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UNLABELLED: We sought to evaluate the efficacy of WEE1 inhibitor adavosertib in patients with solid tumor malignancies (cohort A) and clear cell renal cell carcinoma (ccRCC; cohort B). NCT03284385 was a parallel cohort, Simon two-stage, phase II study of adavosertib (300 mg QDAY by mouth on days 1-5 and 8-12 of each 21-day cycle) in patients with solid tumor malignancies harboring a pathogenic SETD2 mutation. The primary endpoint was the objective response rate. Correlative assays evaluated the loss of H3K36me3 by IHC, a downstream consequence of SETD2 loss, in archival tumor tissue. Eighteen patients were enrolled (9/cohort). The median age was 60 years (range 45-74). The median duration of treatment was 1.28 months (range 0-24+). No objective responses were observed in either cohort; accrual was halted following stage 1. Minor tumor regressions were observed in 4/18 (22%) evaluable patients. Stable disease (SD) was the best overall response in 10/18 (56%) patients, including three patients with SD > 4 months. One patient with ccRCC remains on treatment for >24 months. The most common adverse events of any grade were nausea (59%), anemia (41%), diarrhea (41%), and neutropenia (41%). Nine patients (50%) experienced a Grade ≥3 adverse event. Of eight evaluable archival tissue samples, six (75%) had a loss of H3K36me3 by IHC. Adavosertib failed to exhibit objective responses in SETD2-altered ccRCC and other solid tumor malignancies although prolonged SD was observed in a subset of patients. Combination approaches may yield greater depth of tumor response. SIGNIFICANCE: WEE1 inhibition with adavosertib monotherapy demonstrated limited clinical activity in patients with SETD2-altered solid tumors despite compelling preclinical data indicating a synthetic lethal effect, which did not translate into robust tumor regression. Loss of the H3K36me3 trimethylation mark caused by SETD2-deficiency was confirmed in the majority of evaluable tumors. A subset of patients derived clinical benefit as manifested by minor tumor regressions and prolonged SD.

Abstract We report the basal cell cancer (BCC) cohort of the SWOG/NCI 1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART), a phase II prospective, multicenter basket trial of nivolumab and ipilimumab. The primary endpoint was objective response rate (ORR) (RECIST v1.1). Overall survival (OS), progression-free survival (PFS), and toxicity were secondary endpoints. Sixteen patients with advanced/metastatic BCC were evaluable. The ORR was 31% (95% CI, 19–50%), and the 12-month OS, 75% (95% CI, 57–100%). Median PFS was 9.3 months (95% CI, 3.3–NA). Of 15 patients evaluable for clinical benefit, five partial responses (PRs) and five stable disease >6 months (total = 10/15 (66.7%)) were seen. The most common toxicities included fatigue (37.5%), pruritis (31.3%), and diarrhea (25%). In patients with advanced/metastatic BCC, ipilimumab and nivolumab produced an ORR of 31% and prolonged (>6 months) PFS in 73% of patients, with seven PFS/iPFS of >1 year, including one with prior anti-PD-1. ClinicalTrials.gov ID: NCT02834013 (Registered 7/15/2016; https://clinicaltrials.gov/ct2/show/NCT02834013 ).

ABSTRACT Aims/Introduction The study aim was to investigate sulfonylurea prescription patterns in elderly patients (age ≥65 years) with type 2 diabetes mellitus in Japan. Sulfonylurea use among older adults has been insufficiently examined, despite the associated risks of hypoglycemia. Materials and Methods This retrospective cross‐sectional survey entailed analysis of Japanese pharmacy data, extracted from the Musubi database, for patients (age 20–100 years) prescribed sulfonylureas between November 2022 and October 2023. Dose distribution, adherence to the Diabetes Treatment Guidelines for the Elderly 2023 and coprescription of other diabetes medications were investigated. Results Of the total 91,229 patients, 80.1% were prescribed glimepiride, 16.3% gliclazide and 3.6% glibenclamide. In patients aged ≥65 years, exceeding the recommended dose (>1 mg/day for glimepiride, >40 mg/day for gliclazide) was numerically higher for glimepiride (25.0%) than for gliclazide (7.8%). The most common prescribing patterns were quadruple therapy with a sulfonylurea, a dipeptidyl peptidase‐4 inhibitor, an sodium–glucose transporter 2 inhibitor and a biguanide in patients aged 65 to

Granulosa cell tumor (GCT) is the most common nonepithelial ovarian malignancy. Still, it is considered rare, with a paucity of high-level evidence guiding management, particularly in the metastatic setting. Advancements in molecular pathology allowed the identification of several targetable mutations that play an important role in GCT pathogenesis. Although current management approaches rely on guidelines extrapolated from the more common epithelial subtype, the unique histopathologic and molecular characteristics of GCTs entail a more focused approach. Systemic therapy remains the cornerstone treatment for advanced disease, and although chemotherapy has been the standard for decades, targeted treatments have gained considerable attention lately. Due to the rarity of this disease, validation of new therapies in large trials is the rate-limiting step for developing evidence-based recommendations. This review sheds light on pathogenesis, clinical and molecular characteristics, and prognostic factors, and discusses current treatment options including the role of novel therapies and immune checkpoint inhibitors in advanced GCT.

ABSTRACT Background and Aim In terms of their longitudinal positioning, esophageal squamous cell carcinoma (ESCC) commonly arises in the middle segment of the esophagus. However, limited attention has been given to the circumferential aspect. This study aimed to investigate the prevalence and characteristics of ESCC lesions resected via endoscopic submucosal dissection (ESD), taking into consideration both longitudinal and circumferential positions. Methods We retrospectively evaluated 193 ESD‐resected ESCC lesions and compared the occurrence rate of ESCC development and the degree of histopathological invasion across various circumferential and longitudinal positions. We scrutinized lesion characteristics by location, with a particular focus on the proportion of early‐stage small lesions in each site. Results Regarding lesion location, 27 were situated on the anterior wall, 62 on the left, 66 on the posterior, and 38 on the right. Among the four circumferential positions, the anterior wall group had the smallest median tumor size. Additionally, the anterior wall group had the highest proportions of lesions with invasion depths limited to the epithelial layer and sizes

Abstract Background and Aim Chronic constipation negatively impacts work productivity and patients' quality of life. This retrospective study assessed the correlation between symptoms of chronic constipation and work/activity impairment with and without the use of laxative treatment. Methods This cross‐sectional, observational, web‐based survey was conducted using the Work Productivity and Activity Impairment‐Chronic Constipation Questionnaire and included Japanese patients with chronic constipation receiving prescribed medication. Outcomes of interest included total work productivity and activity impairment and their correlation with constipation symptoms. Results Among the 2351 analyzed patients (mean [SD] age, 51.7 [13.8] years), 80.7% were females, 63.3% had a disease duration of ≥10 years, and 1424 were working. The averages of total activity impairment, total work productivity impairment, presenteeism, and absenteeism were 39.2%, 33.9%, 31.2%, and 5.0%, respectively. The annual work productivity loss per patient was estimated to be 1.343 million Japanese Yen. Symptoms that had a statistically significant positive correlation with total work impairment (P

Extracellular biophysical cues such as matrix stiffness are key stimuli tuning cell fate and affecting tumor progression in vivo. However, it remains unclear how cancer spheroids in a 3D microenvironment perceive matrix mechanical stiffness stimuli and translate them into intracellular signals driving progression. Mechanosensitive Piezo1 and TRPV4 ion channels, upregulated in many malignancies, are major transducers of such physical stimuli into biochemical responses. Most mechanotransduction studies probing the reception of changing stiffness cues by cells are, however, still limited to 2D culture systems or cell-extracellular matrix models, which lack the major cell–cell interactions prevalent in 3D cancer tumors. Here, we engineered a 3D spheroid culture environment with varying mechanobiological properties to study the effect of static matrix stiffness stimuli on mechanosensitive and malignant phenotypes in oral squamous cell carcinoma spheroids. We find that spheroid growth is enhanced when cultured in stiff extracellular matrix. We show that the protein expression of mechanoreceptor Piezo1 and stemness marker CD44 is upregulated in stiff matrix. We also report the upregulation of a selection of genes with associations to mechanoreception, ion channel transport, extracellular matrix organization, and tumorigenic phenotypes in stiff matrix spheroids. Together, our results indicate that cancer cells in 3D spheroids utilize mechanosensitive ion channels Piezo1 and TRPV4 as means to sense changes in static extracellular matrix stiffness, and that stiffness drives pro-tumorigenic phenotypes in oral squamous cell carcinoma.

PurposeGliomagenesis and resistance of glioblastoma (GBM) are believed to be mediated by glioma stem cells (GSC). Evidence suggests that SHH signaling promotes GSC proliferation and self-renewal.MethodsABTC-0904 was a two-arm, multicenter phase 0/II study of GDC-0449, an oral inhibitor of Smoothened (SMO) in patients undergoing resection for recurrent GBM. All patients (Arms I and II) had surgery and received drug post-operatively. Only patients in Arm I received drug prior to surgery. The primary objective was to determine 6-month progression free survival (PFS-6). Secondary endpoints include median PFS (mPFS) and overall survival (mOS), response rate, and toxicity. Correlative studies included bioanalysis of GDC-0449, and inhibition of SHH signaling, GSC proliferation and self-renewal.ResultsForty-one patients were enrolled. Pharmacokinetics of GDC-0449 in plasma demonstrated levels within expected therapeutic range in 75% of patients. The proportion of tumorcells producing CD133+ neurospheres, neurosphere proliferation, self-renewal, and expression of the SHh downstream signaling was significantly decreased in Arm I following GDC-0449 treatment (p

Purpose: To conduct a longitudinal evaluation of sites grafted with autogenous bone prior to implant placement using a dental cast with a 3D modeling system. Materials and Methods: A total of nine patients underwent implant treatment with bone grafting for anterior missing teeth. Informed consent was obtained from each patient. Casts were made and evaluated at three time periods, including before bone grafting (Pre BG), 4 or 5 months after grafting (Post BG), and 4 or 5 months after implant placement (Post IP). 3D data of these casts were acquired using a 3D digital scanner and then superimposed with reference to the remaining teeth. The volume of the anterior area of the cast was evaluated Pre BG and Post BG. Results: Accuracy of superimposition on the remaining teeth was between 20 and 50 |m. Horizontal differences Post BG and Post IP were 0.1 to 1.6 mm. The volume Post IP decreased by 14% to 38% compared to the volume Post BG. Conclusions: This 3D modeling technique allowed 3D evaluation before and after bone grafting. Results suggested that the volume of the maxilla was sequentially decreased after bone grafting. [ABSTRACT FROM AUTHOR]

Proton-transfer mechanisms and hydration states were investigated in chitin films possessing the functionality of fuel-cell electrolytes. The absolute hydration number per chitin molecule (N) as a function of relative humidity (RH) was determined from the OH stretching bands of H2O molecules, and the proton conductivity was found to enhance above N = 2 (80%RH). The FIR spectrum at 500–900 cm−1 for 20%RH (N < 1) together with first-principles calculations clearly shows that the w1 site has the same hydration strength as the w2 site. The molecular dynamics simulations for N = 2 demonstrate that H2O molecules with tiny fluctuations are localized on w1 and w2, and the hydrogen-bond (HB) network is formed via the CH2OH group of chitin molecules. Shrinkage of the O–O distance (dOO), which synchronizes with the barrier height, is required for proton transfer from H3O+ to adjacent CH2OH groups or H2O molecules. Nevertheless, dOO is hardly modulated for N = 2 because H2O molecules are strongly constrained on w1 and w2, and therefore, the transfer probability becomes small. For N = 3, novel HBs emerged between the additional H2O molecules broadly distributed on the w3 site and H2O molecules on w1 and w2. The transfer probability is enhanced because large fluctuations and diffusions in the whole H2O molecule yield large modulations of dOO. Consequently, long-range proton hopping is driven by the Zundel-type protonated hydrates in the water network. [ABSTRACT FROM AUTHOR]

Introduction Previous research has highlighted the association between socioeconomic factors and diabetes management. This study aimed to elucidate the blood glucose control status among individuals with low income (ie, recipients of public assistance (PARs) and free/low-cost medical care (FLCMC) programme beneficiaries) and to investigate the effects of public subsidies for medical expenses on treatment adherence among low-income patients with diabetes.Methods We conducted a secondary analysis of medical records from 910 outpatients with diabetes who underwent pharmacological treatment for >90 days. Data on predictive variables, such as glycated haemoglobin (HbA1c) level and control variables, including sex, age and insurance type, were obtained retrospectively. The HbA1c levels among public health insurance (PHI)-only beneficiaries, FLCMC programme beneficiaries and PARs were compared using logistic regression analysis.Results The analysis included 874 individuals, among whom the majority were men (61.7%) and aged≥65 years (58.4%). Logistic regression analysis revealed that among individuals aged ˂65 years, the adjusted ORs for HbA1c levels above 9% were significantly higher in FLCMC programme beneficiaries (OR=5.37, 95% CI: 2.23 to 12.82) and PARs (OR=5.97, 95% CI: 2.91 to 12.74) than in PHI-only beneficiaries. Among patients aged ˂65 years with HbA1c levels above 7%, the adjusted OR was significantly higher in FLCMC programme beneficiaries (OR=3.82, 95% CI: 1.65 to 10.43) than in PHI-only beneficiaries. Additionally, the adjusted OR was significantly higher in FLCMC programme beneficiaries aged ˂65 years (OR=2.57, 95% CI: 1.02 to 7.44) than in PARs.Conclusions This study highlights the predictive value of public assistance or the FLCMC programme for poor blood glucose control and suggests the inadequacy of current medical expense subsidies to eliminate health disparities in diabetes control.