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.

PURPOSE Predictive biomarkers to better tailor therapy for patients with early-stage human epidermal growth factor 2 (HER2)-positive breast cancer are a priority. We hypothesized that HER2 and immune-based biomarkers would be predictive of pathologic complete response (pCR) to preoperative trastuzumab/pertuzumab (HP). MATERIALS AND METHODS Patients with stage II/III, estrogen receptor (ER)-negative, HER2-positive breast cancer received neoadjuvant HP in the TBCRC026 clinical trial. The pCR after receiving HP alone was 22% (18/83). Tumor biopsies were performed at baseline. Secondary correlative objectives were to determine the relationship between HER2-based biomarkers and immune processes with pCR. NanoString code sets BC360 and IO360 were used to compare differential gene expression in baseline tumors that underwent pCR versus no pCR. NanoString GeoMx digital spatial profiling was used to assess immune protein abundance in intraepithelial and stromal segments. Stromal tumor-infiltrating lymphocytes and Ki67 were evaluated by hematoxylin and eosin and immunohistochemistry, respectively. RESULTS Intraepithelial HER2 protein abundance was significantly associated with pCR ( P = .001). Low HER2 abundance tumors were primarily basal-like, and essentially all (19/20) failed to achieve pCR. High HER2 abundance tumors that achieved pCR (14/51) exhibited a high degree of immune cell activity, whereas high HER2 abundance tumors that failed to achieve pCR tumors (37/51) were enriched for M-phase processes and epidermal growth factor receptor signaling. Baseline Ki67 was significantly higher in nonresponders ( P = .04). CONCLUSION ER-negative, HER2-positive breast cancer has unique molecular and immunologic features that may predict pCR after neoadjuvant HP. Validation of these potential biomarkers and composite biomarker analyses may guide design of future clinical trials.

Abstract Background: Obstructive sleep apnea (OSA) is associated with obesity and cardiovascular risk. Results from the SURMOUNT-OSA studies demonstrated significant reduction of a number of cardiometabolic risk measures in participants with OSA and obesity following treatment with tirzepatide. Objectives: Systematically analyze all tirzepatide treatment related changes of cardiometabolic risk measures in SURMOUNT-OSA studies and investigate to what extent these changes were mediated by reductions in weight and/or OSA-related measures. Methods: The SURMOUNT-OSA master protocol comprised two 52-week, randomized, double-blind, placebo-controlled Phase 3 studies. Study 1 (N=234) and 2 (N=235) included participants with moderate-to-severe OSA and obesity, who at screening reported not using, or using positive airway pressure (PAP) therapy, respectively. The design and rationale of the studies have been published previously (1). The current analysis investigated the association of treatment with tirzepatide or placebo with SURMOUNT-OSA pre-specified cardiometabolic risk measures including blood pressure, and levels of high-sensitivity C-reactive protein (hsCRP), HDL-C, non-HDL-C, triglycerides, fasting insulin. Further analyses included change in HOMA-IR with tirzepatide compared to placebo, and mediation analysis to determine the proportion of observed changes attributable to reductions in body weight, apnea-hypopnea index (AHI) and sleep apnea-specific hypoxic burden (SASHB). Results: In Study 1, participants experienced greater difference in change from baseline with tirzepatide compared to placebo in SBP (-7.9 mmHg; 95% CI -11.0 to -4.9; p<0.001), and DBP (-3.2 mmHg; 95% CI -5.4 to -1.0; p=0.005) at 48 weeks, and hsCRP (-28.9±8.2%; p=0.003), HDL-C (7.2±2.1%; p<0.001), non-HDL-C (-13.0±3.1%; p<0.001), triglycerides (-32.2±3.7%; p<0.001), fasting insulin (-41.4±5.0%; p<0.001), and HOMA-IR (-48.0±4.9%; p<0.001) at 52 weeks. In Study 2, participants experienced greater differences in change from baseline following tirzepatide compared to placebo in SBP (-4.3 mmHg; 95% CI -7.3 to -1.2; p=0.007) at 48 weeks, and hsCRP (-45.1±8.0%; p<0.001), HDL-C (10.0±2.8%; p<0.001), non-HDL-C (-14.3±2.5%; p<0.001), triglycerides (-31.5±3.7%; p<0.001), fasting insulin (-45.4±5.4%; p<0.001), and HOMA-IR (-54.8±5.0%; p<0.001) at 52 weeks. Statistically significant independent mediation effect of changes in OSA metrics was observed on hsCRP, HOMA-IR and triglycerides. In addition, the combination of changes in weight and OSA metrics, but not weight or OSA improvements alone, had a significant mediation effect on non-HDL-C. There was no significant mediation effect of weight or OSA metrics observed on DBP. Conclusions: In the SURMOUNT-OSA program trials, tirzepatide appeared to have significant cardiometabolic benefits for patients with moderate-to-severe OSA and obesity. Based on the mediation analysis, treating both sleep-disordered breathing and obesity is likely required to optimize cardiometabolic benefits for patients with OSA and obesity.

AbstractObjectiveNeuromodulation for pediatric refractory epilepsy (PRE) is preferred when the seizure onset zone is not amenable to surgical resection, due to multifocal onset or involvement of eloquent cortex. Given its rapidly evolving landscape, we describe our institutional experience with neurostimulation therapies including deep brain stimulation (DBS) of the anterior nucleus (DBS‐ANT), the centromedian nucleus (DBS‐CM), responsive neurostimulation (RNS), and chronic subthreshold stimulation (CSS) to treat PRE.MethodsA retrospective chart review was conducted to identify pediatric patients (≤18 years of age) who presented to our institution with PRE. Patients were included who had at least 1 year of follow‐up after neurostimulation was started. Patients with ≥50% seizure frequency reduction at last follow‐up compared to baseline were classified as responders.ResultsA total of 35 patients (21 females) were included in the series. Nine patients underwent DBS‐ANT, 9 underwent DBS‐CM (+ ANT in 7 patients), 5 underwent RNS, and 12 underwent CSS. The median age at seizure onset and surgery was 8 and 16 years, respectively. Structural lesions were the most common etiology of epilepsy (54%). Eighteen patients had prior interventions and 13 received invasive EEG. Post‐operative complications following neurostimulation implantation were noted in three patients (9%). However, no permanent deficits were noted. Median follow‐up time was 46 months (range 13–162 months). Twenty‐three patients (59%) were responders (3/9 DBS‐ANT; 7/9 DBS‐CM; 4/5 RNS; 9/12 CSS). Further, median seizure reduction was 25% (DBS‐ANT), 89% (DBS‐CM), 87% (RNS), and 88% (CSS) across the cohort. Six patients (17%) had improved subjective neurocognitive outcomes while the other 29 had stable neurocognitive outcomes.SignificanceDBS, RNS, and CSS are safe and effective options for PRE. An understanding of treatment approaches can optimize results by tailoring therapy to individual patients.Plain Language SummaryThis study investigates the use of various neurostimulation therapies for treating pediatric refractory epilepsy (PRE) including deep brain stimulation (DBS), responsive neurostimulation (RNS), and chronic subthreshold stimulation (CSS). Overall, neuromodulation was found to be effective in reducing seizures in most patients, with 59% of patients showing at least a 50% reduction in seizure frequency. Additionally, the treatments were generally safe, with few complications and no instances of permanent deficits.

Abstract Background: Resilience, quantified by the brief resilience scale (BRS), has been recognized for its role in pain and symptomatology in musculoskeletal conditions. The role of psychological factors in the clinical presentation and outcomes of FAI surgery continues to be poorly understood. Methods: This is a prospective multicenter study of FAI patients undergoing primary hip arthroscopy. PROMs were administered at baseline, 3-, and 6-months post-op and included the Patient Reported Outcomes Measurement Information System (PROMIS) domains of anxiety and depression, as well as Hip Disability and Osteoarthritis and Outcome Score (HOOS), modified Harris Hip Score (mHHS), and International Hip Outcome Tool (iHOT-12). Resilience was characterized by BRS score and divided into low (“L”, score&lt;3), normal (“N”, score 3-4.3), and high resilience (“H”, score&gt;4.3). Results: 675 patients were included with a mean age of 24.9±7.8 years and female predominance (56%). Mean BRS scores were 3.7±0.7 (1.5-5.0). 13.8% (n=93) had low resilience, 65.9% (n=445) had normal resilience, and 20.3% (n=137) had high resilience. Lower resilience had more severe symptoms in HOOS pain (p&lt;0.001), HOOS sports (p=0.003), HOOS ADL (p&lt;0.001), HOOS QoL (p&lt;0.001), iHOT-12 (p=0.002), and mHHS (p&lt;0.001). Anxiety (L: 50.5%/N: 14.4%/H: 2.2%) and depression (L: 38.7%/N: 8.8%/H: 2.9%) were higher in lower resilience groups (all p&lt;0.001) and this trend stayed consistent in female and male sub-analyses with females having greater anxiety and depression symptoms. The follow-up cohort with 3- and 6-months follow-up was 487 patients and had similar baseline characteristics as the baseline cohort. Lower resilience had lower postoperative PROs (with similar change) (p&lt;0.05). After treatment, rates of anxiety or depression decreased from 22.1% to 15.6% with the low resilience group having the highest change from 62.9% to 45.9%. Conclusion: Low resilience correlates with more severe symptoms and predicts anxiety/depression in FAI. 13.8% had low resilience while 20.3% had high resilience. Lower resilience had worse postoperative PROs. Particularly in patients with low resilience at presentation, rates of anxiety or depression symptoms decreased postoperatively. Further studies are needed to understand the role of resilience in longer-term outcomes of FAI and whether concurrent psychological treatment will help improve patient outcomes after hip arthroscopy for FAI.