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Gotlieb W.H.,McGill University | Amant F.,University Hospital Leuven | Advani S.,Jaslok Hospital and Research Center | Goswami C.,B P Poddar Hospital and Medical Research Ltd | And 6 more authors.
The Lancet Oncology | Year: 2012

Background: Targeting of VEGF is a potential therapeutic option in patients with malignant ovarian ascites. We present the final results of a multicentre study of the efficacy and safety of aflibercept, a potent inhibitor of both VEGF and placental growth factor, in the treatment of malignant ascites. Methods: In this double-blind, placebo-controlled, parallel-group, phase 2 study, patients with advanced chemoresistant ovarian cancer and recurrent symptomatic malignant ascites were randomly assigned (1:1) via an interactive voice response system to either intravenous aflibercept (4 mg/kg every 2 weeks) or placebo, stratified by interval of time (≤2 weeks vs >2 weeks) between the two most recent paracenteses before randomisation. Patients participated in the double-blind period (during which patients, investigators, and sponsor personnel were masked to treatment assignment) until they had a repeat paracentesis and for at least 60 days, and could also participate in an optional open-label period during which all patients received aflibercept. The primary efficacy endpoint was time to repeat paracentesis based on response during the double-blind period alone, and was analysed in the intention-to-treat population with censoring of patients who did not have a repeat paracentesis as of the last day of the double-blind period. Safety analyses included both double-blind and open-label periods. This study is registered at ClinicalTrials.gov, number NCT00327444. Findings: 55 patients with a median of four (range two to 11) previous lines of chemotherapy were randomly assigned to receive placebo (n=26) or aflibercept (n=29). Mean time to repeat paracentesis was significantly longer with aflibercept than with placebo (55·1 [SE 7·3] vs 23·3 [7·7] days; difference 31·8 days, 95% CI 10·6-53·1; p=0·0019). In the aflibercept group, two patients did not need a repeat paracentesis during 6 months of double-blind treatment. The most common grade 3 or 4 treatment-emergent adverse events were dyspnoea (six [20%] aflibercept vs two [8%] placebo), fatigue or asthenia (four [13%] vs 11 [44%]), and dehydration (three [10%] vs three [12%]). The frequency of fatal gastrointestinal events was higher with aflibercept (three intestinal perforations) than with placebo (one intestinal fistula leading to sepsis). Interpretation: This study shows the effectiveness of VEGF blockade in the reduction of malignant ascites, but confirms the significant clinical risk of fatal bowel perforation in this population of patients with very advanced cancer. VEGF blockade should be used with caution in advanced ovarian cancer with abdominal carcinomatosis, and the benefit-risk balance should be thoroughly discussed for each patient. Funding: Sanofi Oncology. © 2012 Elsevier Ltd.


Advani S.H.,Jaslok Hospital and Research Center
Indian Journal of Medical and Paediatric Oncology | Year: 2010

This article highlights the current knowledge of mTOR biology and provides new insights into the role of mTOR in different cancers. An active mTOR coordinates a response in cell growth directly through its effects on cell cycle regulators and indirectly by sustaining nutrient supply into the cell through the production of nutrient transporters and also through the promotion of angiogenesis. A primary way that mTOR exerts its regulatory effects on cell proliferation is by controlling the production of cyclin D1. mTOR increases the translation of hypoxia-inducible factor 1 (HIF-1)/HIF-2. The HIF transcription factors drive the expression of hypoxic stress response genes, including angiogenic growth factors such as vascular endothelial growth factor (VEGF), platelet-derived growth factor β (PDGF- β), and transforming growth factor a (TGF-α). mTOR also increases the surface expression of nutrient transporters proteins. An increase in these proteins results in greater uptake of amino acids and other nutrients by the cell leading to adequate nutrient support to abnormal cell growth and survival. There is also emerging evidence that mTOR activation may play a role in promoting cell survival through the activation of antiapoptotic proteins that contribute to tumor progression. Given that the mTOR pathway is deregulated in a number of cancers, it is anticipated that mTOR inhibitors will have broad therapeutic application across many tumor types. Until now, no treatment demonstrated Phase III evidence after disease progression on an initial VEGF-targeted therapy in advanced renal cell carcinoma. Everolimus is the first and only therapy with Phase III evidence after failure of VEGF-targeted therapy. Everolimus is a once-daily, oral inhibitor of mTOR (mammalian target of rapamycin) indicated for the treatment of advanced renal cell carcinoma in patients, whose disease has progressed on or after treatment with VEGF-targeted therapy.


Chickermane P.R.,Jaslok Hospital and Research Center | Khubchandani R.P.,Jaslok Hospital and Research Center
Clinical and Experimental Rheumatology | Year: 2015

Objective: To evaluate the benefits of the addition of leflunomide (LEF) in children with polyarticular course juvenile idiopathic arthritis (JIA), non-responsive to standard dose parenteral methotrexate (MTX). Methods: In an observational study, 32 children with polyarticular course JIA failing standard dose MTX (up to 15 mg/m2/week sc for at least 3 and up to 6 months) received additional LEF. Permitted concomitant drugs included pulse steroids for flares and/or low bridging dose of prednisolone, intra-articular steroids and non-steroidal anti-inflammatory drugs. No other DMARDs had been used before enrolment. Patients underwent 8-12 weekly assessment. At each visit, core set of outcome variables and laboratory parameters, viz. haemogram and liver enzymes were recorded. The primary efficacy outcome was the ACR Pedi 30 criteria. At the last follow up, Wallace's criteria were used to determine children achieving remission. Results: 25 of 32 children who followed up for at least 3 months were analysed. Mean follow up duration following addition of LEF was 1.61 years (range: 0.29 to 3.0 years). At 3 months, 68% of the patients met the ACR Pedi 30 response. 17 of the 20 children (85%) showed an ACR Pedi 30 response at 6 months and 16 out of 18 (88.8%) at 1 year. Of the 18 children followed up till the end of the study, 12 (66.6%) met the ACR Pedi 30 criteria and 9 (50%) were in clinical remission on medications (off steroids). Adverse effects were observed in 2 children (gastritis in one and elevated liver enzymes in the other). Conclusion: Our findings support further study of the role of this combination in the management of polyarticular course JIA refractory to standard dose MTX, especially in resource challenged settings where biologicals are unaffordable. The open observational nature of the study is its limitation. © Clinical and Experimental Rheumatology 2015.


Desai H.G.,Jaslok Hospital and Research Center
Journal of Association of Physicians of India | Year: 2011

Model for End-stage Liver Disease (MELD) measures serum bilirubin (mg/dL), serum albumin (g/dL), International Normalised Ratio (INR) for prothrombin time. MELD score accurately predicts survival in 3 months for cirrhotic patients on the waiting list of liver transplantation. In about 15% of patients, it does not accurately predict survival and hence MELD-Na is recommended. MELD score is a poor predictor of survival after liver transplantation. Downgrading of MELD score for age of recipient and chance of recurrence of the disease is recommended to accurately predict survival after liver transplantation. © JAPI.


Nagral A.,Jaslok Hospital and Research Center
Journal of Clinical and Experimental Hepatology | Year: 2014

Gaucher disease is the commonest lysosomal storage disease seen in India and worldwide. It should be considered in any child or adult with an unexplained splenohepatomegaly and cytopenia which are seen in the three types of Gaucher disease. Type 1 is the non-neuronopathic form and type 2 and 3 are the neuronopathic forms. Type 2 is a more severe neuronopathic form leading to mortality by 2 years of age. Definitive diagnosis is made by a blood test-the glucocerebrosidase assay. There is no role for histological examination of the bone marrow, liver or spleen for diagnosis of the disease. Molecular studies for mutations are useful for confirming diagnosis, screening family members and prognosticating the disease. A splenectomy should not be performed except for palliation or when there is no response to enzyme replacement treatment or no possibility of getting any definitive treatment. Splenectomy may worsen skeletal and lung manifestations in Gaucher disease. Enzyme replacement therapy (ERT) has completely revolutionized the prognosis and is now the standard of care for patients with this disease. Best results are seen in type 1 disease with good resolution of splenohepatomegaly, cytopenia and bone symptoms. Neurological symptoms in type 3 disease need supportive care. ERT is of no benefit in type 2 disease. Monitoring of patients on ERT involves evaluation of growth, blood counts, liver and spleen size and biomarkers such as chitotriosidase which reflect the disease burden. Therapy with ERT is very expensive and though patients in India have so far got the drug through a charitable access programme, there is a need for the government to facilitate access to treatment for this potentially curable disease. Bone marrow transplantation is an inferior option but may be considered when access to expensive ERT is not possible. © 2014 INASL.


Pandya S.K.,Jaslok Hospital and Research Center
Mens Sana Monographs | Year: 2011

Treatment of diseases of the brain by drugs or surgery necessitates an understanding of its structure and functions. The philosophical neurosurgeon soon encounters difficulties when localising the abstract concepts of mind and soul within the tangible 1300-gram organ containing 100 billion neurones. Hippocrates had focused attention on the brain as the seat of the mind. The tabula rasa postulated by Aristotle cannot be localised to a particular part of the brain with the confidence that we can localise spoken speech to Broca's area or the movement of limbs to the contralateral motor cortex. Galen's localisation of imagination, reasoning, judgement and memory in the cerebral ventricles collapsed once it was evident that the functional units-neurones-lay in the parenchyma of the brain. Experiences gained from accidental injuries (Phineas Gage) or temporal lobe resection (William Beecher Scoville); studies on how we see and hear and more recent data from functional magnetic resonance studies have made us aware of the extensive network of neurones in the cerebral hemispheres that subserve the functions of the mind. The soul or atman, credited with the ability to enliven the body, was located by ancient anatomists and philosophers in the lungs or heart, in the pineal gland (Descartes), and generally in the brain. When the deeper parts of the brain came within the reach of neurosurgeons, the brainstem proved exceptionally delicate and vulnerable. The concept of brain death after irreversible damage to it has made all of us aware of 'the cocktail of brain soup and spark' in the brainstem so necessary for life. If there be a soul in each of us, surely, it is enshrined here. © MSM 2011.


Mesenchymal stem cells (MSCs) have immense therapeutic potential because of their ability to self-renew and differentiate into various connective tissue lineages. The in vitro proliferation and expansion of these cells is necessary for their use in stem cell therapy. Recently our group has developed and characterized mesenchymal stem cells from subcutaneous and visceral adipose tissue. We observed that these cells show a slower growth rate at higher passages and therefore decided to develop a supplemented medium, which will induce proliferation. Choi et-al. have recently shown that the use of ascorbic acid enhances the proliferation of bone marrow derived MSCs. We therefore studied the effect of ascorbic acid on the proliferation of MSCs and characterized their phenotypes using stem cell specific molecular markers. It was observed that the use of 250-μM ascorbic acid promoted the significant growth of MSCs without loss of phenotype and differentiation potential. There was no considerable change in gene expression of cell surface markers CD105, CD13, Nanog, leukemia inhibitory factor (LIF) and Keratin 18. Moreover, the MSCs maintained in the medium supplemented with ascorbic acid for a period of 4-weeks showed increase in pluripotency markers Oct4 and SOX 2. Also cells in the experimental group retained the typical spindle shaped morphology. Thus, this study emphasizes the development of suitable growth medium for expansion of MSCs and maintenance of their undifferentiated state for further therapeutic use. © 2010 The Authors. Human Cell © 2010 Japan Human Cell Society.


Ravishankar K.,Jaslok Hospital and Research Center
Annals of Indian Academy of Neurology | Year: 2012

Headache is a common complaint that makes up for approximately 25% of any neurologists outpatient practice. Yet, it is often underdiagnosed and undertreated. Ninety percent of headaches seen in practice are due to a primary headache disorder where there are no confirmatory tests, and neuroimaging studies, if done, are normal. In this situation, a good headache history allows the physician to recognize a pattern that in turn leads to the correct diagnosis. A comprehensive history needs time, interest, focus and establishment of rapport with the patient. When to ask what question to elicit which information, is an art that is acquired by practice and improves with experience. This review discusses the art of history-taking in headache patients across different settings. The nuances of headache history-taking are discussed in detail, particularly the questions related to the time, severity, location and frequency of the headache syndrome in general and the episode in particular. An emphasis is made on the recognition of red flags that help in the identification of secondary headaches.


Binnani P.,Jaslok Hospital and Research Center
Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia | Year: 2012

The dural sinus thrombosis is an uncommon complication of a commonly done procedure of central venous catheterisation. We present a case of massive hemorrhagic venous infarct with gross cerebral edema due to dural sinus thrombosis along with right internal jugular vein thrombus. A 21-year-old male patient presented to the emergency department with fever and swelling of the right neck four days following discharge after his prior hospitalization two weeks ago for acute renal failure due to severe gastroenteritis, when he underwent hemodialysis through right internal jugular access. On presentation, he was conscious, with swelling on right side of the neck, which was diagnosed as right internal jugular vein occlusion. However, he rapidly deteriorated and developed signs of raised intracranial pressure despite being on treatment with heparin. He was diagnosed as having massive hemorrhagic cerebral venous infarct with gross cerebral edema complicated with shift of the ventricles to the left due to dural sinus thrombosis. Despite emergency decompressive craniotomy, he succumbed in the next two days due to coning. Asymptomatic catheter-related thrombosis is frequent in the intensive care units, but major complications like retrograde extension into dural sinus causing thrombosis is rare. A high index of suspicion is required to diagnose this major catastrophe for an early and meaningful intervention.


Doshi P.K.,Jaslok Hospital and Research Center
Stereotactic and Functional Neurosurgery | Year: 2011

Objective: To evaluate the incidence of surgical and hardware-associated complications of deep brain stimulation (DBS) for a range of movement disorders. Methods: The study design is a retrospective analysis and review of surgical and hardware complications of DBS performed by a single surgeon from 1999 to 2009. A total of 153 cases of DBS (298 electrodes) for various movement disorders and a minimum follow-up of 1 year have been included. Two patients could not be implanted. A further 54 patients who underwent change of the implantable pulse generator (IPG) have been included for analysis of hardware-related complications. Results: The mean follow-up was 64 ± 36.15 (range = 12-129) months for the DBS group. Twenty-four (15.6%) patients developed complications. Confusion occurred in 3.9%, vasovagal attack in 1.9%, lead migration/misplaced lead in 2.5%, erosion and infection in 4.5% and IPG malfunction occurred in 1.4% of the patients. When calculated with respect to the number of electrodes and IPG replacements, the complication rate was lower (11.9%). Three patients had their system explanted, two of them being patients with dystonia who had inadvertently damaged their operative site. Conclusion: DBS surgery is a relatively safe surgery, with most of the complications being minor, without long-term morbidity. The complication rate in elderly (age ≥65 years) is comparable to that in younger patients. However, confusion is more frequent in this age group, and patients and relatives can be prepared to accept this as a transient morbidity. Copyright © 2011 S. Karger AG, Basel.

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