Breast cancer survival in India across 11 geographic areas under the National Cancer Registry Programme.

BACKGROUND: Population-based cancer survival is a key indicator for assessing the effectiveness of cancer control by a health care system in a specific geographic area. Breast cancer is the most common cancer among women in India, accounting for over one quarter of all female cancers. The objective of this study was to estimate the 5-year survival of female patients who were diagnosed with breast cancer between 2012 and 2015 from the existing Population-Based Cancer Registries (PBCRs) in India. METHODS: In total, 17,331 patients who had breast cancer diagnosed between 2012 and 2015 from 11 PBCRs were followed until June 30, 2021. Active methods were used to track the vital status of registered breast cancer cases. The study conducted survival analysis by calculating the difference between the date of first diagnosis and the date of death or censoring to estimate observed survival and relative survival using the actuarial survival approach and the Ederer-II approach, respectively. RESULTS: The 5-year age-standardized relative survival (95% confidence interval [CI]) of patients with breast cancer was 66.4% (95% CI, 65.5%-67.3%). Mizoram (74.9%; 95% CI, 68.1%-80.8%), Ahmedabad urban (72.7%; 95% CI, 70.3%-74.9%), Kollam (71.5%; 95% CI, 69.2%-73.6%), and Thiruvananthapuram (69.1%; 95% CI, 67.0%-71.2%) had higher survival rates than the national average. Conversely, Pasighat had the lowest survival rate (41.9%; 95% CI, 14.7%-68.6%). The 5-year observed survival rates for localized, regional, and distant metastasis in the pooled PBCRs were 81.0%, 65.5%, and 18.3%, respectively. CONCLUSIONS: The overall disparity in survival rates was observed across 11 PBCRs, with lower survival rates reported in Manipur, Tripura, and Pasighat. Therefore, it is imperative to implement comprehensive cancer control strategies widely throughout the country.

Vaccine efficacy against persistent human papillomavirus (HPV) 16/18 infection at 10 years after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a multicentre, prospective, cohort study.

BACKGROUND: A randomised trial designed to compare three and two doses of quadrivalent human papillomavirus (HPV) vaccine in adolescent girls in India was converted to a cohort study after suspension of HPV vaccination in trials by the Indian Government. In this Article, the revised aim of the cohort study was to compare vaccine efficacy of single dose to that of three and two doses in protecting against persistent HPV 16 and 18 infection at 10 years post vaccination. METHODS: In the randomised trial, unmarried girls aged 10-18 years were recruited from nine centres across India and randomly assigned to either two doses or three doses of the quadrivalent HPV vaccine (Gardasil [Merck Sharp & Dohme, Whitehouse Station, NJ, USA]; 0·5 mL administered intramuscularly). After suspension of recruitment and vaccination, the study became a longitudinal, prospective cohort study by default, and participants were allocated to four cohorts on the basis of the number vaccine doses received per protocol: the two-dose cohort (received vaccine on days 1 and 180 or later), three-dose cohort (days 1, 60, and 180 or later), two-dose default cohort (days 1 and 60 or later), and the single-dose default cohort. Participants were followed up yearly. Cervical specimens were collected from participants 18 months after marriage or 6 months after first childbirth, whichever was earlier, to assess incident and persistent HPV infections. Married participants were screened for cervical cancer as they reached 25 years of age. Unvaccinated women age-matched to the married vaccinated participants were recruited to serve as controls. Vaccine efficacy against persistent HPV 16 and 18 infections (the primary endpoint) was analysed for single-dose recipients and compared with that in two-dose and three-dose recipients after adjusting for imbalance in the distribution of potential confounders between the unvaccinated and vaccinated cohorts. This trial is registered with ISRCTN, ISRCTN98283094, and ClinicalTrials.gov, NCT00923702. FINDINGS: Vaccinated participants were recruited between Sept 1, 2009, and April 8, 2010 (date of vaccination suspension), and followed up over a median duration of 9·0 years (IQR 8·2-9·6). 4348 participants had three doses, 4980 had two doses (0 and 6 months), and 4949 had a single dose. Vaccine efficacy against persistent HPV 16 and 18 infection among participants evaluable for the endpoint was 95·4% (95% CI 85·0-99·9) in the single-dose default cohort (2135 women assessed), 93·1% (77·3-99·8) in the two-dose cohort (1452 women assessed), and 93·3% (77·5-99·7) in three-dose recipients (1460 women assessed). INTERPRETATION: A single dose of HPV vaccine provides similar protection against persistent infection from HPV 16 and 18, the genotypes responsible for nearly 70% of cervical cancers, to that provided by two or three doses. FUNDING: Bill & Melinda Gates Foundation.

Histocompatibility locus antigens regions contribute to the ethnicity bias of Epstein-Barr virus-associated nasopharyngeal carcinoma in higher-incidence populations.

Nasopharyngeal carcinoma (NPC) is one the most confusing and rare malignancy in most part of the world with significantly high occurrence in some populations of Southeast Asia, North Africa and Alaska. Apart from the dietary and environmental factors, NPC is well-associated with Epstein-Barr virus (EBV) infection in these ethnic groups. However, the internal molecular mechanism(s) for such association in specific populations is not known till date. Polymorphisms in the genes of histocompatibility locus antigens (HLA) are reported in NPC, but association of any particular polymorphism with ethnicity is not established yet. Here, we report a set of HLA polymorphisms in EBV-infected NPC samples from Northeast Indian population. These polymorphisms might play an important role for the lack of proper immune function against EBV infection and thus, eventually, for NPC generation in endemic populations like those of Northeast India.

Cancer in the NorthEast India: Where we are and what needs to be done?

North East Region in India is showing a peculiar type of cancer incidence pattern. This is an attempt to get a clear picture of cancer in NE India, the gaps in providing cancer care, and a way forward for a healthier NE. For this purpose, a desk review was undertaken along with secondary data analysis in 2018. In NE, the survival rate is comparatively very low, with higher proportion of distant metastasis cases at diagnosis. Even worse, the NE region lacks required infrastructure with respect to specialized treatment facilities, human resources, etc., In view of high burden of the disease with very limited resources, a multidisciplinary, multidimensional, and multilevel approach are needed to protect this vibrant region from becoming the cancer hub.

HIV-malaria interactions in North-East India: A prospective cohort study.

BACKGROUND & OBJECTIVES: The interactions between HIV and malaria co-infection have been shown to influence each other in their clinical outcomes in Sub-Saharan Africa. This study was carried out in the two States of north east India endemic for both HIV and malaria infections, to study the interactions between the two diseases in the HIV-infected population. METHODS: In this prospective study, a total of 333 HIV-infected individuals were followed up for a period of 6-18 months in Mizoram and Manipur during 2010-2011. The study assessed the changes in viral load and also the therapeutic efficacy of artesunate plus sulphadoxine-pyrimethamine (AS+SP) combination therapy in HIV-infected and HIV-uninfected individuals with Plasmodium falciparum malaria. RESULTS: Viral load in HIV-infected malaria patients on day zero (D0) ranged from 1110 to 147,000 copies/ml. The log transformation of the geometric means of HIV viral loads revealed no significant difference on different days of follow up. There was 100 per cent adequate clinical and parasitological response (ACPR) after treating with artemisinin based combination therapy (ACT) both in HIV-infected and HIV-uninfected P. falciparum-positive individuals. Similarly, chloroquine showed 100 per cent ACPR in P. vivax HIV-infected individuals. INTERPRETATION & CONCLUSION: The study showed no significant increase in HIV viral load in malaria cases. All HIV-infected and HIV-uninfected P. falciparum malaria-positive cases responded to the treatment with 100 per cent ACPR.

Immunogenicity and HPV infection after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a multicentre prospective cohort study.

BACKGROUND: An increase in worldwide HPV vaccination could be facilitated if fewer than three doses of vaccine are as effective as three doses. We originally aimed to compare the immunogenicity and frequency of persistent infection and cervical precancerous lesions caused by vaccine-targeted HPV after vaccination with two doses of quadrivalent vaccine on days 1 and 180 or later, with three doses on days 1, 60, and 180 or later, in a cluster-randomised trial. Suspension of the recruitment and vaccination due to events unrelated to our study meant that some enrolled girls could not be vaccinated and some vaccinated girls received fewer than the planned number of vaccinations by default. As a result, we re-analysed our data as an observational cohort study. METHODS: Our study was designed to be done in nine locations (188 clusters) in India. Participants were unmarried girls aged 10-18 years vaccinated in four cohorts: girls who received three doses of vaccine on days 1, 60, and 180 or later, two doses on days 1 and 180 or later, two doses on days 1 and 60 by default, and one dose by default. The primary outcomes were immunogenicity in terms of L1 genotype-specific binding antibody titres, neutralising antibody titres, and antibody avidity after vaccination for the vaccine-targeted HPV types 16, 18, 6, and 11 and incident and persistent infections with these HPVs. Analysis was per actual number of vaccine doses received. This study is registered with ISRCTN, number ISRCTN98283094; and with ClinicalTrials.gov, number NCT00923702. FINDINGS: Vaccination of eligible girls was initiated on Sept 1, 2009, and continued until April 8, 2010. Of 21 258 eligible girls identified at 188 clusters, 17 729 girls were recruited from 178 clusters before suspension. 4348 (25%) girls received three doses, 4979 (28%) received two doses on days 1 and 180 or later, 3452 (19%) received two doses at days 1 and 60, and 4950 (28%) received one dose. Immune response in the two-dose HPV vaccine group was non-inferior to the three-dose group (median fluorescence intensity ratio for HPV 16 1·12 [95% CI 1·02-1·23] and for HPV 18 1·04 [0·92-1·19]) at 7 months, but was inferior in the two-dose default (0·33 [0·29-0·38] for HPV 16 and 0·51 [0·43-0·59] for HPV 18) and one-dose default (0·09 [0·08-0·11] for HPV 16 and 0·12 [0·10-0·14] for HPV 18) groups at 18 months. The geometric mean avidity indices after fewer than three doses by design or default were non-inferior to those after three doses of vaccine. Fewer than three doses by design and default induced detectable concentrations of neutralising antibodies to all four vaccine-targeted HPV types, but at much lower concentration after one dose. Cervical samples from 2649 participants were tested and the frequency of incident HPV 16, 18, 6, and 11 infections was similar irrespective of the number of vaccine doses received. The testing of at least two samples from 838 participants showed that there was no persistent HPV 16 or 18 infections in any study group at a median follow-up of 4·7 years (IQR 4·2-5·1). INTERPRETATION: Despite the limitations imposed by the suspension of the HPV vaccination, our findings lend support to the WHO recommendation of two doses, at least 6 months apart, for routine vaccination of young girls. The short-term protection afforded by one dose of HPV vaccine against persistent infection with HPV 16, 18, 6, and 11 is similar to that afforded by two or three doses of vaccine and merits further assessment. FUNDING: Bill & Melinda Gates Foundation.

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.

Copy number polymorphism of glutathione-S-transferase genes (GSTM1 & GSTT1) in susceptibility to lung cancer in a high-risk population from north-east India.

BACKGROUND & OBJECTIVES: Genetic polymorphisms in glutathione-S-transferase genes ( GSTM1 and GSTT1 ) have been studied intensively for their potential role in lung cancer susceptibility. However, most of the studies on association between the polymorphisms and lung cancer do not distinguish between genotypes with one or two copies of the genes. The present study investigates the gene dosage effects of GSTT1 and GSTM1 copy number and their environmental interactions to examine the association of lung cancer risk with trimodular genotypes of the GSTs in a high-risk population from north-east India. METHODS: A total of 154 lung cancer cases and 154 age and sex matched controls from the high risk region of north-east India were analyzed by multiplex real-time PCR to determine the trimodal genotypes (+/+, +/- and -/-) in both the genes ( GSTM1 and GSTT1 ). RESULTS: No significant association and gene dosage effect of GSTM1 gene copy number with lung cancer risk ( P trend =0.13) were found. However, absence of GSTT1 conferred 68 per cent (OR=0.32;95%CI=0.15-0.71;P=0.005) reduced risk compared to the two copy number of the gene. t0 here was evidence of gene dosage effect of GSTT1 gene ( P trend =0.006). Tobacco smoking was a major environmental risk factor to lung cancer (OR=3.03;95%CI=1.73-5.31;P<0.001). However, its interaction with null genotype of GSTT1 conferred significant reduced risk to lung cancer (OR=0.30;95%CI=0.10-0.91;P=0.03). Further in only tobacco smokers, null genotype was associated with increased reduced risk [0.03(0.001-0.78)0.03; P trend =0.006]. No effect modification of GSTM1 was observed with lung cancer risk by environmental risk factors. INTERPRETATION & CONCLUSIONS: The results suggest that absence of GSTT1 null genotype may be associated with a reduced risk of lung cancer and the effect remains unchanged after interaction with smoking.

Survival of patients with cervical cancer in India - findings from 11 population based cancer registries under National Cancer Registry Programme.

Background: Cancer survival data from Population Based Cancer Registries (PBCR) reflect the average outcome of patients in the population, which is critical for cancer control efforts. Despite decreasing incidence rates, cervical cancer is the second most common female cancer in India, accounting for 10% of all female cancers. The objective of the study is to estimate the five-year survival of patients with cervical cancer diagnosed between 2012 and 2015 from the PBCRs in India. Methods: A single primary incidence of cervical cancer cases of 11 PBCRs (2012-2015) was followed till June 30, 2021 (n = 5591). Active follow-ups were conducted through hospital visits, telephone calls, home or field visits, and public databases. Five-year Observed Survival (OS) and Age Standardised Relative Survival (ASRS) was calculated. OS was measured by age and clinical extent of disease for cervical cancers. Findings: The five-year ASRS (95% CI) of cervical cancer was 51.7% (50.2%-53.3%). Ahmedabad urban (61.5%; 57.4%-65.4%) had a higher survival followed by Thiruvananthapuram (58.8%; 53.1%-64.3%) and Kollam (56.1%; 50.7%-61.3%). Tripura had the lowest overall survival rate (31.6%; 27.2%-36.1%). The five-year OS% for pooled PBCRs was 65.9%, 53.5%, and 18.0% for localised, regional, and distant metastasis, respectively. Interpretation: We observed a wide variation in cervical cancer survival within India. The findings of this study would help the policymakers to identify and address inequities in the health system. We re-emphasise the importance of awareness, early detection, and increase the improvement of the health care system. Funding: The National Cancer Registry Programme is funded through intra-mural funding by Indian Council of Medical Research, Department of Health Research, India, Ministry of Health & Family Welfare.

Cancer awareness, diagnosis and treatment needs in Mizoram, India: evidence from 18 years trends (2003-2020).

Background: Despite being the second least populated state, Mizoram exhibits the highest incidence rate of cancer in India. Its inhabitants, constituting an endogamous and isolated population, have embraced their own distinct culture, way of life and dietary preferences, setting them apart from the rest of mainland India. In 2003, the Mizoram Population Based Cancer Registry (PBCR) was established under the auspices of the National Centre for Disease Informatics and Research (NCDIR), a division of the Indian Council of Medical Research (ICMR), in collaboration with the Department of Health & Family Welfare of the Government of Mizoram, India. Methods: Cancer incidence and mortality data were extracted from the Mizoram PBCR spanning the years 2003-2020. The Age Standardized Incidence Rate (ASIR) and Age Standardized Mortality Rate (ASMR) were computed per 100,000 individuals, utilizing Segi's World Standard Population as the benchmark. The trajectory of these changes was analysed employing the Joinpoint Regression Analysis Program, Version 4.9.1.0.13, to unveil the Annual Percent Change (APC) with a 95% Confidence Interval and a Significance test (p < 0.05) using Monte Carlo Permutation. The resulting graphical visualizations were generated using Flourish Studio.15. Findings: The overall ASIR for all cancer sites among men was 197.2 per 100,000, while for women, it was 164.9 per 100,000. Among men, the most prevalent cancer site was the Stomach (ASIR = 41.4), followed by Head & Neck, Lung, Oesophagus, Colorectal, Liver, Urinary, Non-Hodgkin's Lymphoma and Prostate cancers. Conversely, among women, Lung cancer exhibited the highest incidence (ASIR = 26.7), succeeded by Cervical, Breast, Stomach, Head & Neck, Colorectal, Oesophagus, Liver and Ovarian cancers. Stomach cancer emerged as the leading cause of death among men (ASMR = 22.6) and among women, Lung cancer held the highest ASMR (15.9). Joinpoint regression analysis revealed a rising trend in incidence and mortality over time for overall cancer sites. Among the primary cancer sites contributing to incidence and mortality, an increase in APC was observable for all, except Stomach cancer, in both men and women. The diagnostic approach, except for cases of cancer with unknown primary sites, involved a microscopic method. Interpretation: This cross-sectional study examines PBCR reports spanning from 2003 to 2020, shedding light on a consistent uptick in cancer incidence and mortality trends in Mizoram. Stomach cancer emerges as the most prevalent and primary cause of cancer-related deaths among men, while Lung cancer takes a parallel role in women. The elevated cancer incidence and the growing trend among younger generations might stem from the static lifestyle and dietary patterns prevalent within the endogamous tribal population, potentially contributing to a genetic predisposition. The escalation in mortality rates could be attributed to a dearth of specialized diagnostic facilities and skilled human resources, treatment strategies guided by genomic research and transportation challenges. This underscores the urgent requirement for comprehensive scientific exploration across diverse facets. The implementation of easily accessible diagnostic facilities in proximity and genetic testing for pharmacogenomics to enhance prognoses would also aid in mitigating the burden and advancing the healthcare system's effectiveness. Funding: Population Based Cancer Registry (PBCR) was supported by National Centre for Disease Informatics and Research (NCDIR) of the Indian Council of Medical Research (ICMR), India.

Protocol for the formative phase of a trial (SHE-CAN) to test co-designed implementation strategies for HPV-based cervical screening among vulnerable women in two diverse settings in India.

BACKGROUND: In view of the WHO's call for the elimination of cervical cancer as a public health problem, and current low screening coverage, Indian policy makers need evidence on how to effectively implement cervical screening programmes, ensuring equity in access. Our study will follow the INSPIRE implementation framework to co-design and test HPV-based screening approaches in two states of India with different health system organisation, based on understanding the status of screening as currently implemented, readiness and challenges to transition to HPV-based screening, and preferences of key stakeholders. Here, we describe our protocol for the formative phase of the study (SHE-CAN). METHODS: The study population includes women from vulnerable populations, defined as residents of tribal areas, rural villages, and urban slums, in the states of Mizoram and Tamil Nadu. The baseline assessment will use mixed methods research, with desktop reviews, qualitative studies, and surveys. A capacity assessment survey of screening and treatment facilities will be done, followed by interviews with healthcare providers, programme managers, and community health workers. Interviews will be conducted with previously screened women and focus group discussions with under and never-screened women and community members. Stakeholder workshops will be held in each state to co-design the approaches to delivering HPV-based screening among 30-49-year-old women. DISCUSSION: The quality and outcomes of existing screening services, readiness to transition to HPV-based screening, challenges in providing and participating in the cervical cancer care continuum, and acceptability of screening and treatment approaches will be examined. The knowledge gained about the current system, as well as recognition of actions to be taken, will inform a stakeholder workshop to co-design and evaluate implementation approaches for HPV-based screening through a cluster randomised implementation trial.

Evaluation of immune response to single dose of quadrivalent HPV vaccine at 10-year post-vaccination.

BACKGROUND: The recent World Health Organization recommendation supporting single-dose of HPV vaccine will significantly reduce programmatic cost, mitigate the supply shortage, and simplify logistics, thus allowing more low- and middle-income countries to introduce the vaccine. From a programmatic perspective the durability of protection offered by a single-dose will be a key consideration. The primary objectives of the present study were to determine whether recipients of a single-dose of quadrivalent HPV vaccine had sustained immune response against targeted HPV types (HPV 6,11,16,18) at 10 years post-vaccination and whether this response was superior to the natural antibody titres observed in unvaccinated women. METHODS: Participants received at age 10-18 years either one, two or three doses of the quadrivalent HPV vaccine. Serology samples were obtained at different timepoints up to 10 years after vaccination from a convenience sample of vaccinated participants and from age-matched unvaccinated women at one timepoint. The evolution of the binding and neutralizing antibody response was presented by dose received. 10-year durability of immune responses induced by a single-dose was compared to that after three doses of the vaccine and in unvaccinated married women. RESULTS: The dynamics of antibody response among the single-dose recipients observed over 120 months show stabilized levels 18 months after vaccination for all four HPV types. Although the HPV type-specific (binding or neutralizing) antibody titres after a single-dose were significantly inferior to those after three doses of the vaccine (lower bounds of GMT ratios < 0.5), they were all significantly higher than those observed in unvaccinated women following natural infections (GMT ratios: 2.05 to 4.04-fold higher). The results correlate well with the high vaccine efficacy of single-dose against persistent HPV 16/18 infections reported by us earlier at 10-years post-vaccination. CONCLUSION: Our study demonstrates the high and durable immune response in single-dose recipients of HPV vaccine at 10-years post vaccination.

Impact of age at vaccination and cervical HPV infection status on binding and neutralizing antibody titers at 10 years after receiving single or higher doses of quadrivalent HPV vaccine.

Long-term follow-up of a cohort of unmarried girls who received one, two, or three doses of quadrivalent HPV vaccine, between 10 and 18 years of age, in an Indian multi-centric study allowed us to compare antibody responses between the younger and older age cohorts at 10-years post-vaccination, and study the impact of initiation of sexual activity and cervical HPV infections on antibody levels. Among the younger (10-14 years) recipients of a single dose, 97.7% and 98.2% had detectable binding antibody titers against HPV 16 and HPV 18 respectively at ten years post-vaccination. The proportions among those receiving a single dose at age 15-18 years were 92.3% and 94.2% against HPV 16 and HPV 18 respectively. Mean HPV 16 binding antibody titers were 2.1 folds (95%CI 1.4 to 3.3) higher in those vaccinated at ages 10-14 years, and 1.9 folds (95%CI 1.2 to 3.0) higher in those vaccinated at 15-18 years compared to mean titers seen in the unvaccinated women. Compared to previous timepoints of 36 or 48 months, binding antibodies against HPV 16 and neutralizing antibodies against both HPV 16 and HPV 18 were significantly higher at 10 years. This rise was more pronounced in participants vaccinated at 15-18 years. No association of marital status or cervical HPV infections was observed with the rise in titer. Durability of antibody response in single dose recipients correlated well with the high efficacy of a single dose against persistent HPV 16/18 infections irrespective of age at vaccination, as we reported earlier.

Molecular typing of dengue virus in Mizoram, Northeast India.

INTRODUCTION: Dengue is an emerging vector-borne public health threat and characterization at the molecular level is important for proper management of the disease. The aim of the study is to examine the diversity of the dengue viral serotypes from a hilly mountainous region of Northeast India. METHODOLOGY: Thirty-six blood samples that were positive for dengue virus IgM antibodies identified by the enzyme-linked immunosorbent assay (ELISA) method were collected and quantified for the IL6 gene expression by using reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: All the patients had dengue hemorrhagic fever (DHF); 12 samples had a monotypic infection and 14 samples had dual infection with various dengue virus (DENV) serotypes; one sample had triple infection with DENV-1, DENV-2, and DENV-3. CONCLUSIONS: This study identified DENV-1 as the major serotype in the state of Mizoram and it is the first report on the molecular typing of the dengue virus from the hilly mountainous state located in the Indo-Burma region bordering Myanmar and Bangladesh.

Lifestyle, Epstein-Barr virus infection, and other factors could impede nasopharyngeal cancer survivorship: a five-year cross-sectional study in North Eastern India.

Nasopharyngeal Carcinoma (NPC) is one of the leading cancers in India's north-eastern (NE) region affecting a section of the population each year. A proportion of the NPC cases are observed to recur even after therapy, indicating the involvement of other factors. We aimed to explore the NPC and Epstein-Barr virus (EBV) burden in the NE region and investigate the prognostic factors for the NPC patients' poor survival and recurrence. NPC patients' information was obtained from different state hospitals between 2014 and 2019. PCR and Sanger sequencing were performed to detect EBV types. Statistical analysis, including forest plot analysis, Kaplan-Mayer survival plot, Log-rank test, cox hazard regression, and Aalen's additive regression model, were performed to determine prognostic factors for the NPC patients' lower survival and recurrence. We observed an increased incidence of NPC and EBV infection in the past five years. Step-wise statistical analyses pointed out that variable such as non-professionals (B = 1.02, HR = 2.8, 95%CI = 1.5,4.9) workers (B = 0.92, HR = 2.5, 95%CI = 1.4,4.4), kitchen cum bedroom (B = 0.61, HR = 1.8, 95%CI = 1.2,2.8), mosquito repellent (B = 0.60, HR = 1.7, 95%CI = 1.1,2.7), nasal congestion (B = 0.60, HR = 1.8, 95%CI = 1.2,2.8), lower haemoglobin level (B = 0.92, HR = 2.5, 95%CI = 1.3,4.9), tumor stage IV (B = 2.8, HR = 1.8, 95%CI = 1.6,14.3), N2 (B = 1.4, HR = 4.0, 95%CI = 1.8,9.1), N3 (B = 1.9, HR = 6.4, 95%CI = 2.8,15.3), and M+ (B = 2.02, HR = 7.5, 95%CI = 4.1,13.7) revealed significant correlation with NPC patients' poor prognosis (p < 0.05). The presence of viral factors also showed a significant association with NPC patients' decreased survival. We concluded that factors related to day-to-day life with EBV infection could be the individual predictor for NPC incidence, lower survival, and disease recurrence. Supplementary Information: The online version contains supplementary material available at 10.1007/s13337-022-00789-5.

Seroprevalence and risk factors of herpes simplex virus type-2 infection among pregnant women in Northeast India.

BACKGROUND: Herpes simplex virus type-2 (HSV-2) is one of the most common sexually transmitted infections that facilitate human immunodeficiency virus (HIV) acquisition by over two fold or more. The development of HSV-2 control methods as a measure to control HIV epidemic in high HSV-2/HIV areas has become a priority. Two out of the six high HIV prevalent states of India are located in the Northeastern region of India. Due to lack of documented HSV-2 studies from this part of the country; there was a need for estimating the seroprevalence and risk factors of HSV-2 infection in this defined population. METHODS: Pregnant women (n = 1640) aged18 years and above attending antenatal clinics of tertiary referral hospitals in five Northeastern states of India were screened for type specific HSV-2 IgG antibodies. Blood samples were collected from all the participants after conducting interviews. Univariate and multivariate analyses were performed to identify the risk factors associated with HSV-2 seropositivity. RESULTS: Overall seroprevalence of HSV-2 infection was 8.7% (142/1640; 95% CI 7.3-10.0) with a highest prevalence of 15.0% (46/307; 95% CI 11.0-19.0) in the state of Arunachal Pradesh. Higher seroprevalence was observed with increasing age (Adj. Odds Ratio [AOR] 1.9 for 22-25 years old, AOR 2.29 for > 29 years old). The risk factors associated with HSV-2 seropositives were multiple sex partners (AOR 2.5, p = 0.04), condom non-user's (AOR 4.7, p <0.001), early coitarchal age (age of first intercourse) 'less than 18 years' (AOR 9.6, p = 0.04), middle income group (AOR 2.1, p = 0.001) compared to low income group and low level of education (AOR 3.7, p = 0.02) compared to higher education. HSV-2 seropositivity was higher among Christians (12.6%) compared to Muslims (3.8%). The most frequent clinical symptoms among HSV-2 seropositives were excess vaginal discharge in last one year (53.5%, 76/142) and pelvic pain (26.1%, 37/142). While among subjects with genital ulcers, HSV-2 seroprevalence was 36.8% (7/19). CONCLUSIONS: Overall seroprevalence of HSV-2 infection among pregnant women of Northeast India is relatively low. The generation of awareness among high risk groups may have played key role to limit the infection. The role of vaccination against HSV-2 in near future and elimination of HSV-2 viral shedding along with genital tract inflammation in high HIV/HSV-2 areas may be an option for initiating successful intervention strategies to reduce the transmission and acquisition of HIV infection in Northeast India.

BAX -248 G>A and BCL2 -938 C>A Variant Lowers the Survival in Patients with Nasopharyngeal Carcinoma and Could be Associated with Tissue-Specific Malignancies: A Multi-Method Approach.

BACKGROUND: The association of BAX -248 G>A and BCL2 -938 C>A with different cancers created conflicts.  We studied the correlation and the effect of these polymorphisms in patients with Nasopharyngeal Carcinoma (NPC).  Methods: PCR-RFLP and Sanger sequencing were used to detect polymorphisms. Statistical analysis including forest plot and Kaplan-Meier Log-rank test was conducted to investigate the association and effect of these SNPs on the NPC patients' survival. The computational study was performed to investigate the possible regulatory role between these polymorphisms and the poor survival of NPC patients. Meta-analysis was executed to check the tissue-specific association of these polymorphisms in the context of global cancer prognosis. RESULTS: We observed an increased and significant association of BAX -248 G>A [GA:OR=5.29, 95%CI=1.67,16.67, P=0.004; GA+AA:OR=5.71, 95%CI=1.82,17.90, P =0.002; A:OR=5.33, 95%CI=1.76,16.13, P=0.003], and BCL2 -938 C>A [CA:OR=2.26, 95%CI=1.03,4.96, P=0.04; AA:OR=3.56, 95%CI=0.97,13.05, P=0.05; CA+AA:OR=3.10, 95%CI=1.51,6.35, P=0.002; A:OR=2.90, 95% CI=1.59,5.29, P=0.0005] with the risk of NPC. Also, these SNPs were strongly correlated with poor survival in NPC patients (lower estimated survival mean, lower estimated proportion surviving at 5 years with p <0.05). The computational study showed that these SNPs altered the binding affinity of transcription factors HIF1, SP1, PAX3, PAX9 and CREB towards promoter (Lower p indicates strong affinity). The meta-analysis revealed the tissue-specific association of these polymorphisms. BAX -248 G>A showed a significant correlation with carcinomas [A vs G:OR=1.60, 95%CI=1.09,2.34, P=0.01; AA vs GG:OR=2.61, 95%CI=1.68,4.06, p <0.001; AA+GA vs GG:OR=1.53,95%CI=1.04,2.25, P=0.02); AA vs GG+GA:OR=2.53, 95%CI=1.65,3.87, p <0.001], and BCL2 -938 C>A with other malignancies [A vs C:OR=1.45, 95%CI=1.26,1.66, p <0.001; AA vs CC:OR=2.07, 95%CI: 1.15,3.72, P=0.01; AA+CA vs CC:OR=1.42, 95%CI=1.18,1.72, p <0.001; AA vs CC+CA:OR=1.89, 95%CI=1.02,3.50, P=0.04]. CONCLUSIONS: BAX -248 G>A and BCL2 -938 C>A was associated with poor survival in NPC patients. It may increase cancer susceptibility through transcriptional regulation. Moreover, these SNPs' effects could be tissue-specific.
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Role of epoxide hydrolase 1 gene polymorphisms in esophageal cancer in a high-risk area in India.

BACKGROUND AND AIM: Microsomal epoxide hydrolase 1 (EPHX1) is involved in the metabolism of environmental and tobacco carcinogens. Tobacco smoking, betel quid chewing, and alcohol consumption are the major known risk factors for esophageal cancer. The present case-control study evaluated the influence of EPHX1 genetic variations on esophageal cancer susceptibility in 142 patients and 185 healthy controls from a high-incidence region of India where tobacco use and alcohol consumption are widespread and the users of these two substances are also betel quid chewers. METHODS: EPHX1 polymorphic alleles (exon 3, Tyr113His and exon 4, His139Arg) were genotyped by polymerase chain reaction-restriction fragment length polymorphism method and direct sequencing. The results were analyzed using logistic regression to calculate odds ratios (OR) and confidence intervals (CI). RESULTS: Patients with exon 4 genotypes (139His/Arg, 139Arg/Arg) and the 139Arg allele were significantly associated with a risk of esophageal cancer (OR(His139Arg) 1.887, 95% CI = 1.112-3.201, P = 0.019; OR(Arg139Arg) 7.140, 95% CI = 1.276-393.953, P = 0.025 and OR(Arg) 1.83, 95% CI = 1.19-2.82, P = 0.003). The 139His/Arg genotype was a significant risk factor for esophageal cancer in tobacco chewers and betel quid chewers. Patients with the 139Arg/Arg genotype were at significantly higher risk for developing a well-differentiated and moderately-differentiated grade of tumor. In contrast, the 113His/His genotype of exon 3 was a significant protective factor for esophageal cancer in tobacco smokers (OR 0.291, 95% CI = 0.138-0.616, P = 0.001), betel quid chewers (OR 0.434, 95% CI = 0.236-0.797, P = 0.007), and alcohol users. CONCLUSION: EPHX1 exon 4 139His/Arg, and 139Arg/Arg genotypes were associated with a higher risk of esophageal cancer in a high-risk area of India.

Betel quid chewing as an environmental risk factor for breast cancer.

Northeast region of India shows high incidence of tobacco-related cancer with widespread consumption of betel quid and tobacco in different forms. There is an increasing incidence of breast cancer and eminent use of tobacco in females in this region. Thus, we analysed the role of tobacco exposure and polymorphisms in detoxification enzymes in breast cancer risk. Polymorphisms in five gene variants (GSTT1, GSTM1, GSTP1, TP53 and CYP17) and four environmental exposure variables (tobacco smoking, tobacco chewing, betel quid chewing, alcohol) were analysed in 117 breast cancer cases and 174 cancer free controls. Multifactor dimensionality reduction identified betel quid chewing as the single main risk factor and women with betel quid chewing history had five times the risk of developing breast cancer [4.78 (2.87-8.00) 0.001]. In logistic regression analysis, GSTT1 null and GSTM1 null genotypes conferred 41% less [0.59 (0.34-1.03) 0.06] and 55% less [0.58 (0.30-1.02) 0.05] reduced risk to breast cancer, respectively. However, the risk increased in women with GSTP1 variant G allele which conferred 1.43 times [(0.96-2.11) 0.07] more risk to breast cancer. In conclusion this study suggests betel quid chewing as a significant risk factor for developing breast cancer. Moreover, the lack of detoxification enzymes GSTT1 and GSTM1 are associated with reduced breast cancer risk.

TLR9 Polymorphisms Might Contribute to the Ethnicity Bias for EBV-Infected Nasopharyngeal Carcinoma.

Nasopharyngeal carcinoma (NPC) is a rare malignancy in most parts of the world, but is endemic in some ethnic groups. The association of NPC with the Epstein-Barr virus (EBV) is firmly established; however, the mechanism is still unclear. TLR9 is well known for its essential role in viral pathogen recognition and activation of innate immunity. Here, we report a set of TLR9 polymorphisms in the TIR-2 domain of the TLR9 protein collected from the EBV-infected NPC samples from northeast Indian populations sharing the aforesaid ethnicity. The occurrence of mutations is significantly high in these samples as we found a p value of <0.0001 at a significance level of 0.05. These might play an important role for the lack of function of TLR9 and thus for the higher occurrence of EBV-mediated NPC in such ethnic groups.