The evolving treatment landscape of metastatic urothelial cancer.

Cisplatin-based chemotherapy is currently the first-line standard of care for patients with metastatic urothelial cancer (mUC); however, up to 50% of patients are ineligible for cisplatin, necessitating alternative treatment options. Immune checkpoint inhibitors have been shown to be effective in cisplatin-ineligible patients. However, despite advances in the first-line setting, the prognosis remains poor, and challenges persist in selecting optimal therapies, treatment sequences and combination regimens. Maintenance therapy with avelumab revealed improved overall (OS) and progression-free survival (PFS) compared with best supportive care alone in patients with platinum-responsive mUC. Antibody-drug conjugates and targeted therapy with fibroblast growth factor receptor (FGFR) inhibitors have shown promise in selected patients, particularly in patients with metastatic disease that has progressed despite platinum-based chemotherapy. At the European Society of Medical Oncology Congress in 2023, groundbreaking results were presented from two phase III trials, EV-302/KEYNOTE-A39 and CheckMate 901, focusing on previously untreated mUC. In the former, the combination of enfortumab vedotin and pembrolizumab showed significant improvements in OS, PFS and overall response rate compared with chemotherapy alone; the combination of nivolumab with gemcitabine-cisplatin chemotherapy demonstrated a significant extension in median OS, PFS and overall response rate compared with chemotherapy alone. In addition, erdafitinib therapy resulted in significantly longer OS than chemotherapy among patients with mUC and FGFR alterations after previous treatment with immune checkpoint inhibitors. This comprehensive summary of the current treatment landscape for mUC incorporates clinical trial evidence and discussion of agents that are currently under investigation to provide support for clinical decision making and understanding of future therapeutic approaches.

Real-World Multicenter Study of PD-1 Blockade in HIV-Associated Classical Hodgkin Lymphoma Across the United States.

BACKGROUND: Despite a higher risk of classical Hodgkin lymphoma (cHL) in people with HIV and the demonstrated safety and efficacy of PD-1 blockade in cHL, there are limited data on the use of these agents in HIV-associated cHL (HIV-cHL). PATIENTS/METHODS: We retrospectively identified patients with HIV-cHL from the "Cancer Therapy using Checkpoint inhibitors in People with HIV-International (CATCH-IT)" database who received nivolumab or pembrolizumab, alone or in combination with other agents, and reviewed records for demographics, disease characteristics, immune-mediated adverse events (imAEs), and treatment outcomes. Changes in CD4+ T-cell counts with treatment were measured via Wilcoxon signed-rank tests. Overall response rate (ORR) was defined as the proportion of patients with partial or complete response (PR/CR) per 2014 Lugano classification. RESULTS: We identified 23 patients with HIV-cHL who received a median of 6 cycles of PD-1 blockade: 1 as 1st-line, 6 as 2nd-line, and 16 as ≥3rd-line therapy. Seventeen (74%) patients received monotherapy, 5 (22%) received nivolumab plus brentuximab vedotin, and 1 received nivolumab plus ifosfamide, carboplatin, and etoposide. The median baseline CD4+ T-cell count was 155 cells/µL, which increased to 310 cells/µL at end-of-treatment (P = .009). Three patients had grade 3 imAEs; none required treatment discontinuation. The ORR was 83% with median duration of response of 19.7 months. The median progression-free survival was 21.2 months and did not differ between patients with <200 versus ≥200 CD4+ cells/µL (P = .95). CONCLUSION: Our findings support the use of PD-1 blockade in HIV-cHL for the same indications as the general population with cHL.

Evaluating the Clinical Equivalence of Truwax® and Ethicon® Bone Waxes for Sternal Wound Hemostasis: A Prospective Randomized Study.

BACKGROUND: Incidence of sternal dehiscence, wound infection, and mortality are prevalent following sternotomy. Bone wax is widely used over the sternal edges for augmenting hemostasis. This study evaluated the clinical equivalence of Truwax® (Healthium Medtech Limited, Bengaluru, India) with Ethicon® (Johnson & Johnson, New Brunswick, New Jersey, United States) bone wax for sternal wound hemostasis in subjects undergoing surgical procedures by sternotomy. METHODS: The primary endpoint of this prospective (May 2022-April 2023), parallel-group, two-arm, randomized, single-blind, multicenter study was to evaluate the proportion of subjects having sternal dehiscence within 26 weeks of median sternotomy closure. Secondary endpoints assessed the average time to hemostasis on sternum sides, bone wax properties, number of dressing changes, sternal bone instability (clinically/chest radiography), pain, perioperative/postoperative complications, blood and blood products used, duration of intensive care unit (ICU)/hospital stay, reoperations, time taken to return back to work and normal day-to-day activities, subject satisfaction and quality of life (QoL), and adverse events. A probability of <0.05 was considered significant. RESULTS: No incidence of sternal dehiscence or postoperative complications was witnessed. Time to hemostasis, bone wax properties, number of dressing changes, sternal stability, pain, blood and blood products used, duration of ICU/hospital stay, reoperations, time taken to return back to normal day-to-day activities and to work, and subject satisfaction and QoL were comparable between Truwax® and Ethicon® bone wax groups. CONCLUSION: Truwax® and Ethicon® bone waxes are safe and effective and provide sternal wound hemostasis in people undergoing sternotomy.

Efficacy of Saccharomyces cerevisiae Fermentation Product and Probiotic Supplementation on Growth Performance, Gut Microflora and Immunity of Broiler Chickens.

Concern for global health security and the environment due to the emergence of antibiotic-resistant bacteria and antibiotic residues in meat and other livestock products has led many countries to restrict the use of antibiotics in animal feed. This experiment was performed to assess the impact of dietary supplementation of a probiotic (Bacillus subtilis) and a postbiotic (Saccharomyces cerevisiae fermentation product) on growth performance, carcass traits, blood haemato-biochemical profile, gut microflora, gut morphology, and immune response in broilers as an alternative to antimicrobials in poultry production system to minimize the effect on global health security. A total of 324 one-day-old Ven Cobb 400 broiler chicks were randomly divided into three dietary groups, each containing 12 replicated pens, and each replicate contained nine chickens. The dietary groups consisted of (1) a basal diet without any growth promoters (T1), (2) the basal diet augmented with Bacillus subtilis at 200 g/MT feed (T2), and (3) the basal diet supplemented with Saccharomyces cerevisiae fermentation product at 1.25 kg/MT feed (T3). To calculate body weight gain, all birds and residual feed were weighed on a replicated basis on days 0, 7, 14, 21, 28, 35, and 42; mortality was recorded daily. At the end of the trial (42 d), two chickens from each replicate were slaughtered for carcass traits, gut microflora, and morphology measurements. Blood samples were collected for the haemato-biochemical profile on 35 d and antibody titer on 28 d and 35 d. Feeding with SCFP (T3 group) significantly improved average daily feed intake (ADFI) and average daily gain (ADG) of chickens compared to the T1 (control) and T2 (probiotic) groups from 1 to 14 days of age. Feed conversion ratio (FCR) was significantly improved in SCFP-fed birds (T3) relative to the control (T1) over the entire experimental period. Carcass traits and blood haemato-biochemical parameters remained unaffected by any diets. However, cholesterol levels and concentrations of corticosterone were significantly lower in T3 compared to T2 and T1 groups. Total E. coli, Enterohaemorrhagic E. coli, ESBL-producing Enterobacteriaceae, and Salmonella counts were significantly lower in T2 and T3 groups compared to T1 group and Salmonella counts were lower in T3 when compared to T2. However, there was no significant difference in Lactobacillus count among treatment groups. A significant increase in villi height and villi-height-to-crypt-depth ratio (VH: CD) was observed in both T3 and T2 groups. On day 28, the T3 and T2 groups exhibited a significant increase in antibody titers against Newcastle disease virus and infectious bursal disease virus. It can be concluded that Saccharomyces cerevisiae fermentation product and Bacillus subtilis probiotic could be viable alternatives to antimicrobials in poultry production considering beneficial impacts in broilers fed an antibiotic-free diet.

Health-related Quality of Life in Patients with Previously Treated Advanced Urothelial Carcinoma from EV-301: A Phase 3 Trial of Enfortumab Vedotin Versus Chemotherapy.

BACKGROUND AND OBJECTIVE: In comparison to chemotherapy, enfortumab vedotin (EV) prolonged overall survival in patients with previously treated advanced urothelial carcinoma in EV-301. The objective of the present study was to assess patient experiences of EV versus chemotherapy using patient-reported outcome (PRO) analysis of health-related quality of life (HRQoL). METHODS: For patients in the phase 3 EV-301 trial randomized to EV or chemotherapy we assessed responses to the validated European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) at baseline, weekly for the first 12 wk, and then every 12 wk until discontinuation. We analyzed the QLQ-C30 change from baseline to week 12, the confirmed improvement rate, and the time to improvement or deterioration. KEY FINDINGS AND LIMITATIONS: Baseline PRO compliance rates were 91% for the EV arm (n = 301) and 89% for the chemotherapy arm (n = 307); the corresponding average rates from baseline to week 12 were 70% and 67%. Patients receiving EV versus chemotherapy had reduced pain (difference in change from baseline to week 12: -5.7, 95% confidence interval [CI] -10.8 to -0.7; p = 0.027) and worsening appetite loss (7.3, 95% CI 0.90-13.69; p = 0.026). Larger proportions of patients in the EV arm reported HRQoL improvement from baseline than in the chemotherapy arm; the odds of a confirmed improvement across ten QLQ-C30 function/symptom scales were 1.67 to 2.76 times higher for EV than for chemotherapy. Patients in the EV arm had a shorter time to first confirmed improvement in global health status (GHS)/QoL, fatigue, pain, and physical, role, emotional, and social functioning (all p < 0.05). EV delayed the time to first confirmed deterioration in GHS/QoL (p = 0.027), but worsening appetite loss occurred earlier (p = 0.009) in comparison to chemotherapy. CONCLUSIONS AND CLINICAL IMPLICATIONS: HRQoL with EV was maintained, and deterioration in HRQoL was delayed with EV in comparison to chemotherapy. Better results with EV were reported for some scales, with the greatest difference observed for pain. These findings reinforce the EV safety and efficacy outcomes and benefits observed in EV-301. PATIENT SUMMARY: Patients with previously treated advanced cancer of the urinary tract receiving the drug enfortumab vedotin maintained their HRQoL in comparison to patients treated with chemotherapy. The EV-301 trial is registered on ClinicalTrials.gov as NCT03474107 and on EudraCT as 2017-003344-21.

Circulating tumor DNA as a Predictive and Prognostic Biomarker in the Perioperative Treatment of Muscle-invasive Bladder Cancer: A Systematic Review.

CONTEXT: Predictive and prognostic biomarkers in the perioperative treatment of muscle-invasive bladder cancer (MIBC) are an unmet need. Circulating tumor DNA (ctDNA) holds promise as a biomarker in this setting. OBJECTIVE: To review the evidence of ctDNA as a prognostic and predictive biomarker in the perioperative treatment of MIBC. EVIDENCE ACQUISITION: We systematically reviewed the literature using PubMed, MEDLINE, and Embase databases according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. We included prospective studies investigating neoadjuvant and/or adjuvant chemotherapy and/or immunotherapy for MIBC (T2-T4a, any N, and M0) treated with radical cystectomy. We reported ctDNA results to monitor and/or predict disease status, relapse, and progression. The research retrieved 223 records. Six papers were considered for this review based on prespecified inclusion criteria. EVIDENCE SYNTHESIS: Our review confirms the prognostic role of ctDNA after cystectomy and shows a potential predictive benefit in using neoadjuvant chemotherapy and preoperative immunotherapy. Circulating tumor DNA was used to monitor recurrence, and changes in ctDNA status anticipated radiological progression with a median difference of time from 101 to 932 d. A subgroup analysis of the phase 3 Imvigor010 trial showed that only ctDNA-positive patients treated with atezolizumab had an improvement in disease-free survival (DFS; hazard ratio [HR] = 3.36, 95% confidence interval [CI]: 2.44-4.62). Clearance of ctDNA after two cycles of adjuvant atezolizumab was associated with improved outcomes (DFS HR = 0.26, 95% CI: 0.12-0.56, p = 0.0014; overall survival HR = 0.14, 95% CI: 0.03-0.59). CONCLUSIONS: Circulating tumor DNA is a prognostic factor after cystectomy and may be used to monitor recurrence. In the adjuvant immunotherapy setting, ctDNA might select patients who benefit the most from this strategy. PATIENT SUMMARY: In the perioperative treatment of muscle-invasive bladder cancer, circulating tumor DNA (ctDNA) positivity correlates with the outcomes after cystectomy and might select patients who may benefit from neoadjuvant chemotherapy and/or immunotherapy. Changes in ctDNA status anticipated radiological progression.

Phase I Dose-Escalation Study of the Safety and Pharmacokinetics of AGS15E Monotherapy in Patients with Metastatic Urothelial Carcinoma.

PURPOSE: Effective treatment of locally advanced or metastatic urothelial carcinoma (mUC) remains an unmet need. Antibody-drug conjugates (ADC) providing targeted drug delivery have shown antitumor activity in this setting. AGS15E is an investigational ADC that delivers the cytotoxic drug monomethyl auristatin E to cells expressing SLITRK6, a UC-associated antigen. PATIENTS AND METHODS: This was a multicenter, single-arm, phase I dose-escalation and expansion trial of AGS15E in patients with mUC (NCT01963052). During dose escalation, AGS15E was administered intravenously at six levels (0.10, 0.25, 0.50, 0.75, 1.00, 1.25 mg/kg), employing a continual reassessment method to determine dose-limiting toxicities (DLT) and the recommended phase II dose (RP2D) for the dose-expansion cohort. The primary objective was to evaluate the safety and pharmacokinetics of AGS15E in patients with and without prior chemotherapy and with prior checkpoint inhibitor (CPI) therapy. Best overall response was also examined. RESULTS: Ninety-three patients were recruited, including 33 patients previously treated with CPI. The most common treatment-emergent adverse events were fatigue (54.8%), nausea (37.6%), and decreased appetite (35.5%). Peripheral neuropathy and ocular toxicities occurred at doses of ≥0.75 mg/kg. AGS15E increased in a dose-proportional manner after single- and multiple-dose administration; accumulation was low. Five DLT occurred from 0.50 to 1.25 mg/kg. The RP2D was assessed at 1.00 mg/kg; the objective response rate (ORR) was 35.7% at this dose level. The ORR in the total population and CPI-exposed subgroup were 18.3% and 27.3%, respectively. CONCLUSIONS: DLT with AGS15E were observed at 0.75, 1.00, and 1.25 mg/kg, with an RP2D of 1.00 mg/kg being determined.

Comparative real-world survival outcomes of muscle-invasive bladder cancer treated with bladder-only vs. whole-pelvis concurrent chemoradiation.

INTRODUCTION: Elective pelvic nodal irradiation for patients with muscle-invasive bladder cancer (MIBC) undergoing trimodal therapy (TMT ) is controversial. In patients with node-negative (N0) MIBC, the benefit of elective whole-pelvis concurrent chemoradiation (WP-CCR) compared to bladder-only (BO )-CCR has not been demonstrated. Using real-world data from the National Cancer Database (NCDB ), we sought to compare the overall survival (OS ) between BO-CCR and WP-CCR for MIBC. METHODS: Using the 2020 NCDB Participant User File, we identified cases of MIBC diagnosed between 2017 and 2019. We selected patients with clinical T2-T4aN0M0 disease receiving CCR as first-line treatment. CCR was defined as transurethral resection of bladder tumor followed by ≥40 Gy radiation to the bladder with concurrent single- or multiple-agent chemotherapy. Based on elective nodal irradiation status, patients were stratified as having received BO-CCR vs. WP-CCR. OS analysis was performed using summary three-month conditional landmark, inverse probability treatment weighting (IPTW)-adjusted Kaplan-Meier estimates, and Cox regression. RESULTS: A total of 604 patients receiving CCR for MIBC were identified: 367 (60.8%) BO-CCR and 237 (39.2%) WP-CCR. Before IPTW, the groups were imbalanced in terms of baseline characteristics. The median followup of the weighted population was 42.3 months (interquartile range 18.1-49.1 months). In IPTW-adjusted Cox proportional hazards regression analysis, WP-CCR was associated with a significant OS benefit compared to BO-CCR (adjusted hazard ratio 0.72, 95% confidence interval 0.54-0.96, p=0.026). CONCLUSIONS: In the setting of CCR for N0 MIBC, this retrospective NCDB analysis revealed that WP-CCR was associated with a benefit in OS compared to BO-CCR.

Total Margin Control Is Superior to Traditional Margin Assessment for Treatment of Low-Stage Penile Squamous Cell Carcinoma.

PURPOSE: Penile cancer is rare, with significant morbidity and limited literature assessing utility of peripheral and deep en face margin assessment (PDEMA) vs traditional margin assessment (vertical sections) on treatment outcomes. MATERIALS AND METHODS: This was a 32-year retrospective multicenter cohort study at 3 academic tertiary care centers. The cohort consisted of 189 patients with histologic diagnosis of in situ or T1a cutaneous squamous cell carcinoma of the penis at Brigham and Women's, Massachusetts General Hospital (1988-2020), and Memorial Sloan Kettering Cancer Center (1995-2020) treated with PDEMA surgical excision, excision/circumcision, or penectomy/glansectomy. Local recurrence, metastasis, and disease-specific death were assessed via multivariable Cox proportional hazard models. RESULTS: The cohort consisted of 189 patients. Median age at diagnosis was 62 years. Median tumor diameter was 1.3 cm. The following outcomes of interest occurred: 30 local recurrences, 13 metastases, and 5 disease-specific deaths. Primary tumors were excised with PDEMA (N = 30), excision/circumcision (N = 110), or penectomy/glansectomy (N = 49). Of patients treated with traditional margin assessment (non-PDEMA), 12% had narrow or positive margins. Five-year proportions were as follows with respect to local recurrence-free survival, metastasis-free survival, and disease-specific survival/progression-free survival, respectively: 100%, 100%, and 100% following PDEMA; 82%, 96%, and 99% following excision/circumcision; 83%, 91%, and 95% following penectomy/glansectomy. A limitation is that this multi-institutional cohort study was not externally validated. CONCLUSIONS: Initial results are encouraging that PDEMA surgical management effectively controls early-stage penile squamous cell carcinoma.

Vitamin D Status among the Population Visiting Jigme Dorji Wangchuck National Referral Hospital, Bhutan.

Objective: To study the vitamin D status among the Bhutanese population visiting the Jigme Dorji Wangchuck National Referral Hospital in Thimphu, Bhutan. Materials and Methods: This is a retrospective descriptive study involving the extraction of data from a hospital database. Records of Bhutanese patients who had taken vitamin D tests in the last two years (2020-2021) were included in the study. Result: A total of 1175 individuals took the vitamin D test during the study period, and the age ranged between 1 day and 94 years. Over 60% of the participants were females. The study found that over 83% of our study population had serum vitamin D levels lower than the normal range/deficient. Around 18% of the participants had severe deficiency. Conclusion: The study found that most participants, including children, had vitamin D deficiency, and the finding was homogenous across gender and age groups. Further studies are required to validate these findings and identify the factors associated with vitamin D deficiency in the population for targeted public health interventions.

Pretest Video Education Versus Genetic Counseling for Patients With Prostate Cancer: ProGen, A Multisite Randomized Controlled Trial.

PURPOSE: Germline genetic testing (GT) is recommended for men with prostate cancer (PC), but testing through traditional models is limited. The ProGen study examined a novel model aimed at providing access to GT while promoting education and informed consent. METHODS: Men with potentially lethal PC (metastatic, localized with a Gleason score of ≥8, persistent prostate-specific antigen after local therapy), diagnosis age ≤55 years, previous malignancy, and family history suggestive of a pathogenic variant (PV) and/or at oncologist's discretion were randomly assigned 3:1 to video education (VE) or in-person genetic counseling (GC). Participants had 67 genes analyzed (Ambry), with results disclosed via telephone by a genetic counselor. Outcomes included GT consent, GT completion, PV prevalence, and survey measures of satisfaction, psychological impact, genetics knowledge, and family communication. Two-sided Fisher's exact tests were used for between-arm comparisons. RESULTS: Over a 2-year period, 662 participants at three sites were randomly assigned and pretest VE (n = 498) or GC (n = 164) was completed by 604 participants (VE, 93.1%; GC, 88.8%), of whom 596 participants (VE, 98.9%; GC, 97.9%) consented to GT and 591 participants completed GT (VE, 99.3%; GC, 98.6%). These differences were not statistically significant although subtle differences in satisfaction and psychological impact were. Notably, 84 PVs were identified in 78 participants (13.2%), with BRCA1/2 PV comprising 32% of participants with a positive result (BRCA2 n = 21, BRCA1 n = 4). CONCLUSION: Both VE and traditional GC yielded high GT uptake without significant differences in outcome measures of completion, GT uptake, genetics knowledge, and family communication. The increased demand for GT with limited genetics resources supports consideration of pretest VE for patients with PC.

Unravelling geospatial distribution and genetic diversity of greenhouse whitefly, Trialeurodes vaporariorum (Westwood) from Himalayan Region.

The Greenhouse whitefly (GWF), Trialeurodes vaporariorum (Westwood) (Hemiptera: Aleyrodidae), is a destructive pest that affects protected cultivation worldwide. The Indian Himalayan region is particularly vulnerable to GWF introduction, invasion, and spread due to the expansion of protected cultivation and climate change. In this study, we collected 32 naturally occurring GWF populations, mainly from the Uttarakhand state in the Indian Himalayan region, to investigate the distribution pattern and genetic diversity of T. vaporariorum. Our sampling was representative of the region's vegetation diversity and geographical location, and we collected samples from multiple sites within each locality to account for local variations. The mtCOI gene was used to accurately detect and identify GWF and to sequence haplotypes prevalent in the Uttarakhand state. The maximum likelihood method used for phylogenetic studies revealed that all 32 whitefly samples in this study belonged to T. vaporariorum and were prevalent in all the collected localities. Our population genetic study using mtCOI showed variation within T. vaporariorum populations, with 20 distinct haplotypes present. Notably, haplotype 2 (H2) was the most dominant haplotype among the sampled populations. These results provide fundamental knowledge for understanding the geographical distribution and ecology of T. vaporariorum in the Uttarakhand state of the Indian Himalayan region. The discovery of geospatial and genetic diversity of GWF in the Himalayan region underscores the importance of pest alertness, research prioritization, and the development of sustainable management strategies to protect crops.

X-ray and MR Contrast Bearing Nanoparticles Enhance the Therapeutic Response of Image-Guided Radiation Therapy for Oral Cancer.

INTRODUCTION: Radiation therapy for head and neck squamous cell carcinoma is constrained by radiotoxicity to normal tissue. We demonstrate 100 nm theranostic nanoparticles for image-guided radiation therapy planning and enhancement in rat head and neck squamous cell carcinoma models. METHODS: PEG conjugated theranostic nanoparticles comprising of Au nanorods coated with Gadolinium oxide layers were tested for radiation therapy enhancement in 2D cultures of OSC-19-GFP-luc cells, and orthotopic tongue xenografts in male immunocompromised Salt sensitive or SS rats via both intratumoral and intravenous delivery. The radiation therapy enhancement mechanism was investigated. RESULTS: Theranostic nanoparticles demonstrated both X-ray/magnetic resonance contrast in a dose-dependent manner. Magnetic resonance images depicted optimal tumor-to-background uptake at 4 h post injection. Theranostic nanoparticle + Radiation treated rats experienced reduced tumor growth compared to controls, and reduction in lung metastasis. CONCLUSIONS: Theranostic nanoparticles enable preprocedure radiotherapy planning, as well as enhance radiation treatment efficacy for head and neck tumors.

Underutilized legumes: nutrient status and advanced breeding approaches for qualitative and quantitative enhancement.

Underutilized/orphan legumes provide food and nutritional security to resource-poor rural populations during periods of drought and extreme hunger, thus, saving millions of lives. The Leguminaceae, which is the third largest flowering plant family, has approximately 650 genera and 20,000 species and are distributed globally. There are various protein-rich accessible and edible legumes, such as soybean, cowpea, and others; nevertheless, their consumption rate is far higher than production, owing to ever-increasing demand. The growing global urge to switch from an animal-based protein diet to a vegetarian-based protein diet has also accelerated their demand. In this context, underutilized legumes offer significant potential for food security, nutritional requirements, and agricultural development. Many of the known legumes like Mucuna spp., Canavalia spp., Sesbania spp., Phaseolus spp., and others are reported to contain comparable amounts of protein, essential amino acids, polyunsaturated fatty acids (PUFAs), dietary fiber, essential minerals and vitamins along with other bioactive compounds. Keeping this in mind, the current review focuses on the potential of discovering underutilized legumes as a source of food, feed and pharmaceutically valuable chemicals, in order to provide baseline data for addressing malnutrition-related problems and sustaining pulse needs across the globe. There is a scarcity of information about underutilized legumes and is restricted to specific geographical zones with local or traditional significance. Around 700 genera and 20,000 species remain for domestication, improvement, and mainstreaming. Significant efforts in research, breeding, and development are required to transform existing local landraces of carefully selected, promising crops into types with broad adaptability and economic viability. Different breeding efforts and the use of biotechnological methods such as micro-propagation, molecular markers research and genetic transformation for the development of underutilized crops are offered to popularize lesser-known legume crops and help farmers diversify their agricultural systems and boost their profitability.

Precision Medicine to Treat Urothelial Carcinoma-The Way Forward.

The treatment of urothelial carcinoma (UC) is challenging given its molecular heterogeneity and variable response to current therapies. To address this, many tools, including tumor biomarker assessment and liquid biopsies, have been developed to predict prognosis and treatment response. Approved therapeutic modalities for UC currently include chemotherapy, immune checkpoint inhibitors, receptor tyrosine kinase inhibitors, and antibody drug conjugates. Ongoing investigations to improve the treatment of UC include the search for actionable alterations and the testing of novel therapies. An important objective in recent studies has been to increase efficacy while decreasing toxicity by taking into account unique patient and tumor-related factors-an endeavor called precision medicine. The aim of this review is to highlight advancements in the treatment of UC, describe ongoing clinical trials, and identify areas for future study in the context of precision medicine.

Real-world treatment patterns and clinical outcomes with first-line therapy in patients with locally advanced/metastatic urothelial carcinoma by cisplatin-eligibility.

INTRODUCTION: Patients with locally advanced/metastatic urothelial carcinoma (la/mUC) have a poor prognosis. With recent therapeutic advances, data on real-world treatment patterns and overall survival (OS) in patients with la/mUC treated with first-line therapy are limited, particularly when comparing patients who are cisplatin-ineligible versus cisplatin-eligible. METHODS: This was a retrospective observational study of real-world first-line treatment patterns and OS in patients with la/mUC stratified by cisplatin-eligibility and treatment. Data were from a nationwide electronic health record-derived de-identified database. Eligible patients were adults diagnosed with la/mUC from May 2016 to April 2021 and followed until death or end of data availability in January 2022. OS stratified by first-line treatment and cisplatin eligibility was estimated using Kaplan-Meier methods and compared via multivariable Cox proportional-hazard models adjusted for clinical covariates. RESULTS: Of 4,757 patients with la/mUC, 3,632 (76.4%) received first-line treatment, with 2,029 (55.9%) cisplatin-ineligible and 1,603 (44.1%) cisplatin-eligible. Patients who were cisplatin-ineligible were older (mean age, 74.9 vs. 68.8 years) and had lower CrCl (median, 46.4 vs. 87.0 ml/min). Only 43.8% of patients receiving first-line treatment (37.6% cisplatin-ineligible vs. 51.6% cisplatin-eligible) received second-line therapy. Median OS in all patients receiving first-line treatment was 10.8 (95% CI, 10.2-11.3) months and was shorter in patients who were cisplatin-ineligible than cisplatin-eligible (8.5 [95% CI, 7.8-9.0] vs. 14.4 [13.3-16.1]; hazard ratio [HR], 0.9 [0.7-1.1]). Cisplatin-based therapy was associated with longer OS (17.6 [15.1-20.4] months) than other first-line treatments (the shortest OS was with PD-1/L1 inhibitor monotherapy; 7.7 [6.8-8.8] months), including among patients who were classified as cisplatin-ineligible. CONCLUSIONS: Outcomes for patients with newly diagnosed la/mUC are poor, particularly for patients who are cisplatin-ineligible and/or do not receive cisplatin-based therapy. Many patients with la/mUC did not receive first-line treatment and among those who did, fewer than half received second-line therapy. These data highlight the need for more effective first-line therapies for all patients with la/mUC.

Quantitation and Stability of Nicotine in Canadian Vaping Liquids.

Electronic cigarettes (e-cigarettes, vaping products) have become increasingly popular, with recent increases in use associated with closed systems delivering higher concentrations of nicotine. Most vaping products designed as an alternative to combustible cigarettes contain nicotine. A number of published studies have examined the reported concentrations of nicotine in vaping liquids (e-liquids) and found discrepancies between labelled and measured levels. Some discrepancy can also be explained by the lack of stability of nicotine in these types of products. Recently, a chemical analysis method for the quantitative determination of low and high levels of nicotine in vaping liquids was developed. This method uses dilution with acetonitrile prior to analysis with gas chromatograph mass spectrometry (GC-MS) in single ion monitoring mode (SIM). The developed method was validated using a laboratory-prepared vaping liquid as well as commercially available, nicotine-free products fortified with nicotine in the laboratory. The method detection limit (MDL) and the limit of quantitation (LOQ) for nicotine were calculated to be 0.002 mg/mL and 0.006 mg/mL, respectively. The newly developed method was applied to quantify nicotine in commercially available vaping liquids of various flavour profiles and across a wide range of nicotine concentrations, including those with nicotine salts. Furthermore, a subset of vaping liquids were analyzed to elucidate nicotine stability in various product subtypes. After a period of six months of accelerated storage to mimic one year, the overall mean percent of the original nicotine concentration remaining in the salt-based vaping products was 85% (minimum 64%, maximum 99%) while in the free-base nicotine products it was 74% (minimum 31%, maximum 106%). Nicotine stability in vaping liquids was found to be influenced by the nicotine form (pH) of formulation and its chemical composition. Non-targeted, qualitative analysis of chemical composition of vaping products showed that most constituents were identified and found to be remaining in the products following stability trials; however, three new compounds were tentatively identified in some vaping liquids at the end of the stability trials. Stability studies and the accurate quantitation of nicotine in vaping products can help inform product standards related to the safety, quality and utility of vaping products as a smoking cessation tool.

Circulating and urinary tumour DNA in urothelial carcinoma - upper tract, lower tract and metastatic disease.

Precision medicine has transformed the way urothelial carcinoma is managed. However, current practices are limited by the availability of tissue samples for genomic profiling and the spatial and temporal molecular heterogeneity observed in many studies. Among rapidly advancing genomic sequencing technologies, non-invasive liquid biopsy has emerged as a promising diagnostic tool to reproduce tumour genomics, and has shown potential to be integrated in several aspects of clinical care. In urothelial carcinoma, liquid biopsies such as plasma circulating tumour DNA (ctDNA) and urinary tumour DNA (utDNA) have been investigated as a surrogates for tumour biopsies and might bridge many shortfalls currently faced by clinicians. Both ctDNA and utDNA seem really promising in urothelial carcinoma diagnosis, staging and prognosis, response to therapy monitoring, detection of minimal residual disease and surveillance. The use of liquid biopsies in patients with urothelial carcinoma could further advance precision medicine in this population, facilitating personalized patient monitoring through non-invasive assays.

Phase II trial of CV301 vaccine combined with atezolizumab in advanced urothelial carcinoma.

CV301 comprises recombinant poxviruses, Modified Vaccinia Ankara (MVA) and Fowlpox (FPV), encoding CEA, MUC-1, and co-stimulatory Molecules (TRICOM) ICAM-1, LFA-3, and B7-1. MVA-BN-CV301 is used for priming and FPV-CV301 is used for boosting. A Phase 2, single-arm trial was designed to evaluate CV301 plus atezolizumab as first-line treatment for cisplatin-ineligible advanced urothelial carcinoma (aUC) (Cohort 1) or progressing after platinum chemotherapy (Cohort 2). MVA-CV301 was given subcutaneously (SC) on Days 1 and 22 and FPV-CV301 SC from day 43 every 21 days for 4 doses, then tapered gradually over up to 2 years. Atezolizumab 1200 mg IV was given every 21 days. The primary endpoint was objective response rate (ORR). Overall, 43 evaluable patients received therapy: 19 in Cohort 1; 24 in Cohort 2; nine experienced ≥ Grade 3 therapy-related adverse events. In Cohort 1, one had partial response (PR) (ORR 5.3%, 90% CI 0.3, 22.6). In Cohort 2, 1 complete response and 1 PR were noted (ORR 8.3%, 90% CI 1.5, 24.0). The trial was halted for futility. Patients exhibiting benefit demonstrated T-cell response to CEA and MUC-1. The trial illustrates the challenges in the development of vaccines, which should be guided by robust preclinical data.