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Among 886 patients with advanced renal-cell cancer, median progression-free survival was 13.8 months among those assigned to avelumab plus axitinib and 7.2 months among those assigned to sunitinib. Toxic effects of grade 3 or higher were similar in the two groups.

COVID-19 has impacted the healthcare system across the globe. The study will span three pandemic waves in 2020, 2021, and 2022. The goal is to learn how the pandemic affects antenatal care (ANC) and emergency delivery care for pregnant women in Tamil Nadu, India, and how medical services respond. The study employs counterfactual analysis to evaluate the causal impact of the pandemic. A feedforward in combination with a simple auto-regressive neural network (AR-Net) is used to predict the daily number of calls for ambulance services (CAS). Three categories of the daily CAS count between January 2016 and December 2022 are utilised. The total CAS includes all types of medical emergencies; the second group pertains to planned ANC for high-risk pregnant women and the third group comprises CAS from pregnant women for medical emergencies. The second wave’s infection and mortality rates were up to six times higher than the first. The phases in wave-II, post-wave-II, wave-III, and post-wave-III experienced a significant increase in both total IFT (inter-facility transfer) and total non-IFT calls covering all emergencies relative to the counterfactual, as evidenced by reported effect sizes of 1 and a range of 0.65 to 0.85, respectively. This highlights overwhelmed health services. In Tamil Nadu, neither emergency prenatal care nor planned prenatal care was affected by the pandemic. In contrast, the increase in actual emergency-related IFT calls during wave-II, post-wave-II, wave-III, and post-wave-III was 62%, 160%, 141%, and 165%, respectively, relative to the counterfactual. During the same time periods, the mean daily CAS related to prenatal care increased by 47%, 51%, 38%, and 38%, respectively, compared to pre-pandemic levels. The expansion of ambulance services and increased awareness of these services during wave II and the ensuing phases of Covid-19 pandemic have enhanced emergency care delivery for all, including obstetric and neonatal cohorts.

BackgroundVascular endothelial growth factor inhibitors (VEGFIs) are effective anticancer agents, but are associated with cancer therapy-related cardiac dysfunction (CTRCD) and hypertension. The timing, frequency and magnitude of these toxicities are poorly defined. The objective of this study is therefore to investigate the incidence, time course and mechanisms of VEGFI-associated CTRCD and hypertension.MethodsPatients commencing VEGFI underwent blood pressure (BP) monitoring, echocardiography and cardiac biomarker measurement at baseline and prospectively over 24 weeks. Serial adenosine stress perfusion cardiovascular MRI (CMR) was performed in a substudy. CTRCD was defined as left ventricular ejection fraction (LVEF) decline by ≥10 percentage points from baseline to a value <50%.Results78 patients participated (68% men; age 63±11 years). 15 patients (19%) developed CTRCD, and it was evident at 4 weeks in 93% of cases. Overall, LVEF was 4.2% (95% CI: −6.2% to −2.3%, p<0.001) lower than baseline at 4 weeks. At 4 weeks, N-terminal pro-brain natriuretic peptide, but not troponin, was higher in patients with CTRCD. 62 (77%) patients developed hypertension. Home systolic and diastolic BP increased by 7.2 mm Hg (4.7–9.8, p<0.001) and 4.8 mm Hg (3.1–6.5, p<0.001), respectively, at 1 week. There was no association between change in LVEF and BP.CMR-derived LVEF, T1 relaxation times and resting myocardial blood flow (n=46) were 5.2% (−7.3% to −3.1%, p<0.001), 27 ms (−40 to −14, p<0.001) and 14.7 mL/100mL/min (−24.2 to −5.1, p=0.004), respectively, lower at 4 weeks.ConclusionVEGFI-associated CTRCD is frequent and occurs early. This finding has implications for prioritising early cardiac imaging follow-up after commencing treatment. Underlying mechanisms include myocardial and microvascular effects that are at least partly independent of hypertension.

Background In patients with renal cell carcinoma (RCC) enrolled in the phase III KEYNOTE-564 trial (NCT03142334), disease-free survival (DFS) following nephrectomy was prolonged with use of adjuvant pembrolizumab therapy versus placebo. Patient-reported outcomes (PROs) provide an important measure of health-related quality of life (HRQoL) and can complement efficacy and safety results. Patients and Methods In KEYNOTE-564, 994 patients were randomly assigned to receive pembrolizumab 200 mg (n = 496) or placebo (n = 498) intravenously every 3 weeks for ≤17 cycles. Patients who received ≥1 dose of treatment and completed ≥1 HRQoL assessment were included in this analysis. HRQoL end points were assessed using the EORTC QLQ-C30, FKSI-DRS, and EQ VAS. Prespecified and exploratory PRO end points were mean change from baseline in EORTC QLQ-C30 GHS/QoL score, EORTC QLQ-C30 physical function subscale score, and FKSI-DRS score. Results No clinically meaningful difference in least squares mean scores for pembrolizumab versus placebo were observed at week 52 for EORTC QLQ-C30 GHS/QoL (–2.5; 95% CI –5.2 to 0.1), EORTC QLQ-C30 physical functioning (–0.87; 95% CI –2.7 to 1.0), and FKSI-DRS (–0.7; 95% CI –1.2 to –0.1). Most PRO scores remained stable or improved for the EORTC QLQ-C30 GHS/QoL (pembrolizumab, 54.3%; placebo, 67.5%), EORTC QLQ-C30 physical functioning (pembrolizumab, 64.7%; placebo, 68.8%), and FKSI-DRS (pembrolizumab, 58.2%; placebo, 66.3%). Conclusions Adjuvant treatment with pembrolizumab did not result in deterioration of HRQoL. These findings together with the safety and efficacy findings support adjuvant pembrolizumab treatment following nephrectomy. Trial Registration Clinicaltrials.gov Identifier: NCT03142334 Patient-reported outcomes provide an important measure of health-related quality of life and can complement efficacy and safety results. This article presents analyses of health-related quality of life in patients enrolled in the KEYNOTE-564 trial.

BackgroundWe investigated the first-line activity of vinflunine in patients with penis cancer. Cisplatin-based combinations are commonly used, but survival is not prolonged; many patients are unfit for such treatment or experience toxicity that outweighs clinical benefit.MethodsTwenty-five patients with inoperable squamous carcinoma of the penis were recruited to a single-arm, Fleming–A’Hern exact phase II trial. Treatment comprised 4 cycles of vinflunine 320 mg/m2, given every 21 days. Primary endpoint was clinical benefit rate (CBR: objective responses plus stable disease) assessed after 4 cycles. Seven or more objective responses or disease stabilisations observed in 22 evaluable participants would exclude a CBR of <15%, with a true CBR of >40% being probable.ResultsTwenty-two participants were evaluable. Ten objective responses or disease stabilisations were confirmed. CBR was 45.5%, meeting the primary endpoint; partial response rate was 27.3%. Seven patients received >4 cycles of vinflunine. Dose reduction or treatment delay was required for 20% of cycles. In all, 68% of patients experienced at least one grade 3 adverse event. Two deaths on treatment were not caused by disease progression.ConclusionsPre-specified clinical activity threshold was exceeded. Toxicity was in keeping with experience in other tumours. Vinflunine merits further study in this disease.Trial registrationNCT02057913.

The first-in-class hypoxia-inducible factor-2α (HIF-2α) inhibitor belzutifan is approved for patients with advanced renal cell carcinoma previously treated with immune checkpoint and anti-angiogenic therapy based on results of the phase 3 LITESPARK-005 trial. We present patient-reported outcomes (PROs) from LITESPARK-005. LITESPARK-005 was an open-label, multicentre, randomised, active-controlled phase 3 trial conducted at 147 hospitals and cancer centres in six regions. Eligible participants were 18 years or older with advanced clear cell renal cell carcinoma, had a Karnofsky Performance Status score of 70% or higher, had measurable disease per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, had disease progression on or after treatment with anti-PD-1 or anti-PD-L1 immunotherapy and a VEGF tyrosine kinase inhibitor (in sequence or in combination), and had received no more than three previous systemic lines of therapy. Eligible participants were randomly assigned (1:1) centrally using interactive voice-response and web-response systems to receive either belzutifan 120 mg orally once daily or everolimus 10 mg orally once daily. Randomisation was stratified by International Metastatic Renal Cell Carcinoma Database Consortium prognostic score and number of previous VEGF-targeted or VEGF receptor-targeted therapies. The dual primary outcomes were progression-free survival and overall survival, results of which have been reported previously. In this study, prespecified secondary patient-reported outcomes (PROs) from LITESPARK-005 were assessed using the Functional Assessment of Cancer Therapy-Kidney Cancer Symptom Index: Disease Related Symptoms (FKSI-DRS) and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). The PRO analysis population included all participants who received at least one dose of study therapy and completed at least one PRO assessment. Least-squares mean change from baseline in PROs at week 17 was assessed using a constrained longitudinal data analysis model. Time to deterioration in physical functioning (prespecified) and role functioning (post hoc), as assessed by the EORTC QLQ-C30, were also evaluated in the PRO analysis population. This trial is ongoing, closed to recruitment, and registered with ClinicalTrials.gov, NCT04195750. Between March 10, 2020, and Jan 19, 2022, 996 participants were screened for eligibility and 746 participants were randomly assigned to belzutifan (n=374) or everolimus (n=372). The PRO full analysis set population included 366 participants in the belzutifan group and 354 in the everolimus group. Median time from randomisation to the database cutoff date (June 13, 2023) was 25·7 months (IQR 21·7–30·4). Completion rates for FKSI-DRS and QLQ-C30 were higher than 94% at baseline and higher than 55% at week 17 in each group. Change from baseline to week 17 in FKSI-DRS score (difference in least-squares mean between groups 1·5 [95% CI 0·7 to 2·2]) and QLQ-C30 global health status–quality of life (QOL) score (6·4 [3·2 to 9·6]) suggested stability with belzutifan versus worsening with everolimus. Change from baseline to week 17 was similar between groups for QLQ-C30 physical functioning (difference in least-squares mean 2·5 [95% CI −0·6 to 5·5]) and QLQ-C30 role functioning (4·2 [0·1 to 8·4]) subscale scores. Time to deterioration was similar between the belzutifan and everolimus groups for EORTC physical functioning (median 19·3 months [95% CI 11·1 to not reached] in the belzutifan group vs 13·8 months [10·6 to not reached] in the everolimus group; hazard ratio 0·93 [95% CI 0·72 to 1·20]) and role functioning (median 12·0 months [9·2 to not reached] vs 10·2 months [4·7 to 14·4]; 0·88 [0·69 to 1·11]). Belzutifan for advanced renal cell carcinoma was associated with improved disease-specific symptoms and QOL compared with everolimus. Taken together with the efficacy and safety data from LITESPARK-005, belzutifan could offer a clinical benefit without compromising the QOL of patients in this setting. Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

Chronic Limb Threatening Ischemia (CLTI) is a challenging clinical problem associated with high morbidity and mortality. Endovascular interventions have been the cornerstone of treatment whenever possible. It is estimated that CLTI represents < 10% of all Peripheral Artery Disease patients, yet 50% of the patients end up either with a major amputation of the lower limbs or die of cardiovascular causes within one year period, especially in those with unsuccessful revascularization or “no-option” CLTI. Cell-based therapeutics, especially bone marrow-derived mesenchymal stromal cells have emerged as a potential, promising, and novel alternate therapeutic modality in the management of CLTI, bolstered with positive results in numerous research, including randomized and nonrandomized trials. REGENACIP ® is one such BM-MSC therapy approved by Central Drugs Standard Control Organization in India for the management of “no-option” Atherosclerotic Peripheral Arterial disease / Buerger’s disease patients with established critical limb ischemia in Rutherford Grade III-5 or III-6, not eligible for or have failed traditional revascularization treatment, with rest pain and / or ulcers in the affected limb. The current review aims to deliberate upon the various aspects of CLTI and clinical benefits of REGENACIP ® therein.

Background Window-of-opportunity trials, evaluating the engagement of drugs with their biological target in the time period between diagnosis and standard-of-care treatment, can help prioritise promising new systemic treatments for later-phase clinical trials. Renal cell carcinoma (RCC), the 7 th commonest solid cancer in the UK, exhibits targets for multiple new systemic anti-cancer agents including DNA damage response inhibitors, agents targeting vascular pathways and immune checkpoint inhibitors. Here we present the trial protocol for the WIndow-of-opportunity clinical trial platform for evaluation of novel treatment strategies in REnal cell cancer (WIRE). Methods WIRE is a Phase II, multi-arm, multi-centre, non-randomised, proof-of-mechanism (single and combination investigational medicinal product [IMP]), platform trial using a Bayesian adaptive design. The Bayesian adaptive design leverages outcome information from initial participants during pre-specified interim analyses to determine and minimise the number of participants required to demonstrate efficacy or futility. Patients with biopsy-proven, surgically resectable, cT1b+, cN0–1, cM0–1 clear cell RCC and no contraindications to the IMPs are eligible to participate. Participants undergo diagnostic staging CT and renal mass biopsy followed by treatment in one of the treatment arms for at least 14 days. Initially, the trial includes five treatment arms with cediranib, cediranib + olaparib, olaparib, durvalumab and durvalumab + olaparib. Participants undergo a multiparametric MRI before and after treatment. Vascularised and de-vascularised tissue is collected at surgery. A ≥ 30% increase in CD8+ T-cells on immunohistochemistry between the screening and nephrectomy is the primary endpoint for durvalumab-containing arms. Meanwhile, a reduction in tumour vascular permeability measured by K trans on dynamic contrast-enhanced MRI by ≥30% is the primary endpoint for other arms. Secondary outcomes include adverse events and tumour size change. Exploratory outcomes include biomarkers of drug mechanism and treatment effects in blood, urine, tissue and imaging. Discussion WIRE is the first trial using a window-of-opportunity design to demonstrate pharmacological activity of novel single and combination treatments in RCC in the pre-surgical space. It will provide rationale for prioritising promising treatments for later phase trials and support the development of new biomarkers of treatment effect with its extensive translational agenda. Trial registration ClinicalTrials.gov: NCT03741426 / EudraCT: 2018–003056-21 .

Drugs targeting angiogenesis and immunotherapy have transformed outcomes in renal cancer but may contribute to progressive kidney disease. We linked healthcare databases in the West of Scotland (spanning 2010-2020) to identify adults with renal cancer who received one or both classes of drugs. Over two years following initiation, estimated glomerular filtration rate (eGFR) slope was modelled using linear mixed-effects models. Additional renal outcomes used competing risk regression considering the competing risk of death. Amongst 357 adults (62.5% male; median age 63.0 years, IQI 55.0-71.0), there was no significant change in eGFR (annual eGFR change +1.03 mL/min/1.73 m²/year, 95%CI -1.64 to +3.70), nor in subgroups of patients who had nephrectomy, metastatic cancer or an eGFR < 60 mL/min/1.73 m² prior to systemic therapy. A ≥ 40% decline in eGFR occurred in 82 people (23.0%) within one year of starting systemic therapy and was associated with pre-existing diabetes (subhazard ratio 1.89, 95%CI 1.05-3.41). Anti-angiogenic and immune therapy had no substantial impact on the average change in eGFR but people with diabetes are at higher risk of clinically significant renal events. With appropriate monitoring, more widespread use of these agents in patients with renal impairment may be warranted.

Objective: The objective of the study is to describe the perioperative outcomes, disease-specific, and overall survival status in patients diagnosed with renal cell carcinoma with inferior vena cava (IVC) tumor thrombus. Patients and Methods: We did a retrospective analysis of all patients who underwent radical nephrectomy along with IVC thrombectomy from the year 2013 to 2020. Mayo's classification was used to stratify the level of IVC thrombus. Demographic, perioperative, histopathology data, complications, and survival status were analyzed. Results: Total number of patients included in the study was 39, (Male: Female = 84.6%: 15.4%). Median age of patients was 58 (interquartile range [IQR] 50-63) years. Median size of renal tumor (in cms) was 9.5 (IQR 7.5-12), 8 (IQR 7-11.5), 8.5 (IQR 7-11.75), and 11 (IQR 9.5-11) (P = 0.998) in level 1,2,3, and 4 tumors, respectively. Clear cell variant was seen in 32 patients (82%) with R0 resection in 17 patients. Twelve patients (30.7%) had systemic metastasis on presentation. The overall mean survival time was 66.4 months with 95% confidence interval (CI) (52.4-80.5 months). Mean recurrence-free survival is 76 months with (63-90) CI of 95%. Mean survival in patients who presented with metastasis is 47 months with 95% CI (52.4-80.5). Perioperative mortality rate was 5.12% in this study. Conclusion: The tumor size does not have an influence on the progression of tumor thrombus into IVC. Significant difference in survival was observed between different levels of thrombus with high mortality in level four tumors.