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Joshi N.N.,Cancer Research Institute | Bhat S.,Cancer Research Institute | Hake S.,Cancer Research Institute | Kale M.,Cancer Research Institute | Kannan S.,Epidemiology and Clinical Trials Unit
International Journal of Immunogenetics | Year: 2014

In an earlier study, the genotypes associated with higher level of transforming growth factor-β1 (TGF-β1) were found to reduce the risk for breast cancer in western Indian women. This observation implied that gene polymorphisms affecting the levels of pro- and anti-inflammatory cytokines may influence the risk for breast cancer in this population. Hence, we performed genotyping for three more functional single-nucleotide polymorphisms (SNPs) responsible for variations in the levels of cytokines associated with inflammation. To that effect, polymorphisms in genes coding for IL-4 (IL-4 C-590T; rs2243250), IFN-γ (IFN-G A + 874T; rs2430561) and MCP-1 (MCP-1 A-2578G; rs1024611) were examined in premenopausal, healthy women (N = 239) and patients with breast cancer (N = 182) from western India. In carriers of the IL-4*590T allele, a reduced risk for the disease (dominant model; OR = 0.61, 95% CI 0.37-0.98) was seen similar to that seen in TGF-B1*10C carriers. An opposite trend was observed with respect to the alleles associated with higher expression of MCP-1 or IFN-γ. In individuals positive for three or more alleles associated with higher levels of either pro- or anti-inflammatory cytokines, an additive effect on the modulation of risk for the disease was evident (for TGF-B1 & IL-4, OR = 0.33, 95% CI 0.12-0.87; for IFN-G & MCP-1, OR = 2.29, 95% CI 0.95-5.51). In the context of contrasting observations in other populations, these results indicate a significant contribution of anti-inflammatory genotypes in the modulation of risk for breast cancer in western Indian women. © 2013 John Wiley & Sons Ltd.

Chopra S.,Advanced Center for Treatment Research and Education in Cancer | Dora T.,Advanced Center for Treatment Research and Education in Cancer | Chinnachamy A.N.,Tata Memorial Center | Thomas B.,Advanced Center for Treatment Research and Education in Cancer | And 6 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2014

Purpose The present study investigates relationship between dose-volume parameters and severe bowel toxicity after postoperative radiation treatment (PORT) for cervical cancer. Methods and Materials From June 2010 to December 2012, a total of 71 patients undergoing PORT were included. Small bowel (SB) and large bowel (LB) loops were contoured 2 cm above the target volume. The volume of SB and LB that received 15 Gy, 30 Gy, and 40 Gy was calculated (V15 SB, V15 LB, V30 SB, V30 LB, V40 SB, V 40 LB). On follow-up, bowel toxicity was scored using Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. A reciever operating characteristic (ROC) curve identified volume thresholds that predicted for grade 3 or higher toxicity with highest specificity. All data was dichotomized across these identified cut-off values. Univariate and multivariate analysis was performed using SPSS, version 15. Results The median patient age was 47 years (range, 35-65 years). Of the 71 patients, 46 received image-guided intensity modulated radiation therapy, and 25 received conformal radiation (50 Gy in 25 fractions for 5 weeks). Overall, 63 of 71 patients received concurrent chemotherapy. On a median follow-up of 18 months (range, 8-29 months), grade 2 or higher bowel toxicity was seen in 22 of 71 patients (30.9%) and grade 3 or higher bowel toxicity was seen in 9 patients (12.6%). On univariate analysis, V15 SB <275 cc (P=.01), V30 SB <190 cc (P=.02), V40 SB <150 cc (P=.01), and V15 LB <250 cc (P=.03), and V40 LB <90 cc (P=.04) predicted for absence of grade 3 or higher toxicity. No other patient- or treatment-related factors were statistically significant. On multivariate analysis, only V15 SB (P=.002) and V15 LB (P=.03) were statistically significant. Conclusions V 15 Gy SB and LB are independent predictors of late grade 3 or higher toxicity. Restricting V15 SB and V15 LB to <275 cc and <250 cc can reduce grade 3 or higher toxicity to less than 5%. © 2014 Elsevier Inc.

Chinnachamy A.N.,Tata Memorial Center | Krishnatry R.,Tata Memorial Center | Kannan S.,Epidemiology and Clinical Trials Unit | Mahantshetty U.,Tata Memorial Center | And 2 more authors.
Japanese Journal of Clinical Oncology | Year: 2013

Background: Lack of agreement and inconsistency in capturing late bowel toxicity may be a source of error while reporting trials with toxicity endpoints. Documenting baseline inconsistency while scoring toxicity questionnaires (RTOG/EORTC and CTCAE) may be worthwhile. The present study was conducted as a quality assurance measure prior to initiating a randomized trial (PARCER; NCT01279135) that evaluates the impact of image-guided radiation on bowel toxicity. Methods: From August 2010 to July 2011, patients with cervical cancer who underwent pelvic chemoradiation >6 months ago, with controlled disease and any bowel symptom at follow-up, were included. RTOG and CTCAE questionnaires were filled by two blinded observers. Interscale (RTOG vs CTCAE) and interobserver (observer A and B) agreement were evaluated with Spearman's correlation and kappa statistic. Results: Fifty-five patients were included. Twelve patients with symptoms could not be graded by the RTOG scale. Of those graded as asymptomatic on RTOG, distension, vomiting, pain and nausea were identified as the most common symptoms. Amongst these, grade 1, 2 and 3 toxicity was observed in 6, 5 and 1 patient, respectively. The interscale correlation was moderate (Spearman's correlation ρ = 0.56; P = 0.001). High interobserver agreement (92%) was observed within the RTOG scale [kappa (κ) -0.94; 95% CI 0.77-1]. All disagreements were observed while scoring grade 1-2 toxicity. Among CTCAE, agreement was lower with modules such as distension, anorexia, nausea and constipation. Conclusions: High interobserver agreement was observed for both RTOG and most CTCAE subscales; most disagreements were for grade 1-2. Interscale agreement (RTOG and CTCAE) was moderate. Detailed patient interrogation or use of patient-reported-outcome scores while documenting the aforesaid subscales may be worthwhile. © The Author 2013. Published by Oxford University Press. All rights reserved.

Chopra S.,Advanced Center for Treatment | Krishnatry R.,Tata Memorial Hospital | Dora T.,Advanced Center for Treatment | Kannan S.,Epidemiology and Clinical Trials Unit | And 7 more authors.
British Journal of Radiology | Year: 2015

Objective: This study investigates the correlation between dose-volume histogram derived from three bowel contouring methods and late toxicity in patients undergoing post-operative radiation therapy (PORT) for cervical cancer. Methods: From June 2010 to May 2013, 103 patients undergoing PORT were included. Three different contouring methods were used: (a) individual small bowel (SB) and large bowel (LB) loops, (b) total bowel (TB; including SB and LB) and (c) peritoneal cavity (PC). The volume of SB, LB, TB and PC receiving 15, 30 and 40Gy was calculated. Acute and late bowel toxicities were scored using Common Terminology Criteria for Adverse events v. 3.0. Receiver operating characteristic curve identified thresholds predicting late toxicity with the highest specificity. All data were dichotomized across these thresholds. Univariate and multivariate analyses were performed using SPSS® v. 20 (IBM Corporation, Armonk, NY; formerly SPSS Inc., Chicago, IL). Results: On univariate analysis, V30 PC$900cm3 (p50.01), V40 PC$750cm3 (p50.03) and V40 TB$280cm3 (p50.03) and use of concurrent chemotherapy (p50.03) predicted grade $II acute toxicity. On multivariate analysis, use of concurrent chemotherapy [odds ratio (OR) 3.5, 95% confidence interval (CI) 1.1-11.1, p50.03] and V30 PC$900cm3 (OR 2.3, 95% CI 1-5.5, p50.05) predicted acute grade $II toxicity. On univariate analysis for late toxicity, SB (V30$190cm3, p50.009; V40$150cm3, p50.03), LB (V15$250cm3, p50.04), V40 PC (V40$750cm3, p50.001) and presence of acute grade $III toxicity (p50.006), treatment technique (three-dimensional conformal radiation or intensity modulated radiotherapy, p50.02) predicted more than or equal to grade ll late bowel toxicity. On multivariate analysis, only body mass index $25 kgm22 (OR 7.3, 95% CI 1.6-31.6, p50.008) and presence of acute grade III toxicity predicted toxicity (OR 5.1, 95% CI 1.4-18.1, p50.007). Conclusion: V30 PC$900cm3 and use of concurrent chemotherapy independently predicts acute toxicity. Presence of acute grade $III toxicity independently predicts late toxicity. Minimizing dose to PC subvolumes can therefore reduce both acute and late toxicities. Advances in knowledge: Study establishes PC thresholds that can minimize both acute and late bowel toxicities. © 2015 The Authors. Published by the British Institute of Radiology.

Joshi N.,Cancer Research Institute | Kannan S.,Epidemiology and Clinical Trials Unit | Kotian N.,Cancer Research Institute | Bhat S.,Cancer Research Institute | And 2 more authors.
Human Immunology | Year: 2014

In our earlier studies, single nucleotide polymorphisms (SNPs) associated with anti-inflammatory cytokines were found to influence risk for breast cancer in western Indian women. Analysis of Interleukin 6 (IL-6) -174G>C polymorphism in this cohort (patients. = 182; controls. = 236) suggested a protective role for IL-6 -174C allele associated with the lower expression of the cytokine (OR. = 0.54; 95% CI 0.32-0.89, dominant model). Together these observations suggested that in comparison to Caucasians, inflammation associated-cytokine gene polymorphisms may have higher influence on risk for cancer in this population. To examine this possibility we analyzed data assessing influence of Interleukin 6 (IL-6) -174G>C polymorphism on risk for various cancers. Overall, there was a marginally higher risk for rare allele homozygotes compared to wild type homozygotes (OR. = 1.07; 95% CI 1.00-1.15). Increased risks for genitourinary cancers and for skin cancer were also indicated. The ethnicity based analysis indicated a protective effect of the minor allele in Ancestral North Indians (OR. = 0.73; 95% CI 0.55-0.97). Site by ethnicity analysis once again revealed a significant protection against breast cancer (OR. = 0.51; 95% CI. = 0.37-0.70; dominant model) but an opposite influence on the risk of genitourinary malignancies (OR. = 2.51; 95% CI 1.59-3.96; recessive model) in this population alone. The observations imply that contribution of IL-6 to inflammation or effector immunity may depend on the site of malignancy. Assessment of available data in relation to prognosis in breast cancer patients also revealed trends that are compatible with the observations of the meta-analysis. Thus, IL-6 -174G>C polymorphism clearly represents a potential modulator of risk for malignant disorders with ethnicity and site dependent trends. The results also support the possibility of higher influence of inflammation related cytokine gene polymorphisms on the risk for cancers in Ancestral North Indians. © 2014 American Society for Histocompatibility and Immunogenetics.

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