Memorial Hospital of South Bend

Chemotherapy remains central to cancer management, but its effectiveness is often limited by multidrug resistance (MDR), largely mediated by the ATP-binding cassette (ABC) transporter ABCB1 (P-glycoprotein; P-gp). As no clinically approved inhibitors are available to overcome ABCB1-mediated MDR, this study aimed to evaluate befotertinib (D-0316), a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor approved by the National Medical Products Administration, for its potential to modulate ABCB1 activity. Cytotoxicity and apoptosis assays were used to assess chemosensitization in multidrug-resistant cancer cells. Drug efflux inhibition was examined, while vanadate-sensitive ATPase activity and molecular docking analyses were performed to characterize interactions between befotertinib and ABCB1. Befotertinib significantly enhanced anticancer drug-induced apoptosis and resensitized resistant cells in a concentration-dependent manner. It inhibited ABCB1-mediated efflux, stimulating ATPase activity and demonstrating direct binding to key residues within the ABCB1 substrate-binding pocket. These results identify befotertinib as a functional inhibitor of ABCB1 with the capacity to reverse MDR. The findings support its potential as a repurposed agent for combination therapy in tumors with high ABCB1 expression, offering a practical strategy to enhance chemotherapy efficacy.

A 51-year-old woman had been noted to have anemia since 2019 and developed Raynaud's phenomenon during winter or in air-conditioned environments from 2021. In January 2024, she experienced palpitations, tinnitus, dyspnea on exertion, and fatigue. Twenty-three days later, she was urgently admitted to hospital with severe anemia (Hb 2.8 g/dl). She was diagnosed with primary cold agglutinin disease (CAD) and CAD-associated lymphoproliferative disorder (LPD). While she was under observation, undergoing red blood cell transfusion with avoidance of cold exposure, her anemia progressed without worsening of hemolysis and she was diagnosed with pure red cell aplasia (PRCA). Cyclosporine A (CsA) was administered for 10 days without response, and treatment was switched to bendamustine-rituximab (BR) for LPD. Although her LPD improved, her PRCA persisted; CsA was therefore resumed, leading to improvement in the PRCA. In October, her CAD-LPD relapsed with hemolysis, and BR therapy with continued CsA treatment again achieved improvement in the CAD-LPD without worsening of the PRCA. This rare case of primary CAD-associated LPD complicated by PRCA highlights the importance of accurate disease assessment and appropriate treatment strategies.

<title>Abstract</title> Purpose Stroke is a leading cause of death and disability worldwide. Clopidogrel, an antiplatelet agent that is commonly used for the secondary prevention of ischemic stroke, yet the data on the efficacy and safety of generic versus brand-name clopidogrel remain limited. The aim of this retrospective cohort study was to compare the efficacy and safety of generic clopidogrel with brand-name clopidogrel in the secondary prevention of ischemic stroke. Methods Patients with ischemic stroke prescribed either generic or brand-name clopidogrel were identified from the Taiwan National Health Insurance Research Database between 2008 and 2021. The efficacy was defined as recurrent ischemic stroke and safety as major bleeding. Possible confounding effects were reduced using propensity score matching. Results A total of 5,540 matched pairs were included in the analysis. The incidence rate of recurrent ischemic stroke was 3.95 per 100 person-years in the generic group, and 3.43 per 100 person-years in the brand-name group (subdistribution hazard ratio [SHR] 1.09, 95% confidence interval [CI] 0.97–1.21). The incidence of major bleeding was also similar between the two groups (SHR: 0.95, 95% CI: 0.84–1.08), with rates of 3.35 and 3.28 per 100 person-years for generic and brand-name clopidogrel, respectively. There were no significant differences in other outcomes including gastrointestinal bleeding, intracranial hemorrhage, fatal bleeding, major adverse cardiovascular events, and cardiovascular or all-cause death. Conclusion This study showed that the efficacy and safety of generic clopidogrel was comparable to its brand-name counterpart in patients with ischemic stroke.

Abstract Disclosure: Y. Tsujimoto: None. A. Ishida: None. H. Shichi: None. N. Yamamoto: None. Y. Motomura: None. Y. Oi-Yo: None. Y. Sasaki: None. M. Suzuki: None. S. Urai: None. H. Bando: None. M. Yamamoto: None. M. Takahashi: None. G. Iguchi: None. N. Inoshita: None. S. Yamada: None. W. Ogawa: None. H. Fukuoka: None. Background: Several predictive markers for drug selection in acromegaly (Acro) are known, most based on hormonal suppression effects. Acro is characterized by excessive growth hormone secretion and clinical tumor effects due to the high prevalence of macroadenomas, making it essential to predict drug responsiveness for tumor shrinkage. In oncology, patient-derived 3D tumor culture systems have proven to be reliable tools for evaluating drug responses, bridging the gap between in vitro experiments and clinical studies. This study aimed to develop a similar model for Acro to assess drug responsiveness and evaluate its potential for predicting treatment outcomes. Methods: Tumor specimens from 27 Acro patients (median age: 46 [range: 36-56] years; female/male ratio: 13/14) were collected postoperatively and processed into 3D cell culture, as previously described (Tsujimoto Y, et al. J Endocr Soc. 2021; bvab055.). The culture cells were treated with therapeutic agents—octreotide (Oct) 10 nM, cabergoline (Cab) 10 nM, pasireotide (Pas) 10 nM, or vehicle—under standardized conditions. The drug response was defined as a statistically significant reduction in cell viability compared to vehicle-treated controls, as measured by the RealTime-Glo™ MT Cell Viability Assay, which provided real-time feedback on the drugs' cytotoxic effects. Fisher's exact tests and Mann-Whitney U test evaluated associations between responsiveness and clinical or histological factors. Results: Among the 27 cases, 9 (33%) responded to Oct, with an association observed in tumors with T2WI hypointensity on MRI (p = 0.04). The responsiveness to Cab was observed in 9 cases (33%), with an association in patients who responded to the bromocriptine test (p = 0.04). Pas exhibited the highest response rate (11 cases, 40%), which was associated with sparsely granulated tumors (p = 0.04).Discussion:The use of a 3D tumor culture system derived from Acro patients provided insights into drug-specific responsiveness, aligning with previously identified predictive factors for Oct, Cab, and Pas. However, it is important to note that most previously reported predictive factors focus primarily on biochemical remission. The assay's ability to measure real-time cell viability represents a significant advancement in evaluating treatment efficacy, particularly for tumor shrinkage, which has historically been challenging to predict. Integrating this approach into clinical practice, particularly for postoperative residual cases, could enable personalized medicine by refining drug selection based on tumor characteristics. Further validation in larger cohorts and prospective clinical trials is warranted to establish its broader applicability and cost-effectiveness. Presentation: Saturday, July 12, 2025

ObjectivesWe aimed to understand the factors affecting psychological well-being of patients undergoing haemodialysis (HD). First, we explored how physical symptom severity, emotional distress and social support influence psychological well-being. Second, we examined the impact of different types of social support. Third, we investigated whether any variables mediate the relationship with psychological well-being.Design and settingA cross-sectional study, a type of observational design, was conducted on patients at a medical centre in Taiwan in 2020.ParticipantsA total of 117 outpatients who had undergone regular HD for at least 3 months were enrolled.Primary outcome measuresThe psychological well-being was assessed through self-report questionnaires.ResultsWe found that emotional distress (β=−0.25, p=0.033) had a significant negative impact on psychological well-being. However, the presence of appraisal support mitigated this effect. Specifically, appraisal support fully mediated the adverse impact of emotional distress on psychological well-being. In addition, the severity of physical symptoms was generally mild and did not influence psychological well-being.ConclusionReceiving appraisal support from family, friends and healthcare professionals not only alleviates emotional distress but also enhances psychological well-being both directly and indirectly among patients undergoing HD. Healthcare professionals should address issues of personal importance while serving as consultants, educators and evaluators to support patients in managing their chronic condition.

Current evidence concerning the association between lipoprotein combine index (LCI) and Non-alcoholic fatty liver disease (NAFLD) in non-obese people remains limited. This 5-year longitudinal cohort study aimed to explore the connection between LCI and risk of NAFLD in non-obese Chinese individuals with normal lipids. This retrospective cohort study from January 2010 to December 2014 consecutively and non-selectively collected 9,838 non-obese participants with normal lipid profiles in a Chinese hospital. Using the Cox proportional-hazards regression model, we explored the relationship between baseline LCI and NAFLD risk. We applied cubic spline functions and curve fitting to characterize the non-linear association between LCI and NAFLD. Simultaneously, we conducted sensitivity and subgroup analyses, and employed receiver operating characteristic (ROC) curve analysis to evaluate the predictive potential of LCI for NAFLD incidence. The mean age of participants was 42.46 ± 14.70 years, with males comprising 51.40% of the cohort. During a median follow-up period of 33.10 months, 855 participants (8.89%) progressed NAFLD, with an incidence of 31.51 cases per 1,000 person-years. A significant non-linear relationship was identified between LCI and NAFLD risk with an inflection point at 5.514 mmol2/L2, where the HR was significantly stronger below this threshold (HR = 1.282, 95%CI: 1.162-1.415) compared to above it (HR = 1.063, 95%CI: 1.042-1.084). Subgroup analysis revealed the strongest associations in participants with body mass index (BMI) between 18.5 and 24 kg/m2. LCI demonstrated superior predictive value for NAFLD compared to individual lipid parameters, with an area under the ROC curve of 0.717. This study offers novel insights into the relationship between LCI and NAFLD risk in non-obese Chinese individuals with normal lipid levels. The non-linear association and the moderate discriminatory ability of LCI suggest its potential utility as a practical screening marker for population-level risk stratification and early preventive strategies in seemingly low-risk, normal-weight populations.

The mandible is subjected to multiple surgical interventions, and the procedures pose a risk of injuring the inferior alveolar nerve (IAN) running inside the bone. Comprehensive anatomical information of the IAN within the mandible is required. The authors performed a 3-dimensional imaging study, recruiting cone-beam computed tomography from 355 patients with an average age of 23.3 years. The patients received treatment in their center between 2010 and 2022. Patients were classified into 4 groups: classes I, II, and III, and cleft, based on Angle classification and cleft diagnosis. The images were analyzed to measure the distances at the ramus, angle, and body. The average distance from the lateral cortical bone to the nerve canal was longest around the second molar (5.16 ± 1.42 mm), with the class II group having the longest distance in group comparisons (5.77 ± 1.07 mm). The average distance from the mandibular angle to the nerve canal was longest in the class II group (20.03 ± 2.63 mm) in group comparisons, and longer in male patients (20.55 ± 3.02 mm) in sex comparisons. All the nerves were located above the modified Kamiishi line. In patients with unilateral cleft lip and palate, there were no significant differences in most measurements between the cleft side and the noncleft side. This study provides useful anatomical information of the inferior alveolar nerve for planning and execution of surgery on the mandible. Although there was a general pattern of nerve course, differences were noted.