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Abstract The overexpression of Epidermal Growth Factor Receptor (EGFR) and dysregulation of its downstream effector pathways are important molecular hallmarks of oral cancers. Present study investigates the chemopreventive potential of polymeric black tea polyphenols (PBPs)/thearubigins (TRs) in the hamster model of oral carcinogenesis as well as determine the effect of PBPs on EGFR and the molecular players in the EGFR pathway. In dose-dependent manner, pre and concurrent treatment with PBPs (1.5%, 5%, 10%) decreased the number and volume of macroscopic tumors as well as the number and area of microscopic lesions. Interestingly, at 10% dose of PBPs, no macroscopic or microscopic tumors were observed. We observed PBPs mediated dose-dependent decrease in oxidative DNA damage (8OHdG); inflammation (COX-2); proliferation (PCNA, Cyclin D1); expression of EGFR, and its downstream signaling kinases (pAkt, Akt, and mTOR); hypoxia (HIF1α) and angiogenesis (VEGF). There was also a PBPs mediated dose-dependent increase in apoptosis (Bax). Thus, our data clearly indicate that the observed chemopreventive potential of PBPs was due to modulation in the EGFR pathway associated with cell proliferation, hypoxia, and angiogenesis. Taken together, our results demonstrate preclinical chemopreventive efficacy of PBPs and give an insight into its mechanistic role in the chemoprevention of experimental oral cancer.

Background: There are sparse longitudinal data on SARS-CoV-2 infection after previous infection and after partial or full vaccination. Methods: This study of a cohort of healthcare workers used Kaplan-Meier analysis with appropriate definition of events and censoring and used Cox models to assess outcomes, with data cut-off on June 18, 2021. Results: A total of 1806 individuals with median age of 32 (18-64) years, 1483 (82.1%) with at least one vaccine dose, 1085 (60.1%) with 2 vaccine doses, 408 (22.6%) with at least one episode of SARS-CoV-2 infection, and 6 (1.47%) with 2 episodes of infection were included in the analysis. At median follow-up of 38.4 weeks after first SARS-CoV-2 infection (n=408), the 52-week probability of reinfection was 2.2% (95% CI, 1.0-4.91%); and at median follow-up of 13.3 weeks after second dose, the 16-week probability of breakthrough infection was 5.6% (95% CI, 4.33-7.23%), which was significantly higher among those without previous SARS-CoV-2 infection versus with previous infection (6.4% vs 1.8%, p=0.016, adjusted Cox HR=3.49, 95% CI, 1.09-11.20, p=0.036) and females versus males (7.9% vs 3.8%, p=0.007, adjusted Cox HR=2.06, 95% CI 1.19-3.56, p=0.01). Conclusions: There was low probability of reinfection after previous SARS-CoV-2 infection and higher vaccine breakthrough infections among females and those without previous infection.

Context: A failure to obtain continued Institutional Ethics Committee (IEC) approval for the study before the expiry date assigned by the IEC is considered as “lapse of the IEC approval” to continue the study at the site by the Investigator. Considering this, we had conducted an audit of principal investigators (PI's) compliance for Continuing Review Application (CRA) submission timelines and decision taken on the lapses in the validity of IEC approval continuation. Aim: The aim of this study is to assess the pre- and post-policy trends of non-compliance management of delayed CRA submission and compare the PI's compliance for submission of CRA between Investigator Initiated trial (IIT) and Pharma studies. Setting and Design: The present study was a retrospective audit of CRAs of ongoing projects submitted by PIs to IEC, ACTREC. Materials and Methods: The data from total 199 CRAs submitted for review to the IEC between the year January 2016 and December-2017 were collected and maintained in Microsoft Excel sheet, and later, the data were exported into the SPSS software version 21 for the analysis. Statistical Analysis: All categorical data were presented in numbers and percentage. The first primary objective was assessed by calculating the duration between the dates of approval for any study to the date of next CRA submission. The CRAs submitted after the project expiry date were considered as a lapse in following the IEC SOP. Results: This retrospective audit revealed that CRA reminder sent by the IEC to the PI played an important role in compliance w. r. t timely in following the IEC SOPof the CRA by the PI. As a result, overall, 90% of CRAs showed compliance in submitting CRAs to IEC in both IIT and Pharma study. The number of lapses were reduced to 7 in the postpolicy period as compared to 15 lapses in the prepolicy period. Conclusion: This retrospective audit reveals that CRA reminder sent by the IEC to the PI played an important role in improving the compliance of PIs in submitting CRA to IEC. Each IEC should develop the policy to minimize the delays in CRA submission by the PI and prevent lapses in following the IEC SOP.

Abstract Background There is paucity of data regarding clinical characteristics, laboratory parameters and outcomes of coronavirus disease (COVID‐19) in cancer versus non‐cancer patients, particularly from India. Materials and Methods This was an observational, single‐centre, retrospective analysis of patients with laboratory‐confirmed COVID‐19 hospitalised in our institution between 22 May 2020 and 1 December 2020. We compared baseline clinical characteristics, laboratory parameters and outcomes of COVID‐19 (overall mortality, time to discharge) between cancer and non‐cancer patients. Results A total of 200 COVID‐19 infection episodes were analysed of which 109 (54.5%) were patients with cancer and 91 (45.5%) were patients without cancer. The median age was 43 (interquartile range [IQR]:32–57), 51 (IQR: 33–62) and 38 (IQR: 31.5–49.3) years; of whole cohort, cancer and non‐cancer patients, respectively. Comparison of outcomes showed that oxygen requirement (31.2% [95% CI: 22.6–40.7] vs. 17.6% [95% CI: 10.4–26.9]; p = 0.03), median time to discharge (11 days [IQR: 6.75–16] vs. 6 days [IQR: 3–9.75]; p 1 mg% (12.8% vs. 0%; p = 0.027; OR: 24.69), serum procalcitonin >0.05 ng/ml (22.65% vs. 0%; p = 0.004; OR: 4.49) and interleukin‐6 >6 pg/ml (10.8% vs. 1.3%; p = 0.036; OR: 3.08). In multivariable logistic regression, factors significantly associated with mortality were oxygen requirement (p = 0.005; OR: 13.11) and high baseline procalcitonin level (p = 0.014; OR: 37.6). Conclusion Cancer patients with COVID‐19 have higher mortality and require longer hospital stay. High procalcitonin levels and oxygen requirement during admission are other factors that affect outcomes adversely.

PURPOSEThere are sparse data in patients with human epidermal growth factor receptor 2 (HER2)–positive breast cancer with brain metastases from real-world settings, especially where access to newer targeted therapies is limited.METHODSThis was a single institution, retrospective cohort study of patients with HER2-positive breast cancer diagnosed between January 2013 and December 2017 to have brain metastases and treated with any HER2-targeted therapy. The main objectives were to estimate progression-free survival (PFS) and overall survival (OS) from the time of brain metastases.RESULTSA total of 102 patients with a median age of 52 (interquartile range, 45-57) years were included, of whom 63 (61.8%) had received one line and 14 (13.7%) had received two lines of HER2-targeted therapies before brain metastasis, 98 (96.1%) were symptomatic at presentation, 22 (25.3%) had solitary brain lesion, 22 (25.3%) had 2-5 lesions, and 43 (49.4%) had ≥ 5 lesions. Local treatment included surgical resection in nine (8.9%) and radiotherapy in all (100%) patients. The first HER2-targeted therapy after brain metastasis was lapatinib in 71 (68.6%), trastuzumab in 19 (18.6%), lapatinib and trastuzumab in three (2.9%), trastuzumab emtansine in four (3.9%), and intrathecal trastuzumab in five (4.9%) patients. At a median follow-up of 13.9 months, the median PFS and OS were 8 (95% CI, 6.2 to 9.8) months and 14 (95% CI, 10.8 to 17.2) months, respectively, with a 2-year OS of 25% (95% CI, 16.7 to 34.4). The median PFS in patients who received lapatinib-capecitabine regimen (n = 62) was 9.0 (95% CI, 7.3 to 10.7) months.CONCLUSIONThere was a substantial clinical benefit of local and systemic therapy in patients with brain metastases and HER2-positive disease in a real-world setting with limited access to newer HER2-targeted drugs.

Summary: Background: Adverse event reporting in oncology trials lacks temporal description. We propose a toxicity summarizing method that incorporates time. Methods: Patients recruited in a phase III trial (NCT01279135) that compared three-dimensional conformal radiotherapy (3DCRT) and intensity modulated radiotherapy (IMRT) for late toxicity in cervical cancer were included. Adverse events were reported using Common Terminology Criteria for Adverse Events (CTCAE) v3.0 and quality of life (QOL) with EORTC QLQ-C30 and CX24. A total of six symptoms with a related QOL question (diarrhoea, abdominal pain, anorexia, urinary incontinence, frequency and fatigue) were included. Month and severity score [MOSES= ∑ (CTCAE grade x proportionate time)] was calculated. Cumulative-MOSES (C-MOSES) was calculated by summating these 6 individual MOSES. QoL was categorized as ''substantially symptomatic'' or “not”. Receiver operator curve analysis was performed to determine the MOSES cut off that predicts for substantial QOL symptoms. CTCAE and MOSES were tested for accurately categorizing QOL impact. Findings: In the construction dataset, 201/300 patients had symptoms. MOSES > 0.20 had higher accuracy than CTCAE for predicting impact on QOL related to diarrhoea (85% vs. 69%), anorexia (61% vs 51%), abdominal pain (71% vs. 57%), urinary incontinence (72% vs. 61%) and frequency (62% vs. 59%). C-MOSES > 0·70 correlated with reduction in role functioning and global QOL. While no difference was seen in CTCAE grade ≥1 Gastrointestinal (GI) toxicity between 3DCRT or IMRT arm, 3DCRT had higher C-MOSES than IMRT (HR=0.64;95% CI 0.41–0.99, p = 0.04). Interpretation: MOSES has higher accuracy than CTCAE in categorizing symptom specific and functional QOL. These results require further external validation. Funding: None.

Mucositis is nearly inevitable following high-dose chemotherapy. Several pro-inflammatory cytokines play a role in pathogenesis of mucositis. Curcumin inhibits inflammatory cytokines through inhibition of nuclear factor kappa-β. We studied the effects of curcumin on the acute toxicities and inflammatory cytokines following melphalan (200 mg/m 2 ) for autologous hematopoietic stem cell transplantation (HSCT) for myeloma. The control group (first 10 enrolled patients who received standard supportive care) was compared with curcumin group (next 30 patients who received chewable curcumin lozenges, 4 g twice daily from 2 days before melphalan till day +28 along with standard supportive care). The toxicities were recorded as per World Health Organization (WHO) criteria and CTCAE v3.0 as applicable. Cytokine profiling was done in both groups at similar time points. In the curcumin group, there was significant decrease in grade 3/4 vomiting (3% vs 40%, P = 0.01) and total parenteral nutrition use (47% vs 90%, P = 0.026). Grade 3/4 mucositis (43% vs 60%) and diarrhea (33% vs 70%) were also less, but not statistically significant. This coincided with 3.2-fold lower area under the concentration time curve (AUC) of IL-8 from day –3 to day 14 in curcumin group compared with control group ( P = 0.039). We conclude that curcumin mitigates toxicities of high-dose melphalan, possibly through IL-8 modulation. Randomized studies are warranted to explore benefits of curcumin in HSCT.

BackgroundTransplant related toxicity is a major therapeutic challenge. We have previously reported that the toxicity of chemotherapy is largely not directly because of the drugs themselves; rather it is mainly due to DNA damage, apoptosis and hyper-inflammation triggered by cell-free chromatin particles that are released because of drug-induced host cell death. Cell-free chromatin particles can be inactivated by free-radicals which are generated when the nutraceuticals resveratrol and copper are administered orally. We investigated if a combination of resveratrol and copper would reduce transplant related toxicities in an exploratory, prospective dose-escalation study.Patients and methodsTwenty-five patients with multiple myeloma were enrolled between March 2017 to August 2019. Patients were divided into 3 groups: control (Group 1, N = 5) received vehicle alone; group 2 (N = 15) received resveratrol-copper at dose level I (resveratrol = 5.6 mg and copper = 560 ng); group 3 (N = 5) received resveratrol-copper at dose level II (resveratrol = 50 mg and copper = 5 μg). The dose was given twice daily with the first dose administered 48 hours before administering melphalan and continued until day +21 post-transplant. Common Terminology Criteria for Adverse Events version 4.02 was used to assess toxicities which included oral mucositis, nausea, vomiting and diarrhea. Measurement of inflammatory cytokines was done by ELISA.ResultsAll patients (100%) in the control group developed grade 3/4 oral mucositis compared to 8/20 (40%) in both resveratrol-copper group 2 plus group 3 combined (P = 0.039). Reduction in inflammatory cytokines: salivary TNF - α (p = 0.012) and IL-1β (p = 0.009) in dose level I but not in dose level II was observed.ConclusionsA combination of resveratrol-copper reduced transplant related toxicities in patients with multiple myeloma receiving high dose melphalan. We conclude that relatively inexpensive nutraceuticals may be useful as adjuncts to chemotherapy to reduce its toxicity.RegistrationThe trial was registered under Clinical Trial Registry of India (no.CTRI/2018/02/011905).

Abstract Background SWATH-MS has emerged as the strategy of choice for biomarker discovery due to the proteome coverage achieved in acquisition and provision to re-interrogate the data. However, in quantitative analysis using SWATH, each sample from the comparison group is run individually in mass spectrometer and the resulting inter-run variation may influence relative quantification and identification of biomarkers. Normalization of data to diminish this variation thereby becomes an essential step in SWATH data processing. In most reported studies, data normalization methods used are those provided in instrument-based data analysis software or those used for microarray data. This study, for the first time provides an experimental evidence for selection of normalization method optimal for biomarker identification. Methods The efficiency of 12 normalization methods to normalize SWATH-MS data was evaluated based on statistical criteria in ‘Normalyzer’—a tool which provides comparative evaluation of normalization by different methods. Further, the suitability of normalized data for biomarker discovery was assessed by evaluating the clustering efficiency of differentiators, identified from the normalized data based on p-value, fold change and both, by hierarchical clustering in Genesis software v.1.8.1. Results Conventional statistical criteria identified VSN-G as the optimal method for normalization of SWATH data. However, differentiators identified from VSN-G normalized data failed to segregate test and control groups. We thus assessed data normalized by eleven other methods for their ability to yield differentiators which segregate the study groups. Datasets in our study demonstrated that differentiators identified based on p-value from data normalized with Loess-R stratified the study groups optimally. Conclusion This is the first report of experimentally tested strategy for SWATH-MS data processing with an emphasis on identification of clinically relevant biomarkers. Normalization of SWATH-MS data by Loess-R method and identification of differentiators based on p-value were found to be optimal for biomarker discovery in this study. The study also demonstrates the need to base the choice of normalization method on the application of the data.

Context: Adherence to good clinical practice (GCP) guidelines by the researcher provides public confidence that the rights, safety and well-being of human participants involved in research are protected. It has been observed that researchers require basic GCP training. Considering this, we had decided to conduct a training session on overview of GCP. Aims: To strengthen the knowledge and awareness regarding GCP. Settings and Design: The design of the study was quasi-experimental one group, pre-test and post-test design and the study was conducted at ACTREC among healthcare professionals at Tata Memorial Centre. Methods and Material: A semi-structured questionnaire was used to collect the data in pre and post-test. A total of 138 participants were participated in the study. The training session was pre-planned which included a lecture followed by the question-answer session. Statistical Analysis Used: Wilcoxon Signed Rank test was used to assess the effect of the planned teaching programme. Macnemar test was used for item wise comparison of pre and post-test scores. Mann Whitney test was used to determine the significant difference between knowledge scores and selected demographic variables. Results: This study has resulted in overall improvement of knowledge with a median difference of 5 with P-value

Background: Imaging features may be reflective of inherent disease biology and serve as potentially useful biomarkers in primary brain tumors. This study aimed to correlate conventional magnetic resonance imaging (MRI) features with O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status and survival in glioblastoma. Methods: Conventional semantic imaging features were systematically extracted from preoperative MRI of 34 patients with glioblastoma by two reviewers independently and correlated with MGMT methylation status and survival using appropriate statistical tests. Results: MGMT promoter was methylated in 10 (30%) patients, unmethylated in 15 (44%) patients, and invalid or uninterpretable in 9 (26%) patients. Four imaging features, such as border, edema, contact with subventricular zone (SVZ), and necrosis, showed borderline correlation with methylation status. On multivariate logistic regression analysis, the odds of having methylated tumor were significantly reduced for tumors in contact with SVZ and borderline reduced for tumors with sharp borders. With a median follow-up of 18 months (interquartile range, 13–33 months), the median progression-free survival (PFS) and overall survival (OS) were 12.1 months (95% confidence interval [CI]: 9.9–14.3 months) and 17.1 months (95% CI: 12.6–21.5 months), respectively, for the study cohort. Among the semantic imaging features extracted from conventional MRI, only perilesional edema correlated significantly with PFS as well as OS. The hazards of both progression and death were significantly increased for tumors with moderate-to-severe edema on Cox regression analysis. Conclusion: Contact with SVZ and sharp tumor borders shows weak negative correlation with MGMT promoter methylation status in glioblastoma. Among all MRI features investigated in this work, moderate-to-severe edema is the only imaging feature that independently correlates with significantly inferior survival.

Purpose: The main objective of this study was to evaluate appropriate doses for elective nodal irradiation (ENI) in head and neck squamous cell carcinoma (HNSCC) patients to optimize the therapeutic ratio. Methods and materials: A matched pair analysis of 2 similar cohorts of HNSCC treated with intensity modulated radiation therapy with different dose prescriptions to the elective nodal regions was conducted. One group received 60 Gy, whereas the other received 50 Gy (ENI60 and ENI50 groups, respectively). Isolated regional recurrences (IRR) and locoregional control were evaluated. Doses received by the parotid and thyroid glands were compared among both groups and were clinically correlated with the trend of salivary function recovery and incidence of hypothyroidism. Results: Of the 110 patients studied, 97 were eligible for analysis after matching based on propensity scores. The 3-year locoregional control rate was similar in ENI60 and ENI50 (78.7% and 77%, respectively; P = .93). There were no IRR in ENI regions in either group. The mean ipsilateral parotid dose in ENI60 was significantly higher compared with ENI50 (42 vs 35.7 Gy, P = .03). There was no significant difference in the mean contralateral parotid doses (32.5 vs 31.7 Gy, P = .6). The mean thyroid doses were high in ENI60 compared with ENI50 (54.7 vs 43.3 Gy, P < .001). A significant difference in ipsilateral parotid salivary excretory fraction ratio at 1 year (P = .03) was observed with quicker recovery of salivary function. The salivary excretory fractions were poorer in the ENI60 group with higher mean parotid doses (P = .009). At 2 years, 26 patients (54%) in the ENI60 group and 13 patients (26.5%) in the ENI50 group developed biochemical hypothyroidism (P = .007). Conclusions: Doses of 50 Gy equivalent are sufficient to sterilize the uninvolved nodal regions because the rates of IRR are extremely low. Using ENI50 results in clinically meaningful reduction in salivary and thyroid toxicity in HNSCC.

Background and Aims: Work-related stress is common among medical caregivers and concerns all perioperative care providers. Although anesthesiologists are known to experience stress, there are limited Indian data addressing this issue. This survey was conducted among Indian anesthesiologists to determine their awareness about work stress and views regarding prevention programs. Material and Methods: A survey questionnaire was distributed to delegates visiting the exhibits at the national anesthesiology conference in 2011. The questionnaire had ten questions on the work pattern, five on work-related stress, nine on opinion regarding the need and willingness to participate in stress-related programs. Results: There were 1178 responders. Forty-three percent were faculty in medical institutions, 26% were residents and 25% were in free-lance practice. Ninety-one percent of participants rated their stress as moderate-extreme. There was a significant correlation between the amount of stress and working for more than 8 h (P < 0.001), handling high risk patients (P = 0.002), working on weekends (P = 0.002), and carrying work back home (P < 0.001). Forty-one percent of respondents were very satisfied professionally. Seventy-six percent of doctors agreed that the questionnaire had made them think about work stress. Eighty-four percent of participants felt the need for stress management programs and 69% expressed their willingness to participate in the same. Conclusion: The majority of participants rated their stress as moderate-extreme and was higher in anesthesiologists working long hours, over the weekend and those handling high-risk patients. A majority of participants felt the survey made them think about work-related stress and expressed their willingness to participate in stress management programs.

Aim: To prospectively assess the clinical utility of pretreatment flouro-deoxy-glucose positron emission tomography/computed tomography (18F-FDG-PET/CT) in patients with primary central nervous system (CNS) lymphoma (PCNSL). Materials & methods: Patients with suspected/proven PCNSL underwent baseline whole-body 18F-FDG-PET/CT. Maximum standardized uptake value and tumor/normal tissue ratios were compared between CNS lymphoma and other histological diagnoses. Results: The mean maximum standardized uptake value (27.5 vs 18.2; p = 0.001) and mean tumor/normal tissue ratio (2.34 vs 1.53; p

Introduction: One of the mainstays of chemotherapy in acute myeloid leukemia (AML) is induction with a goal to achieve morphological complete remission (CR). However, not all patients by this remission criterion achieve long-term remission and a subset relapse. This relapse is explained by the presence of measurable residual disease (MRD).Methods: We accrued 451 consecutive patients of adult AML (from March 2012 to December 2017) after informed consent. All patients received standard chemotherapy. MRD testing was done at post-induction and, if feasible, post-consolidation using 8- and later 10-color FCM. Analysis of MRD was done using a combination of difference from normal and leukemia-associated immunophenotype approaches. Conventional karyotyping and FISH were done as per standard recommendations, and patients were classified into favorable, intermediate, and poor cytogenetic risk groups. The presence of FLT3-ITD, NPM1, and CEBPA mutations was detected by a fragment length analysis-based assay.Results: As compared to Western data, our cohort of patients was younger with a median age of 35 years. There were 62 induction deaths in this cohort (13.7%), and 77 patients (17.1%) were not in morphological remission. The median follow-up was 26.0 months. Poor-risk cytogenetics and the presence of FLT3-ITD were significantly associated with inferior outcome. The presence of post-induction MRD assessment was significantly associated with adverse outcome with respect to OS (p = 0.01) as well as RFS (p = 0.004). Among established genetic subgroups, detection of MRD in intermediate cytogenetic and NPM1 mutated groups was also highly predictive of inferior outcome. On multivariate analysis, immunophenotypic MRD at the end of induction and FLT3-ITD emerged as independent prognostic factors predictive for outcome.Conclusion: This is the first data from a resource-constrained real-world setting demonstrating the utility of AML MRD as well as long-term outcome of AML. Our data is in agreement with other studies that determination of MRD is extremely important in predicting outcome. AML MRD is a very useful guide for guiding post-remission strategies in AML and should be incorporated into routine treatment algorithms.

INTRODUCTION:Technological advancements in treatment planning and delivery have propelled the use of intensity-modulated radiation therapy (IMRT) in head and neck squamous cell carcinoma (HNSCC). This review compares IMRT with conventional two-dimensional (2D) and/or three-dimensional (3D) radiotherapy (RT) in curative-intent management of HNSCC. METHODS:Only randomized controlled trials (RCTs) offering curative-intent RT in patients with non-metastatic HNSCC were included. Outcome data was extracted independently by two reviewers, pooled using the Cochrane methodology, and expressed as risk ratio (RR) or hazard ratio (HR) as appropriate with 95% confidence intervals (CIs). Xerostomia was the primary outcome of interest whereas loco-regional control, overall survival and quality-of-life (QOL) were secondary endpoints. RESULTS:Seven RCTs involving 1155 patients directly comparing IMRT with 2D/3D-RT in HNSCC were included. The primary objective in five of seven index RCTs was reduction in xerostomia, with only one trial each using loco-regional control and overall survival as primary endpoints for sample size calculation. The use of IMRT was associated with a 36% relative risk reduction in ≥grade 2 acute xerostomia (RR = 0.64, 95%CI = 0.49-0.84; p = 0.001) compared to 2D/3D-RT. More importantly, IMRT significantly reduced the risk of ≥grade 2 late xerostomia (RR = 0.44, 95%CI = 0.34-0.57; p = 0.00001) compared to non-IMRT techniques at all time-points. Within the limitations of inadequate sample size and low statistical power, IMRT also resulted in 24% relative reduction in the risk of loco-regional relapse (HR = 0.76, 0.57-1.01; p = 0.06) and 30% relative reduction in risk of death (HR = 0.70, 95%CI = 0.57-0.88; p = 0.002) compared to 2D/3D-RT. However, this benefit of IMRT for loco-regional control and overall survival was limited to nasopharyngeal cancer patients alone, with no significant difference in efficacy between the two techniques in patients with cancers of the laryngo-pharynx in this analysis, highlighting the inconsistency in results of subgroup analyses stratified by primary site. Inadequate reporting of data precluded statistically pooling of results for QOL outcomes. CONCLUSIONS:There is consistent moderate-quality evidence that IMRT significantly reduces the risk of moderate to severe acute and late xerostomia compared to 2D/3D-RT in curative-intent radiotherapeutic management of HNSCC. However, the quality of evidence regarding the superiority of IMRT over conventional techniques for disease-related endpoints is rather low due to relative lack of power and inconsistency of results precluding robust conclusions.

BackgroundAltered expression of Mcl-1, an anti-apoptotic member of the Bcl-2 family, has been linked to the progression and outcome of a variety of malignancies. We have previously reported the overexpression of Mcl-1 protein in human oral cancers. The present study aimed to evaluate the clinicopathological significance of the expression of three known Mcl-1 isoforms in oral tumors and the effect of targeting Mcl-1L isoform on chemosensitivity of oral cancer cells.MethodsThe expression of Mcl-1 isoforms- Mcl-1L, Mcl-1S & Mcl-1ES was analyzed in 130 paired oral tumors and 9 oral cell lines using quantitative real-time PCR & protein by western blotting. The Mcl-1 mRNA levels were correlated with clinicopathological parameters and outcome of oral cancer patients. The effect of Mcl-1L shRNA or Obatoclax (a small molecule Mcl-1 inhibitor), in combination with Cisplatin on chemosensitivity of oral cancer cells was also assessed.ResultsAnti-apoptotic Mcl-1L was predominantly expressed, over low or undetectable pro-apoptotic Mcl-1S and Mcl-1ES isoforms. The Mcl-1L transcripts were significantly overexpressed in all cancer cell lines and in 64% oral tumors versus adjacent normals (PConclusionOur studies suggest that overexpression of Mcl-1L is associated with poor prognosis and chemoresistance in oral cancers. Mcl-1L is an independent prognostic factor and a potential therapeutic target in oral cancers.

BACKGROUND: In order to elucidate a combination of genetic alterations that drive tobacco carcinogenesis we have explored a unique model system and analytical method for an unbiased qualitative and quantitative assessment of gene-gene and gene-environment interactions. The objective of this case control study was to assess genetic predisposition in a biologically enriched clinical model system of tobacco related cancers (TRC), occurring as Multiple Primary Neoplasms (MPN). METHODS: Genotyping of 21 candidate Single Nucleotide Polymorphisms (SNP) from major metabolic pathways was performed in a cohort of 151 MPN cases and 210 cancer-free controls. Statistical analysis using logistic regression and Multifactor Dimensionality Reduction (MDR) analysis was performed for studying higher order interactions among various SNPs and tobacco habit. RESULTS: Increased risk association was observed for patients with at least one TRC in the upper aero digestive tract (UADT) for variations in SULT1A1 Arg²¹³His, mEH Tyr¹¹³His, hOGG1 Ser³²⁶Cys, XRCC1 Arg²⁸⁰His and BRCA2 Asn³⁷²His. Gene-environment interactions were assessed using MDR analysis. The overall best model by MDR was tobacco habit/p53(Arg/Arg)/XRCC1(Arg³⁹⁹His)/mEH(Tyr¹¹³His) that had highest Cross Validation Consistency (8.3) and test accuracy (0.69). This model also showed significant association using logistic regression analysis. CONCLUSION: This is the first Indian study on a multipathway based approach to study genetic susceptibility to cancer in tobacco associated MPN. This approach could assist in planning additional studies for comprehensive understanding of tobacco carcinogenesis.

Transforming growth factor β1 (TGFB1) T29C and TGF β receptor type 1 (TGFBR1) 6A/9A polymorphisms have been implicated in the modulation of risk for breast cancer in Caucasian women. We analyzed these polymorphisms and combinations of their genotypes, in pre menopausal breast cancer patients (N = 182) and healthy women (N = 236) from western India as well as in breast cancer patients and healthy women from the Parsi community (N = 48 & 171, respectively). Western Indian women were characterized by a higher frequency of TGFB1*C allele of the TGF β T29C polymorphism (0.48 vs 0.44) and a significantly lower frequency of TGFBR1*6A allele of the TGFBR1 6A/9A polymorphism (0.02 vs 0.068, p

BACKGROUND: Keratins are cytoplasmic intermediate filament proteins expressed in tissue specific and differentiation dependent manner. Keratins 8 and 18 (K8 and K18) are predominantly expressed in simple epithelial tissues and perform both mechanical and regulatory functions. Aberrant expression of K8 and K18 is associated with neoplastic progression, invasion and poor prognosis in human oral squamous cell carcinomas (OSCCs). K8 and K18 undergo several post-translational modifications including phosphorylation, which are known to regulate their functions in various cellular processes. Although, K8 and K18 phosphorylation is known to regulate cell cycle, cell growth and apoptosis, its significance in cell migration and/or neoplastic progression is largely unknown. In the present study we have investigated the role of K8 phosphorylation in cell migration and/or neoplastic progression in OSCC. METHODOLOGY AND PRINCIPAL FINDINGS: To understand the role of K8 phosphorylation in neoplastic progression of OSCC, shRNA-resistant K8 phospho-mutants of Ser73 and Ser431 were overexpressed in K8-knockdown human AW13516 cells (derived from SCC of tongue; generated previously). Wound healing assays and tumor growth in NOD-SCID mice were performed to analyze the cell motility and tumorigenicity respectively in overexpressed clones. The overexpressed K8 phospho-mutants clones showed significant increase in cell migration and tumorigenicity as compared with K8 wild type clones. Furthermore, loss of K8 Ser73 and Ser431 phosphorylation was also observed in human OSCC tissues analyzed by immunohistochemistry, where their dephosphorylation significantly correlated with size, lymph node metastasis and stage of the tumor. CONCLUSION AND SIGNIFICANCE: Our results provide first evidence of a potential role of K8 phosphorylation in cell migration and/or tumorigenicity in OSCC. Moreover, correlation studies of K8 dephosphorylation with clinico-pathological parameters of OSCC patients also suggest its possible use in prognostication of human OSCC.