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Dual-ligand fluorescence microscopy enables chronological and spatial histological assignment of distinct amyloid-β deposits
Adjuvant Nivolumab in High-Risk Muscle-Invasive Urothelial Carcinoma: Expanded Efficacy From CheckMate 274
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported . CheckMate 274 is a phase III, randomized, double-blind trial of adjuvant nivolumab versus placebo for muscle-invasive urothelial carcinoma (MIUC) at high risk of recurrence after radical resection. The primary end points of disease-free survival (DFS) in intent-to-treat (ITT) and tumor PD-L1 expression ≥1% populations were met. We report results at an extended median follow-up of 36.1 months in the ITT population. In addition, we report interim overall survival (OS) data for the first time and an exploratory analysis among patients with bladder primary tumors (muscle-invasive bladder cancer [MIBC]). Consistent DFS benefit with nivolumab versus placebo was observed in both the ITT (hazard ratio [HR], 0.71 [95% CI, 0.58 to 0.86]) and PD-L1 ≥1% (HR, 0.52 [95% CI, 0.37 to 0.72]) patients. The HR for OS with nivolumab versus placebo was 0.76 (95% CI, 0.61 to 0.96) in the ITT population and 0.56 (95% CI, 0.36 to 0.86) in the PD-L1 ≥1 population. Continuous benefit in nonurothelial tract recurrence-free survival and distant metastasis-free survival was also observed in both patient populations. The exploratory analysis of patients with MIBC also showed continued efficacy benefits, irrespective of PD-L1 status. No new safety signals were reported. Overall, these results further support adjuvant nivolumab as a standard of care for high-risk MIUC after radical resection.
The structural basis for high-affinity c-di-GMP binding to the GSPII-B domain of the traffic ATPase PilF from Thermus thermophilus
How We Monitor Cardiac Health in Breast Cancer Survivors
The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology , to patients seen in their own clinical practice.
The putative polyamine transporter Shp2 facilitates phosphate export in an Xpr1-independent manner and contributes to high phosphate tolerance
Menin Inhibition With Revumenib for <i>KMT2A</i> -Rearranged Relapsed or Refractory Acute Leukemia (AUGMENT-101)
PURPOSE Revumenib, an oral, small molecule inhibitor of the menin-lysine methyltransferase 2A (KMT2A) interaction, showed promising efficacy and safety in a phase I study of heavily pretreated patients with KMT2A -rearranged ( KMT2Ar ) acute leukemia. Here, we evaluated the activity of revumenib in individuals with relapsed/refractory (R/R) KMT2Ar acute leukemia. METHODS AUGMENT-101 is a phase I/II, open-label, dose-escalation and expansion study of revumenib conducted across 22 clinical sites in five countries (ClinicalTrials.gov identifier: NCT04065399 ). We report results from the phase II, registration-enabling portion. Individuals age ≥30 days with R/R KMT2Ar acute leukemia or with AML and nucleophosmin 1 ( NPM1 ) mutation were enrolled. Revumenib was administered once every 12 hours, at 163 mg (95 mg/m 2 if weight <40 kg) with a strong cytochrome P450 inhibitor, in 28-day cycles. The primary end points were the rate of complete remission (CR) or CR with partial hematologic recovery (CR + CRh) and safety. At a prespecified interim analysis, safety was assessed in all KMT2Ar treated patients; efficacy was assessed in those with centrally confirmed KMT2Ar . The separate NPM1 cohort of the trial is ongoing. RESULTS From October 1, 2021, to July 24, 2023, N = 94 patients (median [range] age, 37 [1.3-75] years) were treated. Grade ≥3 adverse events included febrile neutropenia (37.2%), differentiation syndrome (16.0%), and QTc prolongation (13.8%). In the efficacy-evaluable patients (n = 57), the CR + CRh rate was 22.8% (95% CI, 12.7 to 35.8), exceeding the null hypothesis of 10% ( P = .0036). Overall response rate was 63.2% (95% CI, 49.3 to 75.6), with 15 of 22 patients (68.2%) having no detectable residual disease. CONCLUSION Revumenib led to high remission rates with a predictable safety profile in R/R KMT2Ar acute leukemia. To our knowledge, this trial represents the largest evaluation of a targeted therapy for these patients.
PRDX4 mitigates diabetic retinopathy by inhibiting reactive gliosis, apoptosis, ER stress, oxidative stress, and mitochondrial dysfunction in Müller cells
Advances in Vulvar Cancer Biology and Management
PURPOSE Vulvar squamous cell carcinoma (VSCC), a rare gynecologic malignancy, has been rising in incidence. Molecular classification on the basis of human papilloma virus (HPV) and tumor protein 53 (p53) status has identified three clinically distinct subtypes, but we still treat all VSCCs the same. Here, we review molecular classification of VSCC, outline treatment landscape, and highlight potential for targeted therapies in advanced VSCC. DESIGN We conducted a comprehensive review of the literature on treatment of advanced VSCC with particular focus on the implications of molecular stratification on the basis of HPV and p53 status on the treatment landscape of advanced VSCC. RESULTS Incorporation of HPV and p53 status in locoregional treatment decision making has the potential to advise (de)escalation strategies. The role of immunotherapy, alone and in combination, requires further exploration particularly earlier in the course of the disease. In advanced stages, potential for targeted therapies in VSCCs include inhibitors of vascular endothelial growth factor, endothelial growth factor receptor, cell cycle, and DNA damage response, particularly in HPV-negative (HPV–) VSCCs. Targeting the phosphoinositide 3 kinase/mammalian target of rapamycin pathway is attractive in HPV-positive and HPV–/p53 wildtype VSCCs. Trials incorporating antibody-drug conjugates (eg, trophoblast cell-surface antigen 2, human epidermal growth factor receptor 2) should be considered, and basket trials in perineal squamous cell cancers are warranted. Preclinical models are limited and should be expanded to inform trial design. CONCLUSION Like other rare cancers, vulvar cancer lags behind in the identification and optimization of precision medicine strategies. Molecular-based preclinical models and rationally designed clinical trials, incorporating high-quality translational studies, are urgently required. These trials will require international collaboration to ensure feasibility and improvement of outcomes for women diagnosed with this disease.
Phosphorylation of Ephexin4 at Ser-41 contributes to chromosome alignment via RhoG activation in cell division
Cardiac Dysfunction Among Breast Cancer Survivors: Role of Cardiotoxic Therapy and Cardiovascular Risk Factors
PURPOSE Cardiac dysfunction is the leading cause of mortality among 10-year breast cancer survivors. Limited information regarding long-term risks of cardiac dysfunction after cardiotoxic therapy (anthracyclines, trastuzumab/pertuzumab, radiation) has precluded development of surveillance guidelines for the survivors. METHODS Patients with breast cancer who completed cardiotoxic therapy underwent echocardiographic screening every 2 years. New-onset cardiac dysfunction was defined as left ventricular ejection fraction (LVEF) <50% after cardiotoxic therapy initiation and included early- and late-onset cardiac dysfunction. RESULTS We evaluated 2,808 echocardiograms in 829 breast cancer survivors; the median age at breast cancer diagnosis was 54.2 years (range, 20.3-86.3); the median follow-up was 8.6 years (1.8-39.8); 39.7% received anthracyclines, 16% received trastuzumab/pertuzumab, 6.2% received both anthracyclines and trastuzumab/pertuzumab, and 38.1% received radiation alone. The cumulative incidence of cardiac dysfunction increased from 1.8% at 2 years to 15.3% at 15 years from cardiotoxic therapy initiation. Multivariable Cox regression analysis identified the following risk factors: non-Hispanic Black race (hazard ratio [HR], 2.15 [95% CI], 1.37 to 3.38), cardiotoxic therapies (anthracyclines: HR, 2.35 [95% CI, 1.25 to 4.4]; anthracyclines and trastuzumab/pertuzumab: HR, 3.92 [95% CI, 1.74 to 8.85]; reference: left breast radiation alone), selective estrogen receptor modulators (HR, 2.0 [95% CI, 1.2 to 3.33]), and precancer hypertension (HR, 3.16 [95% CI, 1.63 to 6.1]). Late-onset cardiac dysfunction was most prevalent among anthracycline- and radiation-exposed patients; early-onset cardiac dysfunction was most prevalent among patients exposed to anthracyclines and trastuzumab/pertuzumab; equal prevalence of both early- and late-onset cardiac dysfunction was observed in trastuzumab-/pertuzumab-exposed patients. Adjusted longitudinal analyses revealed an annual decline in LVEF by 0.29% ( P = .009) over 20 years from breast cancer diagnosis. CONCLUSION These findings provide evidence to support echocardiographic surveillance for several years after cardiotoxic therapy and also suggest a need to examine the efficacy of management of cardiovascular risk factors to mitigate risk.
Restoring Smile with Ceramic Veneers for a Patient with Fractured Anterior Teeth: A Case Report
Background: This case report analyzes the efficient restoration of fractured anterior teeth using ceramic veneers. A 47-year-old female patient suffered from trauma, which caused fractures of the maxillary central incisors. Veneers were considered an adequate treatment option for smile restoration. Case Presentation: A 47-year-old female presented with trauma that resulted in fractures of the maxillary central incisors. After taking the pertinent information, the decision was made to proceed with lithium disilicate ceramic veneers. After taking impressions for the veneers to be custom-made, the veneers were directly bonded to the fractured incisors with an adhesive cement. Conclusion: During the procedure, minimal preparation was needed, which meant that most natural tooth structures were preserved. Also, the veneers with their excellent properties were both functional and pleasing to the eye. When the patient returned for their 12-month follow-up, they had no complications with their new smile and veneers. The patient reported with great satisfaction that their smile was not only new but also brought a high level of confidence.
The zymogenic form of SARS-CoV-2 main protease: A discrete target for drug discovery
Systemic Therapy for Small Cell Lung Cancer: ASCO Guideline Rapid Recommendation Update
ASCO Rapid Recommendation Updates highlight revisions to select ASCO guideline recommendations as a response to the emergence of new and practice-changing data. The rapid updates are supported by an evidence review and follow the guideline development processes outlined in the ASCO Guideline Methodology Manual. The goal of these articles is to disseminate updated recommendations, in a timely manner, to better inform health practitioners and the public on the best available cancer care options. Guidelines and updates are not intended to substitute for independent professional judgment of the treating clinician and do not account for individual variation among patients. See appendix for disclaimers and other important information ( Appendix 1 and Appendix 2 , online only) .
Exploring Gingival Overgrowth Due to Epileptic Medication: A Case Report
Background: Gingival tissue hyperplasia is a condition that affects oral hygiene, aesthetics, and quality of life. Commonly associated with the use of some antiepileptic drugs (AEDs) like phenytoin and sodium valproate, this condition has become a normal occurrence in patients who take ATPs for seizure management because of the side effects that come along with the adverse tissues growth. Case Presentation: A 21-year-old female who had been taking sodium valproate to control her seizures developed severe gingival overgrowth. The clinical exam showed significant overgrowth in the anterior gingival area and with the overgrowth came inflammation along with symptoms of bleeding and bad breath (halitosis). The initial intervention of the problem (overgrowth) was some steps to improve oral hygiene with the use of some chlorhexidine mouthwash along with a short course of some antibiotics. But because of the severity of the overgrowth, surgical intervention to excise some of the overgrown tissue was performed. The tissue that was excised had a histopathological exam that confirmed the diagnosis along with giving some information for the changes in the tissue (cellular) to help understand the condition. Conclusion: This case highlights the importance of a multidisciplinary approach in managing DIGO, which includes regular dental monitoring, improved oral hygiene practices, and surgical interventions when necessary.
A kinetic model for compound heterozygous pathogenic variants in Tyrosyl-tRNA synthetase gene YARS2-Associated neonatal phenotype
Underrated But Significant Risk Factors of Osteoradionecrosis of the Jaw in Patients With Head and Neck Cancer
Differentiating Pathogenic Bacteria through Biochemical Markers: A Study for Clinical Applications
Introduction: Beer has become the world's largest consumed alcohol. Beer brewed on a small scale in terms of quantity by independent breweries that brew traditionally has been termed as craft beer. Small-scale breweries involve testing newer preparation techniques, which also involve the use of raw materials not commonly accepted. However, these practices can increase the incidence of contaminants, awareness of which helps consumers make informed choices. Contamination can occur at any stage of the production process, and microbial contaminants may either improve or deteriorate the quality of beer by producing biochemicals and organic acids, affecting the beer's shelf life. Aim: To analyse various local craft beer samples for contaminants, with a focus on microbial contamination. Methods: Samples of the local craft beers were taken and screened. The samples were diluted serially and spread plated on simple agar media for isolation. Gram staining and biochemical characterisation of bacterial colonies Results: There are several kinds of microorganisms identified to exist in local craft beers. Their existence is detected through the characteristic and biochemical profiling in the samples. Conclusion: The study indicates the presence of microbial contamination in local craft beer, thereby showing the possible effects of such contamination on quality and shelf life. Consumers and producers could use this information to guide decisions to produce and consume craft beers.
The transcription factor CREB regulates epithelial-mesenchymal transition of lens epithelial cells by phosphorylation-dependent and phosphorylation-independent mechanisms
Reply to E. Topkan et al
Knowledge, Attitude, and Practice Study on Cardiovascular Disease Risk Factors in the Mangalore Community
Introduction: Cardiovascular diseases are the leading cause of death in the world, causing 17.9 million deaths annually. In India, with cities like Mangalore included, the burden of cardiovascular disease is increasing rapidly. Methods: A cross-sectional survey was conducted on 215 adults aged 18 years through stratified random sampling. Data collection was accomplished using a validated structured questionnaire; it measured knowledge relating to cardiovascular disease risk factors, attitudes toward prevention, and health practices. High questionnaire reliability was observed; this is because Cronbach's α for the knowledge, attitude, and practice parts appeared to be 0.82, 0.78, and 0.76, respectively. Descriptive statistics, t- t-tests, ANOVA, and multiple regression were used in the analysis. Results: The mean age was 42.3±13.7years, and females were at 51.2%. Awareness that hypertension is a risk factor for cardiovascular disease was 88.4%, 95% CI: 83.9-92.9%. Conversely, awareness of the risk of diabetes was slightly lower, at 72.1%, 95% CI: 65.9-78.3%. The prevention attitude score is positive, with 90.7%, 95% CI: 86.5-94.9% agreeing to exercise regularly. Only 70.0%, 95% CI: 63.7-76.3% agreed to having exercised lately. Education level strongly predicted knowledge scores (β=0.15, p=0.02), and knowledge scores were positively correlated with attitude scores (r=0.45, p