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ABSTRACT: The Indian Council of Medical Research and the Central Drugs Standards Control Organization of the Directorate General of Health Services of the Ministry of Health and Family Welfare' draft guidelines for compensation of research-related injury have evoked strong responses from the clinical research community. All stakeholders, including academic researchers, teachers in medical colleges, the pharmaceutical industry and even members of Institutional Review Boards and Ethics Committees have expressed grave reservations about several clauses in the guidelines. Moreover, these two guidelines differ from each other in important areas, reiterating that more thought and discussion is necessary to refine the guidelines. We present an academic researcher's perspective of the guidelines and our views on how they will affect clinical research in the country. The paper covers the types of research-related injury that are entitled for compensation, controversies on whether injury resulting from standard care should be entitled for compensation, whether causality needs to be established as a prerequisite for eligibility for compensation and whether all forms of research should have mandatory provision for compensation. We also put forward the potential dangers of such recommendations, which could potentially be inducement for patients to participate in clinical research. Finally, we raise the philosophical issue of infringement of an individual's fundamental rights regarding what research he/she wishes to participate in. While these points are based on several formal and informal discussions with stakeholders from various fields of clinical research, the views expressed are the authors' own personal thoughts.
Journal of Postgraduate Medicine 04/2012; 58(2):156-8. · 1.26 Impact Factor
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ABSTRACT: To study the toxicity profile and response rates of weekly paclitaxel given as neoadjuvant chemotherapy (NACT) in patients with locally advanced breast cancer.
The study was planned as a single arm, prospective phase II study. Twenty-six patients with locally advanced breast cancer were enrolled in the study from December 2006 to October 2007. These patients underwent NACT with weekly paclitaxel at 100 mg/m(2) for 8 consecutive weeks followed by surgery. This was followed by anthracycline-based chemotherapy for three to four cycles followed by radiation. The patients received standard adjuvant hormonal therapy. The patients were carefully monitored for side-effects using common toxicity criteria. The clinical and pathological response rates were documented. The response rates were descriptively stated.
The median age of the patients was 52 years (30-67 years) and the median tumour size was 7 cm (2.5-15 cm). Of the 208 planned weekly cycles, 207 could be given. The rates of grade 3-4 neutropenia, thrombocytopenia and neuropathy were 4, 12 and 4%, respectively. A complete clinical response was observed in 10 patients (38.5%) and a completed pathological response, defined as the absence of invasive cancer from the breast and axillary nodes, was seen in 11.5% of patients. Breast-conserving surgery was possible in 23% of patients.
The regimen of weekly single agent paclitaxel is feasible in patients with locally advanced breast cancer with acceptable toxicity. It resulted in a pathological response rate that was comparable with other regimens in this group of advanced stage patients. Considering the efficacy and low toxicity of this regimen, it is worth exploring in larger studies.
Clinical Oncology 10/2011; 24(9):604-9. · 2.07 Impact Factor
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ABSTRACT: Breast conservation surgery after large volume excisions for women with relatively larger or multicentric operable breast cancer (OBC) and in some locally advanced breast cancers (LABC) post neo-adjuvant chemotherapy (NACT), is known to be a feasible option using a latissimus dorsi flap. However, the oncological safety of such a procedure is not well reported in literature. Two hundred and twenty one women with breast cancer (148-OBC, 73-LABC) underwent BCT plus LD during March 1998 to August 2009. One hundred and forty six women (72-LABC, 66-OBC) received prior NACT for downstaging, followed by completion of adjuvant therapy in all, including postoperative radiotherapy and hormone therapy where indicated. Women aged 20-62 years, with tumors 1.5-15 cm (median 5.0 cm), underwent volume replacement surgery with LD flap. All positive cut margins (total-4.9%, gross positive-1.3%) were re-excised to ensure negative margins. The mean surgical time for excision of primary with axillary clearance followed by volume replacement by LD was 5 h and mean hospital stay 6 days. Donor site morbidity was seen in 11 patients and 3 had minor recipient site infection. At a median follow up of 36 months, ten of 221 patients (4.5%) had failed locally (7-OBC, 3-LABC). The determinants of local recurrence were presence of lymphatic vascular invasion (p = 0.016) and axillary metastasis (p = 0.003). BCT plus LD flap is an oncologically safe, technically quick procedure with minimal morbidity, and should be offered to all eligible women as an extended breast conservation procedure.
Indian journal of surgical oncology. 09/2010; 1(3):256-62.
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ABSTRACT: Absence of breast cancer screening in India, lack of awareness in rural population, social inhibitions and poor socioeconomic status leads to a situation where a large proportion of women in India are still presenting with locally advanced breast cancer (LABC) at the time of initial diagnosis, although, there are relatively more of early stage cases detected in the metros and urban areas than maybe a decade ago. With advances in care and introduction of newer chemotherapeutic agents, it has now become feasible to offer neoadjuvant therapy with effective tumor downsizing, thus making it possible to even consider breast conservation surgery in select patients with locally advanced and unresectable disease at presentation. With reports suggesting apparent safety of the procedure, breast conservation treatment after chemotherapy is now being offered as routine care in most major centers for selective women with LABC. Multimodality therapy is the standard of care with neoadjuvant systemic therapy for all women with LABC.
Indian journal of surgical oncology. 01/2010; 1(1):3-7.
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Indian Journal of Surgery 12/2009; 71(6):290-1. · 0.08 Impact Factor
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ABSTRACT: Axillary dissection is the gold standard for treatment of the axilla. It provides important prognostic information, accurately stages the axilla, and has the lowest recurrence rate among all modalities. In today's age of conservation surgery, the axilla is often addressed through a cosmetically acceptable small incision with limited access, thereby making clearance of the level III nodes difficult.
We describe a method of apical lymph node dissection through the interpectoral plane, which effectively clears the apex despite the constraints of limited exposure.
This method has been used in nearly 5,000 axillary dissections performed at our institute, with excellent results. It preserves the innervation of the pectoral muscles and affords access to the interpectoral nodes.
Our method has a short learning curve, provides good exposure of a difficult area and consistently provides a good yield of nodes.
Journal of Surgical Oncology 10/2006; 94(3):252-4. · 2.10 Impact Factor
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ABSTRACT: In absence of randomized evidence to support safety of conservative surgery (BCT) in locally advanced breast cancer (LABC), we analyzed a cohort of 664 women with LABC treated during January 1998 to December 2002 at Tata Memorial Hospital, Mumbai, India.
All were treated with a multimodality regimen comprising of neoadjuvant chemotherapy (NACT) followed by surgery (modified radical mastectomy or BCT) and adjuvant radiotherapy and hormone therapy. The outcome was evaluated to assess safety of BCT.
71% (469/664) women responded to NACT (22% clinical CR and 49% PR) and 28.3% (188/664) underwent BCT. Positive lumpectomy margins were reported in 8.5%, with gross presence of tumor at the margins in 2.3% requiring a revision surgery. At a median follow-up of 30months, local relapse rate was 8% after BCT and 10.7% after mastectomy. The 3-year local DFS was better post-conservation than after mastectomy (87% vs 78%, P=0.02). The disease-free survival (DFS) was also superior after BCT, 72% vs 52% (P<0.001) at 3years and 62% vs 37% (P<0.001) at 5years respectively. On multivariate analysis, presence of lymphatic vascular emboli (LVE) was the major significant predictor of local recurrence (P<0.001, HR 2.52, 95% CI 1.52-4.18). DFS was better after BCT [(P<0.001, HR 2.0 (95% CI 1.38-2.91)]; shorter DFS was noted in LVE positive (HR 1.54, P=0.007) and larger residual disease after NACT (HR 1.13, P=0.001).
BCT is technically feasible and safe post neo-adjuvant chemotherapy in women with LABC with no detriment in outcome.
International journal of surgery (London, England) 01/2006; 4(2):106-14.
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ABSTRACT: The right subclavian artery normally arises from the brachiocephalic artery. Anomalies in development may lead to peculiar problems during surgery. We report a patient with esophageal carcinoma who had an aberrant right subclavian artery, posing specific difficulties during a transhiatal esophagectomy, requiring conversion of the procedure into a transthoracic approach. The embryologic basis of this anomaly and the clinical significance are discussed.
Diseases of the Esophagus 02/2003; 16(2):173-6. · 1.81 Impact Factor
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ABSTRACT: The mechanism responsible for tissue specific localization of gammadelta T cell subsets is not well understood. In order to explain the sequestration of specific gammadelta T cell subsets in the peripheral blood and tumor tissue of patients with esophageal cancer, we examined the function and expression of adhesion molecules on these cells. A hierarchy in the expression of adhesion molecules was observed. In vitro activated gammadelta T cells showed dominant expression of LFA-1 (CD11a), VLA-alpha4 (CD49d), intermediate expression of VLA-alpha5 (CD49e) and L-selectin (CD62L), but low expression of CD44v6 and alphaEbeta7 (CD103). It was observed that the gammadelta T cells use LFA-1, L-selectin and CD44v6 to bind to squamous cell carcinoma (SCC) cells, whereas they adhere to fibroblast cells using LFA-1, VLA-alpha4 and VLA-alpha5. Vdelta1 T cell subsets from the peripheral blood gammadelta T cells utilize a larger array of adhesion molecules, namely LFA-1, VLA-alpha4, VLA-alpha5, L-selectin and alphaEbeta7, to bind to SCC cells compared to the restricted usage of LFA-1, L-selectin and CD44v6 by the Vdelta2 T cells. Flow cytometric analysis of tumor infiltrating lymphocytes from the esophageal tumors confirmed the selective accumulation of Vdelta1+ gammadelta T cells in the tumor compartment. It thus appears that adhesion molecules expressed on these lymphocytes play an important role in the recruitment and retention of Vdelta1 T cells in the tumor milieu.
Cancer Immunology and Immunotherapy 07/2001; 50(4):218-25. · 3.70 Impact Factor
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The Lancet 07/2001; 357(9273):2054. · 38.28 Impact Factor
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ABSTRACT: There are conflicting reports on the differential effect of surgery performed during the two phases of the menstrual cycle, namely, follicular and luteal, and prognosis of operable breast cancer. A statistical meta-analysis of the published evidence suggests a modest survival benefit of 15+/-4% when the operation is performed during the luteal phase. Further research in this area might provide a novel avenue to understand the natural history of breast cancer. A spin off from these studies might be the understanding of the importance of events that occur at the time of surgery in determining long term prognosis.
Journal of Biosciences 04/2000; 25(1):113-20. · 1.65 Impact Factor
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K N Naresh,
J Johnson,
V Srinivas,
C S Soman,
T Saikia,
S H Advani, R A Badwe,
K A Dinshaw,
M Muckaden,
I Magrath,
K Bhatia
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ABSTRACT: Most Epstein-Barr virus (EBV) associated lymphoproliferative disorders have high proliferation indices. However, classical Hodgkin's disease (cHD) is heterogeneous, with respect to proliferation index of the Reed-Sternberg cell (RS cell), and EBV association. Hence, we investigated whether cHD with and without EBV-association differ with respect to the proliferation index of the RS cells. Further we investigated whether this would have a bearing on patients survival.
We investigated 110 cases of cHD for: a) EBV association by immunohistochemical demonstration of EBV-latent membrane protein-1 and EBV encoded nuclear RNA 1 by mRNA in situ hybridisation; b) Proliferating cell nuclear antigen (PCNA) expression in the RS cells.
EBV association was noted in 86 of 110 cases (78%). Higher PCNA expression (P = 0.004) and younger age (P = 0.001) correlated independently with EBV association. The 10 year relapse free survival (RFS) of EBV+ and EBV- patients were 60% and 44%, respectively (P = 0.03). The 10 year overall survival (OS) of EBV+ and EBV- patients were 85% and 64%, respectively (P = 0.03). EBV association maintained its significant impact on RFS and OS within Cox proportional hazard model.
Our study suggests that EBV is likely to confer a higher PCNA expression and also contribute towards maintaining the RS cells of cHD in cell cycle. Hence, RS cells in EBV associated cHD would be more responsive to chemotherapy and radiotherapy associated DNA damage. Thus, EBV-association provides survival advantage to cHD patients treated with standard chemotherapy and radiotherapy protocols.
Annals of Oncology 02/2000; 11(1):91-6. · 6.43 Impact Factor
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ABSTRACT: There is sufficient evidence to support both the hormonal influence on the outcome of breast cancer surgery and the SDA hypothesis. The SDA model produces a paradigm shift in the understanding of the natural history of breast cancer. It offers opportunities to try modifying a tumor's biological potential for metastasis (e.g., by tamoxifen, progesterone, antiprotease, or angiostatin) in the neoadjuvant setting. It continues to support the beneficial effects of detection and surgery early in the natural history of disease. It would be worthwhile to plan a trial comparing standard practice (unplanned surgery as the patient enrolls) with surgery during the luteal phase of the menstrual cycle in premenopausal women. Another possibility, based on studies of circulating progesterone, would be to compare primary progesterone treatment (for 4 to 10 days before surgery) with standard practice. Such a trial of primary progesterone is already under way, conducted by the Indian Breast Group. More than 200 patients have enrolled so far. The details of the trial are available from Clinical Research Secretariat, Tata Memorial Centre, Parel, Mumbai, India (e mail: tmho3@bom2.vsnl.in).
Surgical Clinics of North America 11/1999; 79(5):1047-59. · 2.14 Impact Factor
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ABSTRACT: Preoperative diagnosis of histology and receptor status is important in management of breast cancer. Percutaneous automated core biopsy with biopsy gun (Gun biopsy) was done in fifty patients with palpable breast lump in whom fine needle aspiration cytology (FNAC) was either negative or not done In all patients adequate tissue for histology and receptor status studies was obtained forty-two patients had infiltrating duct carcinoma and eight patients had benign lesions on gun biopsy. There were no complications in this procedure. Twenty of the forty-two patients underwent mastectomy either per primum or after chemotherapy, had the diagnosis substantiated on histopathological examination Thirty-four samples were examined for receptor status and the specimen was found to be adequate and of good quality. We conclude that gun biopsy is a simple and safe procedure which is more sensitive and specific than FNAC.
Indian Journal of Cancer 04/1999; 36(1):43-5.
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ABSTRACT: Surgery is considered the standard treatment for operable esophageal carcinoma, although there is no compelling evidence that surgery can achieve better results than radiotherapy. There has previously been no direct randomized comparison of these two modalities with survival or disease specific outcome end points.
Ninety-nine patients with operable squamous cell carcinoma of the esophagus were randomly allocated to surgery or radiotherapy after stratification for tumor length (< or = or >5 cm). Those randomized to surgery underwent transthoracic esophagectomy with limited lymphadenectomy, whereas those in the radiotherapy arm received 50 gray in 28 fractions followed by a 15-gray boost to the primary tumor. Disease specific outcome was assessed for 4 subgroups: 1) disease specific symptoms, 2) physical symptoms, 3) ability to work, and 4) social/family interaction and global perception of disease specific outcome. The questionnaire was given prior to treatment and posttreatment at 3-month intervals for 1 year. Death was a secondary end point.
There was an overall improvement in the quality of swallowing in both treatment arms after treatment and with the passage of time. The swallowing status was better in the surgery arm than in the radiotherapy arm at 6 months after treatment (P = 0.03, Fisher's exact test). Logistic regression analysis showed randomization arm (P = 0.035), time since treatment (P = 0.003), and pretreatment swallowing status to be significant determinants of posttreatment swallowing status. Surgery was twice as likely to result in improvement in swallowing than radiotherapy after correction for time and pretreatment swallowing status. Overall survival was better in the surgery arm than in the radiotherapy arm (P = 0.002, log rank test) (OR = 2.74 with 95% confidence intervals 1.51-4.98; P < 0.009, Cox proportional hazards model).
Both surgery and radiotherapy can improve the quality of swallowing significantly for patients with operable esophageal carcinoma. Surgery is marginally superior to radiotherapy in improving the quality of swallowing. In this trial, survival in the surgery arm was significantly better than in the radiotherapy arm, although the small number of patients is a limitation.
Cancer 03/1999; 85(4):763-8. · 4.77 Impact Factor
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New England Journal of Medicine 02/1997; 336(5):374-5; author reply 375-6. · 53.30 Impact Factor
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ABSTRACT: Conclusion based on historical controls are known to be fallible in assessing efficacy of treatment due to selection bias. Historical controls have been repeatedly used in investigating efficacy of newer treatment avenues in esophageal cancer. The aim of the study was to assess the efficacy of adjuvant chemotherapy in esophageal cancer after correction for an historical control bias.
The database of 433 patients treated surgically for cancer of the esophagus at our institute between 1980 and 1989 was analyzed. The analysis was carried out using the Cox model for known prognostic factors without any correction for historical bias. Database was reanalysed after introducing registration year as a variable in the model to correct for historical control bias, which was further examined by carrying out a case-control study comparing chemotherapy (n = 83) vs contemporary control (n = 164) matched for lymph-node status, age and sex randomly selected from the same database.
The analysis without correction for historical control bias showed lymph-node metastasis (P = 0.000), female sex (P = 0.002), depth of invasion (P = 0.001) and adjuvant chemotherapy (P = 0.03) as significant predictors of survival. On introduction of registration year as a variable, lymph-node metastasis, sex and depth of invasion continued to be significant factors but chemotherapy was replaced by registration year (P = 0.02). The database with contemporary control showed lymph-node metastasis (P = 0.000), depth of invasion (P = 0.008) and female sex (P = 0.001) as significant factors. Chemotherapy had no effect on survival.
Results from historical controls are unreliable in detecting modest treatment benefits. Adjuvant chemotherapy in esophageal cancer should be tested within the tenets of randomized controlled trials with adequate-sample size to ascertain its efficacy.
Diseases of the Esophagus 02/1997; 10(1):51-4. · 1.81 Impact Factor
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ABSTRACT: To examine the relationship between body weight and vascular invasion (VI) around tumours in post-menopausal women with operable breast cancer, a retrospective study was conducted of 393 patients treated in a breast unit between 1987 and 1991. Weight was measured at the time of diagnosis. Vascular invasion was recorded as being present or absent. Vascular invasion was seen in slightly more of the 50 perimenopausal patients than in the 343 post-menopausal women (44% vs 36%). In the tumour specimens from post-menopausal patients weighing <50 kg, VI was observed in 11% compared with 45% of those weighing more than 80 kg (P= 0.02). Furthermore, the 5-year survival of those with VI was 74% compared with 91% for those without (P < 0.0001). Menopausal status and body weight may influence survival in patients with breast cancer, possibly as a result of the presence of unopposed circulating oestrogens at the time of surgery. Oestrogens may alter cohesiveness of breast cancer cells and modulate secretion of proteases, thereby influencing invasive potential. Excision of tumours in such an environment may have a deleterious impact on survival.
British Journal of Cancer 02/1997; 75(6):910-3. · 5.04 Impact Factor
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ABSTRACT: Postoperative nausea and vomiting are important causes of morbidity after general anesthesia. Nitrous oxide has been implicated as an emetogenic agent in many studies. However, several other trials have failed to sustain this claim. The authors tried to resolve this issue through a meta-analysis of randomized controlled trials comparing the incidence of postoperative nausea and vomiting after anesthesia with or without nitrous oxide.
Of 37 published studies retrieved by a search of articles indexed on the MEDLINE database from 1966 to 1994, 24 studies (26 trials) with distinct nitrous-oxide and non-nitrous oxide groups were eligible for the meta-analysis. The pooled odds ratio and relative risk were calculated. Post boc subgroup analysis was also performed to qualify the result.
The pooled odds ratio was 0.63 (0.53 to 0.75). Omission of nitrous oxide reduced the risk for postoperative nausea and vomiting by 28% (18% to 37%). In the subgroup analysis, the maximal effect of omission of nitrous oxide was seen in female patients. In patients undergoing abdominal surgery and general surgical procedures, the effect of omission of nitrous oxide, although in the same direction, was not significant.
Omission of nitrous oxide reduced the odds of postoperative nausea and vomiting by 37%, a reduction in risk of 28%.
Anesthesiology 12/1996; 85(5):1055-62. · 5.36 Impact Factor
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ABSTRACT: Cervical anastomosis has been advocated to avoid the pulmonary complications and life-threatening anastomotic disruptions following intrathoracic oesophagogastric anastomosis. This is a retrospective review of 111 oesophageal resections followed by an intrathoracic anastomosis. These resections were performed between September 1993 and August 1994 within a residency training program. The left thoracoabdominal approach was used for distal tumours and the Ivor Lewis technique for more proximal tumours. Squamous cell carcinoma accounted for 72% patients (n = 80), adenocarcinoma for 25% (n = 28), and others for 2.7% patients (n = 3). Of the patients, 69% had pathologic Stage III tumours. Operative mortality rate was 1.8% (two patients). Perioperative complications occurred in 39 patients, including anastomotic leak in 10 patients and myocardial infarction in 2 patients. In the absence of a leak, there were no major pulmonary complications requiring intensive care or ventilatory support. Of those patients with anastomotic disruption, 80% were salvaged by early clinical diagnosis and appropriate treatment. We conclude that transthoracic oesophagectomy with an intrathoracic anastomosis is a safe procedure that can be performed with low mortality and acceptable morbidity.
Journal of Surgical Oncology 10/1996; 63(1):52-6. · 2.10 Impact Factor
