

Every 5 years

≥65

Screening is recommended only for those who had not undergone screening from the age of 50 or those with recent abnormal test results

Obstacles for Screening in Developing Countries

Screening programs in developed countries have contributed to a substantial reduction in overall mortality rate due to cervical cancer. However, establishing such programs in developing countries is associated with certain pitfalls and barriers. The major obstacles that impede the successful implementation of populationbased screening programs in most of these countries have been described below:8 1. Competing health needs and reduced financial and human resources 8,9 Increasing healthcare needs due to substantial disease burden along with limited public health budgets and funding pose major hindrances in establishing such screening programs. The following factors contribute to limited access to healthcare in low-resource settings: • Inadequate number of primary health centers to arrange screening programs • Limited human and financial resources to offer cancer diagnostics, treatment, or palliative care services • Existence of urban/rural bias • Urban-rural bias • Inaccessibility owing to remote location of such facilities 2. Illiteracy, disempowerment, and poverty8,9 The key individual factors hindering the design and implementation of such screening programs are: • Lack of education, poverty, and low socioeconomic status • Cultural and societal diversities between distinct populations • Shyness and embarrassment for undergoing a pelvic examination

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• Limited knowledge regarding screening • Fear of the test result • Lack of support from partners and families to undergo such tests • Negative perception about the quality of healthcare services • Subservient status of women to men, contributing to disempowerment 3. Nature of screening tests The nature of the current screening methods can be considered as another factor contributing to meager success of such screening programs. In the US, the wide spread introduction of cytology screening tests in 2006 contributed to the reduction of incidence rate by around 75%; however, the malignant disease still remains as a major cause of morbidity and mortality among women in the country.10 The scenario is different in developing countries, wherein the increase in disease burden is due to the non-establishment or failure of such screening programs owing to inadequate infrastructure, resources, and trained experts.8 A review by Thomas C Wright reported the limited sensitivity of cervical cytology and the need for reserving the technique only for screening HPV-positive women who need further follow-up or colposcopy.10 Exfoliative cytology (conventional Pap smear) has been considered as gold standard for cervical cancer screening. However, when considering the overall reduction in mortality, the test benefit was substantially less. Also, certain epidemiological studies report that the test was not effective in preventing >60% of cervical cancer cases.11 A briefing from Cervical Cancer Action, a global coalition to prevent cervical cancer reported the following key limitations associated with Pap smear:12 • Low sensitivity and the need for frequent re-screening • Need for technical experts to collect cervical specimen, process and interpret the sample and for the confirmation of positive results • Burden related to repeated visits to clinics for performing the test • Dependence of test results on individual interpretation Due to such drawbacks, there is an increased demand for developing low-cost screening strategies that require very simple technology and can be easily learnt by paramedical people working in rural areas of resourcepoor countries.

Alternative Screening Tools

Several novel screening methods including various visual inspection strategies and other cytological screening

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methods, are currently under investigation. Some of these tools are mentioned below:

the outcomes of screening programs over Pap test is unclear.11, 14

Visual Inspection

Other Novel Cytological Screening Techniques13

According to a study by the Indian Council of Medical Research, observing for the high-risk signs of cervix, irrespective of bleeding symptoms, may aid in predicting 50%-60% early-stage cancers. Although the strategy may aid in down-staging the disease and reducing the fatality rates, it would not be suitable for the detection of dysplasias.13

Although alternative cytologic screening tools may aid in improving the efficacy of Pap smear, they are not suitable for low-resource settings due to their increased cost and heavy reliance on technology. Some of these innovative technologies are as follows:13 • Fluid-based thin-layer processing of cervical samples: The technique helps in attenuating sampling errors, thereby improving the specimen adequacy. The procedure involves removal of mucous, bacteria, and yeast prior to the application of the sample to a slidethin layer.

Visual inspection with acetic acid or Lugol’s Iodine Inspection of cervix after the application of acetic acid or Lugol’s iodine may aid in visualization of precancerous lesions using naked eye. Some of the factors that favor the use of this method in low-resource settings are as follows:12 • Aids in visual inspection of precancerous lesions • Easy to carry out without well-equipped laboratories and transport facilities • Simple and inexpensive procedure that can be performed by trained paramedical personnel including nurses, midwives, and other health workers • Immediate test results after screening may aid in providing the treatment also in the same visit • Assists in augmenting the screening coverage, followup care as well as the quality of the overall screening programs However, the test results are purely based on the evaluation of the person, who performs the procedure. Hence, providing regular training to such personnel as well as educating them regarding the standards for identifying the lesions is mandatory. Visual inspection with devices • Speculoscopy: The procedure involves visualization of the cervix under low power magnification (4x – 6x) using chemiluminescent light after the application of 5% acetic acid. However, there is no substantial evidence to validate that the regular addition of this technique to conventional Pap smear may aid in decreasing the disease mortality. An earlier study by Blumenthal reported the reduced sensitivity of such magnified visual techniques in detecting low-grade lesions as opposed to cytologic screening.11,13 • Cervicography: The procedure involves taking a photograph of the cervix after the application of 5% acetic acid, using specialized cameras. Although it is reported to have 59.7% specificity and 71.3% sensitivity, the potential of the technique in improving

• Automated Pap screening: The computerized analysis of smear samples, which are beneficial for primary and secondary screening, helps in reducing sampling errors. The secondary screening comprises of evaluation of abnormal cancer cells by pathologists.

Strategies for Low-Cost HPV DNA Testing Considering the potential of a simple, accurate, HPV testing in reducing the disease burden in the low-resource settings, several international firms are working towards developing such a test kit.14 QIAGEN’s care HPV, based on the current HPV screening technology, is touted as the first such testing tool that allows for field interpretation and the availability of test results within 2.5 hours. The results of the first clinical trial conducted on 2,500 rural subjects in China showed that the accuracy of careHPV is much greater than visual inspection with acetic acid or any other currently used screening approaches. The product is awaiting market authorization both in China and other international markets as well as pre-qualification from WHO. Another diagnostic test, named as AVantage HPV E6 Test, uses affinity monoclonal antibodies (mAb) for the detection of HPV-E6 oncoproteins expressed during the precancer stages. Further validation of the test efficacy could be promising for developing a simple and effective, point-of care test that is appropriate for resource-poor settings. 12,15

Conclusion

Low-screening coverage through nationalized screening programs has been considered as the major factor contributing to its limited success. Hence, clear insight into factors that augment women’s participation in such screening programs is essential for tailoring and

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implementing the programs successfully. Despite this, very few studies had investigated the rationale behind the reduced participation rates for screening in developing countries.16 There is also an urgent need for large multiinstitutional studies to validate the specificity and sensitivity of low-cost screening strategies prior to their adoption into routine screening programs.

screening: comparison of screening policies. J Natl Cancer Inst. 2002 Feb 6;94(3):193-204. 04. Cervical Cancer Screening Guidelines. Centers for Disease Control and Prevention. Last accessed July 22, 2010. 05. ACOG Committee on Practice Bulletins--Gynecology. ACOG Practice Bulletin no. 109: Cervical cytology screening. Obstet Gynecol. 2009 Dec;114(6):1409-20. 06. Smith RA, Cokkinides V, Brawley OW. Cancer screening in the

An earlier review by Kerkar et al reiterated the need for addressing the following issues to improve the success of such programs:11 • Reduced public awareness, accessibility of screening services • Limited lab facilities, funding, and resources • Insufficient number of well-trained service providers and cytological services • Increased cost of screening techniques • Limited number of treatment centers and follow-up services

United States, 2009: a review of current American Cancer Society guidelines and issues in cancer screening. CA Cancer J Clin. 2009 Jan-Feb;59(1):27-41. 07. NHS Cervical Screening Programme. National Health Service. Last accessed July 22, 2010 08. Denny L, Quinn M, Sankaranarayanan R. Screening for cervical cancer in developing countries. Vaccine. 2006 24 Suppl 3:S71-7. 09. Improving Screening Coverage Rates of Cervical Cancer Prevention Programs: A Focus on Communities. ACCP. Last accessed July 22, 2010. 10. Wright TC Jr. Cervical cancer screening in the 21st century: is it time to retire the PAP smear? Clin Obstet Gynecol. 2007 Jun;50(2):313-

During the formulation of such screening programs greater consideration has to be taken to set up longterm realistic goals as well as improve the accessibility to a large population especially those residing in rural areas. Finally, increased collaboration from women’s group, physicians, cytopathologists, local policy makers and health administers are reported to be crucial for the general successes of the programs.

Obstet Gynecol India. March/April 2006;56(2): 115-122. 12. New Options for Cervical Cancer Screening and Treatment in LowResource Settings. Cervical Cancer Action Coalition. Last accessed July 22, 2010. 13. Juneja A, Sehgal A, Sharma S, Pandey A. Cervical cancer screening in India: strategies revisited. Indian J Med Sci. 2007 Jan;61(1):34-47. 14. Ahn TG, Kim TJ, Han SJ. Clinical Usefulness of Double Combined Test

References

(Cytology + Cervicography) for Cervical Cancer Screening. Korean J

01. What is the National Cervical Cancer Coalition (NCCC)? National Cervical Cancer Coalition. Last accessed July 22, 2010.

Gynecol Oncol Colposc. 2001 Sep;12(3):210-216. 15. E6 Based Rapid Diagnostic Test for Cervical Pre-Cancer and Cancer.

02. Human Papillomavirus and related cancers. WHO/ICO HPV Information centre. Last accessed July 22, 2010.

Arbor Vita Corporation. Last accessed July 22, 2010. 16. Winkler J, Bingham A, Coffey P, Handwerker WP. Women’s partici-

03. Van den Akker-van Marle ME, van Ballegooijen M, van Oortmarssen GJ, Boer R, Habbema JD. Cost-effectiveness of cervical cancer

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23. 11. Kerkar RA, Kulkarni YV. Screening for cervical cancer: an overview. J

pation in a cervical cancer screening program in northern Peru. Health Educ Res. 2008 Feb;23(1):10-24. Epub 2007 Jan 17.

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INTERVIEW Cervical Cancer: Current Scenario, Screening, and Intervention Strategies Q: What are the factors that have affected the prevalence of cervical cancer, globally? A: Almost all (more than 99%) cervical cases are related to human papillomavirus (HPV). Of these, about 70% are caused by HPV types 16 or 18. When HPV infection does not clear on its own, it makes the cells abnormal, leading to cancer over a period of time. Though HPV is transmitted by sexual contact, there are also other causes for the disease, like smoking, chemical exposure, even weakened immune systems. Getting pregnant at a young age too can make you susceptible to this cancer, so does having multiple childbirths.

Dr Gagan Saini

Attending Consultant, Radiation Oncology, Max Cancer Centre, Max Hospital

Q: What is the pattern of cervical cancer incidence across India? A: Cervical cancer is the most common cancer in India. However, most people are not aware of this deadly disease. There are about 365.71 million women (aged between 15 years and above) at risk in India. As per WHO, 1,32,082 women are diagnosed with cervical cancer, and 74,118 die from this disease. To an estimated global incidence of 500,000 cervical cancers, India contributes 100,000, i.e., 1/5th of the world burden. In the west, the incidence of this disease has come down because women are required to get themselves screened (with Pap smear, mainly). It is a mandatory part of their health check- up. In India, we still have to start a process of mandatory screening. There are a huge number of people who have not even heard about the term ’Pap smear’. Q: What is the level of awareness among Indian women about the risk factors? A: Preventive healthcare is not a priority for Indian women, due to which they are negligent towards the factors that lead to cervical cancer. Visits to a gynecologist are only made when a woman conceives. A regular Pap smear is almost unheard of in our society. Q: What are the screening methods available? A: The Pap smear can be the greatest defense against cervical cancer. The test can detect cervical changes early, before they turn into cancer. You can also ask the doctor for a visual inspection of the cervix with acetic acid (VIA) or lugol’s (VILI). Alternatively, you can also get a HPV-DNA test done.

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INTERVIEW

Q: Is a positive HPV DNA test indicative of a precancerous or cancerous lesion? What is the way forward for such a woman during routine screening? A: First and most importantly, the HPV DNA test is not recommended for screening women younger than age 30 because infections with HPV are relatively common in this age group, and often resolve without any complications or long-term effects. A positive HPV DNA test indicates the presence of a high-risk type of HPV. This does not mean that you have pre-cancerous or cancerous lesion. Never forget that a very long standing HPV infection can only cause carcinoma cervix, so an infection diagnosed with HPV DNA is probably the proverbial “Stitch in Time”. The routine recommended test for screening is Pap smear. HPV DNA is generally used as an adjunct to the above. Therefore, if you get an abnormal smear test, don’t panic. Your doctor will usually order HPV DNA test after this. Additional testing may be necessary. Some small changes in cells can settle, and you may be advised to get another smear. Other abnormalities and changes might need more tests and you may need to visit a colposcopy clinic at the hospital. A colposcopy is an examination of the cervix using a bright light and a microscope. A sample of the cells may also be taken. During the exam you may be given suitable treatment if needed. Q: What treatment options are available for patients in India? What is the goal of cervical cancer treatment? A: The treatment options available to Indian patients are as good as anywhere in the world. The options range from simple hysterectomy (removal of uterus and ovaries with cervix) to Wertheim’s hysterectomy (removal of uterus, ovaries, and cervix, along with lymph nodes of pelvis, abdominal lymph nodes sampling and about 2 cm of vagina) to radiation therapy. The first option is useful for very early stage treatment, the second for early stages, while radiation therapy is employed for almost all stages. It is usually preferred to avoid surgery and its complications. Sometimes in early stages too radiation therapy is still required after surgery. Q: Is there a real need for HPV vaccine? Kindly elaborate on the role of HPV vaccines and the controversies surrounding its use. A: HPV vaccine has been developed recently and is now available everywhere. They are recommended for women who are 9 to 25 years old who have not been exposed to HPV. Since it is unlikely that a woman would have already contracted all four viruses, and because HPV is primarily

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April - June 2010

transmitted sexually, the US Centers for Disease Control and Prevention has recommended vaccination for women of up to 26 years of age. However, there are controversies linked with this product, ranging from unexplained sideeffects to vested interests of drug companies. Q: Will vaccination impact the overall incidence and stage distribution of this disease? A: What this vaccine definitely does is it reduces the incidence of HPV infection in the vaccinated population, provided they are not infected already; but that may or may not translate into decreased incidence, because according to US statistics, of the 2-3 million abnormal Pap results, only 10,000 cancers are detected. It still has to be seen how much the reduced incidence of HPV infection translates into change in overall incidence of cervical cancer. However, what certainly has proven its benefit towards the decreasing incidence of cervical cancer is a routine Pap smear. Q: Would you advocate the Centres for Disease Control and Prevention Advisory Committee’s recommendation to offer routine 3 doses of quadrivalent HPV vaccine to girls aged between 11-12 years, in India? A: I am a doctor and would like that everyone stays disease free, but I am also a rationalist who knows, for a fact, that as far as a human body is concerned, nothing can be truly extrapolated, because life is not mathematical. I would first like to confirm the western data in Indian population, and considering our heterogeneity, I would like to do so in various parts of our country. Small studies, which are well managed, controlled, and coordinated, should be conducted first. Only after seeing results can one recommend the giant leap towards mass immunization. Q: What is new in cervical cancer research? A: There is work on better forms of radiation therapy, like intensity-modulated radiation therapy (IMRT), and image guided radiation therapy (IGRT), which reduce side effects for cervical cancer treatment. Research has shown that, even for early stages of the disease, radiation therapy provides results as good as surgery minus all the side effects. Targeted systemic therapies are being tested too; which will hit the exact molecular target unlike the usual chemotherapy drugs. Therapeutic cervical cancer vaccine is being worked upon (the one available is prophylactic only, i.e., it will not work if the individual is already infected). Robotic surgery is also being developed. The role of molecular imaging, like PET scan, is also getting more and more defined.

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NEUROLOGY PD Patients have Enhanced Risk of Developing Melanoma The increased risk of melanoma in Parkinson disease (PD) patients has been suggested earlier; although, there has been no substantial scientific evidence to explain the cause of this association. A prospective clinico-pathological study, published in the latest issue of Archives of Neurology, reiterates this association, and proposes the need for performing skin cancer screening in PD patients. John M Bertoni, Professor, Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, and co-researchers sought to evaluate the increased risk of skin cancer associated with idiopathic PD. They enrolled 2,106 patients with a mean age of 68.6 years and 7.1 years mean duration of PD in 31 centers across North America. Majority of patients (84.8%) received levodopa. After consulting with a neurologist, the patients underwent a dermatological assessment, which included a melanoma risk evaluation and whole-body examination. Lesions suspected to be melanoma were subjected to biopsy and evaluated in a central dermatopathology laboratory. A total of 68 patients (3.2%) reported having melanomas in the past; examination revealed 346 pigmented skin lesions, of which 20 were in situ melanomas (0.9%) and 4 invasive melanomas (0.2%). The overall prevalence of the tumor was compared with the American Academy of Dermatology cancer screening programs, and the US Surveillance Epidemiology and End Results (SEER) cancer database. The results revealed a 2.24-fold higher prevalence in the study cohort (n=1692), compared to the age- and sex-matched populations in the US SEER database. The age- and sex-adjusted relative risk of melanoma was more than 7 times in the study cohort compared to confirmed cases in the American Academy of Dermatology skin cancer screening programs. These findings indicate that melanoma is more common in PD than in the general population.

According to the American Cancer Society, melanoma accounts for less than 5% of skin cancers, but is responsible for a majority of skin cancer-related deaths. Some of the risk factors include fair skin, family history, radiation exposure, certain pre-malignant conditions and previous melanomas, and susceptibility to sunburns. The tumor is 10 times more common in whites than in blacks; the lifetime risk is estimated to be around 2% (1 in 50) in whites, 0.5% (1 in 200) in Hispanics and 0.1% (1 in 1,000) in blacks. Regular screening is recommended, as early diagnosis and treatment are vital for improving the outcome and survival. The possible association between levodopa use in PD patients and risk of melanoma was suggested within years of introduction of the drug, in the early 1970s. Despite inadequate scientific evidence to explicate the cause of the link, the association has been encountered in several clinical reports. A possible confounding factor could be the social class, as both melanoma and PD are more common in the upper social strata; the former, probably due to increased recreational sun exposure; but has been questioned by Driver et al (Cancer Epidemiology, Biomarkers and Prevention, 2007). Whatever be the factor influencing this association, special melanoma screening guidelines for PD patients may be issued in future, once gene-environmental studies confirm the present findings.

References 01. Bertoni JM, Arlette JP, Fernandez HH, et al. Increased Melanoma Risk in Parkinson Disease: A Prospective ClinicopathologicalStudy. Arch Neurol. 2010 Mar;67(3):347-352. 02. What Are the Key Statistics About Melanoma? American Cancer Society. Last accessed Mar 17, 2010. 03. Zanetti R, Rosso S, Loria DI. Parkinsonâ&#x20AC;&#x2122;s disease and cancer. Cancer Epidemiol Biomarkers Prev. 2007 Jun;16(6):1081. 04. Driver JA, Logroscino G, Buring JE, Gaziano JM, Kurth T. A prospective cohort study of cancer incidence following the diagnosis of Parkinsonâ&#x20AC;&#x2122;s disease. Cancer Epidemiol Biomarkers Prev. 2007 Jun;16(6):1260-5

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NEUROLOGY

April - June 2010

Herpes Zoster Ophthalmicus Diagnosis, an Indicator for Increased Stroke Risk Varicella-zoster virus (VZV) infection at its primary stage as well as its reactivation, years later (herpes zoster or shingles) within the cerebral artery, has been reported to cause stroke, aneurysms, and arterial ectasia. Now, a recent population-based follow-up study substantiates the high risk of stroke development subsequent to herpes zoster ophthalmicus (HZO) diagnosis within 1 year of follow up. The findings of the study are published in the latest issue of the journal, Neurology. Herng-Ching Lin from the Department of Ophthalmology, Taipei Medical University Hospital, Taiwan, and colleagues, conducted the study in order to evaluate the risk of stroke following the herpes zoster infection of the eye. Retrospective data was collected from the Taiwan National Health Insurance Research Database, and a total of 658 patients diagnosed with HZO between 2003 and 2004 were included in the study cohort. These subjects were matched for age and gender with 1,974 randomly selected patients of the comparison cohort, and were monitored for one year following their index hospital visits. The rate of stroke-free survival during this period was calculated using the Kaplan-Meier method, and analyzed based on the Cox proportional hazards model, following adjustment for possible confounders. It was noted that 8.1% of the patients in the HZO cohort and 1.7% of those in the comparison cohort developed stroke within the study period. The results indicated significantly decreased 1-year stroke-free survival rates among HZO patients in comparison to non-herpes zoster patients. The researchers reported 4.52-times increased stroke risk associated with the study group when compared to the controls following adjustments for patient demographics, chosen co-morbidities, and medication use. Furthermore, it was observed that

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systemic antiviral therapy did not influence stroke risk in patients with herpes infection. Earlier, Kang et al (Stroke, 2009) conducted a populationbased retrospective cohort study to evaluate the risk and incidence of stroke after herpes zoster (shingles) attack. The study findings confirmed an increased risk of stroke following shingles. It was concluded that although VZV-induced vasculopathy could lead to stroke after shingles, the reason for increased stroke risk in patients with herpes zoster remained obscure. According to the June 2008 Morbidity and Mortality Weekly Report (MMWR) published by the Centers for Disease Control and Prevention (CDC), an estimated 1 million new cases of herpes zoster are diagnosed each year in the United States. It is estimated that approximately 10 to 25% of patients with herpes zoster will develop HZO. HZO, caused due to VZV reactivation in the ophthalmic division of the trigeminal nerve, represents an ophthalmologic emergency due to chronic pain and vision loss. The zoster vaccine approved by the U.S. Food and Drug Administration, targeted for elderly group (aged 60 years or older), has a significant impact in reducing the global burden of the disease.

References 01. Lin HC, Chien CW, Ho JD. Herpes zoster ophthalmicus and the risk of stroke: a population-based follow-up study. Neurology. 2010 Mar 9;74(10):792-7. 02. Kang JH, Ho JD, Chen YH, Lin HC. Increased risk of stroke after a herpes zoster attack: a population-based follow-up study. Stroke. 2009 Nov;40(11):3443-8. 03. Catron T, Hern HG. Herpes zoster ophthalmicus. West J Emerg Med. 2008 Aug;9(3):174-6.

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April - June 2010

CARDIOLOGY Atorvastatin Reduces Ischemic Recurrences after Non-ST-elevation Acute MI in Non-revascularizable CAD Patients Non-ST-elevation acute myocardial infarction (NSTEAMI) correlates with significantly increased risk of recurrent ischemic events and death, indicating poor prognosis. The results of a recent trial voices the efficacy of full-dose atorvastatin therapy (80 mg/day) in reducing ischemic recurrences following NSTE-AMI in severe, diffuse non-revascularizable coronary artery disease (CAD) patients. The findings of this trial are published in the latest issue of the journal, Current Medical Research and Opinion. Furio Colivicchi, from the San Filippo Neri Hospital, Italy, and colleagues, conducted the trial to assess the therapeutic potential of atorvastatin in 290 patients (mean age=74.6Âą9.6 years) having NSTE-AMI with angiographic signs of diffuse and severe CAD, who could not be revascularized with angioplasty or coronary surgery. The prospective randomized open label, blinded end point (PROBE) design was employed to perform the study. These patients were randomly administered with full-dose 80 mg/day atorvastatin (n=144) or conventional treatment (n=146). The non-blinding of the study was likely to bias the outcome assessment process. The primary outcome event was the composite of cardiovascular death, fatal stroke, and non-fatal AMI occurring within 12 months following randomization. The study results demonstrated that 16% of patients in the atorvastatin group and 26.7% in the conventional group achieved the primary outcome (HR=0.56; P=0.027; 95% CI=0.33-0.93). Based on the results, the investigators opined that 80 mg/day of atorvastatin confers better protection against the risk

of ischemic recurrences in non-revascularizable CAD patients, when compared to conventional treatment strategies. According to a 2007 report by the American College of Cardiology (ACC) and American Heart Association (AHA), acute coronary syndrome that encompasses NSTE-AMI and unstable angina contributes to an estimated 1.5 million hospitalizations each year in the United States. Early intensive therapy with lipid-lowering, antihypertensive, and antidiabetic agents have been well established in significantly reducing the incidence of recurrent vascular events in patients with NSTE-AMI. Large clinical trials, such as the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) and Pravatatin or Atorvastatin and Infection Therapy (PROVE IT), have demonstrated the efficacy and safety of 80 mg atorvastatin in patients with acute coronary syndrome. The current research, suggesting the use atorvastatin therapy for conferring protection against ischemic recurrences, further substantiates the prominent role of the drug in preventing primary and secondary cerebrovascular diseases.

References 01. Colivicchi F, Tubaro M, Mocini D, et al. Full-dose atorvastatin versus conventional medical therapy after non-ST-elevation acute myocardial infarction in patients with advanced non-revascularisable coronary artery disease. Curr Med Res Opin. 2010 Apr 6. [Epub ahead of print] 02. Gelfand EV, Cannon CP. Management of Acute Coronary Syndromes. West Sussex, UK: John Wiley & Sons Ltd.; 2009:39-40.

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CARDIOLOGY

April - June 2010

Simple Blood Test could Aid in Heart Transplant Rejection Surveillance Heart transplant recipients are required to undergo routine biopsy tests throughout their lifetime in order to monitor the risk for organ rejection; the procedure usually being uncomfortable and nerve-wrecking. Now, a recent study reports that the blood test, AlloMap® (XDx, Inc.), in addition to clinical and echocardiogram evaluation, could help determine the risk for rejection and thereby safely reduce the number of endomyocardial biopsies to be performed. The findings of the multicentered, invasive monitoring attenuation through gene expression (IMAGE) trial are published in the recent online issue of the New England Journal of Medicine. Michael X Pham, a clinical assistant professor of cardiovascular medicine at the Stanford School of Medicine, California, along with co-workers, followed up 602 recipients in 13 heart transplant centers across the US, over a period of two years. The participants had received the transplant in the last 6 months to 5 years and were clinically stable. They were randomized to undergo routine biopsy, or a blood test in adjunct to clinical, and echocardiographic evaluation to assess the graft function. The primary outcomes of the study included first rejection incidence with hemodynamic compromise, retransplantation, dysfunctioning of the graft due to other reasons, or death. The following results were documented during the study: • Through the median 19-month follow-up period, patients examined with gene-expression profiling and routine biopsy tests had comparable two-year cumulative rates of primary outcomes (14.5% vs. 15.3%; 95% CI=0.67-1.68). With gene-expression profiling, the hazard ratio was found to be 1.04. • The two-year death rates due to any cause were similar in both the groups (6.3% vs. 5.5%; P=0.82). • The blood test group underwent fewer biopsies per person-year of follow-up (0.5 vs. 3.0 biopsies per year; P<0.001) and showed higher patient satisfaction compared to the biopsy group.

AlloMap works on genomic technology, and assesses the expression levels of 20 different genes in a heart transplant recipient’s blood sample to depict the immune status. A test score, which represents the collective expression of these genes, may aid a physician in investigating the patient’s risk for rejection, when employed together with a standard assessment. The FDA-approved test is currently available at 65 transplant centers across the US. According to the American Heart Association, 2,210 patients in the US have undergone cardiac transplantation in 2007, and 2,163 in the year 2008. As of June 2009, the one-, three-, and five-year survival rates in men and women were reported to be 88.0 and 77.2; 79.3 and 77.2; and 73.1 and 67.4; respectively. Although the survival rates have improved, the possibilities for acute rejection remain for several years post-transplantation. On an average, a heart transplant recipient undergoes 12 biopsies in the first year, and four the year after that, post-transplantation. Although the surveillance could be continued for several more years if needed, the procedure undertaken is invasive, hence associated with anxiety, discomfort, and serious risk of complications (despite being very rare). Gene-expression profiling, based on the current findings, could make a reasonable alternative tool to routine biopsies for post-cardiac transplant patient management. About XDx, Inc.: Headquartered at Brisbane, CA, XDx is a molecular diagnostics company involved in the discovery, development, and marketing of non-invasive, gene expression-based tests for screening graft rejection and autoimmune diseases.

References 01. Pham MX, Teuteberg JJ, Kfoury AG, et al. Gene-Expression Profiling for Rejection Surveillance after Cardiac Transplantation. N Engl J Med. 2010 May 20;362(20):1890-900. 02. Blood test enables heart-transplant recipients to undergo fewer biopsies, study shows. Press release. Stanford School of Medicine. Last accessed May 13, 2010.

Based on these findings, the researchers concluded that in clinically stable cardiac transplant recipients, geneexpression profiling of peripheral-blood samples, in adjunct to clinical and echocardiographic assessment, considerably reduced the number of biopsy tests, and was not associated with an elevated risk of serious adverse outcomes.

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03. International Society for Heart & Lung Transplantation and XDx Announce Results of IMAGE Study Demonstrating Non-Inferiority of AlloMap® to Routine Biopsy for Routine Surveillance After Heart Transplantation. Paper presented at: International Society for Heart & Lung Transplantation 30th Annual Meeting and Scientific Session;April 22, 2010;Chicago.

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CARDIOLOGY

April - June 2010

RECORD Trial Confirms Increased Risk of Heart Failure Events with Rosiglitazone in Type 2 DM Patient The hypoglycemic effect of thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR) agonists, has been proven through various welldesigned clinical trials. However, since they are reported to cause fluid retention, guidelines from international medical bodies caution the use of these drugs in patients with New York Heart Association (NYHA) class III and IV heart failure (HF). Now, data obtained from a multi-center open-label trial further corroborates the enhanced risk for HF events in type 2 diabetic patients on rosiglitazone medication. The results of the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) study, published in the recent issue of the European Heart Journal, support the warnings put forth for the use of TZDs in diabetic patients on treatment with metformin or sulfonylurea mono or combined therapy. Michel Komajda from the Université Pierre et Marie Curie Paris, France, and coworkers, evaluated the occurrence of fatal and non-fatal HF events and their outcomes in 4,447 type 2 diabetes patients with a mean hemoglobin A1c (HbA1c) level of 7.9%, who were under metformin or sulfonylurea monotherapy. The follow-up was conducted for an average of 5.5 years, and the selected patients were randomized to use rosiglitazone as an add-on (n=2220) or a combination of metformin and sulfonylurea (n=2227). A clinical endpoint committee determined the occurrence of heart failure hospitalization and deaths based on prespecified criteria. From around 30 pre-specified clinical, biological, and demographic variables, independent markers for HF events were determined. The study also ruled out the predictive potential of cardiovascular disease history in HF. The key findings observed in the rosiglitazone group were as follows: • Two-fold increase in the risk for HF death or hospitalization (HR=2.10; 95% CI=1.35–3.27) • Increase in HF-related event rate (around 2.6 per 1,000 person-years) and deaths (10 vs. 2) between rosiglitazone add-on group and sulfonylurea group

• No substantial rise in cardiovascular disease-related hospitalization or mortality (HR=0.99; 95% CI=0.85– 1.16) • Period of hospitalization and rate of re-hospitalization linked to HF events was comparable between the two study groups • Independent predictors of HF identified were ͧͧ Age ͧͧ Body mass index ͧͧ Rosiglitazone assignment ͧͧ Urinary albumin:creatinine ratio ͧͧ Systolic blood pressure at baseline The study, validating the enhanced risk for HF events linked to rosiglitazone, corroborates the following guidelines issued for the management of patients under TZDs: • The treatment should be discontinued in patients developing symptomatic HF associated with the drug use. • Apart from aged individuals, close monitoring of the patients for the following factors are mandatory during the treatment. ͧͧ High body mass index ͧͧ Microalbuminuria/proteinuria ͧͧ Increased systolic blood pressure The rosiglitazone package label cautions the increased risk for HF when used in combination with insulin, and also in NYHA stage III and IV heart failure patients. Currently, the U.S. FDA is reviewing the primary data obtained from the RECORD study, and an update from the review committee on the risks and benefits of rosiglitazone is expected by July 2010.

References 01. Komajda M, McMurray JJ, Beck-Nielsen H, et al. Heart failure events with rosiglitazone in type 2 diabetes: data from the RECORD clinical trial. Eur Heart J. 2010 Apr;31(7):824-31. 02. FDA Drug Safety Communication: Ongoing review of Avandia (rosiglitazone): and Cardiovascular Safety. U.S. FDA. Last Accessed April 16, 2010.

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April - June 2010

ONCOLOGY Study Substantiates Effectiveness of Prophylactic Mastectomy in BRCA1/2 Mutation Carriers Women with BRCA1 or 2 (breast cancer 1 or 2, early onset) mutations are known to be at an increased risk for breast cancer. Once such mutations are detected by genetic testing, the carriers are offered regular surveillance and prophylactic treatment (chemoprevention or prophylactic surgery). However, the usefulness of these prophylactic measures has been a topic of much debate. Now, a study conducted by Dutch researchers has demonstrated that prophylactic mastectomy (PM) is highly effective in preventing the development of invasive breast cancer in BRCA1 or 2 mutation carriers. The results have been published in the latest issue of Annals of Surgery. The study by Reinoutje Kaas at The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, and colleagues, was conducted on 254 BRCA1 or 2 mutation carriers. They underwent a routine surveillance including a breast magnetic resonance imaging. They were then subjected to mastectomy. A total of 147 asymptomatic carriers received bilateral mastectomy and 107 symptomatic carriers, contralateral mastectomy after an average cancer-free period of 3.6 years. The histopathological examination of the removed breasts revealed an occult small invasive breast cancer in one asymptomatic BRCA2 carrier and ductal carcinoma in situ (DCIS) in 6 asymptomatic carriers and 5 symptomatic carriers. Follow-up revealed 1 invasive breast cancer after 580 women-years in the symptomatic group, but none in the asymptomatic group following 778 women-years. It was concluded that PM was highly effective in preventing the development of invasive cancer in BRCA1 or 2 mutation carriers. Further follow-up and surveillance of asymptomatic carriers was deemed unnecessary as they had a very low risk (<0.2% per woman-year) of cancer after the procedure. Based on the age-, cohort-, and gene-specific reference data, it was estimated that PM prevented the occurrence of 15 invasive primary cancers in the asymptomatic carriers during the period of follow-up. Another similar study by Heemskerk-Gerritsen et al (Annals of Surgical Oncology, 2007) concluded that the incidence

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of primary breast cancer after PM was low at the end of a median follow-up of 4.5 years. Among the 236 BRCA1 or 2 mutation carriers who underwent the procedure, only one patient developed metastatic cancer 3.5 years later. This indicates that despite a thorough pathological examination of the mastectomy specimen, the presence of an occult cancer cannot be ruled out. It may therefore be prudent to continue surveillance in such patients even after PM. The BRCA1 and BRCA2 tumor-suppressor genes located on chromosome 17 and 13, respectively, code for proteins crucial for DNA repair. They also prevent rapid uncontrolled cell division, thus maintaining the stability of genetic information. Apart from breast cancer, mutations in the BRCA1 and BRCA2 genes are also linked to the enhanced risk for pancreatic cancer, male breast cancer, and fallopian tube cancer. The presence of two faulty copies of BRCA2 genes can cause Fanconi anemia type D1, and leukemia, subsequently. According to the World Health Organization (WHO), breast cancer is the most common cancer in women, worldwide, accounting for 16% of all female cancers. Several other risk factors have been enumerated, including physical inactivity, overweight or obesity, alcohol use, family history, and prolonged exposure to estrogens. Prophylactic measures in susceptible population and early detection of the tumor remains the key to improving outcome and survival. Although PM has been shown to be an effective prophylactic measure, it is mandatory that the physician inform the patients opting for the procedure regarding the following key limitations of this radical intervention: • The procedure is permanent and irreversible • May adversely affect future sexual life due to substantialoss of sensation in the breasts • Inability to breastfeed the baby • Not a 100% effective prophylactic measure to prevent breast cancer development or recurrence • Chances of developing anxiety and depression due to the adverse effects of the proce dureon body image References available online at www.medinewsdirect.com

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ONCOLOGY

April - June 2010

Dramatic Rise in Nonmelanoma Skin Cancer Prevalence Seen Across the US The prevalence of nonmelanoma skin cancer (NMSC) in the United States is around 5 fold greater than that of prostate or breast cancer: a study, using an incidencebased mathematical model, has recently reported in the latest issue of the Archives of Dermatology. The research also found that the prevalence was higher than the 31year combined incidence of all other malignancies. Robert S Stern, Vice Chairman, Department of Dermatology, Beth Israel Deaconess Medical Center, Boston, created an incidence-based model to determine the prevalence of NMSC in the US for the year 2007. The mathematical model used the age distribution of the population from 1957 to 2006, the age-specific incidence data modified to reveal changes in incidence during the same period, and the possibility that an incident tumor was the first ever for that individual. Sensitivity analyses were performed, which varied the assumption of time- and proportionrelated change in incident tumors in cases with first-time diagnosis of NMSC. Using standard methods of survey data analysis, the number of individuals with a history of the selected tumors was estimated, and the Surveillance, Epidemiology, and End Results (SEER) estimates were used for incidence-based estimates for malignancies other than NMSC. The National Cancer Institute Skin Cancer Incidence data (1977-1978), National Health Interview Survey (NHIS) 2007 data were also included in the analysis. The results revealed the following: • About 13 million white non-Hispanics at the start of the year 2007, reported the dvelopment of at least one NMSC • The 2007 National Health Interview Survey (NHIS) estimates revealed only 5 million cases of skin tumor: less than half the number estimated from incidence and survival data. • Approximately 1 in 5 septuagenarians have been diagnosed with NMSCs, with most of them being diagnosed withmultiple tumors.

databases. On calculating the incidence and prevalence of skin cancer with this data, the study found a sharp rise of 76.9% in the total number of skin cancer procedures from 1992 to 2006. Also, the age-adjusted procedure rate (per year, per 100,000 beneficiaries) nearly doubled (3,514 in 1992 to 6,075 in 2006) during the same period. NMSC chiefly comprises of basal cell carcinoma and squamous cell carcinoma. Basal cell carcinoma is typically a slow-growing tumor, most often located on the face and back of the hands. Squamous cell carcinoma, seen more commonly among the elderly in the region of the head and neck, appears as a moderately rapid-growing exophytic tumor in most cases. Although death from these tumors is rare, they cause considerable morbidity and are associated with a heavy economic burden. The major risk factor is solar ultraviolet exposure in individuals with increased susceptibility, determined by their skin type and increased risk of sunburn. Other risk factors include: • Advancing age • Male sex • Use of coal-tar products, tobacco or psoralens • Past history of NMSC • Chronic osteomyelitis sinus tracts • Burn scars and chronic skin ulcers • Human papilloma infection • Xeroderma pigmentosum Public education on skin cancer preventive measures, such as avoiding sun exposure during peak hours (from 10 am to 4 pm), or using sun-protective gear and sunscreens with a solar protection factor of at least 15, should be further emphasized in the wake of these findings.

References 01. Stern RS. Prevalence of a history of skin cancer in 2007: results of an incidence-based model. Arch Dermatol. 2010 Mar;146(3):27982. 02. Rogers HW, Weinstock MA, Harris AR, et al. Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch

Another study by Rogers et al (Archives of Dermatology, 2010), primarily aimed at detecting the US incidence of NMSC in 2006, concluded that there was a silent epidemic of skin cancer in the United States. The NMSC-related office visits and the total number of skin tumor procedures undertaken on Medicare beneficiaries in the year 1992, and from 1996 to 2006 were estimated using several

Dermatol. 2010 Mar;146(3):283-7. 03. Chen J, Ruczinski I, Jorgensen TJ, et al. Nonmelanoma skin cancer and risk for subsequent malignancy. J Natl Cancer Inst. 2008 Sep 3;100(17):1215-22. 04. Jerant AF, Johnson JT, Sheridan CD, Caffrey TJ. Early detection and treatment of skin cancer. Am Fam Physician. 2000 Jul 15;62(2):357-68, 375-6, 381-2.

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ONCOLOGY

April - June 2010

Swedish Research Says Regular Multivitamin Use can Enhance Risk of Breast Cancer Multivitamins, presumed to confer health benefits and prevent chronic diseases, is consumed as dietary supplements by a substantially high number of individuals in the US. Now, a recent prospective cohort study, published in the American Journal of Epidemiology, cautions the regular multivitamins consumers on the enhanced risk for breast cancer associated with its intake. Susanna C Larsson and coworkers from the Division of Nutritional Epidemiology, The National Institute of Environmental Medicine, Karolinska Institutet, Sweden, investigated the correlation between multivitamin consumption and invasive breast cancer incidence in a cohort of 35,329 cancer-free Swedish women. The study participants were requested to fill up questionnaires pertaining to multivitamin intake and other breast cancer risk factors. Cox proportional hazard models were used to calculate relative risks and 95% confidence intervals, and the same adjusted for cancer risk factors. The mean follow-up, conducted for a period of 9.5 years, demonstrated the occurrence of incident breast cancer in 974 subjects. Also, the multivariable RR calculated in multivitamin consumers was 1.19 (95% CI=1.04, 1.37). However, no significant difference in the association was noted with regard to breast tumor hormone receptor status. In stark contrast, an earlier study conducted by Ishitani et al (American Journal of Epidemiology, 2008) reported that no significant association exists between multivitamin use and the overall risk for breast cancer. Additionally, the researchers reported that the use of multivitamin supplements may reduce (although not significantly) estrogen receptor negative-progesterone receptor negative breast cancer. A recent review study by Rogovik and coworkers (The Annals of Pharmacotherapy,

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2010) evaluated the safety and potential interactions of vitamins. The study findings showed that the use of certain vitamins like pantothenic acid, biotin, thiamine, riboflavin, vitamins K and B12 are associated with trivial and reversible adverse effects. In contrast, fat-soluble vitamins A, E, and D, and water-soluble vitamins, folic acid and niacin, could cause significant adverse effects and toxicities. Based on the key study results, the researchers put forth the following recommendations: • Categorization of vitamins A, E, D, niacin, and folic acid as over-the-counter medicines • Exclusion of vitamin A from the category of multivitamin supplements and food fortificants • Labeling these products, especially those used for pediatrics and other vulnerable groups, with accurate information on ͧͧ Dosage ͧͧ Possible toxicities ͧͧ Recommended upper intake limits ͧͧ Concomitant use with other products In view of the several contradictory results, there is public and medical confusion over the use of multivitamins as dietary supplements. Until ample data, substantiating the benefits of multivitamin intake, is available through large population-based clinical trials, it is preferred to maintain a balanced and healthy diet or seek physician’s advice prior to the initiation of its regular intake

References 01. Larsson SC, Akesson A, Bergkvist L, Wolk A. Multivitamin use and breast cancer incidence in a prospective cohort of Swedish women. Am J Clin Nutr. 2010 May;91(5):1268-72. 02. Ishitani K, Lin J, Manson JE, Buring JE, Zhang SM. A prospective study of multivitamin supplement use and risk of breast cancer. Am J Epidemiol. 2008 May 15;167(10):1197-206. 03. Rogovik AL, Vohra S, Goldman RD. Safety considerations and potential interactions of vitamins: should vitamins be considered drugs? Ann Pharmacother. 2010 Feb;44(2):311-24.

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April - June 2010

GASTROENTEROLOGY Study Recommends Hand-assisted Subtotal and Total Colectomies for Extensive Crohn’s Colitis Hand-assisted laparoscopic surgery (HALS) has demonstrated its value as a versatile therapeutic alternative to laparoscopic (LAP) colorectal resection for complex intestinal diseases such as ulcerative colitis and diverticulitis. However, its efficacy in patients undergoing technically demanding subtotal or total colectomy for Crohn’s colitis has not been ascertained as yet. Now, a recent study reports the safety, viability, and the prognostic benefits of this procedure in treating extensive Crohn’s colitis, owing to reduced operating time and its minimally invasive nature. The findings of the study are published in the recent issue of the journal Surgical Endoscopy. Kiyokazu Nakajima, from the Department of Surgery, Osaka University Graduate School of Medicine, Japan, and coworkers, evaluated the effectiveness of hand-assisted laparoscopic colectomy in patients with extensive colonic Crohn’s. The study was conducted on 38 successive patients on whom subtotal/total colectomy had been performed (between 1992 and 2006) as a preliminary procedure for Crohn’s colitis, affecting 3 or more segments of the colon. The researchers categorized these patients according to the nature of the surgery into three groups that included open (n=14), LAP (n=6), and HALS (n=18) procedures. A retrospective analysis of the patients’ background and their postoperative data was performed. The three groups were matched by their sex, age, body mass index, disease extent and type, indications, and the surgical techniques. The study results are listed in the table below: Operative Techniques

Median Operative Time in minutes (range)

Median Blood Loss in mL (range)

Open surgery

200 (172-315)

438 (280-780)

LAP

330 (154-540)

170 (115-257)

HALS

251 (165-340)

225 (35-890)

The researchers noted a relatively shorter median operative time for open surgery and HALS in contrast to LAP. Furthermore, the study findings reported considerably less blood loss with LAP and HALS as against open technique. However, no statistical difference in postoperative complications and no mortality were noted

among the three groups. Many studies have demonstrated the efficacy of HALS in treating colorectal cancer. A study by Ringley et al (Surgical Endoscopy, 2007) assessed the potential efficacy of handassisted laparoscopic segmental colonic resection against conventional LAP resection in the treatment of colorectal cancer. The study demonstrated markedly reduced operative time and statistically increased lymph node harvest associated with HALS when compared to LAP. Furthermore, LAP technique included a slightly smaller incision of unclear clinical importance as compared to the HALS approach. However, the two groups exhibited equivalent intraoperative blood loss, pedicle lengths, and hospital stay lengths. Hand-assisted laparoscopic colectomy provides sensitive tactile feedback for the surgeon to explore, retract, and perform blunt dissections, and apply immediate hemostasis while maintaining the pneumoperitoneum. With a short learning curve, this technique facilitates the ability to perform more challenging operations, while retaining the short-term surgical benefits of LAP. The current study, indicating the efficacy of this procedure, has suggested the incorporation of this valuable tool into the modern arsenal of surgical alternatives for extensive conditions requiring colon resection. However, larger clinical trials are required to confirm the favorable outcomes of this procedure before recommending it as the most appropriate surgical option for Crohn’s extensive colitis.

References 01. Nakajima K, Nezu R, Hirota M, Nishida T. The role of hand-assisted laparoscopic surgery in subtotal and total colectomy for Crohn’s colitis. Surg Endosc. 2010 Apr 7. [Epub ahead of print] 02. Ringley C, Lee YK, Iqbal A, et al. Comparison of conventional laparoscopic and hand-assisted oncologic segmental colonic resection. Surg Endosc. 2007 Dec;21(12):2137-41. 03. Hassan I, You YN, Cima RR, et al. Hand-assisted versus laparoscopic-assisted colorectal surgery: Practice patterns and clinical outcomes in a minimally-invasive colorectal practice. Surg Endosc. 2008 Mar;22(3):739-43.

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April - June 2010

NEPHROLOGY CAV1 Gene Variant Linked to Increased Risk of Renal Allograft Failure Several factors, such as race, donor age, and compliance with immunosuppressive agents, affect the survival of grafts after transplantation. There has been recent interest in the role of donor and recipient genetics in allograft survival, with extensive studies being conducted to evaluate this relationship. One such study published in the latest issue of The Journal of the American Medical Association reported that the presence of the gene caveolin-1 (CAV1) variant is associated with a high risk of renal allograft failure. Jason Moore from the Renal Institute of Birmingham England, and colleagues conducted the candidate gene association and validation study on the following two cohorts: â&#x20AC;˘ Birmingham cohort, consisting of 785 white renal transplant donors and their recipients, who had undergone the transplant surgery in Birmingham, between 1996 and 2006, with a median follow-up period of 81 months. Genomic DNA was collected from both the donors and recipients of this group. â&#x20AC;˘ Belfast cohort, consisting of 697 independent donorrecipient pairs who had undergone the transplant surgery in Belfast, Northern Ireland, between 1986 and 2005, with a median follow up period of 69 months. This group was used to validate the positive findings obtained from the Birmingham cohort. Utilizing the single nucleotide polymorphism (SNP) tagging method, the genomic DNA obtained from the Birmingham cohort was examined for CAV1 variants. The primary evaluation of the link between the genotype and the allograft outcome was conducted by the KaplanMeier analysis and then through an adjusted Cox model. The primary outcome measure was the death-censored renal allograft failure, as indicated by the return of the transplant recipient to dialysis or retransplantation. The researchers observed a significant difference in the graft survival among donor genotypes for the CAV1 rs4730751 SNP, with a high risk of allograft failure for donor genotype AA in the Birmingham cohort (donor AA vs. non-AA genotype in adjusted Cox model: HR=1.97; P=0.002). The

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Belfast cohort also showed similar findings (adjusted Cox model: HR=1.56; P=0.02). Other tag SNPs did not show a significant association. The overall allograft failure rates were as shown in the table below. Donor Genotype

Number of individuals with the genotype

Percentage failure

Birmingham cohort AA

22 of 57

38.6

96 of 431

22.3

66 of 297

22.2

32 of 48

150 of 358

119 of 273

Belfast cohort

CAV1, located on chromosome 7, encodes for the 21 kDa scaffolding protein, caveolin, which is an integral component of caveolae plasma membranes of many cell types, cytosolic locations, as well as other locations such as the endoplasmic reticulum, Golgi, and vesicles. The caveolin group of proteins plays an important role in many cellular processes such as cholesterol homeostasis, signal transduction, vesicular transport, and tumor suppression; however, their role in diseases is yet to be clearly elucidated. Mutations in CAV1 have been linked to Berardinelli-Seip congenital lipodystrophy. The gene is currently believed to play a paradoxical role in cancer, being both a tumor suppressor as well as in initiating oncogenesis. The findings of the current study have identified a subpopulation who are at a higher risk for allograft failure by virtue of possessing a particular genotype. These results may have further implications in other diseases, such as conditions involving tissue fibrosis, vascular diseases and neoplasia, in which CAV1 is believed to play a role. References available online at www.medinewsdirect.com

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April - June 2010

NEWS Dopamine-based MRI Sensor could Revolutionize Conventional Brain Imaging A team of Massachusetts Institute of Technology (MIT) neuroscientists has succeeded in developing a molecularlevel functional magnetic resonance imaging (fMRI), which responds to dopamine neurotransmitters, thereby enabling a more precise noninvasive brain imaging. The study results have been published in the online issue of the journal, Nature Biotechnology. Alan Jasanoff, associate professor of biological engineering, MIT, Cambridge, and coworkers, employed the directed evolution techniques for developing MRI contrast agents that are sensitive to dopamine. In order to develop the molecular probe, the researchers used sensors derived from the heme domain of the bacterial cytochrome P450BM3 (BM3h). A shift in optical absorbance and reduction in MRI signal enhancements were noted due to the binding of ligand to a site adjacent to BM3h’s paramagnetic heme iron. With the aid of protein engineering, the researchers succeeded in evolving the specificity of BM3h more towards the dopamine and away from its natural ligand. The scientists further tested the efficacy of the sensor in dopamine-producing neuronal cell line (PC12 cells) and brains of live animals. The study findings validated the feasibility of using neural activity-dependent sensors for noninvasive molecular level MRI imaging. The scientists are planning to develop the sensor, enabling the analysis of spatial and temporal patterns of dopamine transmission to new tools for monitoring diverse molecular events across the brain.

Functional magnetic resonance imaging, in conjunction with contrasting agents, is emerging as an effective molecular imaging technique for monitoring brain activity. In recent years, the field of neurology has witnessed significant advancements with the introduction of various contrast agents. However, very few have progressed beyond preclinical or proof-ofconcept studies. Hence, none of these novel techniques are currently being employed in clinical practice as a surrogate for invasive neural imaging techniques or hemodynamic fMRI. Some of the proposed contrasting agents probe the activity of the following for functional brain imaging: • Calcium and other metal ions • pH and the other metabolic processes • Genes and protein expression The use of such cellular-level probes aid researchers to combine the potential of augmenting the spatial and temporal resolutions with the noninvasiveness of the MRI.

References 01. Shapiro MG, Westmeyer GG, Romero PA, et al. Directed evolution of a magnetic resonance imaging contrast agent for noninvasive imaging of dopamine. Nat Biotechnol. 2010 Mar;28(3):264-70. 02. Novel MRI sensor provides molecular view of the brain. Press Release. Massachusetts Institute of Technology. Last accessed March 22, 2010.

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April - June 2010

Disrupted CSF Levels of Tau Protein could Help in Early Detection of Alzheimer Disease Numerous studies have reported hyperphosphorylated tau protein to be one of the candidate cerebrospinal fluid (CSF) biomarkers for diagnosing mild cognitive impairment and disease progression in Alzheimer disease patients. Touting to be for the first time, New York University School of Medicine researchers reported that elevated levels of phosphorylated tau231 (p-tau231) in the CSF could serve as an early diagnostic marker of AD in cognitively healthy adults. The results of the study are published in the latest issue of the journal, Neurobiology of Aging. Lidia Glodzik, Assistant Research Professor at the Center for Brain Health and Center of Excellence on Brain Aging, New York University School of Medicine, and co-workers, subjected 57 cognitively healthy older adults to comprehensive assessment at baseline and after a period of two years. Baseline total tau, p-tau231, amyloid beta (Abeta) Abeta42/Abeta40, p-tau231/ Abeta42, and t-tau/ Abeta42 ratios were assessed in these patients using MRI. On follow-up, decline in memory performance was reported in 20 study subjects. Other key study findings observed in these patients were as follows: • Higher baseline p-tau231 levels (P=0.03) associated with reduction in memory scores • Greater longitudinal medial temporal lobe (MTL) gray matter reductions (P=0.01) • Lower Abeta42/Abeta40 levels (P=0.04)

the accuracy and clinical utility of p-tau, showed that the protein could make a candidate biomarker for diagnosing AD in healthy individuals. Based on the CSF p-tau levels in 2,300 participants from 19 studies, it was observed that AD patients could be distinguished from those without cognitive impairment with 87.9% specificity and 77.6% sensitivity. It was however noted that the protein was less adequate in differentiating AD from other types of dementia. Tau, along with other biomarkers, has been used to distinguish incipient AD from age-related memory impairment, secondary dementia, and depression, according to a study by Blennow et al (Molecular Neurobiology, 2001). Since early diagnosis facilitates immediate treatment initiation, the current findings may serve as a breakthrough in the prevention and management of this neurological disorder.

References 01. Glodzik L, de Santi S, Tsui WH, et al. Phosphorylated tau 231, memory decline and medial temporal atrophy in normal elders. Neurobiol Aging. 2010 Feb 2. [Epub ahead of print] 02. Damaged Protein Identified as Early Diagnostic Biomarker for Alzheimer’s Disease in Healthy Adults. Press Release. NYU Langone Medical Center. Last accessed March 26, 2010. 03. Mitchell AJ. CSF phosphorylated tau in the diagnosis and prognosis of mild cognitive impairment and Alzheimer’s disease: a meta-analysis of 51 studies. J Neurol Neurosurg Psychiatry. 2009

Based on the results, the researchers suggested that elevated p-tau231 levels, which are associated with reduction in declarative memory and progressive atrophy of MTL, holds a diagnostic potential for AD in preclinical stages.

Sep;80(9):966-75. 04. Blennow K, Vanmechelen E, Hampel H. CSF total tau, Abeta42 and phosphorylated tau protein as biomarkers for Alzheimer’s disease. Mol Neurobiol. 2001 Aug-Dec;24(1-3):87-97. 05. Frankfort SV, Tulner LR, van Campen JP, Verbeek MM, Jansen RW, Beijnen JH. Amyloid beta protein and tau in cerebrospinal fluid

Earlier, a meta-analysis by Mitchell (Journal of Neurology, Neurosurgery & Psychiatry, 2009) conducted to investigate

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and plasma as biomarkers for dementia: a review of recent literature. Curr Clin Pharmacol. 2008 May;3(2):123-31.

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April - June 2010

Potential Marker for Amyotrophic Lateral Sclerosis Progression Identified Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with complex pathogenesis, causing death within 2 to 5 years of diagnosis. There are currently no specific diagnostic tests or biomarkers to measure the rapid progression of the disease. Now, a recent study has proposed arterial spin labeling perfusion as a possible effective tool in evaluating ALS disease progression and estimating the effects of ALS therapeutics. The findings of this study are published in the latest issue of the journal Neurology. Randall R Rule, from the Department of Radiology, University of California, San Francisco, and colleagues, conducted the study as an attempt to associate clinical measures of ALS severity with regional brain perfusion values recorded using arterial spin labeling. The researchers used the ALS Functional Rating Scale (ALSFRS) and the forced vital capacity (FVC) values in order to estimate the severity of the disease in 16 ALS patients (age 54Âą11). Rapid tapping of the feet and fingers was used as an index to assess upper motor neuron involvement. Perfusion images were co-registered to T1-weighted structural MRI, and corrected for partial volume using information from the structural images. This data was normalized in order to create a study-specific template. Statistical parametric mapping was used to examine the link between blood flow in the brain and ALS severity with age as a determining factor. The study results demonstrated a positive link between brain perfusion and disease severity; chiefly noted in the hemisphere contralateral to the higher affected limbs. The researchers noted that a reduction in the ALSFRS score correlated with perfusion drop in the ipsilateral frontal lobe (P<0.02), as well as the frontal and parietal lobe on the contralateral side (P<0.001). A linear link was

observed between the FVC values and flow of blood in the gray matter of the frontal lobe contralateral to the affected limb (P<0.001). Results demonstrated a positive link between upper motor neuron lesions and perfusion changes in the bilateral middle cingulate gyrus. However, these correlations showed no evidence of brain atrophy. The study findings demonstrated a complementary relationship between ALS disease severity and gray matter perfusion. The researchers also emphasized the significance of this correlation in indicating upper motor neuron involvement in patients with ALS. According to the ALS Association, approximately 30,000 Americans are living with ALS, with about 5,600 cases newly diagnosed every year. The disease usually occurs in adults of 40-70 years of age, with men having a 20% increased risk in relation to women. Several neuroimaging and neurophysiology studies are being conducted to identify potential biomarkers that aid in the diagnosis of ALS. Magnetic resonance imaging with arterial spin labeling, a noninvasive measure of in vivo brain blood flow, has been employed to obtain highquality cerebral blood flow maps that aid in diagnosis of various cerebral pathologic features. Despite the present study distinctly associating arterial spin labeling perfusion with the ALS disease severity, further research needs to be conducted to validate the sensitivity and specificity of this technique as a biomarker.

References 01. Rule RR, Schuff N, Miller RG, Weiner MW. Gray matter perfusion correlates with disease severity in ALS. Neurology. 2010 Mar 9;74(10):821-7. 02. Who Gets ALS. ALS Association. Last Accessed March 17, 2010.

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April - June 2010

Beta-blockers could Improve Breast Cancer Survival Rates

Beta-blockers are one of the most widely used classes of medications prescribed for hypertension and cardiovascular disorders. Now, a recent breakthrough trial by Nottingham and German researchers suggests a novel therapeutic application of beta-blockers, i.e., in reducing breast cancer metastasis, and thereby enhancing patient survival rate. The findings of the pilot study were presented at the seventh European Breast Cancer Conference (EBCC7) held in Barcelona, on March 26th, 2010. Des Powe, Senior Healthcare Research Scientist, Nottingham University Hospitals NHS Trust, UK, and coworkers, evaluated three groups of breast cancer patients for the study: • Group I: hypertensive patients using beta-blockers • Group II: those using other medications for hypertension • Group III: (control): normotensive individuals not under any medication The researchers noted that 43 of the 466 patients who were on beta-blocker therapy showed a considerable reduction in distant metastasis (57%; HR=0.43; P=0.031), as well as local recurrence (P=0.003). Additionally, the risk of death due to breast cancer was reduced by 71% in this group (HR=0.288; P=0.007). Although, the study showed positive results, the researchers suggested that larger studies are necessary to validate these findings.

An earlier study by Algazi et al (Revue d’Epidémiologie et de Santé Publique, 2004) has suggested the potential of beta-blockers in considerably reducing cancer risk in patients with cardiovascular diseases. A cohort of 839 patients, in which 326 used beta-blockers and the remaining, other treatment, were followed up for a period of 10 years to evaluate for the occurrence of cancer. The study found 15 and 59 cancer incident cases in the corresponding beta-blocker ever-users group and never-users group. The overall relative cancer risk was found to be 0.51 in the ever-use group vs. non-users; the risk reduced by 6% for every year on beta-blockers use. Breast cancer is reported to be the second leading cause of death among women in the US. According to the 2009 statistics provided by the National Cancer Institute, approximately 192,370 new breast cancer cases and 40,170 deaths have been recorded. The current findings of the potential cancer protective effects of the widely available, and used hypertension and CVD medication, could hold promise in reducing this burden associated with breast cancer.

References 01. Beta blockers help improve survival for breast cancer patients – Nottingham study shows. Press release. Nottingham University Hospitals. Last accessed April 22, 2010. 02. Beta-blockers help reduce metastasis and improve survival in breast cancer patients. Press Release. The European Cancer Orga-

Previous in vitro studies have shown that beta-blockers play a positive role in various other cancer types. Betablockers have been reported to bind to specific receptors on cancer cells, thereby preventing the stimulation and activation of these cells by stress hormones.

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nization. Last accessed April 28, 2010. 03. Algazi M, Plu-Bureau G, Flahault A, Dondon MG, LÃ MG. Could treatments with beta-blockers be associated with a reduction in cancer risk [in French]. Rev Epidemiol Sante Publique. 2004 Feb;52(1):53-65.

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April - June 2010

Cleveland Clinic Researchers Design Prophylactic Vaccine against Breast Cancer Cancer vaccines are predominantly developed to offer treatment against established and growing tumors rather than for prophylaxis. Prophylactic vaccines, although very effective, are difficult to develop as they could mediate autoimmune reactions against tumor antigens, which are modified self-proteins. Now, a recent breakthrough study in mice models has reported the development of a prototype vaccine against breast cancer, which not only prevents breast tumor formation, but also inhibits the growth of the existing tumors. The findings of the study are published in the recent online issue of the journal, Nature. Vincent K Tuohy, immunologist at Cleveland Clinicâ&#x20AC;&#x2122;s Lerner Research Institute, Ohio, US, and co-workers, selected alpha-lactalbumin as the target autoantigen for vaccine preparation. Alpha lactalbumin, a breast-specific protein, is expressed in enormous amounts in mammary epithelial cells, exclusively during the lactation period, and in breast carcinomas. Mice models genetically prone to cancer were divided into two groups; one of the groups was administered with a vaccine containing alpha-lactalbumin, while the other group served as a control. It was noted that a single dose of the alpha-lactalbumin vaccine not only prevented tumor formation, but also hindered the growth of autochthonous and 4T1 transplantable breast tumors in mice.

Apart from tumor-associated peptide or protein vaccines, several other strategies, including cell-based vaccines and DNA vaccines, are under investigation. A study by Jaramillo et al (Breast Cancer Research and Treatment, 2004) reported mammaglobin-A, a highly expressed breast cancer-specific antigen, to be one of the potential immunotherapeutic candidates for the treatment and prevention of breast cancer. Another study by Xia et al (Journal of Immunology, 2003) showed that prophylactic vaccination with dendritic or tumor fusion cells offers immunity and prevents spontaneous breast carcinoma. Breast cancer is reported to be the most common type of cancer in women in the US, besides non-melanoma skin cancer. According to the American Cancer Society 2009 statistics, approximately 192,370 new cases (females) and 40,610 deaths (females) were estimated in the US due to breast cancer. With further confirmation of the present findings in human studies, the vaccine could serve as a novel approach to tackle and offer protection against breast cancer to women in their premenopausal and post childbearing phases.

References 01. Jaini R, Kesaraju P, Johnson JM, Altuntas CZ, Jane-Wit D, Tuohy VK. An autoimmune-mediated strategy for prophylactic breast cancer vaccination. Nat Med. 2010 May 30. [Epub ahead of print] 02. Cleveland Clinic Researchers Develop Prototype Vaccine To Pre-

Based on these findings, the researchers suggested that since alpha-lactalbumin is principally expressed only during lactation, vaccination-induced prophylaxis can occur in normal non-lactating breast tissue without any evident inflammation. Hence, the vaccine could be a safe and effective option to prevent the development of breast cancer in women in their premenopausal and post childbearing period, during which lactation is absent and the risk for cancer is high.

vent Breast Cancer. Press Release. Lerner Research Institute. Last accessed June 4, 2010. 03. Jaramillo A, Narayanan K, Campbell LG, et al. Recognition of HLAA2-restricted mammaglobin-A-derived epitopes by CD8+ cytotoxic T lymphocytes from breast cancer patients. Breast Cancer Res Treat. 2004 Nov;88(1):29-41. 04. Xia J, Tanaka Y, Koido S, et al. Prevention of spontaneous breast carcinoma by prophylactic vaccination with dendritic/tumor fusion cells. J Immunol. 2003 Feb 15;170(4):1980-6.

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April - June 2010

PROVENGE Receives FDA Approval for Advanced Prostate Cancer Treatment The U.S. Food and Drug Administration (FDA) has granted approval for PROVENGEÂŽ (sipuleucel-T | Dendreon Corporation) for treating asymptomatic or minimally symptomatic, metastatic, hormone-resistant (castrateresistant) prostate cancer (CRPC). It acts by eliciting an immune response against a prostate cancer-specific antigen, prostatic acid phosphatase (PAP). The drug formulated from patient-specific white blood cells, is not indicated for preventing the development or progression of prostate cancer. Touted as the first FDA okayed autologous cellular immunotherapy that enhances the survival rate of CRPC patients, the approval was based on three Phase 3 studies conducted on 737 patients. Of these, the pivotal Phase 3 Immunotherapy for Prostate AdenoCarcinoma Treatment (IMPACT) evaluated 512 asymptomatic or minimally symptomatic, metastatic CRPC patients. The multi-center, randomized, double blind, placebo-controlled study demonstrated a substantial increase in extended median survival for an average of 4.1 months in the study group, in contrast to the controls (25.8 months vs. 21.7 months). However, in certain patients, the survival extended beyond two years. The new drug also contributed to a reduction in death risk by 22.5%, when compared to the other group (HR=0.775). The assessment of safety was based on the data obtained from four randomized clinical trials, which evaluated 601 patients subjected to at least one leukapheresis procedure. The most common adverse effects reported were back pain, chills, fatigue, fever, joint ache, headache, and nausea. However, the serious adverse effects, such as

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acute infusion reactions and cerebrovascular events, were reported in 3.5% of the subjects in the PROVENGE arm, in contrast to the controls (2.6%). In view of the occurrence of cerebrovascular events and as a post-marketing requirement, the company is planning to analyze a small potential safety signal of such events using a registry of around 1,500 patients. CRPC is one of the biggest challenges confronted by oncologists; having very limited treatment options. Docetaxel-based therapy is considered as the standard treatment for this malignancy, but the toxicity associated with the chemotherapeutic drug, limits its application. Apart from this, the complicated treatment regimen, as well as certain patient-related factors, including age and general health condition, impedes its systemic administration. Considering these limitations, the approval granted for PROVENGE, administered as three infusions at an interval of around two weeks, marks a new treatment paradigm in advanced prostate cancer management. About Dendreon: The US-based biotechnology company focuses on the discovery, development, and marketing of novel cancer therapeutics. The company is mainly engaged in the production of active cellular immunotherapy candidates against multiple tumor types.

Reference 01. FDA Approves PROVENGE(R) for the Treatment of Men with Advanced Prostate Cancer. Press Release. Dendreon Corporation. Last accessed April 04, 2010.

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April - June 2010

Injectable Asclera Receives FDA Nod for Treating Small Varicose Veins The injectable form of Asclera™ (polidocanol | Chemische Fabrik KREUSSLER & Co.) has been recently approved by the U.S. Food and Drug Administration (FDA) to treat small varicose veins which pose a cosmetic problem. The drug is a sclerosant which when injected into spider veins (less than 1 mm in diameter) or reticular veins (1-3 mm in diameter) damage the epithelial lining of the blood vessels. The blood vessels then close and get replaced by other types of tissues. Polidocanol produces adverse effects similar to other sclerosing agents, i.e., bleeding and formation of hematoma, irritation, bruising, discoloration, and pain at the injection site. Polidocanol was developed by a German pharmaceutical company Chemische Fabrik KREUSSLER & Co. in the 1960s and is distributed by BioForm Medical Inc. of Franksville, Wisconsin. It is widely used in Europe, being a constituent of the sclerotherapy treatment, Aethoxysklerol® Sclerosing Agent. The anesthetic property of polidocanol offers an added advantage over the hypertonic saline sclerotherapy and laser treatment currently offered in the United States. Varicose veins refer to enlarged tortuous veins, most commonly occurring in the superficial veins of the legs. It is a very common condition affecting about a third of the Western population. The age of onset can vary, but prevalence rises with age. Other risk factors include genetics, female sex, pregnancy, obesity and occupations requiring prolonged standing.

much distress and concern, prompting the patient to seek treatment. Patients are generally advised to elevate their legs and wear compression stockings. Symptomatic varicose veins may be treated with radiofrequency and laser ablation, sclerotherapy or surgery (saphenofemoral ligation with stripping of long saphenous vein). Each procedure has its own advantages and disadvantages and long-term randomized comparisons are lacking. Until such data becomes available, advice regarding the choice of treatment should be given by the specialist based on his own clinical experience. About Chemische Fabrik Kreussler & Co: Founded in 1912, the company is chiefly involved in producing chemicals for the textile industry. It started developing pharma-related products in 1948, and thus Kreussler Pharma was born. About BioForm Medical Inc: A medical aesthetic company with its US headquarters at San Mateo, California. The company is primarily involved in manufacturing products which are used for the treatment of cosmetic problems. One of their popular products is Radiesse® dermal filler, injectable dermal filler which produces long-term, safe and cost-effective aesthetic results in patients.

References 01. FDA Approves Asclera to Treat Small Varicose Veins. Press Release. FDA. Last Accessed Apr 01, 2010. 02. Aethoxysklerol® Sclerosing Agent. BioForm Medical. Last accessed Apr 01, 2010.

Although information and reassurance is all that is needed in most cases, their unsightly appearance causes

03. Campbell B. Varicose veins and their management. BMJ. 2006 August 5; 333(7562):287–292.

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April - June 2010

EVENTS Event Calendar: September-December 2010

The Alexandria-Frost & Sullivan 2010 India Excellence in Healthcare Awards Date : 23 September, 2010 Location : JW Marriott, Mumbai Link : http://www.frost.com/prod/servlet/summits-details.pag?eventid=201921815 World Congress of The World Society of Cardio Thoracic Surgeons 2010 Date : October 20-23, 2010 Location : Chennai, India Link : http://www.wscts2010.com/ Health Expo 2010 Date : October 22-24, 2010 Location : Jalandhar, India Link : http://www.healthexposindia.com/ The International Critical Care Symposium (ICCS) Date : October 29-30, 2010 Location : Radisson Temple Bay, Mamallapuram, Chennai Link : http://www.iccs2010.com/index.html 38th Research Society for Study of Diabetes in India Annual Conference 2010 Date : November 18-20, 2010 Location : International Conventional Center Hotel Le Meridian, Kochi Link : http://www.rssdi2010.org/ ISGCON 2010 - The 51st annual conference of the Indian Society of Gastroenterology Date : November 20-25, 2010 Location : HICC, Hyderabad Link : http://isgcon2010.com IRACON 2010 (Indian Rheumatology Association) Date : November 26-28, 2010 Location : Swosti Premium, Bhubaneswar Link : www.iracon2010.com 12th Joint Conference of National College of Chest Physicians (India) & Indian Chest Society Department of Respiratory Disease & Tuberculosis (NAPCON) Date : November 26-30,2010 Location : Dr. Sampurnanand Medical College, Residency Road, Jodhpur (Rajasthan) Link : http://napcon2010.com/

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EVENTS

April - June 2010

Hospital Infrastructure India 2010 Date : December 7-9, 2010 Location : Bombay Exhibition Centre, Mumbai Link : http://www.hospitalinfra-india.com/ Medifest 2010 Date : December 10-12, 2010 Location : Pragati Maidan, New Delhi Link : http://www.vantagemedifest.com/ India Lab Expo 2010 Date : December 10-12, 2010 Location : Pragati Maidan, New Delhi Link : http://www.indialabexpo.com/ 55th Annual Conference of Indian Orthopedic Association (IOACON 2010) Date : December 9-14, 2010 Location : Jaipur Link : http://www.ioacon2010.org/text.html The Joint Meeting of 59th Annual Conference of Neurological Society of India (NSI) & Congress of Neurological Society of India (NSI) & Congress of Neurological Surgeons (CNS) Date : December 16-19, 2010 Location : The Birla Science and Technology Centre, Jaipur Link : http://www.neurocon2010.com/ 58 Annual National Conference of Indian Society of Anaesthesiologists (ISACON 2010) Date : December 26-29, 2010 Location : Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Lucknow Link : http://www.isacon2010.com/ 62nd Annual Conference of Cardiology Society of India (CSI) Date : December 26-29, 2010 Location : Kolkata Link : http://www.csi.org.in/ 70th Annual Conference of the Association of Surgeons of India (ASICON 2010) Date : December 26-30, 2010 Location : New Delhi Link : http://www.asiindia.org/ASI-Industry-2010%20Conference.php

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April - June 2010

Best-of-the-Best in Healthcare and Life Sciences Industry to be Recognized

“The roots of all goodness lie in the soil of appreciation for goodness” ..Dalai Lama Medical Devices

Healthcare Delivery

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Pharmaceuticals • • • • •

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Healthcare IT • Indian Hospital Information Systems (HIS) Company • Picture Acrhiving and Communication System (PACS) Company • Electronic Medical Records (EMR) Company

Others • Diagnostic Services Provider Company • Wellness Services Provider Company • Healthcare Retail Company

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