Household cooking fuel and gallbladder cancer risk: a multi-centre case-control study in India.

PURPOSE: Gallbladder cancers (GBC), unique to certain geographical regions, are lethal digestive tract cancers, disproportionately affecting women, with limited information on risk factors. METHODS: We evaluated the association between household cooking fuel and GBC risk in a hospital-based case-control study conducted in the North-East and East Indian states of Assam and Bihar. We explored the potential mediation by diet, fire-vents, 'daily exposure duration' and parity (among women). We recruited biopsy-confirmed GBC (n = 214) men and women aged 30-69 years between 2019 and 2021, and controls frequency-matched by age, sex and region (n = 166). Information about cooking fuel, lifestyle, personal and family history, female reproductive factors, socio-demographics, and anthropometrics was collected. We tested associations using multivariable logistic regression analyses. RESULTS: All participants (73.4% women) were categorised based on predominant cooking fuel use. Group-1: LPG (Liquefied Petroleum Gas) users in the previous 20 years and above without concurrent biomass use (26.15%); Group-2: LPG users in the previous 20 years and above with concurrent secondary biomass use (15.9%); Group-3: Biomass users for ≥ 20 years (57.95%). Compared to group-1, accounting for confounders, GBC risk was higher in group-2 [OR: 2.02; 95% CI: 1.00-4.07] and group-3 [OR: 2.01; 95% CI: 1.08-3.73] (p-trend:0.020). These associations strengthened among women that attenuated with high daily consumption of fruits-vegetables but not with fire-vents, 'daily exposure duration' or parity. CONCLUSION: Biomass burning was associated with a high-risk for GBC and should be considered as a modifiable risk factor for GBC. Clean cooking fuel can potentially mitigate, and a healthy diet can partially reduce the risk among women.

Health-related quality of life and its determinants among cancer patients: evidence from 12,148 patients of Indian database.

BACKGROUND: Cancer survivors experience a decrement in health-related quality of life (HRQoL) resulting from the disease as well as adverse effects of therapy. We evaluated the HRQoL of cancer patients, stratified by primary cancer site, stage, treatment response and associated adverse events, along with its determinants. METHODS: Data were collected from 12,148 patients, sampled from seven purposively chosen leading cancer hospitals in India, to elicit HRQoL using the EuroQol questionnaire comprising of 5-dimensions and 5-levels (EQ-5D-5L). Multiple linear regression was used to determine the association between HRQoL and various socio-demographic as well as clinical characteristics. RESULTS: Majority outpatients (78.4%) and inpatients (81.2%) had solid cancers. The disease was found to be more prevalent among outpatients (37.5%) and inpatients (40.5%) aged 45-60 years and females (49.3-58.3%). Most patients were found to be in stage III (40-40.6%) or stage IV (29.4-37.3%) at the time of recruitment. The mean EQ-5D-5 L utility score was significantly higher among outpatients [0.630 (95% CI: 0.623, 0.637)] as compared to inpatients [0.553 (95% CI: 0.539, 0.567)]. The HRQoL decreased with advancing cancer stage among both inpatients and outpatients, respectively [stage IV: (0.516 & 0.557); stage III (0.609 & 0.689); stage II (0.677 & 0.713); stage I (0.638 & 0.748), p value < 0.001]. The outpatients on hormone therapy (B = 0.076) showed significantly better HRQoL in comparison to patients on chemotherapy. However, palliative care (B=-0.137) and surgery (B=-0.110) were found to be associated with significantly with poorer HRQoL paralleled to chemotherapy. The utility scores among outpatients ranged from 0.305 (bone cancer) to 0.782 (Leukemia). Among hospitalized cases, the utility score was lowest for multiple myeloma (0.255) and highest for testicular cancer (0.771). CONCLUSION: Older age, lower educational status, chemotherapy, palliative care and surgery, advanced cancer stage and progressive disease were associated with poor HRQoL. Our study findings will be useful in optimising patient care, formulating individualized treatment plan, improving compliance and follow-up.

Dysbiosis of salivary microbiome and cytokines influence oral squamous cell carcinoma through inflammation.

Advanced combinatorial treatments of surgery, chemotherapy, and radiotherapy do not have any effect on the enhancement of a 5-year survival rate of oral squamous cell carcinoma (OSCC). The discovery of early diagnostic non-invasive biomarkers is required to improve the survival rate of OSCC patients. Recently, it has been reported that oral microbiome has a significant contribution to the development of OSCC. Oral microbiome induces inflammatory response through the production of cytokines and chemokines that enhances tumor cell proliferation and survival. The study aims to develop saliva-based oral microbiome and cytokine biomarker panel that screen OSCC patients based on the level of the microbiome and cytokine differences. We compared the oral microbiome signatures and cytokine level in the saliva of OSCC patients and healthy individuals by 16S rRNA gene sequencing targeting the V3/V4 region using the MiSeq platform and cytokine assay, respectively. The higher abundance of Prevotella melaninogenica, Fusobacterium sp., Veillonella parvula, Porphyromonas endodontalis, Prevotella pallens, Dialister, Streptococcus anginosus, Prevotella nigrescens, Campylobacter ureolyticus, Prevotella nanceiensis, Peptostreptococcus anaerobius and significant elevation of IL-8, IL-6, TNF-α, GM-CSF, and IFN-γ in the saliva of patients having OSCC. Oncobacteria such as S. anginosus, V. parvula, P. endodontalis, and P. anaerobius may contribute to the development of OSCC by increasing inflammation via increased expression of inflammatory cytokines such as IL-6, IL-8, TNF-α, IFN-γ, and GM-CSF. These oncobacteria and cytokines panels could potentially be used as a non-invasive biomarker in clinical practice for more efficient screening and early detection of OSCC patients.

RUNX1T1, a potential prognostic marker in breast cancer, is co-ordinately expressed with ERα, and regulated by estrogen receptor signalling in breast cancer cells.

BACKGROUND: RUNX1T1 is extensively studied in the context of AML1-RUNX1T1 fusion protein in acute myeloid leukemia. Little is known about the function of RUNX1T1 itself, although data on its function and regulation have begun to emerge from clinical, and in vitro studies. It is a putative tumor suppressor, whose expression is altered in a variety of solid tumors. Recently, reduced expression of RUNX1T1 in triple-negative breast tumors, and its influence on prognosis was reported. METHODS AND RESULTS: The Kaplan-Meier Plotter online tool was used to study the relationship between RUNX1T1 expression and survival of breast cancer patients. High RUNX1T1 expression was associated with longer overall survival (OS), relapse-free survival (RFS) and distant metastasis free survival (DMFS). RUNX1T1 expression positively and negatively influenced OS of patients with ERα-positive and ERα-negative breast tumors, respectively. It was also associated with prolonged RFS, and DMFS in tamoxifen-treated patients. Expression of RUNX1T1 and ERα mRNA was analyzed in 40 breast tumor samples, and breast cancer cell lines using RT-PCR. TCGA-BRCA data was mined to study the relationship between RUNX1T1 and ERα mRNA expression. ERα-positive breast tumors showed significantly higher RUNX1T1 mRNA expression compared to ERα-negative tumors. RUNX1T1 mRNA expression was analyzed by qRT-PCR in MCF-7 or T47D cells, which were treated with 17ß-estradiol, or the ERα agonist PPT, alone or in combination with 4-hydroxytamoxifen. Effect of ERα knockdown was also investigated. Results indicate that estrogen downmodulated RUNX1T1 mRNA expression via ERα. CONCLUSION: Higher expression of RUNX1T1 in breast tumors is associated with favourable prognosis. RUNX1T1 and ERα show co-ordinated expression in breast tumors, and breast cancer cell lines. Estrogen-ERα signalling downmodulates the expression of RUNX1T1 mRNA in ERα-positive breast cancer cells. In-depth investigations on the interaction between RUNX1T1 and ERα are warranted to unravel the role and relevance of RUNX1T1 in breast cancer.

Alterations of salivary microbial community associated with oropharyngeal and hypopharyngeal squamous cell carcinoma patients.

The highest number (35.1% of global incident cases) of new oropharyngeal (OP) and hypopharyngeal (HP) cancer cases was reported in South-Central Asia. The highest incidence of HP cancer in India was reported in East Khasi Hills District of Meghalaya, Aizawl District of Mizoram, and Kamrup Urban District of Assam. HP and OP cancer showed the highest mortality rate, worst prognoses and the highest rate of nodal metastases and distant metastases. Thus, research is required to detect specific biomarkers for early prevention and diagnosis for these cancers. Oral microbiome signatures in saliva are considered as a potential diagnostic biomarker for OP and HP cancer. Bacterial profile alterations in OP and HP cancer have not been reported in India population, to establish the association of oral bacteria in the progression of OP and HP cancer; we studied bacterial communities in saliva of eight OP and seven HP cancer patients as compared to healthy controls using 16S rRNA V3-V4 region sequencing. The higher abundance of Haemophilus parainfluenzae, Haemophilus influenzae and Prevotella copri and lower abundance of Rothia mucilaginosa, Aggregatibacter segnis, Veillonella dispar, Prevotella nanceiensis, Rothia aeria, Capnocytophaga ochracea, Neisseria bacilliformis, Prevotella nigrescens and Selenomonas noxia in saliva of OP and HP cancer patients may be considered as a non-invasive diagnostic biomarker for OP and HP cancer patients. Streptococcus anginosus may be considered as a non-invasive diagnostic biomarker for OP cancer patients only. Therefore, evaluation of salivary microbial biomarkers may be informative to understand the pathobiology and carcinogenesis of OP and HP cancer.

Assessment and clinicopathological correlation of matrix metalloproteinase 9 expression in nasopharyngeal carcinoma.

INTRODUCTION: Nasopharyngeal cancer is not a common disease in most parts of the world. In India also, nasopharyngeal carcinoma (NPC) is not a common cancer, except for the Northeastern region of the country. Expression of matrix metalloproteinase 9 (MMP9) in the tumor cells is related to tumor invasion and metastasis. The aim of the present study is to analyze the expression of MMP9 in NPC and evaluate its prognostic implications. MATERIALS AND METHODS: A total of 32 histologically confirmed tissue samples of NPC were examined by immunohistochemical staining to assess the expression of MMP9. Clinicopathological parameters and levels of MMP9 expression in the tumor tissue were analyzed using Chi-square test. Survival analysis was done using the Kaplan-Meier method and was compared using log-rank test. P <0.05 was considered statistically significant. RESULTS: Of the 32 tissue samples of NPC, 23 (71.9%) were male and 9 (28.1%) were female. 7 (21.9%) patients presented in T1 Stage, 8 (25.0%) in T2, 12 (37.5%) in T3, and 5 (15.6%) in T4 Stages, respectively. 29 (90.6%) patients presented with lymph node metastasis. MMP9 expression level was significantly correlated with patient's age (P = 0.033), tumor histology (P = 0.017), tumor stage (P = 0.021), and lymph node metastasis (P = 0.011). The 5-year overall survival is higher for low-level expression as compared to high-level expression of MMP9 (P = 0.046). CONCLUSION: MMP9 is an important prognostic factor for NPC. High expression of MMP9 is associated with cervical lymph nodes metastasis and poor survival outcome.

Association of mRNA expression of toll-like receptor 2 and 3 with hepatitis B viral load in chronic hepatitis, cirrhosis, and hepatocellular carcinoma.

During Hepatitis B virus infection, the pathogen sensors Toll-like receptors (TLRs) play a role in innate immunity system. The study aimed to investigate mRNA expression levels of TLR2 and TLR3 in Hepatitis B virus (HBV) mediated chronic hepatitis B (CHB), cirrhosis (CIRR), and hepatocellular carcinoma (HCC), and to correlate viral load with severity of these diseases and expression of TLRs. A total of 180 HBV DNA positive samples were selected for the study. HVB-DNA was detected by multiplex PCR. Viral load estimation was done by using the Ampisure HBV Quantitative kit as per manufacture instructions. Expression levels of TLR2 and TLR3 were determined by real time PCR. The viral load was estimated to be 6.64log10 IU/ml in CHB, 4.88log10 IU/ml in CIRR, and 4.86log10 IU/ml in HCC. No significant association of viral load was found with increasing age. Upregulation of TLR2 expression in CHB when individually compared with CIRR and HCC was found to be statistically significant. Downregulation of TLR3 expressions in CIRR when compared to both CHB and HCC individually were found to be statistically significant. No significant effect of viral load on the expression of TLR2 and 3 were found. With severity of the disease from CHB to HCC, the HBV load decreases. The study suggests the possibility of HBV interacting with signalling of both analysed TLR receptors which partially explains the induction of immune tolerance pathways by Hepatitis B virus. J. Med. Virol. 89:1008-1014, 2017. © 2017 Wiley Periodicals, Inc.

Study of single nucleotide polymorphisms of tumour necrosis factors and HSP genes in nasopharyngeal carcinoma in North East India.

Nasopharyngeal carcinoma (NPC) is an epithelial tumour with a distinctive racial and geographical distribution. High incidence of NPC has been reported from China, Southeast Asia, and northeast (NE) region of India. The immune mechanism plays incredibly role in pathogenesis of NPC. Tumour necrosis factors (TNFs) and heat shock protein 70 (HSP 70) constitute significant components of innate as well as adaptive host immunity. Multi-analytical approaches including logistic regression (LR), classification and regression tree (CART) and multifactor dimensionality reduction (MDR) were applied in 120 NPC cases and 100 controls to explore high order interactions among TNF-α (-308 G>A), TNF ß (+252 A>G), HSP 70-1 (+190 G>C), HSP 70-hom (+2437 T>C) genes and environmental risk factors. TNF ß was identified as the primary etiological factor by all three analytical approaches. Individual analysis of results showed protective effect of TNF ß GG genotype (adjusted odds ratio (OR2) = 0.27, 95 % CI = 0.125-0.611, P = 0.001), HSP 70 (+2437) CC genotype (OR2 = 0.17, 95 % CI = 0.0430.69, P = 0.013), while AG genotype of TNF ß was found significantly associated with risk of NPC (OR2 = 1.97, 95 % CI = 1.019-3.83, P = 0.04). Analysis of environmental factors demonstrated association of alcohol consumption, living in mud houses and use of firewood for cooking as major risk factors for NPC. Individual haplotype association analysis showed significant risk associated with GTGA haplotype (OR = 68.61, 95 % CI = 2.47-190.37, P = 0.013) while a protective effect with CCAA and GCGA haplotypes (OR = 0.19, 95 % CI = 0.05-0.75, P = 0.019; OR = 0.01 95 % CI = 0.05-0.30, P = 0.007). The multi-analytical approaches applied in this study helped in identification of distinct gene-gene and gene-environment interactions significant in risk assessment of NPC.

Contribution of susceptibility locus at HLA class I region and environmental factors to occurrence of nasopharyngeal cancer in Northeast India.

High incidence of nasopharyngeal carcinoma (NPC) has been reported from China, Southeast Asia and Northeast (NE) region of India. Populations at geographic regions having higher incidence of NPC display human leukocyte antigen (HLA) distribution patterns different from areas having low incidence. The current study has investigated the contribution of environmental risk factors and ethnic variation of microsatellite markers in HLA region for the high incidence of NPC in NE India. Genotyping of HLA region using 33 microsatellite markers by fragment length analysis was done in 220 study subjects (120 NPC patients and 100 healthy controls). Association analysis showed two adjacent microsatellite markers HL003 (allele 121) and D6S2704 (allele 218) in the HLA class I region having association with high risk of NPC while allele 127 of HL003 and allele 255 of D6S2678 conferred a protective effect. The environmental factors mainly use of firewood (odds ratio (OR) = 3.797385, confidence interval (CI) = 1.97-7.30, P < 0), living in mud house (OR = 3.46, CI = 1.19-10.08, P = 0.022) and consumption of alcohol (OR = 2.11, CI = 1.02-4.37, P = 0.043) were found as major risk factors for NPC. Higher-order interaction showed combination of smoked food consumption and firewood use for cooking in multifactor dimensionality reduction (MDR) analysis and interaction of non-firewood users, non-ventilated houses and residence in mud houses in classification and regression tree (CART) analysis as the significant risk factors for NPC. Expression of Epstein-Barr virus (EBV) RNA was found in 92% (23/25) of NPC cases suggesting its significant role in NPC aetiopathogenesis. This study identified association of NPC with a susceptibility locus in the HLA class I region which has complex interaction with viral DNA and environmental factors.

Evaluation of Tongue Cancer Using High-Resolution Sonography: Comparison With Magnetic Resonance Imaging.

OBJECTIVES: To evaluate the role of sonography in assessing tongue cancer compared with magnetic resonance imaging (MRI). METHODS: A randomized prospective study was performed on 40 cases of tongue cancer. Magnetic resonance imaging and sonography of the tongue were performed, tumor spreading to particular sites was recorded in all cases. Sonographic and MRI findings were correlated with histopathologic findings in 18 operable cases. In 22 inoperable cases, sonography was compared only with MRI. RESULTS: In operable patients, sonography achieved sensitivity of 61.1%, whereas MRI achieved sensitivity of 94.4%. The difference was statistically significant (P < .05). The results for detection of individual site involvement on sonography and MRI were as follows: intrinsic muscles only, 0 and 6, respectively; tongue base, 5 and 5; genioglossus muscle, 34 and 34; mylohyoid muscle, 9 and 8; sublingual space, 12 and 14; sublingual neurovascular bundle, 12 and 12; submandibular gland, 3 and 3; spread across the lingual septum, 17 and 17; and alveolar involvement, 0 and 1. There was no significant difference (P> .05) between sonography and MRI in detecting involvement of the above-mentioned sites except for cases with only intrinsic muscles and alveolar involvement. Tumors involving intrinsic tongue muscles only were not visualized on sonography. They all underwent surgery, resulting in reduced sensitivity of sonography in operable cases. CONCLUSIONS: Even though small tumors were difficult to visualize, sonography can play an important role in assessment of tumor extension in large growths, especially when MRI is unavailable, contraindicated, or unaffordable, and for posttreatment follow-up.

Association of DNA repair and cell cycle gene variations with breast cancer risk in Northeast Indian population: a multiple interaction analysis.

Polymorphisms in DNA repair and cell cycle genes contribute to increased breast cancer (BC) risk. Their association and interaction in relation to betel quid and tobacco chewing habits need exhaustive multi-analytical investigation to explain BC predisposition due to DNA damage. Polymorphism in TP53-72Arg>Pro, RAD51-135G>C, BRCA2, and CCND1-G870A were examined in 204 BC cases and 217 controls from Northeast Indian population. Multifaceted analytic approaches were used to explore relationships between polymorphisms, tobacco history, and BC susceptibility. Betel quid chewing was identified as the predominant risk factor. CCND-AA and dominant model showed protection towards BC in betel quid chewer (BQC) [(0.28 (0.10-0.77), 0.01 and 0.32 (0.12-0.81), 0.01)] and non-betel quid chewers (NBQC) [(0.26 (0.09-0.78), 0.01 and 0.37 (0.16-0.87), 0.02)]. TP53-Pro/Pro genotype showed protection towards BC in NBQC (0.29 (0.10-0.81), p=0.01) and (0.51 (0.32-0.80), p=0.003, respectively). RAD51-C allele was associated with BC risk (2.03 (1.26-3.30) 0.002) in BQC. Two BQC cases had BRCA2 8415G>T:K2729N mutation in Exon18. MDR analysis showed best four locus model with TBA 0.6765 (0.005) and CVC of 10/10 in NBQC. Interaction diagram concurred the interactions between TP53 and RAD51 (1.32 %) with independent effect (1.89 %) of CCND1in NBQC. In CART analysis, BQC with CCND1 GG genotype were at risk (OR=33.0; 95 % CI=6.08-179.07), p<0.001) followed by combination of BQC, CCND1, No-Smk, and Alc (OR=42.00; 95 % CI=5.11-345.11, p<0.001). Risk was also observed in BQC, CCND1, No-Smk, Non-Alc, and TP53 combination (OR=14.84; 95 % CI=3.13-70.34, p<0.001) and BQC, CCND1, No-Smk, Non-Alc, TP53 (OR=9.40; 95 % CI=1.99-44.34, p<0.001). NBQC group showed risk with combination of NBQC and TP53 (OR=5.54; 95 % CI=1.11-27.42, p=0.03). Genetic variants in DNA repair and cell cycle genes contribute to BC risk through gene-gene and gene-environmental interactions.

A pilot study evaluating genetic alterations that drive tobacco- and betel quid-associated oral cancer in Northeast India.

The susceptibility of an individual to oral cancer is mediated by genetic factors and carcinogen-exposure behaviors such as betel quid chewing, tobacco use, and alcohol consumption. This pilot study was aimed to identify the genetic alteration in 100 bp upstream and downstream flanking regions in addition to the exonic regions of 169 cancer-associated genes by using Next Generation sequencing with aim to elucidate the molecular pathogenesis of tobacco- and betel quid-associated oral cancer of Northeast India. To understand the role of chemical compounds present in tobacco and betel quid associated with the progression of oral cancer, single nucleotide polymorphisms (SNPs) and insertion and deletion (Indels) found in this study were analyzed for their association with chemical compounds found in tobacco and betel quid using Comparative Toxogenomic Database. Genes (AR, BRCA1, IL8, and TP53) with novel SNP were found to be associated with arecoline which is the major component of areca nut. Genes (BARD1, BRCA2, CCND2, IGF1R, MSH6, and RASSF1) with novel deletion and genes (APC, BRMS1, CDK2AP1, CDKN2B, GAS1, IGF1R, and RB1) with novel insertion were found to be associated with aflatoxin B1 which is produced by fermented areca nut. Genes (ADH6, APC, AR, BARD1, BRMS1, CDKN1A, E2F1, FGFR4, FLNC, HRAS, IGF1R, IL12B, IL8, NBL1, STAT5B, and TP53) with novel SNP were found to be associated with aflatoxin B1. Genes (ATM, BRCA1, CDKN1A, EGFR, IL8, and TP53) with novel SNP were found to be associated with tobacco specific nitrosamines.

Evaluation of hypopharyngeal carcinoma using high-resolution ultrasound: comparison with CT.

BACKGROUND: To evaluate the role of sonography (US) in assessing hypopharyngeal carcinoma when compared with CT. METHODS: A randomized prospective study was performed on 40 biopsy-proven cases of hypopharyngeal carcinoma.Contrast-enhanced CT of the neck was performed in all patients, followed by US. Sonographic identification of any tumor extension into the extralaryngeal soft tissues, postcricoid space, subglottis, thyroid gland, esophagus, and across the midline was recorded. US observations and CT findings were compared and then correlated with the histopathologic findings in 14 operative cases. In the remaining 26 inoperable cases, US was compared only with CT. RESULTS: Our cohort was composed of 38 men and 2 women ranging in age from 36 to 59 years. In a subset of 14 operative patients, US had a sensitivity of 71.4% (10/14), while CT achieved a sensitivity of 92.8% (13/14), and the difference was not statistically significant (p > 0.05). US and CT findings concurred in 67.5% (27/40) of cases. CONCLUSIONS: Even though small tumors are difficult to visualize, US can play a significant role in the assessment of tumor extension within and beyond the larynx, especially when cross-sectional imaging is either unavailable or unaffordable.

Continuous low-dose oral chemotherapy in recurrent and persistent carcinoma of cervix following chemoradiation: a comparative study between prolonged oral cyclophosphamide and oral Etoposide.

AIM: To compare the efficacy and toxicities of low-dose oral cyclophosphamide and oral etoposide in patients with persistent and recurrent cervical cancer with gross pelvic disease following full course of chemoradiation therapy. MATERIALS AND METHODS: 30 patients with recurrent and persistent cervical cancer with gross pelvic disease were enrolled in this trial. The patients were randomly divided into two groups of 15 patients each with one group receiving low dose oral cyclophosphamide (100 mg/day) and the other group receiving low-dose oral etoposide (50 mg/day). Results were statistically analysed by IBM SPSS Statistics 19. RESULTS: Oral etoposide was not well tolerated with grade 2 neutropenia occurring in 33.3% and grade 3 neutropenia in 6.6% and thrombocytopenia occurring in 13.3%. Oral cyclophosphamide group on the other hand was better tolerated with none of the patients having thrombocytopenia and 6.6% patients having grade 2 neutropenia. There were two complete response (15.38%) and one partial response at the end of study (7.6%) in the cyclophosphamide group whereas there was no complete response and two partial response (16.6%) in the oral etoposide group. CONCLUSION: Long-term, low-dose oral etoposide was found to be less tolerated without any significant effect with patients with persistent and recurrent cervical cancer with gross pelvic disease following full course of chemoradiation therapy in contrast to oral cyclophosphamide which was found to be effective and well-tolerated by the patients.

Cost-Effectiveness of Novel Agent Regimens for Transplant-Eligible Newly Diagnosed Multiple Myeloma Patients in India.

BACKGROUND: Survival outcomes for multiple myeloma have improved dramatically since the introduction of novel therapeutic agents. While these drugs are highly effective in improving survival outcomes and quality of life in patients with multiple myeloma, they come at a significant cost. We assessed the cost-effectiveness of bortezomib-based triplet or quadruplet drug regimens in isolation and followed by autologous hematopoietic stem cell transplantation (AHSCT) for the treatment of newly diagnosed multiple myeloma (NDMM) in the Indian context. METHODS: A Markov model was developed to assess the health and economic outcomes of novel drug regimens with and without AHSCT for the treatment of NDMM in India. We estimated the lifetime quality-adjusted life-years (QALYs) and costs in each scenario. The incremental cost-effectiveness ratios (ICERs) were computed and compared against the current willingness-to-pay threshold of a one-time per capita gross domestic product of ₹146,890 (US$1,927.70) for India. Parameter uncertainty was assessed through Monte Carlo probabilistic sensitivity analysis. RESULTS: Among seven treatment sequences, the VCd (bortezomib, cyclophosphamide, dexamethasone) alone arm has the lowest cost and health benefits as compared to four treatment sequences, namely VTd (bortezomib, thalidomide, dexamethasone) alone, VRd (bortezomib, lenalidomide, dexamethasone) alone, VRd plus AHSCT and DVRd (Daratumumab, bortezomib, lenalidomide, dexamethasone) plus AHSCT. It was found that VTd plus AHSCT and VCd plus AHSCT arms were extendedly dominated (ED) by combination of two alternative treatments. Among the five non-dominated strategies, VRd has a lowest incremental cost of ₹ 2,20,093 (US$2,888) per QALY gained compared to VTd alone followed by VRd plus AHSCT [₹3,14,530 (US$4,128) per QALY gained] in comparison to VRd alone. None of the novel treatment sequences were found to be cost-effective at the current WTP threshold of ₹1,46,890 (US$1,927.7). CONCLUSION: At the current WTP threshold of one-time per capita GDP (₹ 146,890) of India, VRd alone and VRd plus AHSCT has 38.1% and 6.9% probability to be cost-effective, respectively. Reduction in current reimbursement rates of novel drugs, namely VRd, lenalidomide, and pomalidomide plus dexamethasone under national insurance program and societal cost of transplant by 50%, would make VRd plus AHSCT and VTd plus AHSCT cost-effective at an incremental cost of ₹40,671 (US$34) and ₹97,639 (US$1,281) per QALY gained, respectively.

Population-based incidence and patterns of cancer in Kamrup Urban Cancer Registry, India.

BACKGROUND: Cancer is not a notifiable disease in India. The Indian Council of Medical Research (ICMR) initiated the National Cancer Registry Programme in 1982 to measure the burden and pattern of cancer in India. However, no data were available from the northeastern region till 2001 when a WHO- sponsored, ICMR project showed a relatively high frequency of microscopically diagnosed cases of cancer in the region. A population-based cancer registry was established in January 2003 in Guwahati to cover the Kamrup Urban district in the northeastern region of India. We report the data generated in the first 6 years of the registry (2003-08). METHODS: Information on cancer was obtained by voluntary participation of different sources including major hospitals, diagnostic centres, state referral board and birth and death registry centres within the registry area. A total of 6608 cases were registered during the 6-year period (1 January 2003- 31 December 2008); 3927 were men and 2681 women. RESULTS: The age-adjusted incidence rates were 167.9 per 100000 among men and 133.8 per 100000 among women. The oesophagus was the leading site of cancer among men, comprising 18.3% of all cancers with an age-adjusted rate of 30.7 per 100000. Among women, the breast followed by the cervix uteri were the leading sites of cancer. These two cancers comprised 30% of all cancers among women. Tobacco-related cancers accounted for 58.2% of cancers among men and 26.9% of cancers among women. CONCLUSION: The patterns observed from the analysis of data from the cancer registry at Guwahati provide comprehensive information on occurrence of cancer and can be valuable for planning cancer control programmes in the region.

Cost-effectiveness analysis of different combination therapies for the treatment of chronic lymphocytic leukaemia in India.

Background: Over the years, there has been introduction of newer drugs, like bendamustine and ibrutinib, for the management of chronic lymphocytic leukaemia (CLL). Though these drugs lead to better survival, they are also associated with higher cost. The existing evidence on cost effectiveness of these drugs is from high-income countries, which has limited generalisability for low-income and middle-income counties. Therefore, the present study was undertaken to assess the cost-effectiveness of three therapeutic regimens, chlorambucil plus prednisolone (CP), bendamustine plus rituximab (BR) and ibrutinib for CLL treatment in India. Methods: A Markov model was developed for estimating lifetime costs and consequences in a hypothetical cohort of 1000 CLL patients following treatment with different therapeutic regimens. The analysis was performed based on a limited societal perspective, 3% discount rate and lifetime horizon. The clinical effectiveness of each regime in the form of progression-free survival and occurrence of adverse events were assessed from various randomised controlled trials. A structured comprehensive review of literature was undertaken for the identification of relevant trials. The data on utility values and out of pocket expenditure was obtained from primary data collected from 242 CLL patients across six large cancer hospitals in India. Findings: As compared to the most affordable regimen comprising of CP as first-line followed by BR as second-line therapy, none of the other therapeutic regimens were cost-effective at one time per capita gross-domestic product of India. However, if the current price of either combination of BR and ibrutinib or even ibrutinib alone could be reduced by more than 80%, regimen comprising of BR as first-line therapy followed by second-line ibrutinib would become cost-effective. Interpretation: At the current market prices, regimen comprising of CP as first-line followed by BR as second-line therapy is the most cost-effective strategy for CLL treatment in India. Funding: Department of Health Research, Government of India.

Financial toxicity of cancer treatment in India: towards closing the cancer care gap.

Background: The rising economic burden of cancer on patients is an important determinant of access to treatment initiation and adherence in India. Several publicly financed health insurance (PFHI) schemes have been launched in India, with treatment for cancer as an explicit inclusion in the health benefit packages (HBPs). Although, financial toxicity is widely acknowledged to be a potential consequence of costly cancer treatment, little is known about its prevalence and determinants among the Indian population. There is a need to determine the optimal strategy for clinicians and cancer care centers to address the issue of high costs of care in order to minimize the financial toxicity, promote access to high value care and reduce health disparities. Methods: A total of 12,148 cancer patients were recruited at seven purposively selected cancer centres in India, to assess the out-of-pocket expenditure (OOPE) and financial toxicity among cancer patients. Mean OOPE incurred for outpatient treatment and hospitalization, was estimated by cancer site, stage, type of treatment and socio-demographic characteristics. Economic impact of cancer care on household financial risk protection was assessed using standard indicators of catastrophic health expenditures (CHE) and impoverishment, along with the determinants using logistic regression. Results: Mean direct OOPE per outpatient consultation and per episode of hospitalization was estimated as ₹8,053 (US$ 101) and ₹39,085 (US$ 492) respectively. Per patient annual direct OOPE incurred on cancer treatment was estimated as ₹331,177 (US$ 4,171). Diagnostics (36.4%) and medicines (45%) are major contributors of OOPE for outpatient treatment and hospitalization, respectively. The overall prevalence of CHE and impoverishment was higher among patients seeking outpatient treatment (80.4% and 67%, respectively) than hospitalization (29.8% and 17.2%, respectively). The odds of incurring CHE was 7.4 times higher among poorer patients [Adjusted Odds Ratio (AOR): 7.414] than richest. Enrolment in PM-JAY (CHE AOR = 0.426, and impoverishment AOR = 0.395) or a state sponsored scheme (CHE AOR = 0.304 and impoverishment AOR = 0.371) resulted in a significant reduction in CHE and impoverishment for an episode of hospitalization. The prevalence of CHE and impoverishment was significantly higher with hospitalization in private hospitals and longer duration of hospital stay (p < 0.001). The extent of CHE and impoverishment due to direct costs incurred on outpatient treatment increased from 83% to 99.7% and, 63.9% to 97.1% after considering both direct and indirect costs borne by the patient and caregivers, respectively. In case of hospitalization, the extent of CHE increased from 23.6% (direct cost) to 59.4% (direct+ indirect costs) and impoverishment increased from 14.1% (direct cost) to 27% due to both direct and indirect cost of cancer treatment. Conclusion: There is high economic burden on patients and their families due to cancer treatment. The increase in population and cancer services coverage of PFHI schemes, creating prepayment mechanisms like E-RUPI for outpatient diagnostic and staging services, and strengthening public hospitals can potentially reduce the financial burden among cancer patients in India. The disaggregated OOPE estimates could be useful input for future health technology analyses to determine cost-effective treatment strategies.

The G-protein-coupled estrogen receptor, a gene co-expressed with ERα in breast tumors, is regulated by estrogen-ERα signalling in ERα positive breast cancer cells.

GPER is a seven transmembrane G-protein-coupled estrogen receptor that mediates rapid estrogen actions. Large volumes of data have revealed its association with clinicopathological variables in breast tumors, role in epidermal growth factor (EGF)-like effects of estrogen, potential as a therapeutic target or a prognostic marker, and involvement in endocrine resistance in the face of tamoxifen agonism. GPER cross-talks with estrogen receptor alpha (ERα) in cell culture models implicating its role in the physiology of normal or transformed mammary epithelial cells. However, discrepancies in the literature have obfuscated the nature of their relationship, its significance, and the underlying mechanism. The purpose of this study was to assess the relationship between GPER, and ERα in breast tumors, to understand the mechanistic basis, and to gauge its clinical significance. We mined The Cancer Genome Atlas (TCGA)-BRCA data to examine the relationship between GPER and ERα expression. GPER mRNA, and protein expression were analyzed in ERα-positive or -negative breast tumors from two independent cohorts using immunohistochemistry, western blotting, or RT-qPCR. The Kaplan-Meier Plotter (KM) was employed for survival analysis. The influence of estrogen in vivo was studied by examining GPER expression levels in estrus or diestrus mouse mammary tissues, and the impact of 17ß-estradiol (E2) administration in juvenile or adult mice. The effect of E2, or propylpyrazoletriol (PPT, an ERα agonist) stimulation on GPER expression was studied in MCF-7 and T47D cells, with or without tamoxifen or ERα knockdown. ERα-binding to the GPER locus was explored by analysing ChIP-seq data (ERP000380), in silico prediction of estrogen response elements, and chromatin immunoprecipitation (ChIP) assay. Clinical data revealed significant positive association between GPER and ERα expression in breast tumors. The median GPER expression in ERα-positive tumors was significantly higher than ERα-negative tumors. High GPER expression was significantly associated with longer overall survival (OS) of patients with ERα-positive tumors. In vivo experiments showed a positive effect of E2 on GPER expression. E2 induced GPER expression in MCF-7 and T47D cells; an effect mimicked by PPT. Tamoxifen or ERα-knockdown blocked the induction of GPER. Estrogen-mediated induction was associated with increased ERα occupancy in the upstream region of GPER. Furthermore, treatment with 17ß-estradiol or PPT significantly reduced the IC50 of the GPER agonist (G1)-mediated loss of MCF-7 or T47D cell viability. In conclusion, GPER is positively associated with ERα in breast tumors, and induced by estrogen-ERα signalling axis. Estrogen-mediated induction of GPER makes the cells more responsive to GPER ligands. More in-depth studies are warranted to establish the significance of GPER-ERα co-expression, and their interplay in breast tumor development, progression, and treatment.