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Dynamic interactions within the tumor micro-environment drive patient response to immune checkpoint inhibitors. Existing preclinical models lack true representation of this complexity. Using a Head and Neck cancer patient derived TruTumor histoculture platform, the response spectrum of 70 patients to anti-PD1 treatment is investigated in this study. With a subset of 55 patient samples, multiple assays to characterize T-cell reinvigoration and tumor cytotoxicity are performed. Based on levels of these two response parameters, patients are stratified into five sub-cohorts, with the best responder and non-responder sub-cohorts falling at extreme ends of the spectrum. The responder sub-cohort exhibits high T-cell reinvigoration, high tumor cytotoxicity with T-cells homing into the tumor upon treatment whereas immune suppression and tumor progression pathways are pre-dominant in the non-responders. Some moderate responders benefit from combination of anti-CTLA4 with anti-PD1, which is evident from better cytotoxic T-cell: T-regulatory cell ratio and enhancement of tumor cytotoxicity. Baseline and on-treatment gene expression signatures from this study stratify responders and non-responders in unrelated clinical datasets. Tumor histocultures have been exploited as tools to predict response to cancer therapy. Here the authors report the development and testing of a tumor histoculture platform to study response to immune checkpoint inhibitors in head and neck squamous cell carcinoma.

BackgroundOnly 1–3 % of patients with Head and Neck Squamous Cell Carcinoma (HNSCC) in low- and middle-income countries can afford Nivolumab treatment even though it is approved for recurrent and metastatic disease.1 Low Dose Nivolumab (LDN) has shown similar efficacy compared to Standard Dose Nivolumab (SDN) in renal and lung cancer.2 3 A recent study demonstrated that HNSCC patient sub-cohort treated with chemotherapy (CT) and LDN showed improved progression-free and overall survival compared to sub-cohort treated with CT alone.1 To better understand the added benefit of the combination treatment, it is important to rule out the contribution of CT alone in the responding patients that might not result in a durable response. To address this, we employed the FarcastTM TruTumor, a near native human histoculture platform which can compare multiple treatment response simultaneously for the same patient sample.MethodsFresh surgically resected HNSCC samples (n=20) along with matched blood were collected from consented patients. Thin explants were generated and distributed into arms. These arms were treated in culture with either LDN (7.3 µg/ml) or SDN (132 µg/ml) and CT (Methotrexate (220.8µg/ml)+erlotinib (2.5µg/ml)+celecoxib (0.7µg/ml) or Paclitaxel (2.7µg/ml)+Carboplatin (37.1µg/ml) alone or CT+LDN for 72 hours. The response was evaluated using histopathology, interferon-γ (IFN-g) cytokine release and flow cytometry.ResultsBoth SDN and LDN treatment led to effective masking of Programmed cell death protein 1 (PD1) expression. No significant difference was observed in tumor cytotoxicity response between LDN and SDN in the same samples (n=8). Analysis of immune cell types and activation markers such as CD8+Granzyme-B+, CD8+Ki67+ T cells also showed no significant difference between LDN and SDN treatments. Comparable IFN-g response was observed in 7/8 samples.We next compared response to CT alone or CT+LDN in the same sample (n=12). Ten out of 12 samples did not show a significant difference in tumor content on treatment with CT+LDN compared to CT alone. Five out of these 10 samples showed a significant increase in cleaved caspase expression in tumor, primarily driven by CT treatment. In two samples CT+LDN showed significant drop in tumor content but not in CT or SDN alone, clearly implicating the benefit of combination treatment.ConclusionsThe FarcastTM TruTumor platform thus provides the unique opportunity to identify patients who would truly benefit from treatment with LDN+CT combination. An observational trial is underway to correlate the response observed in our platform with response of the patient in the clinic.ReferencesPatil VM, Noronha V, Menon N, Rai R, Bhattacharjee A, Singh A, Nawale K, Jogdhankar S, Tambe R, Dhumal S, Sawant R, Alone M, Karla D, Peelay Z, Pathak S, Balaji A, Kumar S, Purandare N, Agarwal A, Puranik A, Mahajan A, Janu A, Kumar Singh G, Mittal N, Yadav S, Banavali S, Prabhash K. Low-dose immunotherapy in head and neck cancer: A randomized study. J Clin Oncol. 2023;41(2):222–232Zhao JJ, Kumarakulasinghe NB, Muthu V, Lee M, Walsh R, Low JL, Choo J, Tan HL, Chong WQ, Ang Y, et al. Low-dose Nivolumab in renal cell carcinoma: A real-world experience. 2021;99(3):192–202Yoo SH, Keam B, Kim M, Kim SH, Kim YJ, Kim TM, Kim DW, Lee JS, Heo DS. Low-dose nivolumab can be effective in non-small cell lung cancer: alternative option for financial toxicity. ESMO Open. 2018;3(5):e000332Ethics ApprovalThe Institutional Ethics Committee (IEC) from the sample collection centers approved the protocol (protocol # FCB-PROTOCOL-01) and informed consent for participation in the approved study was obtained from every donor.

BackgroundA 3D histo-culture platform provides a near native Tumor immune Micro-Environment (TiME), making it best suited for evaluating response to immunotherapy drugs. Farcast™ TiME is a human 3D tumor histo-culture platform that preserves TiME and maintains functional fidelity of intra-tumoral immune cells (IIC). In this study we investigated the utility of this platform in demonstrating treatment induced Antibody-Dependent Cellular Cytotoxicity (ADCC) mechanism driven by IICs alone versus co-culture with autologous peripheral blood immune cells.MethodsHead and neck squamous cell carcinoma tissue samples (n=5) along with matched blood from consented patients were used in this study. All Peripheral Blood Nucleated Cells (PBNCs) including lymphocytes, monocytes, NK cells and neutrophils were isolated and stained with a tracking dye to distinguish them from IICs. Tumor tissues were processed to generate explants, treated with 184 µg/ml Cetuximab (anti-EGFR) or vehicle control, and cultured with or without PBNCs for 72 hrs. Response was evaluated using flow cytometry and cytokine release assay.ResultsAmount of infiltrated autologous PBNCs showed a strong negative correlation (R2=0.98) with the amount of IICs in the absence of drug treatment. The proportions of infiltrated immune cell sub-populations were similar to the composition of PBNCs added in culture. Cetuximab treatment, however, led to enhanced infiltration of the effector cells for ADCC driven tumor killing, namely NK cells, macrophages, neutrophils, and cytotoxic T cells (CTLs). Notably the unique infiltration pattern of effector cell populations observed in each sample was reflected in the secretion of specific cytokine/chemokines associated with that cell population. NK cell increase (fold change: 1.6 ± 0.8) was observed in all samples with a concomitant increase in MCP-1 secretion (fold change: 1.7 ± 0.9). Granzyme-B expressing NK cells increased (>1.7 fold) in a subset of samples. Samples showing increase in neutrophil infiltration exhibited increased MMP9 secretion, involved in neutrophil infiltration via stromal remodeling. Sample with highest increase in infiltration of CD16+ Monocyte/Macrophages (>2.4 fold) showed maximum increase in Granzyme-B secretion with respect to the untreated arm. Increase in fold secretion (>1.4) of CXCL9/CXCL10 was associated with the sample that showed highest fold increase of Granzyme-B expressing CTL in comparison to untreated arm. IICs alone were not sufficient in eliciting optimal ADCC response.ConclusionsThe study demonstrated ADCC response in the explant/PBNC co-culture platform leading to specific infiltration of effector sub-populations. FarcastTM TiME thus provides a unique platform to explore for heterologous adoptive cell and CAR-T therapies that involve immune cell infiltration.Ethics ApprovalAll samples included in the study were approved by institutional review boards of the centers providing the samples.

Mean platelet volume (MPV) is an inflammatory marker indicative of platelet activation. There are several studies that suggest an association between the neoplastic process and cancer metastasis. We performed a retrospective analysis to investigate the role of MPV as a prognostic informative marker in gallbladder cancer. This study included 73 patients who underwent treatment for gallbladder cancer with curative or palliative intent. MPV was obtained and statistically analysed to investigate the association between the nodal status (N), the overall stage as per the American Joint Committee on Cancer (AJCC) staging system, perineural invasion, and differentiation of the tumor. The statistical analysis was done using SPSS Statistics, version 23 (IBM Corp., Armonk, NY). We found that the MPV values were significantly high in node-positive cases (OR = 3.623, 95% CI = 7.778-1.687, p value = -0.0001), cases in the advanced stage (OR = 3.623, 95% CI = 7.778-1.687, p value = 0.0001), cases with perineural invasion (OR = 3.396, 95% CI = 8.319-1.387, p value = -0.0001), and poor differentiation (OR = 2.327, 95% CI = 4.651-1.164, p value = -0.002 ). MPV is an inexpensive and convenient inflammatory marker that correlates with nodal positivity in the staging and prognostication of gallbladder cancer. This marker can be used to ascertain the risk status of gallbladder cancer.Mean platelet volume (MPV) is an inflammatory marker indicative of platelet activation. There are several studies that suggest an association between the neoplastic process and cancer metastasis. We performed a retrospective analysis to investigate the role of MPV as a prognostic informative marker in gallbladder cancer. This study included 73 patients who underwent treatment for gallbladder cancer with curative or palliative intent. MPV was obtained and statistically analysed to investigate the association between the nodal status (N), the overall stage as per the American Joint Committee on Cancer (AJCC) staging system, perineural invasion, and differentiation of the tumor. The statistical analysis was done using SPSS Statistics, version 23 (IBM Corp., Armonk, NY). We found that the MPV values were significantly high in node-positive cases (OR = 3.623, 95% CI = 7.778-1.687, p value = -0.0001), cases in the advanced stage (OR = 3.623, 95% CI = 7.778-1.687, p value = 0.0001), cases with perineural invasion (OR = 3.396, 95% CI = 8.319-1.387, p value = -0.0001), and poor differentiation (OR = 2.327, 95% CI = 4.651-1.164, p value = -0.002 ). MPV is an inexpensive and convenient inflammatory marker that correlates with nodal positivity in the staging and prognostication of gallbladder cancer. This marker can be used to ascertain the risk status of gallbladder cancer.

18% of the world's population lives in India, and many states of India have populations similar to those of large countries. Action to effectively improve population health in India requires availability of reliable and comprehensive state-level estimates of disease burden and risk factors over time. Such comprehensive estimates have not been available so far for all major diseases and risk factors. Thus, we aimed to estimate the disease burden and risk factors in every state of India as part of the Global Burden of Disease (GBD) Study 2016. Using all available data sources, the India State-Level Disease Burden Initiative estimated burden (metrics were deaths, disability-adjusted life-years [DALYs], prevalence, incidence, and life expectancy) from 333 disease conditions and injuries and 84 risk factors for each state of India from 1990 to 2016 as part of GBD 2016. We divided the states of India into four epidemiological transition level (ETL) groups on the basis of the ratio of DALYs from communicable, maternal, neonatal, and nutritional diseases (CMNNDs) to those from non-communicable diseases (NCDs) and injuries combined in 2016. We assessed variations in the burden of diseases and risk factors between ETL state groups and between states to inform a more specific health-system response in the states and for India as a whole. DALYs due to NCDs and injuries exceeded those due to CMNNDs in 2003 for India, but this transition had a range of 24 years for the four ETL state groups. The age-standardised DALY rate dropped by 36·2% in India from 1990 to 2016. The numbers of DALYs and DALY rates dropped substantially for most CMNNDs between 1990 and 2016 across all ETL groups, but rates of reduction for CMNNDs were slowest in the low ETL state group. By contrast, numbers of DALYs increased substantially for NCDs in all ETL state groups, and increased significantly for injuries in all ETL state groups except the highest. The all-age prevalence of most leading NCDs increased substantially in India from 1990 to 2016, and a modest decrease was recorded in the age-standardised NCD DALY rates. The major risk factors for NCDs, including high systolic blood pressure, high fasting plasma glucose, high total cholesterol, and high body-mass index, increased from 1990 to 2016, with generally higher levels in higher ETL states; ambient air pollution also increased and was highest in the low ETL group. The incidence rate of the leading causes of injuries also increased from 1990 to 2016. The five leading individual causes of DALYs in India in 2016 were ischaemic heart disease, chronic obstructive pulmonary disease, diarrhoeal diseases, lower respiratory infections, and cerebrovascular disease; and the five leading risk factors for DALYs in 2016 were child and maternal malnutrition, air pollution, dietary risks, high systolic blood pressure, and high fasting plasma glucose. Behind these broad trends many variations existed between the ETL state groups and between states within the ETL groups. Of the ten leading causes of disease burden in India in 2016, five causes had at least a five-times difference between the highest and lowest state-specific DALY rates for individual causes. Per capita disease burden measured as DALY rate has dropped by about a third in India over the past 26 years. However, the magnitude and causes of disease burden and the risk factors vary greatly between the states. The change to dominance of NCDs and injuries over CMNNDs occurred about a quarter century apart in the four ETL state groups. Nevertheless, the burden of some of the leading CMNNDs continues to be very high, especially in the lowest ETL states. This comprehensive mapping of inequalities in disease burden and its causes across the states of India can be a crucial input for more specific health planning for each state as is envisioned by the Government of India's premier think tank, the National Institution for Transforming India, and the National Health Policy 2017. Bill & Melinda Gates Foundation; Indian Council of Medical Research, Department of Health Research, Ministry of Health and Family Welfare, Government of India; and World Bank

Background: Diabetes mellitus is a complex multisystem metabolic disorder characterized by a deficit in the production of insulin. The oral complications of uncontrolled diabetes mellitus are devastating. Saliva is an organic fluid that can be collected noninvasively and by individuals with limited training. These reasons create an interest in evaluating the possibility of using saliva as a diagnostic tool.Aims and Objectives: The aim of this study was to determine, if saliva can be used as a noninvasive tool to monitor glycemic control in Type 2 diabetes. Comparative assessment of salivary (glucose, amylase, total protein levels) in patients with Type 2 diabetes and controls. Materials and Methods: A total of 40 individuals, 20 with Type 2 diabetes and 20 controls of age group 40-60 years were selected for the study. Diabetic status was assessed by estimating random blood glucose levels. Unstimulated saliva was collected from each participant and investigated for glucose, amylase, and total protein levels. Salivary glucose estimation was performed using glucose-oxidase method, amylase by the direct substrate kinetic enzymatic method, and total protein by pyrogallol red dye end point method. All the parameters were subjected to statistical analysis using SPSS version 20.0. Results: Significantly higher salivary glucose, lower amylase, and total proteins were observed in patients with Type 2 diabetes than controls. There was no significant correlation between salivary and blood glucose levels. Conclusion: These results suggest that diabetes influences the composition of saliva. Since a significant correlation was not observed between salivary and blood glucose levels, further research is needed to determine salivary glucose estimation as a diagnostic tool for diabetes mellitus.

Pulmonary artery pseudoaneurysm (PAP) is a rare but potentially fatal entity caused by a variety of underlying conditions. They may be congenital in origin or occur due to infective complications or occasionally secondary to pulmonary arterial hypertension. Among infective processes, tuberculosis and bacterial infections are the most common causative agents. There are few isolated reports of angio-invasive mucormycosis causing PAP; many of them were detected postmortem. Diagnosis of specific aetiology is often overlooked due to lack of clinical suspicion, as a result of incomplete investigations or due to inappropriate imaging. This report presents a case of pulmonary mucormycosis complicated by PAP in a patient with clinically unsuspected, uncontrolled diabetes. We highlight how the combination of heightened clinical suspicion, appropriate imaging and timely intervention helped us to treat a potentially fatal complication in our patient.

Introduction: Coronavirus 19 (COVID-19) disease spread rapidly over the world since its inception in December 2019 in Wuhan, China. India too was crippled by the burden of high caseloads and deaths. The first death caused by COVID-19 in Karnataka was reported on March 13, 2020. There is a plethora of information on the descriptive statistics, epidemiology, and management of COVID-19 cases. However, there has not been an in-depth and extensive exploration of COVID-19 mortality data in terms of published research from India. The study area was a 300 bedded tertiary care center in Ramnagara district, Karnataka. During the second wave, 150 beds were dedicated to COVID-19 cases referred from government centers. This study was carried out to assess the in-hospital mortality at this institute during the second wave. The expected outcome of this study was to shed light on co-morbidities associated with mortality, the age and sex distribution in mortality, and any other significant factors influencing mortality due to COVID-19.Methodology: A hospital-based, retrospective, and observational-analytical study was carried out during April-August 2021, the second wave of COVID-19. The data included all deaths recorded in-hospital during the dedicated COVID-19 referral center status. Data were collected from case sheets and mortality audit forms that included basic demographics, symptoms, co-morbidities, admission pathway, transfer to ICU, oxygen therapy, ventilator requirement, duration of hospitalization, laboratory profile, and management modalities prior to death. Data were compiled into Microsoft Excel and were analyzed with JASP software (open source). Data were interpreted in terms of frequencies, averages with standard deviation, and bivariate and multivariate analysis.Results: We analyzed mortality audits of 91 adult patients and one neonate. The male-to-female ratio was 1.67:1 (> 60% male), with an average age of 53.4 years (standard deviation 15.4 years). Most of the patients fell in the age range of 36 to 65 years (65%). The average duration was 5.6 days (range 0-35 days). The most common symptom was fever (84, 92.31%), followed by breathlessness (77, 84.62%) and fatigue (65, 71.43%). Only 10 had a positive contact history and only one patient reported travel to a containment zone. The source of infection was indeterminate in the majority of cases. Diabetes mellitus and hypertension were the commonest associated comorbidities. Almost three-quarters of the patients were tachypneic at admission and nearly 90% had low levels which included 43 patients with critically low SpO2. The inflammatory indicators, such as WBC count, CRP, and d-dimer, were raised in many patients (WBC count raised in 40% and d-dimer, CRP raised in > 50% of cases). A striking 83% of the patients had hyperglycemia. The most common immediate cause of death pertained to the respiratory system (ARDS, refractory hypoxia, respiratory) in more than half of the patients.Conclusion: This study reported the clinical and laboratory characteristics of 91 adult COVID-19 mortality cases at a teaching hospital at the peak of the Delta wave in Karnataka. While inflammatory indicators such as WBC count, CRP, and d-dimer were raised in many patients, our most remarkable finding was the high frequency of hyperglycemia. The findings of our study would contribute to enhancing the understanding of the clinical correlates and progression of COVID-19.

Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are closely related severe, acute mucocutaneous reactions usually caused by drugs. They are acute life-threatening conditions and cause widespread necrosis of the epithelium. There is persistence of a high risk of SJS or TEN in relation to human immunodeficiency virus (HIV) infection associated with exposure to nevirapine (NVP). In this article, we present nine cases of SJS and one case of TEN in HIV-seropositive individuals who developed cutaneous, oral, ocular and genital lesions while being treated with NVP.

Background: Aggressive periodontitis (AP) is a complex disease whose phenotype is determined by genetic and environmental influences on the affected individuals. About 45% of the adult population in India has periodontitis. In Tumkur district of Karnataka, India, consanguineous first cousin and uncle-niece marriages are common, with a high incidence of AP. These discrepancies in the expression of periodontal disease directed us to find genetic etiology with respect to the Tumkur population. The clinical and genetic aspects of AP from this area have been presented in this paper. Materials and Methods: A total of nine families were ascertained at the Department of Periodontics, Sri Siddhartha Dental College and Hospital (Sri Siddhartha University), Tumkur. The clinical and radiographic data were gathered according to 1999 Consensus Classification of Periodontal Diseases. Peripheral blood samples were collected for total genomic DNA isolation using a Wizard TM Genomic Purification Kit (Promega, USA). The homozygosity mapping was carried out in a large consanguineous family to map a novel locus using autosomal markers from the CHLC/Weber Human Screening Set 10 (Research Genetics Inc., USA) at Indian Institute of Sciences, Bangalore. Results: The pedigree analysis suggested that the disorder is segregating as an autosomal trait. The homozygosity mapping failed to identify a locus for generalized AP in the family. Conclusion: The disorder may not be segregating as an autosomal recessive trait and we could have been misled by consanguinity in the family. It could be a multifactorial trait, or it could be still segregating as an autosomal recessive trait, but the region of homozygosity could be small and we failed to detect it using microsatellite markers. Therefore, SNP-marker-based analysis is warranted in future.