Citations

ABSTRACT Purpose Malignant rhabdoid tumor of the kidney (MRTK) is a rare, aggressive tumor seen in young children. The optimal timing of resection for locally advanced tumors is not well‐defined. The purpose of this study is to evaluate modern oncologic outcomes and the impact of surgical timing. Methods A multicenter retrospective review was performed by institutions participating in the Pediatric Surgical Oncology Research Collaborative. Children younger than 21 years old with MRTK diagnosed between 2000 and 2022 were included. Results Sixty‐nine patients were identified with MRTK and met the inclusion criteria. Median age of diagnosis was 10.1 months. Overall survival (OS) at 1, 5, and 10 years was 49%, 32%, and 19%, respectively. Patients with local Stage III disease who underwent upfront resection ( n = 18) compared to those who had delayed resection after NAT ( n = 15) had a similar OS, median OS greater than 60 months versus 14.6 months, respectively; p = 0.396. The surgical timing groups were balanced in terms of the presence of metastasis, length of follow‐up, and tumor characteristics. There was one occurrence of primary intraoperative tumor spill and two occurrences of organ injury in the upfront resection group compared to none in the delayed resection group. Conclusion MRTK carries a poor prognosis despite multimodal treatment. Histologic diagnosis may not be confirmed at presentation, and MRTK cannot be reliably distinguished from Wilms tumor on imaging alone. As overall survival is similar, the decision regarding surgical timing in locally advanced tumors should be individualized based on perceived resectability, balancing the risk of intraoperative complications against the possibility of tumor progression during neoadjuvant therapy.

RET fusions appear in 1%-2% of non–small cell lung cancers (NSCLCs). The results from the ARROW study (ClinicalTrials.gov identifier: NCT03037385 ) supported US Food and Drug Administration approval of pralsetinib, an oral selective RET inhibitor, for metastatic RET -altered NSCLC and RET fusion–positive thyroid cancers. ARROW was a phase I/II open-label study of pralsetinib 400 mg once daily in RET fusion–positive NSCLCs. Coprimary end points were overall response rate (ORR) and safety. Key secondary end points included duration of response, progression-free survival, and overall survival (OS). At data lock (May 20, 2024), 281 patients initiated pralsetinib (median treatment duration, 15.0 months). ORR (measurable disease patients; n = 259) was 78% (95% CI, 69 to 86) for treatment-naïve patients and 63% (95% CI, 54 to 71) for prior platinum-based chemotherapy patients. Median OS was 44.3 months (95% CI, 30.9 to 53.1), 50.1 months (95% CI, 28.3 to not reached) in treatment-naïve patients, and 39.7 months (95% CI, 27.8 to 53.2) in prior platinum patients. Common grade ≥3 treatment-related adverse events were anemia (21%), hypertension (15%), and decreased neutrophils (13%). Three treatment-related deaths occurred (pneumonia, n = 2; interstitial lung disease and rhabdomyolysis, n = 1 each). Safety was consistent with previous ARROW reports; no hypersensitivity was reported in patients receiving prior immunotherapies. Pralsetinib produced robust, durable responses with manageable safety in treatment-naïve and previously treated patients with RET fusion–positive NSCLCs, confirming previous findings with longer follow-up.

Background: Sinonasal malignancies (SNM) are rare cancers associated with poor prognosis and impaired quality of life (QOL). The 22-question Sino-Nasal Outcome Test (SNOT-22) has been used to assess QOL in patients with SNM. Objective: To determine the minimal clinically important difference (MCID) for the SNOT-22 in patients with SNM. Methods: About 264 patients with SNM were drawn from a prospective, longitudinal, multi-institutional study. SNOT-22 scores were collected at pre-treatment baseline and follow-up through 5 years post-treatment. Cronbach’s alpha was used to assess the internal consistency of the SNOT-22. Distribution-based approaches were used to estimate the MCID. Multivariable regression identified factors associated with SNOT-22 improvement exceeding the determined MCID. Results: Cronbach’s alpha was >.85. The estimated MCIDs were: 1.44 (Cohen’s effect size), 1.32 (standard error of the mean), 10.45 (1/2 of baseline standard deviation), and 3.67 (minimum detectable change). The mean MCID across methods was 4.22. Multivariable regression demonstrated higher odds of clinically meaningful improvement from baseline in patients with early-stage disease (odds ratio (OR) 3.510, P = .035), no neck irradiation (OR 11.050, P = .014), and neoadjuvant therapy (OR 16.667, P = .047). Conclusions: The SNOT-22 MCID was estimated as 4.22 in a large multi-center cohort of patients with SNM, suggesting that relatively small QOL changes are clinically relevant. When applying the MCID to the current cohort, advanced stage, treatment of neck disease, and not requiring neoadjuvant therapy were predictive of worse QOL.

Abstract Purpose: Standard care for high-grade gliomas (HGG) involves maximal surgical resection followed by radiation and temozolomide. Postoperative adjuvant therapy frequently causes lymphopenia, which is associated with poor prognosis. Interleukin 7 (IL7) is essential for lymphocyte development, homeostasis, and survival. NT-I7 (efineptakin alfa), a long-acting recombinant IL7, reverses lymphopenia and improves survival in murine glioma models. However, the safety, maximum tolerated dose (MTD), and impact of NT-I7 on immune cells in patients with HGG remain unknown. Patients and Methods: We conducted a phase I trial (NCT03687957) examining the MTD and effect of NT-I7 on lymphocytes in patients with newly diagnosed HGG. The primary endpoint was dose-limiting toxicity; secondary endpoints included absolute lymphocyte count (ALC) changes over time, overall response, progression-free survival, and overall survival. Exploratory endpoints included immune profiling at different time points using single-cell RNA sequencing (scRNA-seq) in a subset of patients. Results: NT-I7 was well tolerated with a MTD of 720 µg/kg. Moreover, NT-I7 significantly increased ALCs for more than 12 weeks in duration. Early elevations in CD4+, CD8+ T cells and NK cells further coincided with increased TNF and CXCL9 cytokine levels. Comprehensive immune profiling of peripheral blood T cells revealed selective clonotype expansion within CD8+, but not CD4+, T cells following NT-I7 administration. Finally, a subset of our patients with MGMT promoter–unmethylated glioblastoma, which are typically associated with a poorer prognosis, demonstrated promising clinical responses. Conclusions: NT-I7 has the potential to maintain and increase lymphocyte counts in patients with HGG and warrants further investigation, particularly in combination with immune-based therapies.

While most cases of human muscle-invasive bladder cancer (MIBC) are diagnosed as conventional urothelial carcinoma (UC), there is growing recognition of histologic subtypes and divergent differentiation within conventional UC. In this study, 31 dogs with UC (33 slides) were evaluated for histologic subtypes and divergent differentiation, as specified by the recent World Health Organization update on the classification of urinary bladder cancers. Slides were reviewed by a medical uropathologist and 3 board-certified veterinary pathologists and assessed for expression of uroplakin III, vimentin, and E-cadherin. All tumors were classified as UC. Fifteen cases were identified as conventional UC. Among the remainder, 8 displayed glandular differentiation, 4 were classified as sarcomatoid UC, 2 showed squamous differentiation, 1 case was classified as a large nested subtype, and 1 case was classified as a tubular/microcystic subtype. This study found a higher frequency of certain histologic subtypes and divergent differentiation in canine UC, particularly sarcomatoid UC and UC with glandular differentiation, compared to previous reports of both canine UC and human MIBC. The relatively high prevalence of the sarcomatoid UC and UC with glandular differentiation in dogs observed in this study suggests that canine UC may serve as a valuable translational model for evaluating novel therapeutic agents, particularly for these rare and aggressive subtypes in humans.

Summary The American Society of Clinical Psychopharmacology convened a 45-member international expert task force to identify circumstances supporting the deprescribing of core psychotropic medications for major depressive disorder (MDD) and bipolar disorders. Three Delphi survey rounds plus a selective literature review identified points of consensus (predefined as ≥75% agreement) about when antidepressant, antipsychotic, mood stabiliser and sedative-hypnotic deprescribing is warranted. Twenty out of 32 statements (63%) achieved consensus across seven thematic areas. In MDD, panellists favoured discontinuing antidepressants when mechanisms of action are duplicative, adequate trials produce ≤25% improvement or loss of prior efficacy cannot be regained through dose increases or augmentations. Indefinite antidepressant maintenance in MDD was favoured after three or more lifetime episodes. In bipolar disorder, antidepressant deprescribing was favoured in the setting of rapid cycling, mixed features or emerging mania/hypomania symptoms; and discouraged if prior antidepressant cessation led to relapse. In nonpsychotic mood disorders, panellists favoured deprescribing antipsychotics that caused significant weight gain or tardive dyskinesia over adding pharmacological antidotes. Deprescribing to achieve an eventual medication-free status was considered inappropriate, in bipolar type 1, but not necessarily bipolar type 2 disorder. Although individualised circumstances necessarily inform psychopharmacology management, clinical presentations that misalign with existing pharmacotherapies may signal the desirability of cautious deprescribing.

Background: We aimed to develop automated data extraction pipelines with large language models (LLMs) to extract registry data from total hip arthroplasty (THA) operative notes and compare the performance with that of existing natural language processing (NLP) algorithms. Methods: We randomly sampled 1,000 primary THA cases from our institutional registry. Two human annotators manually reviewed each operative note for 3 data points: surgical approach, bearing surface, and fixation technique. All labeled THA notes were split into the development set (n = 239) and the testing set (n = 719). We developed a custom data extraction pipeline for each data point by combining an iteratively customized prompt with an LLM. The performance was compared with that of existing rules-based NLP algorithms. Results: The accuracy of LLMs was superior to that of NLP algorithms for all data points: surgical approach (96% compared with 94%), bearing surface (89% compared with 74%), and fixation technique (96% compared with 95%). Furthermore, the LLM accurately inferred the bearing surface for 80% of the notes that were ambiguous about the bearing surface. Conclusions: We developed LLM pipelines for extracting 3 registry-relevant data points from THA operative notes, demonstrating superior performance to existing NLP algorithms. Clinical Relevance: LLMs have the potential to impact clinical care, including the evaluation of electronic medical record free-text data. As registries serve as a cornerstone of orthopaedic evidence, this work demonstrates promise for LLMs to simplify, improve, and democratize the construction of registry databases from operative notes.

Importance Exploring the relationship between moral distress and occupational burnout is necessary to understand the association between these constructs. Objective To evaluate moral distress among physicians and US workers, and to explore the association of moral distress with burnout, intent to leave (ITL) current position, and intent to reduce clinical work hours (ITR). Design, Setting, and Participants This cross-sectional national survey study included physicians from all specialties and a probability-based sample of employed nonphysicians. Participants were aged 29 to 65 years. Data were collected between October 19, 2023, and March 5, 2024. Data were analyzed from June 30 to October 20, 2025. Main Outcomes and Measures Moral distress was measured using the Moral Distress Thermometer (MDT, range 0-10), with a high level of moral distress defined by a score of 4 or higher. Burnout was measured using the complete Maslach Burnout Inventory (MBI). Professional fulfillment was measured using the Stanford Professional Fulfillment Index. ITL and ITR were measured using a standardized item with response options of none, slight, moderate, likely, and definitely. Results This survey study included 5741 physicians and 3501 nonphysician US workers. The median (IQR) age of physicians was 53 (44-62), and included 3262 men (58.0%), 2255 women (40.1%), and 107 individuals who responded other (1.9%). The mean (SD) moral distress score for physicians was 3.29 (2.81), with 2243 (39.1%) reporting a high level of moral distress (4 or more considered high). On multivariable analysis, women physicians had higher odds of moral distress (OR, 1.29; 95% CI, 1.12-1.48). Compared with internal medicine subspecialists, emergency medicine physicians (OR, 3.16; 95% CI, 2.27-4.4) and general internal medicine physicians (OR, 1.92; 95% CI, 1.42-2.59) were more likely to report high levels of moral distress. Mean emotional exhaustion and depersonalization scores, as well as the proportion of physicians with burnout, were higher with each 1-point increase in moral distress score. The overall correlation between the emotional exhaustion score and moral distress score was R = 0.55 ( P < .001) while the correlation between the depersonalization score and moral distress score was R = 0.50 ( P < .001). Additionally, 1068 of 3477 physicians (30.7%) with a moral distress score less than 4 had burnout symptoms compared with 1675 of 2231 physicians (75.1%) with scores of 4 or more ( P < .001). The prevalence of ITL and ITR was higher for each 1-point increase in moral distress score. For example, 619 of 3404 physicians (18.2%) with low moral distress reported ITL within 24 months compared with 748 of 2171 (34.5%) among those with high moral distress ( P < .001). Compared with other US workers, physicians had markedly higher odds of experiencing moral distress (OR, 4.40; 95% CI, 3.84-5.06). Conclusion and Relevance In this survey study, moral distress was common among physicians and experienced at higher rates than the general US working population. Understanding the differences between moral distress and burnout may allow organizations to more effectively implement interventions to address both concerns among clinicians.