Citations

Abstract Lineage switch (LS), defined as the immunophenotypic transformation of acute leukemia, has emerged as a mechanism of relapse after antigen-targeted immunotherapy, which is associated with dismal outcomes. Through an international collaborative effort, we identified cases of LS after a host of antigen-targeted therapies (eg, CD19, CD22, CD38, and CD7), described how LS was diagnosed, reviewed treatment approaches, and analyzed overall outcomes for this form of postimmunotherapy relapse. Collectively, 75 cases of LS were evaluated, including 53 (70.7%) cases of B-cell acute lymphoblastic leukemia (B-ALL) transforming to acute myeloid leukemia (AML), 17 (22.7%) cases of B-ALL transforming to mixed phenotypic acute leukemia (MPAL)/acute leukemias of ambiguous lineage (ALAL), and 5 (6.7%) cases of rare LS presentation (ie, T-cell ALL to AML). An additional 10 cases with incomplete changes in immunophenotype, referred to as “lineage drift” were also described. With a primary focus on the 70 cases of LS from B-ALL to AML or MPAL/ALAL, LS emerged at a median of 1.5 months (range, 0-36.5) after immunotherapy, with 81.4% presenting with LS within the first 6 months from the most proximal immunotherapy. Although most involved KMT2A rearrangements (n = 45, 64.3%), other rare cytogenetic and/or molecular alterations were uniquely observed. Treatment outcomes were generally poor, with remission rates of <40%. The median overall survival after LS diagnosis was 4.8 months. Outcomes were similarly poor for those with rare immunophenotypes of LS or lineage drift. This global initiative robustly categorizes lineage changes after immunotherapy and, through enhanced understanding, establishes a foundation for improving outcomes of LS.

AimsTo evaluate the role of autophagy in primary knee fibroblasts undergoing myofibroblast differentiation as an in vitro model of arthrofibrosis, a complication after total knee arthroplasty characterized by aberrant intra-articular scar tissue formation and limited range of motion.MethodsWe conducted a therapeutic screen of autophagic-modulating therapies in primary human knee fibroblasts undergoing transforming growth factor-beta 1 (TGF-β1)-mediated myofibroblast differentiation. Autophagy was induced pharmacologically with rapamycin or by amino acid deprivation. Picrosirius red staining was performed to quantify collagen deposition. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting were conducted to evaluate fibrotic gene expression levels.ResultsRapamycin, an mTOR complex 1 (mTORC1) inhibitor and autophagy inducer, reduced TGF-β1-mediated collagen deposition. Interestingly, we simultaneously report that myofibrogenic genes, including ACTA2, were highly upregulated following rapamycin-TGF-β1 treatment. When autophagy was induced through amino acid deprivation, we demonstrated suppressed extracellular matrix levels, fibrotic gene expression (e.g. ACTA2), and SMAD2 phosphorylation levels in TGF-β1-stimulated fibroblasts.ConclusionOur findings demonstrate that the induction of cellular autophagy suppresses TGF-β1-induced collagen deposition in primary human knee fibroblasts. Taken together, these data suggest that cellular autophagy may be prophylactic against the pathogenesis of arthrofibrosis.Cite this article: Bone Joint Res 2025;14(4):328–337.

Abstract Objectives: Radiologist participation in multidisciplinary tumor board can be time-consuming and demanding, requiring substantial preparation. Anecdotally radiologist participation is felt to help identify discrepancies in previous interpretations; however, there are limited data assessing the actual impact of their tumor board review on patient management. This prospective study aims to evaluate how the reinterpretation of outside imaging and review at hepatobiliary tumor board (HBTB) affects the diagnosis and management of patients with hepatobiliary neoplasms. Methods: This prospective analysis included all patients presented at the weekly HBTB between 6/13/2023 - 6/25/2024. One radiologist reviewed the available reports of outside imaging, the local reinterpretation of outside imaging, the updated local imaging, and documented conclusions from discussion of the case at HBTB. HBTB included 4 radiologists who had reviewed each case. Discrepancies (presence/absence, number, and reasons for) were recorded. When discrepancies occurred, the impact on patient management (5-point Likert scale) was determined by two of the radiologists present at the HBTB in consensus, with input from clinicians if needed. A six-month follow-up was performed to confirm suspected diagnoses. Results: 208 cases (128 males, 104 chronic liver disease patients) were presented at HBTB. Disagreements in the detection or characterization of lesions were found in 59/208 (28.4%) of cases. A change in management occurred in 38/59 (64.6%) of these discrepant cases. In cases with recorded discrepancies in which follow-up confirmation was available, the final interpretation was confirmed in 34/41 (82.9%) of cases. Conclusion: Our study found a discrepant interpretation in nearly one-third of cases presented at a weekly HBTB and a resultant change in management in 65% of those cases. These findings highlight the importance of reinterpretation of prior imaging studies and the presence of radiologists at HBTB to guide optimal patient management.

Introduction: Guideline recommended surveillance of nonmuscle invasive bladder cancer (NMIBC) involves frequent cystoscopies. Cxbladder Monitor (CxbM) is a noninvasive urinary genomic test with high negative predictive value for NMIBC recurrence. Incorporation of CxbM into surveillance could reduce the frequency, burden, and cost of surveillance. We studied this impact using a theoretical health economic model. Materials and Methods: A Markov model for disease dynamics and decision tree model for surveillance pathways were created for 100 patients with theoretical NMIBC risk stratified by AUA criteria over 5 years from diagnosis. In the standard of care (SOC) arm, cystoscopy was performed per AUA guidelines. In the CxbM surveillance arm, CxbM was used starting 9 months after diagnosis. If positive, cystoscopy was performed per guidelines, but if negative, the cystoscopy was not performed and on the next scheduled encounter. Primary outcome was total budgetary impact. Additional outcomes included number of diagnostic tests, test-related complications, and patients with delayed diagnosis. Results: Compared with SOC, CxbM reduced mean total costs by $68,621 for 100 patients over 5 years or $137.24 per patient per year. Cystoscopy was reduced by 129 (0.31 per patient per year), and there was no difference in delayed cancer diagnosis. Using a probabilistic model, the median cost reduction per patient per year was $160 (95% credible interval −520 to 109) with 86.2% probability of cost savings. Conclusions: In this Markov model, incorporation of CxbM into surveillance for NMIBC reduced cystoscopy without negative impact on cancer detection with cost savings for the majority of simulations run.

ImportanceThere is a lack of reliable, patient-reported quality-of-life (QOL) instruments to address the multidimensional nature of patient-centered outcomes for patients undergoing parotidectomy. The Parotidectomy Quality of Life Index is a new 35-item validated patient-reported outcome instrument specific to recovery after parotidectomy.ObjectiveTo establish and validate a comprehensive English-language patient-reported QOL instrument specific to parotidectomy.Design, Setting, and ParticipantsThis survey study was conducted in 2 phases: first, in a single-institution cohort (October 12, 2021, to March 7, 2022), and second, as an anonymous web-based survey enrolled via printed promotional brochures and social media platforms (March 13 to July 31, 2023). Inclusion criteria were age at least 18 years and parotidectomy within the last year. For test-retest reliability, a subset of phase II participants volunteered to answer the survey a second time within 2 weeks. Data were analyzed from March 8, 2022, to November 3, 2023.Main Outcomes and MeasuresItem rankings from phase I participants were used to narrow the original 61-item survey down to 45 items in the phase II survey. To assess construct validity, an exploratory factor analysis was performed. Cronbach α and pairwise Pearson correlation coefficients were used to measure internal consistency, reliability, and redundancy. Test-retest reliability was evaluated using intraclass correlation coefficients.ResultsPhase I enrolled 38 individuals, of whom 30 completed the survey (15 women [60%]; 21 participants [84%] aged >40 years). Phase II enrolled 342 participants, of whom 317 completed the survey (305 women [89%]; 284 participants [83%] aged >40 years). A total of 42 items across 7 domains were selected based on exploratory factor analysis. After Cronbach α and pairwise correlation analysis, 33 items across 6 multi-item domains and 2 standalone items were incorporated into the final QOL instrument. Cronbach αs for each of the final 6 domains were at least 0.77, suggesting excellent internal validity. Pairwise correlations did not show strong correlations (ie, none ≥0.80), suggesting minimal redundancy between domains. Younger age was significantly associated with a lower global score. Participants with malignant tumors scored lower on 4 of the 6 multi-item domains. Test-retest reliability coefficients for the domains ranged from 0.82 to 0.93, indicating very good reproducibility over a 2-week interval.Conclusions and RelevanceThese findings suggest the Parotidectomy Quality of Life Index demonstrated excellent internal validity and test-retest reliability. With further external validation, this instrument may provide opportunity for quality improvement in clinical practice and has potential as a key patient-reported outcome in future parotidectomy clinical trials.