MediNEWS.Direct! Journal by iLogy iLogy

CONTENTS

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INTERVIEW Editorial Advisory Board

Dr Milena Braga-Basaria

Dr Nanette K Wenger

Director, Voxmed Medical Communications, LLC, USA

Dr Terry Ann Glauser Medical Director, CE Outcomes LLC, USA

Perspectives on CVD Management with a Special Focus on Women

INTERVIEW

Recent Advancements in CVD Diagnosis Dr Gillian Whalley

Karen Harrop Adjunct Faculty, American Public University System, Director of Website communications; Mid-Atlantic Chapter, American Medical Writers Association (AMWA)

REVIEW ARTICLE

Dhanya Mohan

Dr B M Hegde Visiting Professor of Cardiology, The Middlesex Hospital Medical School, University of London; Rtd Vice Chancellor, Manipal University, India

Dr Pratap Kumar Professor & Head, Dept of Obstetrics & Gynecology, Kasturba Medical College, Manipal, India

Dr Chih-Kun (Ken) Huang Director, Bariatric & Metabolic International Surgery Center, International Minimally Invasive Surgery Training Center, E-Da hospital, Taiwan President, Taiwan Obesity Support Association

Dr Shaheenah Dawood Consultant Medical Oncologist, Department of Medical Oncology, Dubai Hospital, Dubai Health Authority, Dubai, UAE

Role of Managing Hypertension in Preventing CVD: Review of Evidences and Clinical Recommendations

MINI REVIEWS IMMUNOLOGY

Meta-analysis Reiterates Association between Thyroid Autoimmunity and Obstetric Complications

Systematic Review Reaffirms Value of Inflammatory Markers in Excluding Serious Infections in Children

GASTROENTEROLOGY

Exploratory Study Demonstrates Long-term Remission of GERD using Laparoscopic Antireflux Surgery or Esomeprazole Treatment

NEUROLOGY

Complete Resection of Anatomic and Electrocorticographic Lesions in MCD Predicts Long-term Seizure Freedom

PHARMACOLOGY

Triple Marker Combination may Improve Diagnosis of Chronic Kidney Disease and Prediction of Risk for Kidney Failure and Death

Statins Reduce Risk of Short-term Mortality following an Episode of Pneumonia

Editorial Team Managing Editor Dr B M John

Assistant Editor Dhanya Mohan

ONCOLOGY

Assistant Copy Editor Amoolya Moses Dr Vidya V Murthy

Research Analysts Dr Raghavendra Rao Dr Shylaja B Dr Chinmaya Chigateri Dr Pradeep Balu Dr Bobby Mathew

Design

Researchers Propose Incessant Menstruation Hypothesis to Explain Ovarian Cancer Pathogenesis

Swedish Study Reaffirms the Benefit of Mammographic Screening in Reducing Breast Cancer Mortality

NEWS

Veeresh Mathapati Abhilash A

Study Validates Maternal Vaccination to Reduce Hospitalization of Infants due to Influenza

Researchers Propose a Two-step Half-match Procedure to Augment Bone Marrow Transplantation Outcomes

HPTN 052 Results Advocate Antiretroviral Treatment to Prevent HIV Transmission in Serodiscordant Couples

Study Reports Efficacy of Salpingo-oophorectomy Compared to Cystectomy for Mucinous Borderline Ovarian Tumors

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INTERVIEW Perspectives on CVD Management with a Special Focus on Women Q. Which is the preferred strategy for outpatient diagnostic evaluation of patients with suspected coronary artery disease (CAD)? Several studies suggest a higher false-positive rate associated with the use of electrocardiogram (ECG) in women. What is your opinion regarding this?

Dr Nanette K Wenger

A. For women presenting with chest pain symptoms or anginal equivalents due to suspected coronary heart disease (CHD), stress testing is the preferred mode of evaluation. The American Heart Association statement on the role of noninvasive testing in the clinical evaluation of women with suspected CAD suggests that treadmill exercise test is the optimal initial assessment for women able to exercise and who have a normal resting ECG. For women unable to exercise, in whom a pharmacologic stress must be administered, an imaging study, such as echocardiography or nuclear imaging, must be undertaken. For women with an abnormal resting ECG in whom the exercise ECG cannot be interpreted, an echocardiographic or nuclear imaging study is similarly recommended. For the intermediate- to high-risk women, an initial imaging study may be appropriate.

MD, MACC, MACP, FAHA

Professor of Medicine (Cardiology), Emory University School of Medicine, Atlanta, Georgia Dr Nanette K Wenger is also a consultant to the Emory Heart and Vascular Center. She chaired the U.S. National Heart, Lung, and Blood Institute Conference on Cardiovascular Health and Disease in Women, and the WHO Expert Committee on Rehabilitation after Cardiovascular Diseases. She co-chaired the Guideline Panel on Cardiac Rehabilitation for the US Agency for Health Care Policy and Research. She also served as the President, Society of Geriatric Cardiology, and as Editorin-Chief, the American Journal of Geriatric Cardiology, for more than 15 years. She is a recipient of the Lifetime Achievement Award (2009) of the Georgia Chapter of the American College of Cardiology; Hatter Award (2006), an international award for the advancement of cardiovascular science; Gold Heart Award (2004), the highest award of the American Heart Association; to name a few. Coronary heart disease in women is one of Dr Wengerâ&#x20AC;&#x2122;s major clinical and research interests; and she has authored or co-authored over 1,400 scientific and review articles, and book chapters. She is a sought-after lecturer for issues related to heart disease in women and elderly, cardiac rehabilitation, coronary prevention, and contemporary cardiac care. She is listed in Best Doctors in America.

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Q. Since you were one of the writing group members of the 2011 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) Focused Update of the Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction, could you brief us on the major recommendations of the 2011 update? A. The 2011 focused update to the Unstable Angina/Non-ST-Elevation Myocardial Infarction (UA/NSTEMI) Guideline highlighted the following 5 issues: 1. Timing of acute interventional therapy in non-ST-elevation myocardial infarction (MI) 2. Emphasis on the timing, duration, and application of dual and triple antiplatelet therapy 3. Specific recommendations for patients with diabetes mellitus 4. The role and potential benefit of invasive therapy in patients with advanced renal dysfunction 5. Issues of quality improvement for acute coronary syndromes Except for the very high-risk patients, immediate cardiac catheterization and intervention do not offer benefit over initial medical stabilization and subsequent early cardiac catheterization and intervention, when appropriate. Emerging evidence supports the role of triple antiplatelet therapy in high-risk patients, but dual antiplatelet therapy is appropriate in all others. Question has been raised about genotype testing with the use of clopidogrel, but the guideline does not routinely recommend such an approach, because no prospective studies have demonstrated that routine genotype testing, coupled with resultant modification of antiplatelet therapy, improves clinical outcomes or reduces subsequent clinical events. There has been a question as to whether proton pump inhibitors (PPIs) interfere with clopidogrel; recommendations are for the use of PPI medications in appropriate clinical settings considering the potential risks and benefits with combined clopidogrel and PPI agents.

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For a diabetic patient, in keeping with other recent guidelines, the recommendation was changed from more stringent control of blood glucose in UA/NSTEMI to a more moderate target range. Diabetes mellitus has been added to the list of characteristics for which an early invasive strategy is generally preferred; in that clinical trial, results have shown that patients with acute coronary syndrome (ACS) and diabetes mellitus benefit from an early invasive approach. For patients with advanced renal dysfunction, recommendations for those undergoing cardiac catheterization using contrast media advocate that they should receive adequate preparatory hydration, with adjustment of maximal contrast dose to each patient’s renal function. Participation in quality of care registries was recommended to evaluate adherence to evidence-based processes of care, designed to eliminate healthcare disparities and enable the conduct of comparative effectiveness research. Q. Chest pain is regarded as the second most frequent cause for the visit of adult patients to emergency department. Considering this, what are the strategies to be implemented for risk stratification and identification of serious conditions? Please elaborate on the role of clinical judgment in such scenarios. A. The clinical history of chest pain is probably the most important feature in the evaluation of adult patients presenting to the emergency department (ED), coupled with an immediate ECG, and beginning of serial biomarker evaluation, if the pain is considered to be compatible with myocardial ischemia. The clinical history is also of extreme importance to ascertain whether the patient does or does not have a history of prior heart disease. Physical examination can often also exclude other causes for the chest pain. For patients in whom the initial ECG and biomarker studies are negative and where clinical suspicion for ischemia remains, subsequent approaches include exercise stress testing and/or coronary CT angiography (CTA). With the increasing availability of coronary CTA and the decreased radiation exposure with current equipment and protocols, this approach is increasingly undertaken. Q. Could you brief us on the treatment objectives of CVD management in elderly, with particular emphasis on lipid management strategies to be adopted in such patients? A. Risk reduction in an elderly population is challenging in

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that it is often difficult to differentiate between primary and secondary prevention. Many asymptomatic elderly individuals have occult CHD. For elderly patients with defined CHD, the objectives are to decrease symptoms and improve survival, as in a younger population, with the intensity of intervention dependent on patient’s comorbidities and preferences. Risk stratification is appropriate with standard antianginal therapies employed and consideration for revascularization in the high-risk symptomatic patient without countermanding comorbidities. Risk reduction is appropriate in otherwise functional elderly individuals without serious comorbidities, with control of blood pressure as per newly recommended guidelines, lipid management with statins, smoking cessation, weight maintenance, a hearthealthy diet, and an exercise regimen compatible with functional status and comorbidities. Q. As per the 2011 European Menopause and Andropause Society (EMAS) position statement, hormone therapy (HT) is not recommended for primary or secondary prevention of CHD in postmenopausal women. Could you elaborate on the other therapeutic options available for the management of such patients? A. In addition to the 2011 EMAS position statement, the U.S. Food and Drug Administration has now, for almost a decade, suggested that HT is not indicated for primary or secondary prevention of CHD in postmenopausal women. Such women should adopt the standard preventive strategies including lifestyle and pharmacologic management of major risk factors. This would comprise smoking cessation, blood pressure and lipid control, weight management, control of diabetes to recommended targets, and implementation of an exercise regimen. The AHA’s 2011 guidelines for the prevention of CVD in women detail such interventions. Q. What do the results of major studies imply regarding the adoption of novel biomarkers [high sensitivity C-reactive protein (hs-CRP) or advanced lipid testing] and imaging techniques [coronary calcium scoring (CCS)] in assessing CVD risk? A. The ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults (Circulation, 2010) addresses the role of novel biomarkers and imaging techniques for evaluation of CVD risk. Although many of the biomarkers and imaging techniques correlate with CHD, their value in assessment of CVD risk must demonstrate that they are additive to conventional global risk scores in identifying such risk. This guideline advocates taking a family history, a very inexpensive but additive technique, and cites the

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INTERVIEW

potential benefit of hs-CRP in a population distinguished by the recruitment characteristics for Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, and does not currently recommend additional testing modalities as a class I recommendation. Subsequent to publication of these guidelines, the MESA JUPITER study failed to find predictive value of hs-CRP, but the study has suggested CCS to improve the risk stratification for women. These novel modalities may be reserved for refining risk estimates in intermediate-risk patients when there is uncertainty about the need to start pharmacotherapy; however, research is still required on the benefits, risks, and costs associated with such strategies. Although recent evidence suggests that CCS and carotid ultrasound to demonstrate the presence of advanced atherosclerosis has the greatest utility for classifying risk in those at intermediate-risk on the basis of equations, such as the Framingham Risk Score, their value in improving clinical outcomes has not been established. Q. Based on current clinical trials and studies, which group of women should be considered as at high risk for developing CVD? Is there any specific test or biomarker that should be favored for identifying women at high risk? A. Women considered at high risk for developing CVD are those with traditional coronary risk factors, with diabetes appearing to play a prominent role in increasing the risk. Standard coronary risk factors should be assessed, with family and pregnancy histories. The concordance of multiple risk factors or high levels of these risk factors should be considered as imparting high risk. The 2011 update to the guidelines for the prevention of CVD in women suggests a simplified system of classification of cardiovascular risk for women, defining them as at high risk, at risk, or at ideal cardiovascular health. • High-risk women are those with clinically manifest CHD, cerebrovascular disease, peripheral arterial disease, or abdominal aortic aneurysm; those with end-stage or chronic kidney disease or diabetes mellitus; or with a 10-year predicted cardiovascular risk >10%. • At-risk individuals should have at least one of the following major risk factors: cigarette smoking; hypertension or treated hypertension; elevated total cholesterol or being treated for dyslipidemia; obesity (particularly central adiposity); poor diet; physical inactivity; family history of premature CVD; metabolic syndrome; evidence of advanced subclinical atherosclerosis; poor exercise capacity on treadmill testing and/or abnormal heart rate recovery after

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October - December 2011

stopping exercise; systemic autoimmune collagen vascular disease; or a history of preeclampsia, gestational diabetes, or pregnancy-induced hypertension. • Ideal cardiovascular health involves untreated total cholesterol <200 mg/dL, untreated blood pressure <120/80 mm Hg, untreated fasting glucose <100 mg/ dL, BMI <25 kg/m2, abstinence from smoking, physical activity at goal for adults, and a healthy, light diet. Q. What is the role of pregnancy as a risk factor in the development of CVD in women? What should be the future course of clinical trials/studies associated with CVD in women, especially with regard to risk factors in various groups of women? A. Complications of pregnancy, rather than pregnancy per se, are important risk markers for CVD in women, particularly hypertensive complications. Because of the cardiovascular and metabolic stress, pregnancy provides a unique opportunity to estimate a woman’s risk. For example, a history of preeclampsia doubles the risk for subsequent ischemic heart disease, stroke, and venous thromboembolism over the next 5-15 years subsequent to pregnancy. Gestational diabetes predicts increased chances of developing diabetes in future. Therefore, healthcare professionals should take a careful, detailed history of pregnancy complications, with focused questions on gestational diabetes mellitus, preeclampsia, preterm birth, or birth of an infant small for gestational age. Q. Kindly elaborate the rationale behind evolution from evidence-based to effectiveness-based guidelines for prevention of CVD in women and the differences between the two. What is the impact of this change on the incidence of CVD in women? A. The change from the previous guideline to the 2011 update is that effectiveness, i.e., the benefits and risks observed in clinical practice of preventive therapies, is strongly considered and the recommendations are not limited to the evidence that documents the efficacy, i.e., the benefits observed in clinical research. Thus, in the transformation from ‘evidence-based’ to ‘effectivenessbased’ guidelines, the updated recommendation includes those therapies that have been shown to have sufficient evidence of clinical benefit for CVD outcomes. The guidelines continue to prioritize lifestyle approaches to the prevention of CVD as likely the most cost-effective strategy. The change in the guideline that impacts issues of potential incidence of CVD in women involves evolution from using the Framingham 10-year predicted CHD risk

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INTERVIEW

of >20% as identifying a woman at high risk, to the use of 10-year predicted total CVD risk, and using a value of â&#x2030;Ľ10% as the indication for high-risk status. Q.Could you brief us on the international applicability of the AHA guidelines for preventing CVD in women, and whether any studies are currently underway to assess the applicability of these recommendations in other populations such as Asians, as there has been an epidemic rise in the incidence of CVDs? A. As identified in the recent UN Summit on noncommunicable diseases, CVD is a problem for women worldwide, both in developing and industrialized nations. Approximately 81% of all CVD deaths in women occur in low- and middle-income countries. With CVD emerging as a global pandemic among women, the international applicability of the 2011 update to the AHA guidelines

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for prevention of CVD in women is critical. As per the World Health Organization, the criteria for evaluating the international applicability of a guideline document are cost-effectiveness, efficacy and safety, affordability, and population benefits. The international applicability is an important asset of the updated womenâ&#x20AC;&#x2122;s guideline because majority of the recommendations can be used in most countries and regions, either directly or with slight modifications. Description of the recommendations is easy to comprehend and easy to apply in clinical practice; risk classification is practical and should be feasible for clinicians and patients worldwide. Additionally, there is emphasis on lifestyle alterations, and generic drugs are available for most of the therapies recommended in the guideline document. The guideline notes that modifications may be required, depending on the specific demands of countries or regions such as definitions of generalized overweight, obesity, and central obesity.

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October - December 2011

Recent Advancements in CVD Diagnosis Q. Tissue Doppler imaging (TDI) is recognized as an effective tool in the detection of left ventricular dysfunction in patients with heart failure (HF). Could you brief us on its prognostic significance in the general population? A. The role of TDI for prognosis is reasonably well established in patient populations, such as those with HF and post acute myocardial infarction (AMI). In particular, the ratio of mitral Doppler E velocity to annular e velocity (E:e’ or E:Ea) has been very useful for detecting elevated left ventricular (LV) filling pressure. There are some limited population data showing that both the mitral e’ and systolic annular velocity (s’ or Sa) are predictive of outcome. Unfortunately, there have been few studies large enough to determine the independence of these relationships from other echocardiographic and clinical variables.

Dr Gillian Whalley PhD, FASE, FCSANZ

Associate Professor, Associate Dean Research, Faculty of Social and Health Sciences, Unitec Institute of Technology, Auckland, New Zealand

Dr Gillian Whalley, in her PhD, explored the role of echocardiography in the diagnosis and management of patients with heart failure. She was co-director of the Cardiovascular Research Laboratory at the University of Auckland until 2010, when she moved to the position of Associate Professor and Head of Department, Medical Imaging at the Unitec Institute of Technology. In 2011, she took up the role of Associate Dean of Research at the same institution. Dr Whalley is the coprincipal investigator of several large studies, including two large individual patient metaanalyses: MeRGE (evaluating the prognostic independence of diastolic dysfunction) and MAGGIC (study determining outcome in patients with heart failure with preserved and reduced ejection fraction); and the echo sub-studies of the CAPRICORN Study (RCT of Carvedilol in heart failure), the ADVANCE trial (blood pressure and glucose management in type 2 diabetes), and the IDEAL trial (timing

Mitral annular systolic velocity is a measure of longitudinal LV function and evidence suggests longitudinal dysfunction can be detected by TDI before overt systolic dysfunction is apparent, such as might be detected by conventional measures like ejection fraction (EF). Strain imaging offers similar promise, but remains a troublesome method in terms of reproducibility and therefore is sometime away from being applied in a population setting. Q. Could you brief us on the clinical significance of noninvasive assessment of LV filling pressures? Kindly explain the role of clinical, echocardiographic, and biochemical assessment in stratifying patients after AMI. A. Noninvasive measurement of filling pressure was first introduced 15 years ago. The typical measurement is E:e’. The first studies in this area (by Nagueh et al in Texas and Ommen et al at the Mayo Clinic) showed good correlation with invasive measurements of LV filling pressure; but at that time, the ability to differentiate mild and moderately raised filling pressure was not proven, nor has it been since. As such, the primary use of E:e’ is to differentiate ‘normal filling’ and ‘severely elevated filling.’ When the cut-off point of 15 is used as the measure of elevated filling pressure, this ratio is extremely useful as a prognostic variable. At first, it seemed it was just another measure of advanced diastolic dysfunction such as the restrictive filling pattern. But eventually, larger studies (Hillis et al from the Mayo Clinic) showed that if E:e’ was >15, this conveyed additional risk beyond that already explained by EF, restrictive filling, and clinical findings in an AMI patient. Similar studies have now shown that this information can be combined with neurohormone measurements, such as B-type natriuretic peptide, to estimate the total risk, as the clinical assessment and echocardiography measurements contribute independently to prognosis. Q. What are the important updated strategies for the diagnosis and exclusion of heart failure with normal ejection fraction (HFNEF)? How can we exclude HFNEF in patients presenting with breathlessness and no signs of fluid overload?

of renal dialysis).

A. Heart failure with normal ejection fraction (HFNEF) is commonly seen these

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days and arises due to various reasons. It is important to remember that when a patient presents with HFNEF, the EF may be normal for several reasons. Although many of these patients may present with a history of hypertension, have evidence of left ventricular hypertrophy (LVH) and atrial dilatation, and clear evidence of diastolic abnormities, it is important to remember that a single assessment of EF tells you nothing of the patient’s history. It may be important to ask the question, ‘has the EF ever been abnormal?’ In other words, the patient may have had impaired systolic function in the past, but now the EF is normal. That may arise in response to therapy, remodeling, or unloading of the ventricle. This is not HFNEF. The first step in the diagnosis is to exclude LV dilatation. A normal EF in the presence of severe LV dilatation suggests other underlying pathology. These patients should be considered to have heart failure with reduced ejection fraction (HFREF). The next stage is to document diastolic filling abnormalities. The key steps, in my opinion, are to demonstrate abnormal mitral filling pattern (taking into account that a grade 1 pattern or abnormal relaxation is often found in older patients). Pseudonormal filling pattern (grade 2) or restrictive filling pattern (grade 3) suggest moderate and severe diastolic dysfunction, but the E:e’ will provide evidence of elevated filling pressure (perhaps leading to breathlessness). If there are no demonstrable abnormalities, then one should consider other causes for breathlessness. Evidence is emerging for the use of exercise in such patients. If E:e’ increases with exercise, this is an indicator of diastolic dysfunction. Coupled with symptoms on the treadmill, this is an excellent way to diagnose HFNEF in some patients. Q. What are the non-diastolic abnormalities in cardiovascular function contributing to HFNEF, apart from the important diastolic dysfunction? A. As mentioned above, HFNEF is a rather crude term for a heterogeneous group of patients. The etiology may be ischemic heart disease, cardiomyopathy, atrial fibrillation, valve disease, or diabetes and hypertension, to name a few. The history of the patient is crucial in determining the etiology and thus, the likely abnormalities. For example, patients with a history of hypertension and diabetes may have LVH and there may be signs of early longitudinal systolic dysfunction (measured by s’). Cardiomyopathic processes all have their own characteristics; some may affect the right side of the heart, in which case the tricuspid annular plane systolic excursion (TAPSE) is an important measurement of right ventricular (RV) systolic function. TAPSE is one of the most reliable echocardiographic measures of RV function. RV function is poorly assessed by conventional 2D echo techniques, but TAPSE has been

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shown to be of prognostic importance in patients with HF. In patients with atrial fibrillation, size of the right and left atria offer important information both in terms of etiology and prognosis, and the likelihood of successful cardioversion. Q. Which are the early-stage determinants of subclinical left ventricular dysfunction (LVD) in type 2 diabetes? How does the knowledge of these factors help in developing preventive strategies? A. Heart failure is a common occurrence in response to type 2 diabetes, and LVH can be detected in 50-60% of asymptomatic type 2 diabetics. LVH is easily detected by echocardiography, and almost never reliably detected by electrocardiography, especially in populations prone to obesity. LVH precedes both diastolic and systolic dysfunction in such patients and is therefore a marker of risk. But because LVH is so prevalent, it is probably not the optimal target for subclinical screening. This is confounded by the fact that patients with type 2 diabetes often have co-existing hypertension, another cause of LVH. However, there are prognostic implications of further defining the type of LVH into concentric LVH (worst prognosis), eccentric LVH (intermediate prognosis), and concentric remodeling (no increase in prognosis). Many patients with type 2 diabetes, about two-thirds, will have subclinical abnormalities of diastolic function, and a similar number will have subclinical systolic dysfunction (either strain or s’). Currently, there are no preventive strategies beyond aggressive blood pressure and glucose control that can be targeted at this high-risk group. But despite the detection of significant abnormalities, no trial has shown an impact on these surrogate endpoints. Q. Studies suggest that data obtained from the clinical history and examination is inadequate to ‘rule in’ or ‘rule out’ a diagnosis of left ventricular systolic dysfunction (LVSD). What is your opinion regarding this? Could you brief us on the current diagnostic algorithm to be followed for the diagnosis of LVSD in a primary care setting? A. We follow an approach of neurohormonal assessment (using NT-proBNP) to ‘rule out’ HF. Even in symptomatic patients with a high BNP level, highly suggestive of heart failure, an echocardiogram is still required to confirm the diagnosis of HF and to detect systolic or diastolic dysfunction, and also any underlying pathology (eg., valve disease, cardiomyopathy, etc). There is no getting away from it; if there is a suspicion of HF, the patient needs an echo. Where that echo occurs is the next question. The latest range of laptop-based ultrasound machines is perfect for use in the primary care setting.

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And although it is attractive (and certainly feasible) for primary care physicians to perform a limited diagnostic echo that would be able to ‘rule in’ or ‘rule out’ systolic dysfunction, it is probably not the best practice. Patients, especially those with a new diagnosis of HF, need a full echocardiogram to identify the etiology, to quantify the degree of dysfunction, and to identify any remediable abnormalities. Ultimately, accurate assessment of EF will be required to determine treatment strategies. Q. What should be the focus of future studies, in view of recent research showing inadequacy of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in early detection of LVH, in type 2 diabetes patients? A. This is a challenging area. The reasons why NT-proBNP doesn’t work in this population are multifactorial and largely unexplained. The BNP levels are extraordinarily low, which may be related to obesity per se. Most of the evidence for using BNP has been in patients with established heart disease (post AMI and HF, for example), and as mentioned above, LVH is a very common finding in these patients. It may be that BNP is not a good marker of LVH. If strain rate imaging was more robust, this might be useful to identify subclinical dysfunction. The key will be to detect pathologically harmful LVH; this may incorporate methods to detect fibrosis and/or myocardial fiber disarray, or myocardial calcium or edema. These all require stable and reproducible noninvasive measurements. These studies in conjunction with changes in longitudinal measures of diastolic function might shed insight into the pathophysiologic process involved, which might be useful for optimizing both the prognosis and management of these patients, perhaps through the identification of novel therapeutic pathways. Q. Kindly elaborate on the role of carotid intima thickness in assessing CV risk in asymptomatic type 2 diabetes patients. A. Carotid intima-media thickness (CIMT) has been used widely in the last 25 years to assess risk in general populations, and it has been linked to LVH. This is a very valid and useful tool in the type of studies it was designed and tested within, which are large population studies, where minute changes in thickness are prognostically very significant. But, as with many tests, once applied in an individual, they rarely perform as well. Furthermore, the premise that this was a surrogate marker of atherosclerosis, was in part, predicated on the relationship between CIMT and LVH, which was at best moderate in population studies and poor in diabetic populations. CIMT is an alluring test – it appears to be a quick and

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easy test. But, the large population studies were very carefully controlled and mostly did not use automated measurements as they do now. These attractive packages on small machines purport to give a vascular age, but I am not sure of the value of ‘vascular age’ in a group of patients with widespread vascular involvement. I remain skeptical of the widespread integration of these measurements into practice. Q. Kindly elaborate on the topic of LV longitudinal systolic function assessment and its advantages, if any, over the conventional methods of LV function assessment. A. Since the demonstration of LV longitudinal function may contribute to one-third of total systolic cardiac output, much work has gone into detecting longitudinal dysfunction. Most current techniques use tissue Doppler technology pulsed wave annular TDI and strain. At the moment, the best evidence is for pulsed wave TDI (s’ velocity) as it is reproducible and relatively operatorand machine-independent. Strain imaging has shown promise for years but not really realized its full potential. When done well, strain imaging adds significant amounts of information to our understanding of regional and longitudinal function. Unfortunately, it is neither operator- nor machine-independent. All the methods used to assess longitudinal function measure a single component of overall systolic function. EF (measured by a biplane method) has been our gold stand echocardiographic measure of systolic dysfunction. It is less reliable than magnetic resonance measurements of EF, but is accessible. Even the 2D approach makes important assumptions about the shape of the LV cavity. However, 3D echocardiography has shown promise for decades as a tool to improve the assessment of EF, and it has really only recently come to the front of the queue again. The reason is the true real-time methods that are now available on most of the larger ultrasound machines. These 3D techniques still make assumptions, but significantly fewer than other methods. I think that although our measures of diastolic dysfunction are multifaceted and fairly robust, there is still plenty of room for improvement with systolic function assessment by echo. Q. What are the arguments on DHF evolving as a single syndrome with HFNEF preceding HFREF, or as two syndromes with: a) concentric LV remodeling and DHF, b) eccentric LV remodeling and combined systolicdiastolic dysfunction? A. I think there should be no argument today. The syndrome, we have now come to describe as HFNEF, is

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an honest way of describing a heterogeneous group of patients with many different causes for their symptoms. Just as patients with HFREF have multiple contributing factors, so do patients with HFNEF, and some of them are the same. In fact, HFNEF may be preceded by HFREF in some cases. The term diastolic HF per se suggests a diastolic cause of symptoms only, and in such cases, it is likely that a number of these patients will have underlying abnormalities such as LVH. This forms an important

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subgroup of HFNEF patients but not all of them. We need to overcome our desire to characterize HFNEF patients in such a constrained way. We do not do that with systolic HF, so why force a ‘one-size fits all model’ when the EF is within the normal range? Heart failure patients have multiple underlying causes for their condition, and echocardiography is but one step in the process of helping us to understand the cause of their symptoms and identify a therapeutic target, if one exists.

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October - December 2011

REVIEW ARTICLE Role of Managing Hypertension in Preventing CVD: Review of Evidences and Clinical Recommendations Dhanya Mohan

increase in death rates due to stroke, ischemic heart disease, and other vascular conditions.8

Assistant Editor, MediNEWS.Direct! Email: dhanya.mohan@ilogy.com

Evidence from previous studies demonstrate that cardiovascular diseases (CVD) commence in early age, with a substantial influence of both modifiable and nonmodifiable behaviors, environmental exposures, and risk factors.1 As per the 2007 mortality data, around 2,200 individuals die due to CVD in US daily. The 20052008 National Health and Nutrition Examination Survey (NHANES) has reported that 33.5% of US adults of ≥20 years of age are suffering from hypertension.2 The increasing prevalence of noncommunicable diseases (NCDs) is emerging as a matter of serious concern, with 80% of deaths due to NCDs occurring in low- and middleincome countries.3 According to the Global Burden of Diseases (GBD) study, around 64 million cases of CVD were estimated in India for the year 2015.4 Analysis of other global and US epidemiological data reveal astounding facts regarding morbidity, mortality, and direct and indirect costs associated with blood pressure (BP)-related diseases.5 Interpretations and estimations drawn by some of the important studies are given below. • A study conducted in the year 2001 by Lawes et al reported that the burden related to such diseases is substantial in low- and middle-income countries, in individuals with prehypertension, and in middle-age groups. Considering ≥115 mm Hg systolic pressure as high BP, the study reported around 7.6 million premature deaths, 92 million disability-adjusted life years, 47% of ischemic heart disease, and 54% of stroke attributed to hypertension.6 • The INTERHEART STUDY conducted in 52 countries by Yusuf et al (2004) identified hypertension as one among the nine risk factors for myocardial infarction.7 • A meta-analysis (2002) based on the individual data of one million adults reported a strong and direct correlation between vascular mortality and BP within the usual range, starting at around 115/75 mm Hg. It has been noted that in the age group of 40-69 years, each 20 mm Hg rise in the systolic BP (around 10 mm Hg diastolic BP) is associated with more than two-fold

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Among the risk factors, hypertension is considered as significant in predisposing individuals to stroke, heart failure, and coronary heart disease (CHD). Evidence indicates that increase in BP accelerates atherosclerosis, and its persistent rise could cause destabilization of vascular lesions and precipitation of acute coronary events.9 Hence,optimal BP control is crucial in reducing the risk for CVD, and it is significant to consider the treatment for hypertension as a primary as well as secondary prevention strategy.10 The special report released by the American Heart Association in 2010 states the following as the strategic impact goals to be achieved by 2020 and beyond: “By 2020, to improve the cardiovascular health of all Americans by 20% while reducing deaths from cardiovascular diseases and stroke by 20%.”11 The report defines ‘ideal cardiovascular health’ by the presence of: 11 • Ideal health behaviors »» No smoking »» Physical activity at suggested levels »» Body mass index <25 kg/m2 »» Diet complying with current recommendations • Ideal health factors »» Fasting blood glucose <100 mg/dL »» Untreated total cholesterol <200 mg/dL »» Untreated blood pressure <120/80 mm Hg

Goals of Antihypertensive Treatment Diverse national and international guidelines recommend treatment for patients with high BP and confirmed atherosclerotic disease to attain the target of <140/90 mm Hg.10 The present guidelines of the American Heart Association and the American Stroke Association (AHA/ ASA) for prevention of primary stroke, considering the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7), advocates reduction of high BP. However, the secondary stroke prevention guidelines put forth by the same organization reports ambiguity regarding the absolute target BP level and reduction, reiterating the need for individualizing the same.12

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As per JNC- 7 report, the goal of the therapy should be to achieve the target of <140/90 mm Hg in healthy individuals and <130/80 mm Hg in patients with chronic kidney disease (CKD) or diabetes.13 The algorithm for treating blood pressure based on the JNC-7 report is given below (Figure 1).13

Antihypertensives in Preventing CVD Substantial evidence validate the potential of pharmacological intervention for hypertension in

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reducing the risk of CVD. A recent, large, populationbased, prospective cohort study by Giovannia et al (2011) reiterated the significance of better compliance to antihypertensive drugs in primary prevention of cardiovascular risk. The follow-up conducted for 6 years on 12,016 subjects from a cohort of 242,594 patients demonstrated that the risk for cardiovascular outcomes reduced by 37% in subjects who continued the treatment for hypertension when compared to those who discontinued at least one treatment episode.14

Figure 1: Algorithm for Treating Hypertension based on JNC-7 Report

* CKD, diabetes, heart failure, high coronary disease risk, postmyocardial infarction, recurrent stroke † Drug abbreviations: CCB-calcium channel blocker, BB- beta-blocker, ARB-angiotensin receptor blocker, ACEI- angiotensin converting enzyme inhibitor ‡Individual drug classes are decided based on clinical trial studies and existing guidelines Source: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure

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A meta-analysis of 32 randomized trials by Sébastiena et al (2011) concluded that it is highly improbable that the beneficial effects of blood pressure-lowering regimens are dependent on the baseline blood pressure. The study favored the use of such regimens in high-risk groups, with and without hypertension.15 The key recommendations put forth by the World Health Organization (WHO) on the use of antihypertensive drugs for CVD prevention are shown in Table 2.16

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upon evaluation of two trials involving 5,520 subjects were 39% and 28%, respectively.17 A network meta-analysis by Psaty et al (2003) reported low-dose diuretics as the most effective first-line therapy for prevention of CVD-linked morbidity and mortality. The data of 42 clinical trials (192,478 patients randomized to 7 treatment strategies) showed the efficacy of low-dose diuretics, in contrast to placebo in reducing outcomes such as CHF (RR=0.51), stroke (RR=0.71), CVD events (RR=0.76),

Table 2: WHO Recommendations on Antihypertensive Drugs for CVD Prevention 10-year risk of cardiovascular event (%)

>30

Recommendations One of the following drugs should be advocated in individuals with persistent BP of ≥130/80 mm Hg to decrease BP and CVD risk: • ACE inhibitor • Beta-blocker • Calcium-channel blocker • Thiazide-like diuretic The recommended first-line therapy includes a low-dose thiazide-like diuretic, ACE inhibitor, or calcium channel blocker.

20-30

In individuals with persistent BP of ≥140/90 mm Hg and inability to manage BP through lifestyle modifications within 4-6 months of medical care, one of the following drugs should be recommended to decrease BP and CVD risk: • ACE inhibitor • Beta-blocker • Calcium-channel blocker • Thiazide-like diuretic The recommended first-line therapy includes a low-dose thiazide-like diuretic, ACE inhibitor, or calciumchannel blocker.

10-20

Patients with persistent hypertension of ≥140/90 mm Hg, should continue the lifestyle interventions and undergo reassessment of BP and total CVD risk annually based on the resource availability and clinical scenarios.

<10

Patients with persistent hypertension of ≥140/90 mm Hg, should continue the lifestyle interventions and undergo reassessment of BP and total CVD risk every 2 to 5 years based on the resource availability and clinical scenarios.

Patients with blood pressure ≥160/100 mm Hg, or a lower degree of increase in BP with target organ damage should receive drug treatment and specific lifestyle recommendations to decrease their BP and CVD risk Source: WHO (2007) Guidelines for assessment and management of cardiovascular risk

Various placebo-controlled trials have validated the beneficial effects of ACE inhibitors and calcium antagonists in reducing mortality and major cardiovascular morbidity. Neal et al (2000) performed an overview of randomized trials to compare between more and less intensive treatment strategies and regimens, based on different therapeutic classes. The investigation of four trials involving 12,124 patients mainly with CHD treated using ACE inhibitors showed a decline in CHD (20%), stroke (30%), and major cardiovascular events (21%). The reduction in the incidence of stroke and major cardiovascular events noted with calcium antagonists,

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CHD (RR=0.79), CVD mortality (RR=0.81), and total mortality (RR=0.90). The researchers also noted better efficacy with low-dose diuretics than other first-line treatment strategies, such as ACE inhibitors, α-blockers, β-blockers, calcium-channel blockers (CCBs), and angiotensin receptor blockers, in reducing the above outcomes. The reduced risks noted with low-dose diuretics for various outcomes when compared to other strategies are given below:18 • CVD events, RR=0.94; CHF, RR=0.74, compared to CCBs • CHF, RR=0.88; CVD events RR=0.94; stroke, RR=0.86, compared to ACE inhibitors

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• CVD events, RR=0.89, compared to β-blockers • CHF, RR=0.51; CVD events, RR=0.84, compared to α-blockers

Use of Antihypertensive Drugs in Patients without Hypertension Several previous trials suggest the use of antihypertensive agents, such as β-blockers and ACE inhibitors, in CVD patients without hypertension, to reduce the risk for stroke, CHF, and all-cause mortality. All major national and international recommendations are along the same line regarding the initiation of such treatment in healthy individuals. As per these recommendations, it is significant to consider both the patient’s overall CHD or CVD risk, and BP level along with the occurrence of subclinical CVD or end-organ damage, before treatment initiation in healthy subjects.10 A recent meta-analysis by Thompson et al (2011) reiterated the potential of antihypertensive treatment in reducing CVD outcomes in patients with history of CVD, but no clinically defined hypertension. The absolute risk reductions noted per 1,000 persons were -13.3 for myocardial infarction, -27.1 for composite CVD events, -43.6 for CHF events, -7.7 for stroke, -15.4 for CVD mortality, and -13.7 for all-cause mortality.19

Lifestyle Interventions Studies reiterate the role of diverse lifestyle behaviors, including physical inactivity, smoking, and unhealthy diet, in promoting the development of CHD and associated comorbidities.19 Implementation of healthy lifestyle is crucial for management, as well as prevention of hypertension and associated comorbidities. The AHA guidelines validate adoption of such interventions as the basis of primary prevention.1 The lifestyle management strategies proposed by JNC-7 report are enlisted in Table 3 below.13

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Debatable Role of Dietary Salt Reduction The 2010 guidelines put forth by the National Institute for Health and Clinical Excellence (NICE), UK, call for expediting the reduction of maximum salt intake per day per adult to 6g and 3g by 2015 and 2025, respectively.20 Although international guidelines recommend reduction in dietary salt to manage hypertension, the benefits conferred by the intervention is a matter of debate among researchers.21 Based on an analyses of systematic overviews and RCTs published up to 2010, Evaa et al (2011) concluded that the benefits of reducing dietary salt intake in patients with hypertension is not proven, with respect to patientrelevant outcomes. However, the study suggests a blood pressure-lowering effect in hypertensive patients due to reduced salt consumption.22 Contradictory to these findings, investigation of data from the Third National Health and Nutrition Examination Survey Linked Mortality File (1988-2006) suggested an elevated risk for CVD and all-cause mortality linked to higher sodium-potassium ratio. The prospective cohort study that evaluated 12,267 US adults, over a mean follow-up period of 14.8 years, also showed an increase in all-cause mortality linked to higher sodium consumption (HR=1.20), while a decrease in mortality risk was associated with higher potassium intake (HR=0.80).23 A recent meta-analysis by Taylor et al (2011) highlighted that evidence is insufficient to rule out the clinically significant effects of dietary salt reduction on CVD morbidity or mortality. Analyses of seven RCTs demonstrated that reduced salt intake was associated with a decrease in excretion of urinary salt between 27 and 39 mmol/24 hours and decrease of systolic BP between 1 and 4 mm Hg. The study results also showed an increase in all-cause mortality risk on reducing salt

Table 3: Lifestyle Interventions to Manage Blood Pressure based on JNC-7 Report Interventions

Recommendation

Estimated reduction in systolic BP range

Following a diet plan based on Dietary Approaches to Stop Hypertension (DASH)

Follow a diet rich in vegetables, fruits, and low-fat dairy products, with less saturated and total fat content

8-14 mm Hg

Physical activity

Perform regular physical exercise like brisk walking (minimum 30 minutes daily)

4-9 mm Hg

Reducing intake of dietary sodium

Reduce daily dietary sodium intake to not more than 100 mmol (2.4 g sodium or 6 g sodium chloride)

2-8 mm Hg

Limiting the consumption of alcohol

Restrict to not more than 2 drinks/day in men, and not more than 1 drink/day in women and light weight individuals

2-4 mm Hg

Reducing excessive body weight

Maintain normal body weight (BMI 18.5–24.9 kg/m2)

5-20 mm Hg/10 kg weight loss

Source: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure

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intake in patients with a history of heart failure. Based on the study findings, the scientists warrant further large long-term RCTs to clearly define the association between dietary salt reduction and cardiovascular beneﬁts, and also to explore population level interventions contributing to persistent reduction in salt intake.24

Practical Aspects of Implementing the Guidelines and Policies

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• Aid policy makers to understand the various CVD components. • Inclusion of professional societies from diverse specialties in the development and implementation of guidelines, to augment ownership and reduce guideline committees’ fragmentation. References 01. Hayman LL, Helden L, Chyun DA, Braun LT. A life course approach to cardiovascular disease

In spite of extensive dissemination of international policies and guidelines, the prevalence of CVD, as the cause for one-third of global deaths, demonstrates a significant dearth in the implementation of these recommendations.25 Several studies evaluating the implementation of health policies have highlighted the significance of developing and coordinating such policies at multiple levels, with the aid of government, as well as nongovernment organizations, professional bodies, and private firms than only at the societal level.26 The 2004 scientific statement from the World Heart and Stroke Forum reports that a population-based approach to CVD prevention is the basis of all clinical strategies.10

prevention. J Cardiovasc Nurs. 2011 Jul-Aug;26(4 Suppl):S22-34. 02. Executive Summary: Heart Disease and Stroke Statistics--2011 Update: A Report From the American Heart Association. Circulation. 2011; 123: 459-463. 03. Bloom DE, Cafiero ET, Jané-Llopis E, et al. (2011). The Global Economic Burden of Noncommunicable Diseases. Geneva: World Economic Forum. 04. Shah B, Mathur P. Surveillance of cardiovascular disease risk factors in India: the need & scope. Indian J Med Res. 2010 Nov;132(5):634-42. 05. Appel LJ, Frohlich ED, Hall JE, et al. The importance of population-wide sodium reduction as a means to prevent cardiovascular disease and stroke: a call to action from the American Heart Association. Circulation. 2011 Mar 15;123(10):1138-43. 06. Lawes CM, Vander Hoorn S, Rodgers A; International Society of Hypertension. Global burden of blood-pressure-related disease, 2001. Lancet. 2008 May 3;371(9623):1513-8. 07. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study.

Various surveys conducted in India have reported an alarming rise in the major CVD risk factors in both rural and urban population. A review by Bela Shah and Prashant Mathur (2010) investigated the requirement and scope of CVD risk factor surveillance in India and suggested that a sound public health approach is mandatory to curtail the epidemic. The study also indicated the need for complementing the efforts of implementing an intervention program with a robust surveillance mechanism, in order to assess, monitor, and guide policies and programs. According to the review, enduring partnerships, timeliness, and systems approach are significant in determining the future of surveillance systems.4

Lancet. 2004 Sep 11-17;364(9438):937-52. 08. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R; Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002 Dec 14;360(9349):1903-13. 09. Olafiranye O, Zizi F, Brimah P, et al. Management of Hypertension among Patients with Coronary Heart Disease. Int J Hypertens. 2011;2011:653903. 10. Smith SC Jr, Jackson R, Pearson TA, et al. Principles for national and regional guidelines on cardiovascular disease prevention: a scientific statement from the World Heart and Stroke Forum. Circulation. 2004 Jun 29;109(25):3112-21. 11. Lloyd-Jones DM, Hong Y, Labarthe D, et al. Defining and setting national goals for cardiovascular health promotion and disease reduction: the American Heart Association’s strategic Impact Goal through 2020 and beyond. Circulation. 2010 Feb 2;121(4):586-613. 12. Aoki J, Uchino K. Treatment of risk factors to prevent stroke. Neurotherapeutics. 2011 Jul;8(3):463-74.

A focus panel meeting of 21 experts in the CVD field, in UK, has indicated that the primary efforts for implementing the recommendations for preventing CVD should be mainly directed towards high-risk subjects. Once the target is achieved, it is crucial to pay more attention to the identification of untreated subjects at risk. The expert panel also put forth the following key recommendations for improving the adoption of strategies and tactics for CVD prevention:25 • Harmonization of guidelines, focusing on common areas of consensus instead of state-of-the-art science. • Integrating the classification of primary and secondary prevention and focusing on overall risk.

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13. Chobanian AV, Bakris GL, Black HR,et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003 May 21;289(19):2560-72. 14. Corrao G, Parodi A, Nicotra F,et al. Better compliance to antihypertensive medications reduces cardiovascular risk. J Hypertens. 2011 Mar;29(3):610-8. 15. Czernichow S, Zanchetti A, Turnbull F, et al. The effects of blood pressure reduction and of different blood pressure-lowering regimens on major cardiovascular events according to baseline blood pressure: meta-analysis of randomized trials. J Hypertens. 2011 Jan;29(1):4-16. 16. Prevention of Cardiovascular Disease. Guidelines for assessment and management of cardiovascular risk. http://www.who.int/cardiovascular_diseases/guidelines/Full%20text. pdf Published 2007. Accessed October 20, 2011.

More references available online at www.medinewsdirect.com

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IMMUNOLOGY Meta-analysis Reiterates Association between Thyroid Autoimmunity and Obstetric Complications There is substantial evidence to validate thyroid autoimmunity as a major risk factor for adverse pregnancy outcomes. Now, a recent systematic review and meta-analysis, published in the British Medical Journal, reaffirms the association of maternal thyroid autoantibodies with miscarriage and early parturition. The study also reports reduced adverse pregnancy risks with levothyroxine treatment. Shakila Thangaratinam, Clinical Lecturer, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, and co-researchers, evaluated 31 studies (12,126 women) and 5 studies (12,566 women) to validate the association of thyroid antibodies with miscarriage and preterm birth, respectively. Out of the 31 studies, 28 demonstrated a positive correlation between thyroid autoantibodies and miscarriage. The meta-analysis on the association of miscarriage and the presence of thyroid autoantibodies in the cohort studies reported an OR of 3.90, a 3-fold increase (95% CI=2.486.12; P<0.001), and an OR of 1.80 for case-control studies (95% CI=1.25-2.60; P=0.002). The researchers also noted a 2-fold increase in the odds of preterm birth in the presence of thyroid antibodies (OR=2.07; 95% CI=1.173.68; P=0.01). The analysis of the effect of levothyroxine treatment, as seen in two randomized studies, showed a decrease in the rates of occurrence of miscarriage. Additionally, 52% reduction in the relative risk was noted in the metaanalysis. The evaluation of the drug’s effect on preterm birth by a single study reported a 69% reduction in relative risk. An earlier prospective study by Negro et al (The Journal of Clinical Endocrinology & Metabolism, 2006) demonstrated that impaired thyroid function in euthyroid pregnant women, positive for thyroid peroxidase antibody, is associated with elevated risk of pregnancy loss (miscarriage) and premature births. The study reported the beneficial effect of levothyroxine as a substitutive treatment in reducing these obstetric complications.

reported that the rate of miscarriage is higher in women with low antibody titers when compared to those with high titers. Three possible rationales have been proposed to explain the association between thyroid autoimmunity and pregnancy loss. • Miscarriage is an epiphenomenon and is not due to the direct effect of thyroid autoantibodies. It could be due to generalized activation of the immune system by the autoantibodies. • Antibody positivity could cause delay in conception. Hence, the risk of miscarriage increases with progression of age in such individuals. • Miscarriage could be the secondary effect of subtle deficiency in thyroid hormone levels or a reduced potential of the thyroid to meet the demands during pregnancy. Apart from these adverse obstetric outcomes, the presence of maternal thyroid autoantibodies, which is relatively common among women during child-bearing age, causes neurodevelopmental sequelae in the offspring. However, the mechanisms underlying these associations are unclear. The 2007 guidelines put forth by The Endocrine Society, for the management of thyroid dysfunction during pregnancy and postpartum, reports that universal screening and plausible treatment strategies cannot be recommended for antithyroid antibodies. Further substantiation of the current study findings will have major clinical implications in performing systematic screening for autoimmune thyroid disease or mild thyroid dysfunction in pregnant women, and recommending thyroid hormone treatment to prevent such obstetric complications. References 01. Thangaratinam S, Tan A, Knox E, Kilby MD, Franklyn J, Coomarasamy A. Association between thyroid autoantibodies and miscarriage and preterm birth: meta-analysis of evidence. BMJ. 2011 May 9;342:d2616. 02. Negro R, Formoso G, Mangieri T, Pezzarossa A, Dazzi D, Hassan H. Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: effects on obstetrical complications. J Clin Endocrinol Metab. 2006 Jul;91(7):2587-91. 03. Kaprara A, Krassas GE. Thyroid autoimmunity and miscarriage. Hormones. 2008 Oct-

A review by Kaprara and Krassas (Hormones, 2008) has

Dec;7(4):294-302.

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October - December 2011

Systematic Review Reaffirms Value of Inflammatory Markers in Excluding Serious Infections in Children Several studies have been conducted to evaluate the differential diagnostic value of laboratory tests to distinguish between various conditions, such as viral pneumonia from bacterial pneumonia or parenchymal involvement in children with urinary tract infection. Now, a recent study, published in the British Medical Journal, reiterates the diagnostic value of inflammatory markers, such as C-reactive protein (CRP) and procalcitonin (PCT), in the detection of infections in febrile children. Different cut-off values were considered to rule in or rule out the occurrence of serious infections. Ann Van den Bruel, Academic Clinical Lecturer, Department of Primary Health Care, University of Oxford, UK, and coworkers, gathered evidences from electronic databases, expert consultation, and reference tracking, on the diagnostic value of different laboratory tests for detecting serious infections in febrile children. The review included 14 studies carried out in an emergency department or pediatric assessment unit. The researchers compared the diagnostic value of various tests such as CRP, PCT, erythrocyte sedimentation rate, interleukins, white blood cell count, absolute neutrophil count, band count, and left shift. The median prevalence of the serious infections was 20.5% (range=4.5-29.3%). White blood cell indicators (positive likelihood ratio=0.87-2.43) were shown to be less useful for ruling in serious infections compared to inflammatory markers and were not useful in ruling out serious infections (negative likelihood ratio=0.61-1.14). Tests for CRP and PCT were identified as providing the most diagnostic value. The meta-analysis for CRP showed pooled positive and negative likelihood ratios of 3.15 (95% CI=2.67-3.71) and 0.33 (95% CI=0.22-0.49), respectively. The best performing prediction rule involves the combined testing for PCT, CRP, and urinalysis with a positive likelihood ratio of 4.92 (95% CI=3.26-7.43) and a negative likelihood ratio of 0.07 (95% CI=0.02-0.27). Cut-off levels of 2 ng/mL for PCT and 80 mg/L for CRP were recommended to rule-in serious infections, while lower cut-off values of 0.5 ng/mL for PCT and 20 mg/L for CRP were suggested for ruling out serious infections. Concluding on the diagnostic value of CRP and PCT in detecting serious infections in febrile children, the study did not provide substantial evidence to validate the superiority of one test over the other.

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Similar findings with regard to the effectiveness of PCT and CRP markers when compared to white blood cell count and absolute neutrophil count in predicting severe bacterial infections in febrile children were reported in an earlier prospective study by Andreola et al (The Pediatric Infectious Disease Journal, 2007). The researchers suggested that the PCT test is accurate at the initial stages of infections, while the overall CRP may be the most convenient marker due to its better feasibility and sensitivity. Several previous studies have suggested CRP and PCT as the most valuable tools in the investigation of the etiology of fever in children. An earlier study by Lacour et al (European Journal of Pediatrics, 2001) indicated that PCT and CRP provide good sensitivity and specificity in predicting serious bacterial infections in children with fever without localizing signs. These were in comparison to screening methods, such as McCarthy score, leucocyte count, and other inflammatory markers, such as interleukin-6, interleukin-8, and interleukin-1 receptor antagonist. The investigation of acute febrile illnesses in infants and children is considered to be one of the most challenging diagnostic problems in primary care medicine. Although CRP is considered in routine practice by clinicians, the test lacks specificity to distinguish viral from bacterial infections. A prospective observational and multicenter study by Lopez et al (The Pediatric Infectious Disease Journal, 2003) reported that PCT offers better sensibility and improved specificity in differentiating between the viral and bacterial etiology of fever compared to CRP. The researchers confirmed PCT as a good marker for severe infection in febrile children between 1 and 36 months of age. Thus, the study findings have suggested that the measurement of PCT levels in these children may aid in reducing the duration of hospital stay and also the number of hospitalizations. The integrated management of childhood illness guidelines put forth by the World Health Organization to improve the identification and treatment of five important diseases, such as pneumonia, diarrhea, malaria, measles, and malnutrition, does not include any recommendations on laboratory tests. However, the guidelines encourage triage, depending on clinical signs and symptoms, and subsequent treatment at a local facility or referral to a regional center.

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The current study findings augment the need for further research in primary care to identify the diagnostic value of point-of-care testing for CRP and PCT combined with clinical and vital signs and also determine their feasibility, acceptability, and cost effectiveness.

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02. Andreola B, Bressan S, Callegaro S, Liverani A, Plebani M, Da Dalt L. Procalcitonin and C-reactive protein as diagnostic markers of severe bacterial infections in febrile infants and children in the emergency department. Pediatr Infect Dis J. 2007 Aug;26(8):672-7. 03. Lacour AG, Gervaix A, Zamora SA, et al. Procalcitonin, IL-6, IL-8, IL-1 receptor antagonist and C-reactive protein as identificators of serious bacterial infections in children with fever without localising signs. Eur J Pediatr. 2001 Feb;160(2):95-100.

References

04. Fernández Lopez A, Luaces Cubells C, García García JJ, Fernández Pou J; Spanish Society

01. Van den Bruel A, Thompson MJ, Haj-Hassan T, et al. Diagnostic value of laboratory tests

of Pediatric Emergencies. Procalcitonin in pediatric emergency departments for the early

in identifying serious infections in febrile children: systematic review. BMJ. 2011 Jun

diagnosis of invasive bacterial infections in febrile infants: results of a multicenter study and

8;342:d3082.

utility of a rapid qualitative test for this marker.Pediatr Infect Dis J. 2003 Oct;22(10):895-903.

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GASTROENTEROLOGY Exploratory Study Demonstrates Long-term Remission of GERD using Laparoscopic Antireflux Surgery or Esomeprazole Treatment Maintenance treatment using proton pump inhibitors (PPI) is shown to be effective in providing increased rates of symptom resolution, as well as improved healing of esophagitis during the management of gastroesophageal reflux disease (GERD). However, on considering long-term medication, some patients prefer the antireflux surgery over PPI. Now, an exploratory, randomized, open, parallel group trial, published in The Journal of the American Medical Association, reiterates the potential of contemporary antireflux therapy using either laparoscopic antireflux surgery (LARS) or druginduced acid suppression with esomeprazole treatment in achieving long-term remission of GERD. The study named Long-Term Usage of Esomeprazole vs Surgery for Treatment of Chronic GERD (LOTUS) was conducted in medical institutions across 11 countries in Europe, and instituted among 554 participants (18 to 70 years of age) with an established diagnosis of GERD. Patients who responded to esomeprazole therapy, across a 3-month evaluation period, were considered eligible to participate in the study. This cohort was randomly relegated to either undergo LARS (n=288) or receive esomeprazole treatment (n=260). The esomeprazole treatment protocol followed was 20 mg once a day initially, which was gradually increased to 40 mg once per day. Participants who had difficulty in controlling their heartburn and regurgitation with a single dose were prescribed 20 mg, twice per day. The entire cohort was followed up for 5 years, and the final analysis was carried out statistically through an intention-to-treat approach. The primary endpoint was the time to treatment failure that was defined for both the esomeprazole and LARS randomized groups. For the corresponding groups, this was defined by the increase in GERD severity and requirement of alternative drug therapy, despite a 40 mg/day for 8 weeks (adjustable to 20 mg twice/day for further 8 weeks if symptoms did not resolve) increase in dosage, and the need for acid-suppressive drugs to control post-surgery symptoms. The remission rates of GERD noted was 85% (95% CI=81%90%) for the LARS group and 92% (95% CI=89%-96%) for the esomeprazole group (P=0.048). However, this was

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not statistically significant due to dropouts during the study. The corresponding adverse effects were 24.1% and 28.6%. Mortality reported during the study period was low for both the LARS (n=1) and esomeprazole (n=4) groups, and not attributed to treatment. The severity and prevalence of symptoms noted at 5 years in the two groups are enlisted in Table 1. Table 1: Prevalence and Severity of Symptoms at 5-year Follow-up Symptoms

Esomeprazole (%)

LARS (%)

P value

Heartburn

0.14

Acid regurgitation

<0.001

Dysphagia

<0.001

Bloating

<0.001

Flatulence

<0.001

The study concluded that either PPI therapy with esomeprazole or LARS for GERD control has similar beneficial effects on the patients, by facilitating them to remain in a state of remission for 5 years. An intermediate analysis of the same LOTUS study cohort (Gut, 2008) reported that 90% of the surgical patients compared to 93% patients on esomeprazole (P=0.25) remained in remission after a 3-year follow-up period. The analysis concluded that both these treatment modalities are effective and tolerable for providing disease remission. However, LARS was associated with post-fundoplication issues (although not a major postoperative complication) in comparison to ESO, which was well tolerated. In contrast to the recent findings, an earlier study by Lundell et al (Journal of the American College of Surgeons, 2001) reported higher treatment failures in PPI group (omeprazole) compared to those who had undergone surgery (P<0.001). The study population comprised of 310 subjects followed up for 5 years. Two groups of 155 subjects each were randomized to either undergo surgery or to be recipients of omeprazole therapy. The results revealed that 83 patients in the surgery group

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and 65 patients in the PPI group remained in remission (P<0.001). Based on the study findings, the researchers inferred that anti-reflux surgery could be more effective than omeprazole therapy for managing reflux symptoms and achieving long-term clinical remission. The global prevalence of GERD, determined through a systematic review by Salis G (Acta gastroenterologica Latinoamericana, 2011), was reported to be between 10% and 20% in Europe and North America, respectively, with Asia accounting for 5% of the prevalence. Among the Asian countries, Eastern Asia had a prevalence of 5.2% to 8.5% between 2005 to 2010 (2.5-4.8% before 2005), with the Southeast and Western Asian prevalence significantly higher than Eastern Asia at 6.3% to 18.3% after 2005, according to a study by Hye-Kyung Jung (Journal of Neurogastroenterology and Motility, 2011).

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• Subsequently, the protocol should involve over-thecounter antacids and acid suppressants to control symptoms of GERD. • If antacids prove ineffective, treatment for acid suppression should include PPIs or histamine-2 receptor blockers. • Promotility agents in select patients may be used as an adjuvant to acid suppression therapy. Currently used agents are not ideal as monotherapy. • Continuous therapy is advised for the control of symptoms and prevention of complications, since GERD is a chronic condition. • Anti-reflux surgery can be a maintenance option for effective control and suppression of the symptoms of GERD. References 01. Galmiche JP, Hatlebakk J, Attwood S, et al. Laparoscopic Antireflux Surgery vs Esomeprazole

Inappropriately treated GERD, which could advance to Barrett’s esophagus and potentially transform into cancer of the esophagus, poses a significant burden on the healthcare system and economy. A study by Josep Darbaa et al (Expert Review of Pharmacoeconomics & Outcomes Research, 2011) reported that the economic burden of GERD with Barett’s disease on the healthcare systems in Spain, Germany, and Italy were estimated to be €18 million (US $24.32 million), €12 million (US $16.22 million), and €7 million (US $9.46 million), respectively.

Treatment for Chronic GERD: the LOTUS Randomized Clinical Trial. JAMA. 2011 May 18;305(19):1969-77. 02. Lundell L, Attwood S, Ell C, et al. Comparing laparoscopic antireflux surgery with esomeprazole in the management of patients with chronic gastro-oesophageal reflux disease: a 3-year interim analysis of the LOTUS trial. Gut. 2008 Sep;57(9):1207-13. 03. Lundell L, Miettinen P, Myrvold HE, et al. Continued (5-year) followup of a randomized clinical study comparing antireflux surgery and omeprazole in gastroesophageal reflux disease. J Am Coll Surg. 2001 Feb;192(2):172-9; discussion 179-81. 04. Salis G. Systematic review: Epidemiology of gastroesophageal reflux disease in Latin America [Article in Spanish]. Acta Gastroenterol Latinoam. 2011 Mar;41(1):60-9. 05. Jung HK. Epidemiology of Gastroesophageal Reflux Disease in Asia: A Systematic Review. J Neurogastroenterol Motil. 2011 Jan;17(1):14-27.

The 2005 updated guidelines published by the American College of Gastroenterology (ACG) investigated the role of diverse treatment modalities for GERD; the important recommendations are as follows: • Initial management strategy needs to be lifestyle modification, such as changes in eating habits.

06. Darbaa J, Kaskens L, Plans P, et al. Epidemiology and societal costs of gastroesophageal reflux disease and Barrett’s syndrome in Germany, Italy and Spain. Expert Rev Pharmacoecon Outcomes Res. 2011 Apr;11(2):225-32. 07. DeVault KR, Castell DO; American College of Gastroenterology. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol. 2005 Jan;100(1):190-200.

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October - December 2011

NEUROLOGY Complete Resection of Anatomic and Electrocorticographic Lesions in MCD Predicts Long-term Seizure Freedom Malformations of cortical development (MCD) are one of the main causes of pharmacoresistant epilepsy in adults and children. MCD encompass a variety of structural abnormalities with various underlying pathologies and clinical manifestations. Although established as an option for the management of MCD-associated epilepsy, surgery can be challenging. Many studies have been conducted to determine prognostic factors associated with a favorable outcome post surgery. A recent retrospective review, published in the journal Annals of Neurology, has reported complete resection of electrocorticographic and anatomic abnormalities to be the most predictive indicator of long-term seizure control in patients with pharmacoresistant epilepsy due to MCD. Edward F Chang, Assistant Professor, Department of Neurological Surgery, University of California, San Francisco, and colleagues, investigated 143 patients treated surgically for medically refractory seizures due to MCD, between 1990 and 2009, to identify the prognostic factors associated with long-term seizure control. As opposed to earlier studies that evaluated specific subtypes of MCDs, such as focal cortical dysplasia (FCD) and dysembryoplastic neuroepithelial tumor (DNET), the current study involved a wide spectrum of patients with MCDs. The study considered patients with gross macroscopic findings of polymicrogyria, cortical dysplasia associated with mesial temporal sclerosis, hemimegalencephaly, and DNET. The researchers reviewed data pertaining to the patient’s demographics, electrocorticographic abnormalities, preoperative findings on MRI, and histopathologic and surgical variables. The primary outcome measure was seizure status at 1 to 10 years following surgery, which was based on the International League Against Epilepsy (ILAE) seizure classification system. The median follow-up period was 5.9 years, ranging from 0.2 to 18 years. Analysis of data revealed that during the last follow-up, around 68% of patients were seizure free, approximately 20% had significant seizure reduction, and about 12% showed no improvement or experienced worsening of their seizures after surgery. Univariate analysis revealed the following factors to be predictive of freedom from seizures: • Smaller lesions

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• Gray-white blurring on MRI • Complete removal of structural lesions and abnormal electrocorticographic areas • Electrocorticographic abnormalities restricted to a localized region The study findings also concluded that none of the demographic or histopathological features, or the new ILAE FCD classification was able to predict the surgical outcome. However, patients belonging to class I (abnormal proliferation) under Barkovich classification showed better control of seizures, postoperatively, compared to patients in class II (abnormal neuronal migration), class III (abnormal cortical organization), and class IV MCD (MCDs not otherwise classified). Complete resection of tissues exhibiting anatomic and/ or electrocorticographic abnormalities was revealed to be the main independent predictor of freedom from seizures, post-surgery based on multivariate logistic regression. Similar findings were reported by Krsek et al (Neurology, 2009), upon evaluating 28 clinical, neuropsychological, surgical, EEG, MRI, and histopathologic parameters in 149 subjects with FCD, with a minimum of 2 years of post-operative follow up. The retrospective analysis concluded that the most significant factor predictive of a favorable surgical outcome is complete resection of anatomical lesions detected on MRI, along with the epileptogenic cortical regions as determined by intracranial EEG. The recent study finding demonstrates an association between detectability and resectability of anatomical and functional lesions, irrespective of etiology, and a favorable surgical outcome in MCD patients. The study also shows no appreciable association between many of the disease characters and surgical outcomes in MCD patients. Further improvements in imaging technologies, surgical procedures, and extensive invasive characterization with intracranial recording may improve the surgical outcome in patients with pharmacoresistant epilepsy related to MCD. References available online at www.medinewsdirect.com

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October - December 2011

PHARMACOLOGY Triple Marker Combination may Improve Diagnosis of Chronic Kidney Disease and Prediction of Risk for Kidney Failure and Death The measurement of albumin in urine and estimated glomerular filtration rate (eGFR) have been considered as two major markers for the detection of chronic kidney disease (CKD). Now, a prospective cohort study, published in The Journal of the American Medical Association, reports that the inclusion of another biomarker: the combination of cystatin C to GFR creatinine and urine albumin-to-creatinine ratio (ACR) could enhance the predictive accuracy of end-stage kidney disease and allcause mortality associated with CKD. Carmen A Peralta at the Department of Medicine, San Francisco VA Medical Centre, California, and colleagues, investigated the efficacy of the triple-marker approach for CKD evaluation. The study involved 26,643 participants (mean age=65 years) from the large population cohort of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. The study subjects included 40% African Americans and 54% women; 21% with diabetes and 59% with hypertension. Participants with baseline data for serum creatinine, serum cystatin C, and ACR with accurate follow-up recordings were included in the study. The participants were classified into 8 groups, based on the following criteria: • Estimated GFR, determined by creatinine and cystatin C of either <60 or ≥60 mL/min/1.73 m2 • ACR of either <30 or ≥30 mg/g Participants who were on dialysis or recipients of kidney transplant at the entry point to the cohort were excluded. The primary outcomes measured were the incidence of end-stage renal disease and mortality due to all causes. During the study, 2,904 participants with CKD were classified based on creatinine levels. • 24% by creatinine, based on GFR alone • 5% by creatinine and ACR • 40% based on creatinine and cystatin C • 30% based on all the 3 biomarkers Among the remaining 23,739 participants categorized as not having CKD based on GFR creatinine levels, slightly >16% were categorized as having CKD based on ACR,

cystatin C, or a combination of both the biomarkers. The categorization of the group was as follows: • 10.46% based on ACR alone • 4% solely based on cystatin C levels • 1.85% based on both ACR and cystatin C The study cohort was followed for a median period of 4.6 years, during which death of 1,940 participants and end-stage renal disease in 177 subjects were reported. In comparison to participants classified as having CKD with GFR creatinine alone, the hazard ratios for death in participants defined with CKD by creatinine and ACR was 3.3 (95% CI=2.0-5.6), CKD by creatinine plus cystatin C was 3.2 (95% CI=2.2-4.7), and CKD by all 3 biomarkers combined was 5.6 (95% CI=3.9-8.2). The study results showed that the risk for developing end-stage renal disease increased in those categorized as having CKD based on the values of all 3 biomarkers (34.1 per 1,000 person years; 95% CI=28.7-40.5) compared to those categorized by creatinine GFR alone (0.33 per 1,000 person years; 95% CI=0.05-2.3). Participants who were first classified as not having CKD based solely on creatinine GFR, but later classified with the disease based on ACR and cystatin C together, were observed to have a significantly high risk of developing end-stage renal disease (6.4 per 1,000 patient years; 95% CI=3.6-11.3) during the follow-up duration. The addition of cystatin C values to the GFR creatinine levels for detection, reclassified 5.2% of the cohort into a higher risk group, and 3.2% of the subjects to a lower risk group for CKD. Further, patients reclassified for a higher risk for the two outcomes considered had a 3-fold and 4-fold increased risk for death and end-stage renal disease when compared to those reclassified as lower risk group. The study findings concluded that the addition of cystatin C to the existing combination of GFR creatinine and ACR may aid in significantly improving the prediction of CKD and its associated outcomes. An earlier study by Shlipak et al (Annals of Internal Medicine, 2006) has favored the usage of cystatin C as a biomarker, indicative of CKD. The research, conducted on 4,663 US elderly patients without CKD for a period

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of four years, demonstrated a 4-fold increased risk for developing CKD in patients who had elevated cystatin C levels (â&#x2030;Ľ1 mg/L) compared to those with normal levels (<1 mg/dL). The study concluded that cystatin C has the potential to identify the pre-clinical stage of kidney disease that is not readily detectable by creatinine-based tests performed individually. A prospective study by Keller et al (European Heart Journal, 2008) emphasized on the clinical application of cystatin C levels as an indicator for future cardiovascular mortality in individuals with normal or slightly reduced kidney function. The study conducted on a cohort of 1,827 participants reported 66 cardiovascular deaths over a median follow-up period of 3.65 years. Standardized cystatin C level was associated with cardiovascular death by logarithmic transformations, with a HR of 1.94 (95% CI=1.59-2.37; P<0.001). The subsequent statistical analysis in the upper quartile recorded a 3.87-fold increased risk of cardiovascular mortality (95% CI=2.336.42; P<0.001) with elevated cystatin C levels, compared to the lower quartile; thereby demonstrating a potential threshold effect even after adjusting for potential confounders.

October - December 2011

Serum creatinine, the most commonly adopted biomarker for detecting CKD cannot be considered highly reliable since its levels are influenced by biological factors like age, sex, muscle mass, and race. Therefore, there exists a high probability of misclassifying patients with CKD, when based solely on creatinine levels. Since ACR, another commonly adopted biomarker, is recommended only for patients with diabetes, primary detection and screening of CKD is limited only through creatinine-based estimated GFR, in the present time. The current study demonstrating the improvement of prediction models for mortality and end-stage kidney disease with the addition of cystatin C may help triage the individuals more accurately, thereby providing targeted care to those at higher risk. Due to minimal influence on its levels by age, race, or muscle mass, cystatin C biomarker is known to be a better predictor of CKD and its outcomes like end-stage renal disease and all-cause mortality. The findings of the study, recommending the triple marker approach for detection could establish newer universal protocols in screening for CKD. References 01. Peralta CA, Shlipak MG, Judd S, et al. Detection of Chronic Kidney Disease With Creatinine,

According to the Centers for Disease Control and Prevention (CDC), there were 20 million people in America affected with CKD in 2010; the incidence known to be higher in women than in men. More than 35% and 20% of individuals aged 20 years and above with diabetes and hypertension, respectively, are shown to have a greater prevalence of CKD. Epidemiological data suggest that there is an increased burden of this disease on the healthcare system. Hence, the development of distinct protocols that would influence definite identification of individuals at risk for CKD has gained immense attention.

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Cystatin C, and Urine Albumin-to-Creatinine Ratio and Association With Progression to EndStage Renal Disease and Mortality. JAMA. 2011 Apr 20;305(15):1545-52. 02. Shlipak MG, Katz R, Sarnak MJ, et al. Cystatin C and Prognosis for Cardiovascular and Kidney Outcomes in Elderly Persons without Chronic Kidney Disease. Ann Intern Med. 2006 Aug 15;145(4):237-46. 03. Keller T, Messow CM, Lubos E, et al. Cystatin C and cardiovascular mortality in patients with coronary artery disease and normal or mildly reduced kidney function: results from the AtheroGene study. Eur Heart J. 2009 Feb;30(3):314-20. 04. Peralta CA, Katz R, Sarnak MJ. et al. Cystatin C Identifies Chronic Kidney Disease Patients at Higher Risk for Complications. J Am Soc Nephrol. 2011 Jan; 22(1): 147-55. 05. Centers for Disease Control and Prevention. National Chronic Kidney Disease Fact Sheet 2010. Accessed July 10, 2011.

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October - December 2011

Statins Reduce Risk of Short-term Mortality following an Episode of Pneumonia A study by the London School of Hygiene and Tropical Medicine, published in the British Medical Journal, has suggested that long-term statin therapy before the onset of pneumonia considerably reduces the risk of mortality within a six-month interval when compared to non-users of the drug. A team of epidemiologists, funded by the Wellcome Trust and the Medical Research Council, UK, conducted this study to observe whether statins have a protective effect against mortality in patients with pneumonia. The study population comprised of 129,288 statin users aged above 40 years, registered in The Health Improvement Network (THIN), the UK healthcare repository, between January 1995 and December 2006. The subjects were subsequently matched with the control group of non-statin users (n=600,241) in the ratio of 1:5. The main outcome measured was allcause mortality within 6 months from the diagnosis of pneumonia. During the study, pneumonia was diagnosed in 9,073 patients. Among these patients, 1,396 were recipients of statin therapy at the time of diagnosis, and the remaining 7,675 were non-users. Propensity scoring on the eligible population finally restricted the cohort of patients considered for analysis to 942 statin-users and 3,615 non-users. The number of deaths reported on the day of pneumonia diagnosis among the statin users and non-users were 95 (10%) and 686 (19%), respectively. During the 6-month follow-up period, the corresponding deaths recorded were 109/847 and 578/2,927. Based on the data, the fully adjusted hazards ratio calculated was 0.67 (95% CI=0.49â&#x20AC;&#x201C;0.87). Analysis of the study findings showed that the risk for mortality during the six-month period subsequent to an episode of pneumonia in those not on statin therapy, was significantly higher when compared to those on previously established statin therapy before the onset of pneumonia. The therapeutic effects of statins are not exclusively limited to regulating hypercholesterolemia. Statins are also known to possess adjunct antioxidative, antiinflammatory, and immunomodulatory properties. Numerous observational studies have reported certain

additional properties of the drug, but none have been evident to prove a causal effect through clinical trials. A population-based case-control study by Myles et al (Pharmacoepidemiology & Drug Safety, 2009) was conducted to estimate the association between statin usage and pneumonia. The study reported an odds ratio of 0.78 (95% CI=0.65-0.94) with statin usage after adjusting for all known confounding factors. The researchers concluded that statin usage was associated with reduced risk of pneumonia, but the results measuring this relation was much lower when compared to other studies. A previous trial by Thomsen et al (Archives of Internal Medicine, 2008) on a cohort of 29,900 pneumonia patients followed up for 90 days, reported reduced mortality rate (16.8%) in statin users when compared to non-users (22.4%). The study concluded that statin usage is associated with reduced mortality in pneumonia patients, adding further credence to the findings of the present study. However, a research conducted by Mazumdar et al (British Medical Journal, 2006) on 3,415 patients, reported contrasting findings for the link. The evaluation initially demonstrated beneficial effects of the therapy with reduced mortality and hospitalization rates among statin users (without adjusting for confounding factors). Finally, with further analysis and adjustments for most confounding factors, an odds ratio (OR=1.1; 95% CI=0.76â&#x20AC;&#x201C;1.60) that signified potential harm rather than a beneficial effect on mortality was reported in patients with community-acquired pneumonia. According to the Centers for Disease Control and Prevention (CDC), 1.2 million people in the US were diagnosed with pneumonia, with 52,000 deaths due to the illness in 2007. The disease, in addition, burdened the health system with 1.1 million hospital discharges in a year, with an average 5 days of hospitalization. Based on the epidemiological data and disease burden, there is a need for an effective and economical treatment strategy that would assist in achieving desirable outcomes in treating pneumonia. A major significance of the present study findings would be to ascertain whether initiating statin therapy at the

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beginning of pneumonia would result in the same desired effect as the reduction of mortality risk observed with the established regimen of statins before the onset of pneumonia.

October - December 2011

acquired pneumonia and the use of statins, ace inhibitors and gastric acid suppressants: a population-based case窶田ontrol study. Pharmacoepidemiol Drug Saf. 2009 Apr;18(4):26975. 03. Thomsen RW, Riis A, Kornum JB, Christensen S, Johnsen SP, Sﾃｸrensen HT. Preadmission Use of Statins and Outcomes After Hospitalization With Pneumonia. Arch Intern Med. 2008 Oct

References

27;168(19):2081-7.

01. Douglas I, Evans S, Smeeth L. Effect of statin treatment on short term mortality after pneumonia episode: cohort study. BMJ. 2011 Apr 6;342:d1642.

admitted to hospital with community acquired pneumonia: population based prospective

02. Myles PR, Hubbard RB, McKeever TM, Pogson Z, Smith CJ, Gibson JE. Risk of community-

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04. Majumdar SR, McAlister FA, Eurich DT, Padwal RS, Marrie TJ. Statins and outcomes in patients

cohort study. BMJ. 2006 Nov 11;333(7576):999.

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October - December 2011

ONCOLOGY Researchers Propose Incessant Menstruation Hypothesis to Explain Ovarian Cancer Pathogenesis Several hypotheses have been proposed to explain the role of diverse hormonal factors, including androgens, estrogens, progesterone, gonadotropin, insulin, and insulin-like growth factor-I, in the pathogenesis of ovarian cancer. Now, the ‘incessant menstruation hypothesis’ proposed by a group of Italian researchers explains the cause for frequent occurrence of endometriosisassociated cancers in the ovary in contrast to extragonadal sites. The scientists hypothesize that retrograde menstruation-derived oxidative stress, induced by iron, may be the common pathogenic mechanism of serous, endometrioid, and clear cell cancers. Paolo Vercellini, Professor, Clinica Ostetrica e Ginecologica, Università Statale di Milano, Italy, and colleagues, scrutinized data pertaining to hormonal factors and related gynecological conditions, to define a carcinogenic model for sporadic epithelial ovarian cancer, which complies with pathologic and epidemiologic results. The study, published in the recent issue of the journal Human Reproduction, hypothesizes a common oncogenic pathway for the development of epithelial ovarian cancer histotypes such as serous, endometrioid, and clear cell, while a different mechanism is followed by the mucinous tumors. The conclusion was based on the findings that oral contraceptives and tubal ligation substantially reduced the risk of developing endometrioid, serous, and clear cell cancer types, but had no significant effect on mucinous tumors. As per the hypothesis, the occurrence of tubal intraepithelial neoplasia at a distal site could be explained by exposure of the fallopian tube fimbriae to the genotoxic effect of reactive oxygen species (ROS) and catalytic iron generated by erythrocyte hemolysis. Similar ROS genotoxic insult on gonadal endometrial implants, due to accumulation of blood inside the endometriomas explains the more frequent development of endometriosis-associated cancers in the ovary in contrast to extragonadal sites. Based on the study findings, the researchers suggest that bilateral salpingectomy should be recommended in women not wishing to conceive, while considering surgery for independent indications. The surgical procedure may aid in reducing the risk of ovarian cancer, while conserving the ovarian function. Several previous studies have provided evidence to

substantiate the reduced occurrence of ovarian cancer in women undergoing hysterectomy or tubal ligation. Similar findings were reported in a recent review and metaanalysis of 13 selected studies by Cibula et al (Human Reproduction Update, 2011), which demonstrated a 34% reduction in the risk of epithelial ovarian cancer in women who had undergone tubal ligation. Further assessment of a subgroup of women established the existence of the protective effect even 10 to 14 years following the procedure. The study showed decrease in the risk for both serous (RR=0.73) and endometrioid (RR=0.40), but not for mucinous neoplasms. The scientists concluded that the results would prompt more research on the cause of ovarian epithelial cancers, concentrating primarily on the significance of retrograde transport of endometrial cells. An earlier population-based case-control study by TitusErnstoff et al (British Journal of Cancer, 2001) conducted a multivariate logistic regression to analyze the factors associated with the risk of ovarian cancer and the major tumor histologic subtypes. Reproductive and menstrual factors had significant influence on the risk of clear cell/ endometrioid tumors, but the effect was minimal on mucinous tumors. Other important hypotheses proposed to explain ovarian cancer pathogenesis are given below. • The cumulative effects of postovulatory trauma on the ovarian epithelium could increase the risk of malignant transformation (Incessant ovulation hypothesis by Fathalla MF) • Exposure to increased gonadotropin secretion and the subsequent enhanced stimulation of estrogen, increases the risk for malignant transformation of ovarian epithelium (Gonadotropin hypothesis by Cramer and Welch) • According to various other hypotheses, androgens, progesterone, and chronic ovarian inflammation have a role in increasing the ovarian cancer risk. The clearance of these transforming cells by pregnancy is suggested to reduce the risk for cancer, thereby supporting the decreased risk noted in parous women. Based on data from the National Cancer Institute (NCI), around 21,990 new cases and 15,460 deaths due to

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ovarian cancer are estimated to occur in the US in 2011. The high degree of heterogeneity of ovarian carcinomas poses a major challenge in the diagnosis and treatment of the neoplasm. Further elucidation of the origin and pathogenesis of these neoplasms will have major implications in developing a more rational approach for their detection, treatment, and prevention, thereby substantially reducing the disease mortality.

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October - December 2011

References 01. Vercellini P, Crosignani P, Somigliana E, et al. The ‘incessant menstruation’ hypothesis: a mechanistic ovarian cancer model with implications for prevention. Hum Reprod. 2011 Sep;26(9):2262-73. 02. Cibula D, Widschwendter M, Májek O, Dusek L. Tubal ligation and the risk of ovarian cancer: review and meta-analysis. Hum Reprod Update. 2011 Jan-Feb;17(1):55-67. 03. Titus-Ernstoff L, Perez K, Cramer DW, Harlow BL, Baron JA, Greenberg ER. Menstrual and reproductive factors in relation to ovarian cancer risk. Br J Cancer. 2001 Mar 2;84(5):714-21.

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ONCOLOGY

Swedish Study Reaffirms the Benefit of Mammographic Screening in Reducing Breast Cancer Mortality A recent Swedish trial that concluded after a period of three decades reiterates the potential benefit of mammographic screening in reducing breast cancerspecific mortality. The study, published in the recent issue of the journal Radiology, provides evidence to support the recommendation for periodic mammography screening in order to reduce the mortality associated with breast cancer. László Tabár from the Department of Mammography, Falun Central Hospital, Sweden, and co-researchers, investigated the long-term absolute and relative effects of mammographic screening on breast cancer mortality rates. The study, supported by the Swedish National Board of Health and Welfare, evaluated 133,065 subjects aged between 40 and 74 years. Women invited to undergo one-view mammographic screening constituted the study group, and those receiving usual care formed the controls. The researchers determined the case status and cause of death with the help of local trial end point committees and an external committee (independently). Negative binomial regression was utilized for mortality analysis. A substantial reduction in breast cancer-related mortality rate was noted in subjects invited for mammographic screening, based on both local end point committee data (RR=0.69; 95% CI=0.56-0.84; P<0.0001) and external committee consensus data (RR=0.73; 95% CI=0.59-0.89; P=0.002). As per the 29-year follow-up, the number of patients required to undergo the imaging examination for 7 years, noted by the local data and consensus data, to prevent one breast cancer death were 414 and 519, respectively. The study findings estimated that the most prevented deaths due to breast cancer would have occurred following the first 10 years of follow-up, without the screening. The researchers noted an increase in the observed number of breast cancer deaths prevented with longer follow-up time. They also reiterated the need for long-term evaluation exceeding 20 years to clearly elucidate the absolute benefit of screening. Similar findings were reported in a case-referent study by Schoor et al (British Journal of Cancer, 2011), which investigated the effect of mammographic screening on breast cancer mortality during the period 1975-2008. A total of 282 deaths due to the malignancy were reported; and 1,410 referents, aged 50 to 69 years, from the total

population (n=55,529) were invited to undergo screening. The study results showed that the rate of breast cancer death was 35% lower among the screened patients when compared to the unscreened group (OR=0.65; 95% CI=0.49–0.87). Analysis based on the calendar year demonstrated a substantial reduction in breast cancer mortality from 28% during 1975-1991 to 65% for the period 1992-2008, denoting the increased effectiveness of the screening. As per the American Cancer Society guidelines (CA: A Cancer Journal for Clinicians, 2010), early detection of breast cancer in average-risk individuals involves a combination of regular clinical breast examination and counseling to enhance the awareness of breast symptoms from the age of 20 years, and annual mammography starting at 40 years of age. The guidelines suggest continued screening as long as the individual is in good health and if the risk of becoming a candidate for breast cancer treatment is high. There are no specifications on the upper age limit for discontinuation of the mammography screening; however, the decision on cessation should be personalized based on the benefits and risks of the technique, while considering the estimated life expectancy and general health status of the individual. Despite years of research and a number of consensus by diverse international organizations, guidelines on the use of mammography for screening breast cancer among women between 40 to 49 years is a matter of debate. A recent study by Schousboe et al (Annals of Internal Medicine, 2011) reported mammography as an expensive technique, considering the cost attributed to the detection of nonprogressive and nonlethal invasive cancer, and the lack of usefulness of false-positive results. The researchers also reiterated the need for individualizing the mammography screening, based on the history of breast biopsy, woman’s age, family history of malignancy, breast density, and perspectives on the potential benefits and limitations of screening. References 01. Tabár L, Vitak B, Chen TH, et al. Swedish Two-County Trial: Impact of Mammographic Screening on Breast Cancer Mortality during 3 Decades. Radiology. 2011 Sep;260(3):658-63. 02. van Schoor G, Moss SM, Otten JD, et al. Increasingly strong reduction in breast cancer mortality due to screening. Br J Cancer. 2011 Mar 15;104(6):910-4.

More references available online at www.medinewsdirect.com

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October - December 2011

NEWS Study Validates Maternal Vaccination to Reduce Hospitalization of Infants due to Influenza A recent population-based, laboratory-confirmed influenza surveillance supports the currently proposed guidelines for immunizing pregnant women against influenza. The study results, published in the American Journal of Obstetrics & Gynecology, show the reduced risk for influenza-attributable hospitalization among infants, born to vaccinated mothers, during their first 6 months of life. Katherine A Poehling, Associate Professor at the Department of Pediatrics and Department of Epidemiology & Prevention, Wake Forest School of Medicine, North Carolina, and coworkers, used logistic regression analyses to compare the maternal exposure to influenza vaccination during gestation, and determine the positive/negative outcome of influenza testing on 1,510 less than 6-month–old hospitalized infants. Laboratory-confirmed influenza was observed in 151 (10%) of these infants, and immunization against influenza was received in 294 (19%) mothers during pregnancy. The number of vaccinated mothers of influenza-positive and influenza-negative infants was 18 (95% CI=0.32-0.88) and 276 (95% CI=0.30-0.91), respectively. The study concluded that hospitalization due to influenza was 45% to 48% lesser among infants of immunized mothers compared to unvaccinated mothers. Similar findings were reported in a matched case-control study, conducted by Benowitz et al (Clinical Infectious Diseases, 2010), on infants aged <12 months, hospitalized due to laboratory-confirmed influenza. The study results showed the administration of influenza vaccine to pregnant women to be 91.5% effective in preventing hospitalization of their infants due to influenza in the first six months after birth.

in children <6 months of age compared to any other pediatric age group. However, since there is no approved vaccine for immunizing infants aged <6 months, currently, the administration of the vaccine during pregnancy could serve as an effective strategy to transfer antibodies to the infants and ensure their protection. The Advisory Committee on Immunization Practice (ACIP) of the Centers for Disease Control and Prevention recommends immunization of all women who get pregnant during the influenza season. According to the Committee, the benefits of immunizing pregnant women outweigh the potential risk if • there is enhanced risk for disease exposure • infection can pose a risk to the health of the mother or fetus • complications associated with vaccine administration is unlikely The American College of Obstetricians and Gynecologists (ACOG) also supports the recommendations put forth by ACIP. The ACOG Committee also emphasized that till date, there has been no study that has reported an adverse influence of inactivated influenza vaccine on pregnant women or their offspring. The recent findings highlight the significance of adopting maternal influenza vaccination as a cost-effective strategy to reduce the morbidity associated with influenza, mainly in the two vulnerable groups: pregnant women and young infants. References 01. Poehling KA, Szilagyi PG, Staat MA, et al. Impact of maternal immunization on influenza hospitalizations in infants. Am J Obstet Gynecol. 2011 Jun;204(6 Suppl 1):S141-8. 02. Benowitz I, Esposito DB, Gracey KD, Shapiro ED, Vázquez M. Influenza vaccine given to

Various public health surveillance programs and scientific research have indicated the rising burden of influenzaassociated illness among infants globally. Studies conducted on the US population reported that the rates of influenza-associated hospitalization are more

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pregnant women reduces hospitalization due to influenza in their infants. Clin Infect Dis. 2010 Dec 15;51(12):1355-61. 03. American College of Obstetricians and Gynecologists Committee on Obstetric Practice. ACOG Committee Opinion No. 468: Influenza vaccination during pregnancy. Obstet Gynecol. 2010 Oct;116(4):1006-7.

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NEWS

Researchers Propose a Two-step Half-match Procedure to Augment Bone Marrow Transplantation Outcomes Bone marrow transplantation has emerged as a potential cure for leukemia in the recent decades; however, identification of a perfectly matched donor is a major challenge. Now, a team of US researchers has developed an innovative two-step myeloablative approach with optimized T-cell dosing for haploidentical hematopoietic stem cell transplantation (HSCT), which holds promise in enhancing the overall survival of leukemia patients. The phase I/II trial conducted by Dolores Grosso from Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, United States, and coworkers, investigated the optimal T-cell dose below which there is usually no severe graft-versus-host disease (GVHD). The first step of HSCT involved administration of a fixed dose of donor T cells after conditioning the patients (n=27) with total body irradiation, and subsequently, cyclophosphamide (CY) for tolerization of T cells. The second step included infusion of CD34 selected HSC product after CY. The key findings of the study, published in the journal Blood, are as follows: • Administration of 2×108/kg T cells contributed to persistent engraftment, immune reconstitution, and restriction of GVHD to acceptable rates • The corresponding cumulative incidences of relapserelated mortality, non-relapse mortality, and grade III-IV GVHD were 29.6%, 22.2%, and 7.4% • The 3-year probability of survival noted after 28-56 months of follow-up was 48% for the whole population and 75% among patients in remission at the time of transplantation.

that administration of an elevated, fixed dose of haploidentical T cells was linked to encouraging outcomes, mainly in good-risk patients, based on CY tolerization. The researchers also anticipate that this inference may form the basis for further investigation and optimization of the two-step procedure. Evaluating the current status of HSCT, an earlier review by Xiao-jun Huang (Journal of Hematology & Oncology, 2008) reported that the procedure with the potential for graft engineering, contributed to unlimited availability of donors without delaying transplantation. Some of the recent strategies that are being investigated to improve the transplantation outcomes are the use of ‘mega’ dose of stem cells, T-cell depleted graft, manipulation of the graft, and intensive post-transplant immunosuppression. Although the adoption of these strategies aids in reducing the transplant-associated mortality and GVHD, the occurrence of disease relapse and infection, linked to late immune reconstitution, restrict the wide use of haploidentical HSCT. The review stated the need for identifying the best approach and enhancing the posttransplant immune reconstitution to achieve the target goal, i.e., effective circumvention of the HLA barrier and achievement of an optimal graft-versus-leukemia effect without GVHD. References 01. Grosso D, Carabasi M, Filicko-O’Hara J, et al. A two-step approach to myeloablative haploidentical stem cell transplantation: a phase I/II trial performed with optimized T-cell dosing. Blood. 2011 Aug 25. [Epub ahead of print] 02. Huang XJ. Current status of haploidentical stem cell transplantation for leukemia. J Hematol

Based on the study findings, the researchers concluded

Oncol. 2008 Dec 31;1:27.

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October - December 2011

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HPTN 052 Results Advocate Antiretroviral Treatment to Prevent HIV Transmission in Serodiscordant Couples HIV infected serodiscordant couples can reduce the risk of transmission by 96% to their partners by initiating oral antiretroviral therapy (ART) when their immune systems are still relatively competent, according to the HIV Prevention Trial Network (HPTN 052) results. Funded by the National Institute of Allergy and Infectious Diseases, the findings were released to the media by its parent organization, the US National Institutes of Health. The phase III randomized clinical trial was constituted primarily to assess the effect of ART in preventing transmission of infection among serodiscordant couples. The study, led by Myron Cohen, Director, Institute for Global Health & Infectious Diseases, University of North Carolina, enrolled 1,763 serodiscordant couples from Africa, Asia, Latin America, and USA. The participants aged ≥18 years had a CD4+ T-cell count (the fundamental estimator of immune capability) between 350 and 550 cells/mm3. The median CD4+ T-cell count at enrollment was 436 cells/mm3, much higher than the World Health Organization (WHO) recommendation of 350 cells/mm3 for ART eligibility. (The difference here is important because, the infected individuals were asymptomatic and clearly not eligible for treatment at enrollment.) Participants were assigned to either receive ART immediately (n=886), or defer till CD4 counts fell below 250 cells/mm3 or an AIDS-related event like pneumocystis pneumonia occurred (n=877). All participants were provided with comprehensive HIV care education on safe sex practices and free condoms, regular CD4 testing, and treatment for sexually transmitted infections. In the deferred treatment arm, 27 HIV transmissions occurred in comparison to only a single case in the immediate treatment arm, a 96% reduction in risk of transmission (P<0.0001). In addition, the study reported a reduction in the incidence of extrapulmonary tuberculosis: 17 and 3 in the corresponding groups. The study clearly finds that early ART not only benefits the patient individually, but also has a significant public health impact in controlling the spread of infection at large. Although, the study was scheduled to conclude in 2015, the Data and Safety Monitoring Board (DSMB), an independent study monitoring committee, decided to publicize the results fours years in advance after observing a strong correlation between ART therapy and reduction in transmission during an interim analyses of the data.

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Another recent retrospective cohort study by Reynolds et al (AIDS, 2011) concluded that serodiscordant couples initiated on ART may have a lower probability to transmit the infection to their partners due to reductions in viral load and frequent use of barrier contraception. The study was conducted on a cohort of 250 HIV-1 serodiscordant couples followed up for 5 years (2004–2009). Forty-two HIV-1 transmissions, at an incidence rate of 9.2/100 person-years (95% CI=6.59-12.36) had occurred prior to ART initiation. Among 32 couples, ART was initiated in the infected partner, and there were no reports of HIV transmission over a 53.6 person-years follow-up duration (95% CI=-11.91 to -6.38; P=0.0097). Patient history revealed consistent use of condoms with minimal changes in the number of sexual partners or other risk factors during ART. Additionally, a substantial reduction in viral load was observed in this group. According to the Joint United Nations Program on HIV/ AIDS (UNAIDS), there were more than 34 million people across the globe living with HIV at the end of 2010. For the same year, the number of HIV-positive patients in the middle- and low-income countries undergoing ART was about 6.6 million, and the number of eligible patients not receiving the treatment was around 9 million. The revision of guidelines will have to address the ethical issue in treating patients with higher CD4 count than what the present guidelines recommend (CD4 count 350 cells/mm3 or below), resulting in an increased number of patients being eligible for treatment. This inordinate escalation in the number of patients would certainly increase public health expenditure significantly. International aid agencies, like UNAIDS, will have to devise strategies to execute large public health challenges, which would deal with the availability of medicines, accessibility to treatment, and quality of care. References 01. Treating HIV-infected People with Antiretrovirals Protects Partners from Infection [News release]. National Institutes of Allergy and Infectious Diseases. Bethesda, MD: NIH News; May 12, 2011.http://www.niaid.nih.gov/news/newsreleases/2011/Pages/HPTN052.aspx Accessed May 16, 2011. 02. The HPTN 052 Study: Preventing Sexual Transmission of HIV with Anti-HIV Drugs. National Institutes of Allergy and Infectious Diseases. Questions and Answers Page. http://www.niaid. nih.gov/news/QA/Pages/HPTN052qa.aspx Updated May 12, 2011. Accessed May 16, 2011.

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October - December 2011

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Study Reports Efficacy of Salpingo-oophorectomy Compared to Cystectomy for Mucinous Borderline Ovarian Tumors A recent retrospective cohort study has reported that unilateral salpingo-oophorectomy (USO) rather than cystectomy should be the preferred treatment of choice for patients with mucinous borderline ovarian tumors (MBOTs) during conservative surgery, as the former decreases the recurrence risk and does not hinder fecundity. Martin Koskas from the Department of Gynecologic Surgery, Institut Gustave Roussy, France, and coworkers, conducted the study on 31 MBOT patients (excluding peritoneal pseudomyxoma) desiring pregnancy, to compare the outcomes of salpingo-oophorectomy and cystectomy. Of the total study subjects, 19 underwent USO and 12 were treated with cystectomy. The researchers analyzed surgical, histological and epidemiological parameters, and other prognostic factors that may affect fertility outcomes. The study results, published in the journal Human Reproduction, showed higher 5-year recurrence-free survival rate in the USO group (94.7%) when compared to cystectomy patients (49.1%; P=0.041). Similar 5-year probabilities of pregnancy were observed in cystectomy and salpingo-oophorectomy groups (41.8 vs. 45.9%; P=0.66). Twelve women were pregnant out of the 31 patients. The researchers did not find any association between fertility results, and surgical, histological, and epidemiological parameters. Similar findings were reported in another retrospective review conducted by the same group of researchers (Annals of Surgical Oncology, 2011). The study included 97 MBOT patients, out of whom 28 and 69 underwent radical and conservative surgery, respectively. Use of the cystectomy procedure was shown to be the lone prognostic factor for recurrence, and thus USO should be the preferred treatment method for MBOT patients undergoing conservative surgery.

Previous studies have shown conservative surgery with USO or cystectomy to be safe in patients with stage I BOT. In one such research, Yinon et al (Fertility and Sterility, 2007) concluded that cystectomy and oophorectomy are adequate treatment options for BOT in women who wish to retain fertility, if the patients undergo careful and prolonged follow-up. The tumor recurrence rates were shown to be 22.7% and 27.5% in patients who had undergone cystectomy (n=22) and USO (n=40), respectively. Among the 62 patients considered for the study, 25 were pregnant (40.3%). The mean follow-up period was less in cystectomy-treated group compared to USO group. Traditionally, the standard treatment for BOT involved total hysterectomy with bilateral adnexectomy, but the need for fertility-preserving surgery and increase in the use of laparoscopy has shown a shift from radical surgery to conservative surgery. Fertility-sparing surgery has been suggested as the treatment of choice in young BOT patients for retaining fertility. However, BOT patients who have completed childbearing or with advanced-stage BOT are commonly treated by radical surgery, which includes total abdominal hysterectomy, infracolic omentectomy, BSO, complete peritoneal resection of macroscopic lesions or multiple peritoneal biopsies, peritoneal washings, and appendectomy in case of MBOT. Although molecular studies have helped in increasing our knowledge on BOT, further studies comparing radical with conservative surgery, and laparoscopy with laparotomy are required to determine the effective treatment strategies for the management of the condition. References 01. Koskas M, Uzan C, Gouy S, et al. Fertility determinants after conservative surgery for mucinous borderline tumours of the ovary (excluding peritoneal pseudomyxoma). Hum Reprod. 2011 Apr;26(4):808-14. 02. Koskas M, Uzan C, Gouy S, et al. Prognostic factors of a large retrospective series of mucinous borderline tumors of the ovary (excluding peritoneal pseudomyxoma). Ann Surg Oncol. 2011

An earlier French retrospective multi-centered study by Poncelet et al (Annals of Surgical Oncology, 2006) indicated that cystectomy is associated with high intra-operative risk for cyst rupture and probability of recurrence in stage I borderline ovarian tumor (BOT) patients compared to USO or bilateral salpingo-oophorectomy (BSO).

Jan;18(1):40-8. 03. Poncelet C, Fauvet R, Boccara J, DaraĂŻ E. Recurrence after cystectomy for borderline ovarian tumors: results of a French multicenter study. Ann Surg Oncol. 2006 Apr;13(4):565-71. 04. Yinon Y, Beiner ME, Gotlieb WH, Korach Y, Perri T, Ben-Baruch G. Clinical outcome of cystectomy compared with unilateral salpingo-oophorectomy as fertility-sparing treatment of borderline ovarian tumors. Fertil Steril. 2007 Aug;88(2):479-84.

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