Ewing sarcoma among children 5 years of age or younger: Is it a different disease?

INTRODUCTION: Children ≤5 years of age with Ewing's sarcoma (ES) possibly have a distinct disease biology, data on which are scarce. We evaluated clinical features, outcomes, and prognostic factors of ES among children with age ≤5 years. METHODS: Children with ES registered between 2003 and 2019 were included. Baseline clinical and treatment details were retrieved from medical records. Prognostic factors were identified using multivariable Cox regression. Clinical features and outcomes of children ≤5 years were compared with those greater than 5 years by chi-square and log-rank tests. Propensity score-matched (PSM) analysis was done to evaluate the impact of age on survival in the metastatic and localized subgroups. RESULTS: Out of the 859 patients, 86 (10%) were ≤5 years of age (median age 4 years, 60 males [69.8%]). The most common location was the extremities (37.2%), followed by thorax (27.9%) and head and neck (H&N) (22.1%); baseline metastases were seen in 25 patients (29.8%). The median event-free-survival (EFS) and overall survival (OS) were 25.6 and 68.7 months, respectively. Metastatic disease predicted inferior OS (hazard ratio [HR] = 2.54, p = .018) and EFS (HR = 2.47, p = .007], symptom duration ≤3 months predicted an inferior OS (HR = 2.17, p = .048). Compared to age greater than 5 years, younger children had more H&N and less pelvic primaries (p < .001) and lesser baseline metastases (p = .037). PSM analysis did not reveal any significant impact of age on OS in the metastatic (HR = 1.59, p = .29) or localized cohort (HR = 1.77, p = .09). CONCLUSIONS: Children with ES ≤5 years of age have a distinct favorable clinical presentation. However, age is not an independent prognostic factor for survival outcomes when adjusted for confounders.

The Role of Dietary Anthocyanins for Managing Diabetes Mellitus-Associated Complications.

Diabetes mellitus (DM) is an intricate metabolic disorder marked by persistent hyperglycemia, arising from disruptions in glucose metabolism, with two main forms, type 1 and type 2, involving distinct etiologies affecting ß-cell destruction or insulin levels and sensitivity. The islets of Langerhans, particularly ß-cells and α-cells, play a pivotal role in glucose regulation, and both DM types lead to severe complications, including retinopathy, nephropathy, and neuropathy. Plant-derived anthocyanins, rich in anti-inflammatory and antioxidant properties, show promise in mitigating DM-related complications, providing a potential avenue for prevention and treatment. Medicinal herbs, fruits, and vegetables, abundant in bioactive compounds like phenolics, offer diverse benefits, including glucose regulation and anti-inflammatory, antioxidant, anticancer, anti-mutagenic, and neuroprotective properties. Anthocyanins, a subgroup of polyphenols, exhibit diverse isoforms and biosynthesis involving glycosylation, making them potential natural replacements for synthetic food colorants. Clinical trials demonstrate the efficacy and safety of anthocyanins in controlling glucose, reducing oxidative stress, and enhancing insulin sensitivity in diabetic patients, emphasizing their therapeutic potential. Preclinical studies revealed their multifaceted mechanisms, positioning anthocyanins as promising bioactive compounds for managing diabetes and its associated complications, including retinopathy, nephropathy, and neuropathy.

Folate and Vitamin B12 Status in Women of Reproductive Age in Rural Haryana, India: Estimating Population-Based Prevalence for Neural Tube Defects.

BACKGROUND: Folate and vitamin B12 deficiencies in pregnant women are associated with increased risk for adverse maternal and infant health outcomes, including neural tube defects (NTDs). METHODS: A population-based cross-sectional survey was conducted in two rural areas in Ambala District, Haryana, India in 2017 to assess baseline folate and vitamin B12 status among women of reproductive age (WRA) and predict the prevalence of NTDs. We calculated the prevalence of folate and vitamin B12 deficiency and insufficiency by demographic characteristics among 775 non-pregnant, non-lactating WRA (18-49 years). Using red blood cell (RBC) folate distributions and an established Bayesian model, we predicted NTD prevalence. All analyses were conducted using SAS-callable SUDAAN Version 11.0.4 to account for complex survey design. RESULTS: Among WRA, 10.1% (95% CI: 7.9, 12.7) and 9.3% (95% CI: 7.4, 11.6) had serum (<7 nmol/L) and RBC folate (<305 nmol/L) deficiency, respectively. The prevalence of RBC folate insufficiency (<748 nmol/L) was 78.3% (95% CI: 75.0, 81.3) and the predicted NTD prevalence was 21.0 (95% uncertainly interval: 16.9, 25.9) per 10,000 live births. Prevalences of vitamin B12 deficiency (<200 pg/mL) and marginal deficiency (≥200 pg/mL and ≤300 pg/mL) were 57.7% (95% CI: 53.9, 61.4) and 23.5% (95% CI: 20.4, 26.9), respectively. CONCLUSIONS: The magnitude of folate insufficiency and vitamin B12 deficiency in this Northern Indian population is a substantial public health concern. The findings from the survey help establish the baseline against which results from future post-fortification surveys can be compared.

DOTAP Modified Formulations of Aminoacid Based Cationic Liposomes for Improved Gene Delivery and Cell Viability.

The liposomal systems proved remarkably useful for the delivery of genetic materials but enhancing their efficacy remains a significant challenge. While structural alterations could result in the discovery of more effective transfecting lipids, improving the efficacy of widely used lipid carriers is also crucial in order to compete with viral vectors for gene delivery. Herein, we developed formulations of commercially available lipid, 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) with synthetic cationic lipids containing amino acids,  cystine (CTT) or arginine (AT) in the head group. These lipids were used to formulate with different co-lipid compositions and were broadly categorised into two types: amino acid-based liposomes without DOTAP (CTTD and ATD) and those with DOTAP (DtATD and DtCTTD). Optimized lipid-DNA complexes of DOTAP-incorporated formulations (DtATD and DtCTTD) exhibited enhanced efficacy in transfection compared to formulations lacking DOTAP as well as commercial formulations such as DOTAP:DOPE. Notably, DtCTTD displayed superior transfection capabilities in prostate cancer (PC3) and lung cancer (A549) cell lines when compared to the widely used commercial transfection reagent, Lipofectamine. Collectively, the findings from this study suggest that DOTAP-incorporated formulations derived from amino acid-based liposomes, hold promise as effective tools for improving transfection efficacy with reduced toxicity, offering potential advancements in gene delivery applications.

Bioactive Milk Peptides as a Nutraceutical Opportunity and Challenges.

The biotechnology field has witnessed rapid advancements, leading to the development of numerous proteins and peptides (PPs) for disease management. The production and isolation of bioactive milk peptides (BAPs) involve enzymatic hydrolysis and fermentation, followed by purification through various techniques such as ultrafiltration and chromatography. The nutraceutical potential of bioactive milk peptides has gained significant attention in nutritional research, as these peptides may regulate blood sugar levels, mitigate oxidative stress, improve cardiovascular health, gut health, bone health, and immune responses, and exhibit anticancer properties. However, to enhance BAP bioavailability, the encapsulation method can be used to offer protection against protease degradation and controlled release. This article provides insights into the composition, types, production, isolation, bioavailability, and health benefits of BAPs.

Autologous Stem Cell Transplantation in Adult Hodgkin Lymphoma at a Tertiary Care Center in India: Analysis of Outcomes and Prognostic Factors.

High-dose chemotherapy and autologous stem cell transplant (ASCT) is the standard of care treatment in relapsed/refractory Hodgkin lymphoma (rrHL). Published long-term follow-up data concerning this modality from the Indian subcontinent is lacking. In this retrospective study, the data on adults (> 16 years) with biopsy-confirmed rrHL who were autografted from 1 January 2000 to 31 December 2021 at our transplant unit were analyzed. Progression-free survival (PFS) was defined as time from transplant to disease progression or death due to any cause. Overall survival (OS) was determined from date of transplant to date of death due to any cause. Overall, 134 patients with Hodgkin lymphoma underwent ASCT. At a median follow-up of 38.2 (range, 0.1-240) months, 5 years PFS was 45.3% (95% CI 35.4-54.4). The probability of OS at 5 years was 60.5% (95% CI 49.6-69.6). Eleven (8.2%) patients suffered transplant-related mortality by 100 days. Post-transplant persistent disease, pre-transplant serum hypoalbuminemia (< 3.5 g/dl) and chemo-resistance (< PR after last salvage regimen) of tumour at transplant were independent prognostic factors associated with worse PFS in multivariable analysis. Likewise, age ≥ 30 years, ECOG performance status ≥ 1 and residual disease after transplantation correlated with inferior OS. Long-term outcomes of rrHL patients undergoing ASCT in India match those from the developed world in the era of peripheral blood stem cell transplantation. Pre-transplant performance status, chemo-sensitivity of disease, serum albumin and post-transplant remission status determined survival in our cohort. Supplementary Information: The online version contains supplementary material available at 10.1007/s12288-023-01690-x.

Carboplatin in Patients With Metastatic Castration-Resistant Prostate Cancer Harboring Somatic or Germline Homologous Recombination Repair Gene Mutations: Phase II Single-Arm Trial.

BACKGROUND: Approximately 20%-25% of patients with metastatic castration-resistant prostate cancer (mCRPC) harbor a deleterious germline or somatic mutation in the homologous recombination repair (HRR) pathway genes, which is involved in the repair of double-stranded DNA damage. Half of these mutations are germline, while the remaining are exclusively somatic. While polyadenosine 5'diphosphoribose [poly (ADP-ribose)] polymerase inhibitors, such as olaparib and rucaparib, are effective in this subgroup, their widespread use is limited due to the associated high cost, especially in resource-constrained settings. Notably, platinum agents like carboplatin have exquisite sensitivity to cells with defective DNA repair machinery. Carboplatin, a conventional, inexpensive chemotherapeutic agent, offers a potential alternative treatment in such patients. Several retrospective small case series support this hypothesis. However, there are no prospective clinical trials of carboplatin in patients with mCRPC with HRR mutations. OBJECTIVE: The primary objective is to assess the objective response rate of 3 weekly carboplatin treatments in patients with mCRPC harboring deleterious mutations in the HRR pathway genes and previously treated with a taxane or a novel antiandrogen agent. The secondary objectives include progression-free survival, health-related quality of life, and safety profile of carboplatin. METHODS: Patients diagnosed with mCRPC harboring HRR pathway mutations previously treated with docetaxel or novel antiandrogen agents (abiraterone, enzalutamide, apalutamide, or darolutamide) or both will be eligible. Genes involved directly or indirectly in the HRR pathway will be tested. In this single-arm phase II study, we will screen approximately 200 patients to enroll 49 patients, and carboplatin (dosing at the area under curve=5) will be administered every 3 weeks until progression or intolerable side effects. The primary end point will be assessed as the proportion of patients with a reduction of serum prostate-specific antigen by more than 50% from enrollment. Secondary outcomes include progression-free survival-soft-tissue disease progression (by response evaluation criteria in solid tumors, version 1.1, and bone lesion progression using Prostate Cancer Clinical Trials Working Group 3 criteria), health-related quality of life during carboplatin treatment using the Functional Assessment of Cancer Therapy-Prostate questionnaire and the European Organisation for Research and Treatment of Cancer questionnaire and safety profile of carboplatin (National Cancer Institute's Common Terminology Criteria for Adverse Events version 5.0). RESULTS: The trial started enrollment in September 2023. This trial is ongoing, and 12 patients have been recruited to date. All 49 participants will be enrolled according to plan. CONCLUSIONS: This prospective phase II trial represents a critical step toward addressing the therapeutic gap in patients with mCRPC harboring HRR pathway mutations, particularly in demographic regions with limited access to poly (ADP-ribose) polymerase inhibitors. Outcomes from this study will inform clinical practice and guide future phase III randomized trials, ultimately improving patient outcomes globally. TRIAL REGISTRATION: Clinical Trials Registry of India CTRI/2023/04/051507; https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=Njc0NjU=&Enc=&userName=. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/54086.

Comprehensive germline profiling of patients with breast cancer: initial experience from a Familial Cancer Clinic.

Introduction: Breast cancer is the most common cancer among Indian females. There is limited data on germline profiling of breast cancer patients from India. Objective: The objective of the current study was to analyse the frequency and spectrum of germline variant profiles and clinicopathological characteristics of breast cancer patients referred to our Familial Cancer Clinic (FCC). Materials and methods: It is a single-centre audit of patients with a confirmed diagnosis of breast carcinoma referred to our FCC from January 2017 to 2020. All patients underwent pretest counselling. Genetic testing was done by multigene panel testing by next-generation sequencing along with reflex multiplication ligation-dependent probe amplification for BRCA1 and 2. The variants were classified based on American College of Medical Genetics guidelines. Demographic and clinicopathological details were extracted from the case record files. Results: One hundred and fifty-five patients were referred to the FCC and underwent pretest counselling. A total of 99 (63.9%) patients underwent genetic testing. Among them, 62 patients (62/99 = 62.6%) had a germline variant. A pathogenic/likely pathogenic (P/LP) germline variant was identified in 41 (41.4%) of the patients who underwent testing. Additional variants of unknown significance (VUS) were identified in seven patients who also carried a P/LP variant. VUS alone was detected in 21 patients (21/99 = 21.2%). Among the P/LP pathogenic variants (PV), BRCA 1 PV were seen in 27 patients (65.8%), BRCA 2 variants in 7 patients (17.1%), ATM variants in 3 patients (7.3%) and RAD51, TP53, CHEK2 and HMMR in 1 patient each. Variants were significantly more common in patients with a family history (FH) of malignancy than those without FH (58.5% versus 29.5%; p = 0.013). Age and triple-negative histology were not found to be significantly associated with the occurrence of P/LP PVs. Conclusion: We report a 41% P/LP variant rate in our selected cohort of breast cancer patients, with variants in BRCA constituting 83% and non-BRCA gene variants constituting 17%.

Topical Diclofenac for Prevention of Capecitabine-Associated Hand-Foot Syndrome: A Double-Blind Randomized Controlled Trial.

PURPOSE: Hand-foot syndrome (HFS) is a dose-limiting side effect of capecitabine. Celecoxib prevents HFS by inhibiting cyclooxygenase-2 (COX-2) that is upregulated because of the underlying associated inflammation. However, systemic side effects of celecoxib have limited routine prescription. Topical diclofenac inhibits COX-2 locally with minimal risk of systemic adverse events. Therefore, we conducted this study to assess the efficacy of topical diclofenac in the prevention of capecitabine-induced HFS. METHODS: In this single-site phase III randomized double-blind trial, we enrolled patients with breast or GI cancer who were planned to receive capecitabine-based treatment. Participants were randomly assigned in a 1:1 ratio to receive topical diclofenac or placebo gel for 12 weeks or until the development of HFS, whichever occurred earlier. The primary end point was the incidence of grade 2 or 3 HFS (Common Terminology Criteria for Adverse Events version 5), which was compared between the two groups using simple logistic regression. RESULTS: In total, 264 patients were randomly assigned to receive topical diclofenac gel (n = 131) or placebo (n = 133). Grade 2 or 3 HFS was observed in 3.8% of participants in the diclofenac group compared with 15.0% in the placebo group (absolute difference, 11.2%; 95% CI, 4.3 to 18.1; P = .003). Grade 1-3 HFS was lower in the diclofenac group than in the placebo group (6.1% v 18.1%; absolute risk difference, 11.9%; 95% CI, 4.1 to 19.6). Capecitabine dose reductions because of HFS were less frequent in the diclofenac group (3.8%) than in the placebo group (13.5%; absolute risk difference, 9.7%; 95% CI, 3.0 to 16.4). CONCLUSION: Topical diclofenac prevented HFS in patients receiving capecitabine. This trial supports the use of topical diclofenac to prevent capecitabine-associated HFS.

In silico identification of chikungunya virus replication inhibitor validated using biochemical and cell-based approaches.

Discovering an alternative therapy with a long-lasting effect on symptoms caused by chikungunya virus (CHIKV) infection is prompted by the lack of a vaccine and the absence of safe, effective and non-toxic medications. One potential strategy is synthesizing or identifying small compounds that can specifically target the active site of an essential enzyme and prevent virus replication. Previous site-directed mutagenesis studies have demonstrated the crucial role of the macrodomain, which is a part of non-structural protein 3 (nsP3), in virus replication. Exploiting this fact, the macrodomain can be targeted to discover a natural substance that can inhibit its function and thereby impede virus replication. With this aim, the present study focused on potential CHIKV nsP3 macrodomain (nsP3MD) inhibitors through in silico, in vitro and cell-based methods. Through virtual screening of the natural compound library, nine nsP3MD inhibitors were initially identified. Molecular dynamics (MD) simulations were employed to evaluate these nine compounds based on the stability of their ligand-receptor complexes and energy parameters. Target analysis and ADMET (i.e. absorption, distribution, metabolism, excretion and toxicity) prediction of the selected compounds revealed their drug-like characteristics. Subsequent in vitro investigation allowed us to narrow the selection down to one compound, N-[2-(5-methoxy-1H-indol-3-yl) ethyl]-2-oxo-1,2-dihydroquinoline-4-carboxamide, which exhibited potent inhibition of CHIKV growth. This molecule effectively inhibited CHIKV replication in the stable embryonal rhabdomyosarcoma cell line capable of producing CHIKV. Our findings demonstrate that the selected compound possesses substantial anti-CHIKV nsP3MD activity both in vitro and in vivo. This work provides a promising molecule for further preclinical studies to develop a potential drug against the CHIKV.

SMART-ESAS: Smartphone Monitoring and Assessment in Real Time of Edmonton Symptom Assessment System Scores for Patients With Cancer.

PURPOSE: Serial patient-reported outcome (PRO) measurements in clinical practice are associated with a better quality of life and survival. Recording electronic PROs using smartphones is an efficient way to implement this. We aimed to assess the feasibility of the electronically filled Edmonton Symptom Assessment System (e-ESAS) scale in the lower-middle-income country (LMIC) setting. METHODS: Baseline clinical features and conventional paper-based ESAS (p-ESAS) were collected in newly diagnosed patients with solid organ tumors. Text message link was sent to these patients for filling e-ESAS. ESAS was categorized into physical, psychological, and total symptom domains. Scores were divided into none to mild (0-3) and moderate to severe (4-10). Intraclass correlation coefficients (ICCs) were used to determine the correlation between p-ESAS and e-ESAS. Multivariable logistic regression was used to identify independent factors affecting symptom burden. RESULTS: Of 1,160 participants who filled out p-ESAS, 595 completed both e-ESAS and p-ESAS questionnaires and were included in the final analysis. Moderate to severe physical, psychological, and total symptom scores were seen in 39.8%, 40%, and 39% of participants. Tiredness and anxiety were the most common physical and psychological symptoms, respectively. ICCs between the p-ESAS and e-ESAS varied between 0.75 and 0.9. Total symptom scores were independently predicted by metastatic disease (odds ratio [OR], 1.83; 95% CI, 1.26 to 2.67; P = .001) and a higher level of education (OR, 0.42; 95% CI, 0.25 to 0.72; P = .001). CONCLUSION: Paper-based and electronically filled ESASs have good intraobserver reliability across individual symptoms and domain scores in a representative cohort at a tertiary care institute in the LMIC. This may help us incorporate e-ESAS in routine clinical care in the real-world setting with financial, infrastructural, and manpower limitations.

Platelet-to-albumin ratio and radiation-induced lymphopenia-prognostic biomarker for carcinoma esophagus.

BACKGROUND: Esophageal cancer has a poor survival outcome with 5-year OS at 16.7% despite treatment. Some inflammation-based prognostic indicators like the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been previously studied as potential biomarker for predicting outcome in esophageal cancer. Recently, platelet-to-albumin ratio (PAR) has been reported as a promising prognostic factor in gastrointestinal malignancies. METHODS: We performed a retrospective analysis of prospectively treated patients of carcinoma esophagus to evaluate the prognostic significance of inflammation-based prognostic indicators-neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and a composite inflammation-nutrition index: platelet-to-albumin ratio (PAR) in esophageal cancer. Based on previous studies, the optimal cut-off value of PAR was kept at 5.7 × 10^9, and 2.62 for NLR. RESULTS: A total of 71 patients of locally advanced esophageal cancer treated between 2019 and 2022, with either neoadjuvant or definitive chemoradiotherapy, were included. Median follow-up time was 19 months [range: 7-44 months]. Median OS and PFS in our study cohort were 11.3 months [range: 7-23 months] and 7.8 months [range: 3-17 months], respectively. In univariate analysis, lower PAR was found to be significantly correlated with shorter survival time (HR = 2.41; 1.3-4.76; p = 0.047). There was no association found between the OS and the NLR [HR = 1.09; 0.95-1.26; p = 0.222]. Univariate and multivariate linear and logistic regressions found no association between V15, V10, V5, or V2 of spleen and nadir lymphocyte count or between Dmax or Dmean and nadir lymphocyte counts. CONCLUSION: Present analysis found a trend toward an inverse association between PAR and OS. PAR, in the not-so-distant future, may evolve as a novel, convenient, and inexpensive prognostic indicator in esophageal cancer.

Treatment outcomes in patients with Ewing sarcoma of the spine in a resource-challenged setting: 17-year experience from a single center in India.

Ewing sarcoma (ES) of the spine is a rare childhood cancer with sparse literature on treatment outcomes. We aimed to describe survival outcomes and prognostic factors in patients with spinal ES treated at a single institute in a resource-challenged setting. We conducted a retrospective analysis of patients with spinal ES registered at a tertiary care oncology center between 2003-2019. Clinical patient data was retrieved from hospital records. Cox regression analysis was used to identify the association of baseline clinical parameters with event free survival (EFS) and overall survival (OS). A cohort of 85 patients was analyzed including 38 (45%) patients with metastatic disease. The median age was 15 years with 73% being male. Local therapy was administered in 62 (72.9%) patients with surgery alone in 8 (9.4%), radiotherapy alone in 36 (42.4%) and both in 18 (21.2%) patients. A higher proportion of males received local therapy than females (80.3% versus 59.1%; p = 0.049). The median EFS and OS were 20.1 and 28.6 months, respectively. On univariable analysis, age ≤ 15 years, female sex, serum albumin ≤3.5 g/dL and hemoglobin ≤11 g/dL were associated with inferior EFS while younger age, female sex, hypoalbuminemia and metastatic disease were associated with inferior OS. On multivariable analysis, only hypoalbuminemia was predictive for inferior EFS (HR:2.41; p = 0.005) while hypoalbuminemia (HR:2.06;p = 0.033) and female sex (HR:1.83; p = 0.046) were associated with inferior OS. We concluded that hypoalbuminemia confers poor prognosis in ES spine. Survival outcomes are poorer in females treated in our setting, possibly due to prevailing sex-based biases.

Effect of landfilling time on physico-chemical properties of combustible fractions in excavated waste.

Excavated waste is a byproduct of microbial decomposition and fermentation following landfill disposal. The effective management and utilization of excavated waste offer broad prospects for environmental and resource protection, as well as economic growth. While current research predominantly focuses on plastics in landfills, the physico-chemical properties of excavated waste over extended landfilling time remain unclear. This study aimed to address this gap by excavating waste from a landfill in Tianjin, China, with a maximum landfilling time of 18 years. The findings revealed that, compared to municipal solid waste (MSW), the excavated waste exhibited increased calorific value, ash content, and fixed carbon content after screening the landfill-mined-soil-like-fine fraction. The average calorific value of the excavated waste could reach 57.8 MJ/kg. Additionally, the oxygen content in the excavated combustible waste exceeded that of MSW, increasing from 25.59 % to 34.22 %. This phenomenon is potentially linked to the oxidation of attached soil impurities and waste. The study identified polyethylene (PE), polypropylene (PP), expanded polystyrene (EPS), polyethylene terephthalate (PET), and wood as the primary combustible components. Notably, the excavated waste exhibited a significant decrease in surface gloss, adopting a rough texture with apparent holes, potentially attributed to the acidification and corrosion of organic matter during fermentation. Nevertheless, the breaking of molecular bonds could also contribute to waste fragmentation. Furthermore, an increase in landfilling time resulted in a more pronounced decrease in mechanical properties. For instance, the failure load of PE decreased from 15.61 N to 6.46 N, and PET reduced from 884.83 N to 186.56 N. The chemical composition of excavated waste has changed, with -OH and CO observed in PE with an 18-year landfilling time. In conclusion, these results provide a theoretical foundation for the recycling of excavated waste and contribute to the advancement of waste management and recycling technologies.

Dexamethasone-free antiemetic strategy for highly emetogenic chemotherapy: safety and efficacy-pilot study.

OBJECTIVES: Dexamethasone sparing strategies have shown success. The feasibility of a dexamethasone-free antiemetic strategy remains undetermined. A prospective, single-arm, pilot study was planned to determine the efficacy of an olanzapine-based, dexamethasone-free, three-drug antiemetic regimen. METHODS: Chemotherapy naïve, adult patients (≥18 years) who received ondansetron, aprepitant and olanzapine during the first cycle of highly emetogenic chemotherapy were enrolled. The primary endpoint was the rate of complete response (CR: no vomiting and no use of rescue medications) during the overall period (0-120 hours). RESULTS: Out of the total of 101 patients enrolled, most were women (82%) and received anthracycline cyclophosphamide (73%) combination therapy. The rate of CR for the overall period was 65% (95% CI 55.2% to 74.5%). The rate of CR for the acute and delayed period was 79% (95% CI 70% to 86.7%) and 76% (95% CI 66.7% to 84.1%). The rate of nausea control rates for the acute, delayed and overall periods were 34%, 29% and 24%, respectively. The grade I, II and III sedation rates over the 5 days were 8%, 5% and 1%, respectively. CONCLUSIONS: The dexamethasone-free antiemetic strategy showed modest efficacy with low incidence of clinically significant somnolence. There is a need to prospectively investigate the role of dexamethasone in the era of newer potent antiemetics in a randomised fashion. TRIAL REGISTRATION NUMBER: CTRI/2021/07/034813.

Rapid and sensitive electrochemical detection of oxidized form of glutathione in whole blood samples using Bi-metallic nanocomposites.

We report a facile one-pot synthesis of bimetallic nickel-gold (Ni-Au) nanocomposite for ultra-sensitive and selective electrochemical detection of oxidized glutathione (GSSG) by electrochemical deposition on fluorine doped tin oxide (FTO) substrate. The electrodeposition of Ni-Au nanocomposite on FTO was confirmed by various characterization techniques such as field emission scanning electron microscopy (FE-SEM), X-ray diffractometer (XRD) and Fourier transform infra-red (FTIR) spectroscopy. The cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) was utilized for the electrochemical characterization of glutathione reductase (GR)/Ni-Au/FTO working electrode at each stage of modification. The GR enzyme immobilized on the Ni-Au/FTO working electrode via glutaraldehyde cross-linking exhibited excellent selectivity against GSSG in the presence of nicotinamide adenine dinucleotide phosphate (NADPH). The immobilized GR enzyme breaks down the GSSG to reduced glutathione (GSH) and converting NADPH to NADP+ whereby generating an electron for the electrochemical sensing of GSSG. The synergistic behavior of bimetals and good electro-catalytic property of the fabricated sensor provided a broad linear detection range from 1 fM to 1 µM with a limit of detection (LOD) of 6.8 fM, limit of quantification (LOQ) of 20.41 fM and sensitivity of 0.024 mA/µM/cm2. The interference with other molecules such as dopamine, glycine, ascorbic acid, uric acid and glucose was found to be negligible due to the better selectivity of GR enzyme towards GSSG. The shelf-life and response time of the fabricated electrode was found to be 30 days and 32 s, respectively. The real sample analysis of GSSG in whole blood samples showed average recovery percentage from 95 to 101% which matched well with the standard calibration plot of the fabricated sensor with relative standard deviation (RSD) below 10%.

Comprehensive molecular analysis of driver mutations in non-small cell lung carcinomas and its correlation with PD-L1 expression, An Indian perspective.

BACKGROUND: The understanding of molecular mechanisms involved in non-small cell lung carcinoma (NSCLC) has revolutionized significantly in the recent years. These have helped to develop personalized management strategies by identifying specific molecular alterations such as mutations in EGFR, ROS1, BRAF, ERBB2, MET, ALK, and KRAS genes. These mutations are targetable ensuring a better clinical outcome. Next-generation sequencing (NGS) methodology is the recommended technique for the identification of driver mutations in the five hot-spot genes (EGFR, ALK, ROS1, MET, and BRAF) involved in the NSCLC. NGS has numerous advantages including multiplexing, tissue conservation, identification of rare and novel variants, and reduced cost over the sequential single gene testing. Herein, we sought to demonstrate the mutational profile in NSCLC and their clinicopathologic correlation in a contemporary cohort of Indian NSCLC patients. Additionally, we studied the correlation of oncogenic driver mutations with PD-L1 status in these patients. MATERIALS AND METHODS: Five fifty-two stage IV NSCLC patients (adenocarcinoma=490; squamous cell carcinoma=51; adenosquamous carcinoma=5; large cell carcinoma=2; sarcomatoid carcinoma=3; spindle cell carcinoma=1) underwent broad molecular profiling by a custom-made, targeted DNA- and RNA-based five hot-spot genes lung cancer panel (EGFR, ALK, ROS1, BRAF, and MET), compatible with the NGS Ion S5 system. The mutations were correlated with the clinicopathologic characteristics. Additionally, PD-L1 expression status, available on 252 tumors, was correlated with the oncogenic drivers. RESULTS: Validation of the 5 gene panel yielded the following results: a) specificity of 99.74%; b) sensitivity of 100% for single nucleotide variants (SNVs) (>5% variant allele frequency, VAF), indels (>10% VAF) and fusions; c) 100% intra- and inter-run reproducibility; d) 88% inter-laboratory agreement. Validated panel was then used to analyze clinical samples. Sixty percentage tumors harbored either one (54.71%) or multiple (3.26%) mutations. EGFR and BRAF V600E mutations, ALK and ROS1 rearrangements, and MET exon 14 skipping mutation were observed in 38.41% (n = 212) and 2.72% (n = 15) patients, 12.14% (n = 67) and 3.62% (n = 20) patients, and 1.09% (n = 6) patients, respectively. EGFR exon 19 deletion accounted for 52.83% of all mutations, followed by L858R (35.85%), T790M (5.19%), exon 20 insertions (6.6%), and other rare mutations (G719X, L861Q, S768I) (9.91%). Concurrent EGFR with ALK, EGFR with ROS1, EGFR with MET, and EGFR with BRAF were observed in 10, 4, 1, and 3 patients, respectively. PD-L1 was expressed in 134 patients (53.2%). Exon 19 deletion was more prevalent in PD-L1 negative tumors whereas exon 21 substitution (L858R) was seen more in PD-L1 positive tumors. CONCLUSIONS: This is one of the largest cohorts of NSCLC for comprehensive targeted mutational profiling and correlation with the PD-L1 expression. The mutations are more prevalent in non-smoker females for all genes, except ALK (non-smoker males). MET and BRAF mutations are more common in elderly population whereas EGFR mutations, and ALK and ROS1 genes rearrangements are more prevalent in younger population. The most common histopathologic subtype/feature associated with various mutations was as follows: acinar with EGFR, solid with ALK, macronucleoli with ROS1, signet ring with MET, and micropapillary with BRAF.

Methotrexate, an anti-inflammatory drug, inhibits Hepatitis E viral replication.

Hepatitis E Virus (HEV) is a positively oriented RNA virus having a 7.2 kb genome. HEV consists of three open reading frames (ORF1-3). Of these, ORF1 codes for the enzymes Methyltransferase (Mtase), Papain-like cysteine protease (PCP), RNA helicase, and RNA-dependent RNA polymerase (RdRp). Unavailability of a vaccine or effective drug against HEV and considering the side effects associated with the off-label use of ribavirin (RBV) and pegylated interferons, an alternative approach is required by the modulation of specific enzymes to prevent the infection. HEV helicase is involved in unwinding the double-stranded RNA, RNA processing, transcriptional regulation, and pre-mRNA processing. Therefore, we screened FDA-approved compounds from the ZINC15 database against the modelled 3D structure of HEV helicase and found that methotrexate and compound A (Pubchem ID BTB07890) inhibit the NTPase and dsRNA unwinding activity leading to inhibition of HEV RNA replication. This may be further authenticated by in vivo study.

Anterolateral and Medial Locking Compression Plates for the Management of Distal Tibial Fractures: A Comparative Prospective Study.

INTRODUCTION: Open/close reduction (OR/CR) and internal fixation (IF) of displaced fractures of distal tibia with either a medial or anterolateral plate is a commonly performed procedure. Anterolateral plating avoids an incision along the medial subcutaneous border of tibia and has been shown to have reduced risk of wound complications. The aim of our study was to determine the functional outcome of these fractures treated with anterolateral and medial distal tibial locking compression plates. METHODS: This was a prospective study that included 60 patients with distal tibial fractures (close or grade I open injury) divided into two groups with 30 patients in each where one group was treated with OR/CR and IF using an anterolateral distal tibial locking plate (Group A) and the other using a medial distal tibial locking plate (Group B). The duration of surgery and intraoperative blood loss and time to union were recorded for all the patients. Functional evaluation was done at one year in terms of pain, function and alignment using the American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot scale, and complications, if any, were noted. RESULTS: Both the groups were comparable in terms of age, gender, time of presentation, AO classification and presence of wound. The mean duration of surgery as well as the intraoperative blood loss were more in the anterolateral plate group than in the medial plate group, but the difference was statistically insignificant. Ten patients (33%) with medial plates had symptomatic hardware and 7 (23.3%) underwent removal while only 3 (10%) patients in the anterolateral plate group had similar complaints and none had to undergo removal. Two patients with anterolateral plate and one with medial plate had malunion. The mean time to fracture union as well as the rate of infection was less and the functional outcome at one year was better in the group treated with anterolateral plates as compared to the one with medial plates, but the difference again was not statistically significant for all the parameters. CONCLUSION: With reduced risk of soft tissue complications and by obviating the need for implant removal, anterolateral plates can prove to be a better alternative to the medial plates especially in elderly patients in the management of these fractures.