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.

ABSTRACTIL‐17 inhibitors effectively treat psoriasis and psoriatic arthritis but may increase the risk of inflammatory bowel disease (IBD). We assessed their association with IBD compared to apremilast. Utilising the TriNetX database, we analysed patients with psoriasis or ankylosing spondylitis initiating IL‐17 inhibitors or apremilast. We used propensity score matching and Cox models to estimate IBD risk. Among 13,216 matched patients per group, 142 developed IBD with IL‐17 inhibitors versus 60 with apremilast (aHR = 2.50, 95% CI: 1.85–3.39). IL‐17 inhibitors increase IBD risk, necessitating careful patient selection and monitoring.

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.

Introduction Superficial parasternal intercostal plane blocks have grown in clinical use for cardiac surgery as a targeted fascial plane block for median sternotomy. Despite this, there remains no consensus on technique for optimal parasternal spread of injectate. The primary objective of this cadaveric study was to evaluate parasternal spread of injectate of single versus two-level superficial parasternal intercostal plane injections with the needle tip positioned on the anterior surface of the costal cartilage. Methods We performed 10 single-level injections at T4 and 10 two-level injections at T3 and T5 on alternating sides in 10 fresh frozen cadavers. All injections were ultrasound guided with a parasagittal ultrasound probe orientation and an in-plane needle orientation. Anatomic dissections were performed immediately following injections. Results Parasternal spread of injectate was greater with two-level injections at T3 and T5 costal cartilages than with single-level injections at the T4 costal cartilage, with two-level injections consistently spreading to the T2–T5 intercostal spaces. Median (Q1, Q3) intercostal space spread for single-level injections was 2.0 (2.0–2.5). Median (Q1, Q3) intercostal space spread for two-level injections was 4.0 (4.0–4.375). Conclusions Two-level injections with the needle tip located on the anterior surface of the costal cartilage resulted in improved parasternal spread compared with single-level injections.

Key Points Pediatric preemptive kidney transplantation rates in the United States vary by socioeconomic status (SES). The HOUsing-based index of SES, an individual-level SES measure derived from residential addresses, effectively predicts pediatric preemptive kidney transplant rates. Background Preemptive kidney transplantation in children is associated with better patient and graft survival compared with transplants after dialysis. However, preemptive kidney transplantation rates in children remain low. This study aimed to evaluate the effect of socioeconomic status (SES) on preemptive transplantation in children. Methods Our study included 173 Minnesota-resident pediatric kidney transplant recipients (younger than 18 years) transplanted at the University of Minnesota from 2010 to 2020. Using the HOUsing-based index of SES (HOUSES) index, a validated, individual SES measure based on housing units categorized into quartiles (Q1: lower SES; Q2–Q4: higher SES), we applied mixed-effects multivariable logistic models to examine the effects of HOUSES on preemptive kidney transplants and pretransplant dialysis duration. Results Of 173 pediatric kidney transplant recipients, 46 (26.6%) received a preemptive transplant, and of 109 recipients with dialysis duration data, 39 (35.8%) received dialysis for >1 year. After adjusting for age at kidney failure, sex, donor type, insurance type, and underlying cause of kidney failure, we observed significantly lower odds of preemptive transplantation among Q1 recipients compared with Q2–4 recipients (adjusted odds ratio, 0.31; 95% confidence interval, 0.11 to 0.90; P = 0.03). Conclusions Using the HOUSES index, we found significant socioeconomic disparities in preemptive kidney transplantation rates among children.

ABSTRACTRubinstein‐Taybi syndrome (RTS) is a rare genetic disorder featuring craniofacial abnormalities, intellectual disability, and multi‐organ involvement, including increased risk of keloid formation, pilomatricomas, and hypertrichosis. Hidradenitis suppurativa (HS), a chronic inflammatory skin condition characterized by recurrent abscess formation and draining tunnels, has never been described in a patient affected by RTS. In this report, we detail the history of a 32‐year‐old male with RTS and refractory Hurley stage III HS and discuss the important considerations and risks of managing this unique patient population.

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.

Abstract Historically, cancers diagnosed via the emergency department (ED) portend a poor prognosis. Recent data from the United States are sparse, and analyses of cancers detected in the years following ED visits are lacking. Thus, we analyzed data from nine rural U.S. Midwest counties included within the population-based Rochester Epidemiology Project (2015–2021). Participants without a history of cancer (N = 42,074) who did not receive ED care were matched 1:1 to ED participants on the date of ED visit, age, sex, race, ethnicity, and county of residence. Analyses were restricted to participants with records ≤2 years prior to ED or index visit and ≥30 days after. HRs and 95% confidence intervals (CI) comparing cancer incidence and deaths among ED and non-ED participants were estimated from Cox proportional hazards regression models, either unadjusted or adjusted for covariates. Cumulative cancer incidence curves accounting for competing risks of death and survival (all cause and cancer-specific) were estimated. The median follow-up was 6.3 years, with 2,719 (6.46%) cancers diagnosed among ED participants and 3,139 (7.46%) among non-ED participants. ED participants experienced lower cancer risk overall (HRAdjusted = 0.70; 95% CI, 0.66–0.74; P = 8.89 × 10−31), specifically for breast cancer, prostate cancer, melanoma, and secondary cancers. Cancer-specific mortality was higher among ED participants (HRAdjusted = 1.76; 95% CI, 1.49–2.08; P = 3.62 × 10−11). Compared with non-ED participants, ED participants experienced a lower incidence of cancer but higher overall cancer-specific mortality, suggesting that subsets of ED patients may benefit from postvisit preventive interventions. Prevention Relevance: This cohort analysis shows that cancer incidence over 6 years was lower among participants after an ED visit than among matched non-ED participants, whereas cancer-specific mortality was higher in the ED group (HRAdjusted = 1.76; 95% CI, 1.49–2.08; P = 3.62 × 10−11), suggesting the potential benefit of preventive interventions.

Abstract Reprogramming of aged donor tissue cells into induced pluripotent stem cells (A-iPSC) preserved the epigenetic memory of aged-donor tissue, defined as genomic instability and poor tissue differentiation in our previous study. The unbalanced expression of RNA exosome subunits affects the RNA degradation complex function and is associated with geriatric diseases including premature aging and cancer progression. We hypothesized that the age-dependent progressive subtle dysregulation of EXOSC2 (exosome component 2) causes the aging traits (abnormal cell cycle and poor tissue differentiation). We used embryonic stem cells as a tool to study EXOSC2 function as the aging trait epigenetic memory determined in A-iPSC because these aging traits could not be studied in senesced aged cells or immortalized cancer cells. We found that the regulatory subunit of PP2A phosphatase, PPP2R5E, is a key target of EXOSC2 and this regulation is preserved in stem cells and cancer.