Citations

ABSTRACT The prognostic relevance of multiple myeloma (MM)‐defined high‐risk (HR) cytogenetic abnormalities in AL amyloidosis is incompletely defined. We retrospectively evaluated 517 newly diagnosed AL amyloidosis patients seen at Mayo Clinic between 2012 and 2021 who had baseline plasma cell FISH. HR cytogenetics were defined as t (4;14), t (14;16), t (14;20), del(17p), or 1q gain/amplification (+1q). HR abnormalities were identified in 151 patients (29%); +1q accounted for most HR cases (122/151, 81%). Compared with standard‐risk (SR), patients harboring +1q demonstrated a greater clonal disease burden, including higher dFLC and bone marrow plasma cells, greater intact immunoglobulin secretion, higher plasma cell proliferative index, and enrichment for modified SLiM‐CRAB features. Hematologic and organ response patterns of +1q patients were generally comparable to SR patients, whereas non‐1q HR patients had a higher proportion of early hematologic responses. Patients harboring +1q demonstrated significantly inferior overall survival (OS) compared with both non‐1q HR patients and SR patients (median OS 57 months vs. not reached vs. 120 months, p = 0.02). In multivariable piecewise Cox analysis, the adverse prognostic impact of +1q was most evident beyond 24 months from diagnosis (HR 2.89, 95% CI 1.64–5.09, p < 0.001), whereas non‐1q HR lesions were not independently prognostic. These findings suggest that +1q identifies a biologically distinct AL amyloidosis subset characterized by plasma cell–dominant features and inferior long‐term disease control. In contrast, other MM‐defined HR cytogenetic abnormalities appear to have limited prognostic relevance in AL amyloidosis.

CD19-directed CAR T-cells (CTL019) can produce durable remissions in chronic lymphocytic leukemia (CLL), but therapeutic success depends on whether autologous T-cells expand, persist, and retain cytotoxic function after manufacturing. Failure of CLL T-cells is often attributed to exhaustion, although many dysfunctional CLL T-cells retain inflammatory cytokine production. We tested whether this paradox reflects immunosenescence, an aging-like program defined by costimulatory loss, DNA damage, inflammatory secretion, repertoire restriction, and proliferative arrest. In response-linked preinfusion CTL019 products, nonresponders and short partial responders had higher senescence and senescence-associated secretory phenotype (SASP) programs than the functional-responder group, comprising complete responders and partial responders with transformed disease. These programs were detectable before infusion and became more prominent during manufacture in susceptible products. They tracked with weak in vivo CAR T-cell expansion and were associated with inferior survival. Serum proteomics revealed a circulating, CLL-associated SASP-like inflammatory milieu in nonresponders. Flow cytometry and T-cell receptor (TCR) profiling showed that poor responders carried CD27⁻CD28⁻ and KLRG1⁺ CD8 T-cells at apheresis, lower product CD27, and reduced product TCR diversity. Research-manufactured CAR T-cells from treatment-naïve CLL samples displayed the same state, most prominently in CD4 CAR T-cells, with SA-β-gal, p16, p53, DNA damage, depletion of less-differentiated states, and senescence-enriched transcriptomes. Under repeated CD19 stimulation, CLL-derived products reached a proliferative ceiling, and p53-high products lost cytotoxic reserve. Ibrutinib improved proliferative fitness, attenuated senescence-associated features and SASP output in paired patient and direct-exposure assays, and enhanced CAR T-cell expansion in an ibrutinib-resistant CLL model. Together, these data identify immunosenescence as a measurable and functionally consequential barrier to CAR T-cell efficacy in CLL and a candidate for therapeutic modulation.

Abstract Purpose: Inhibitors of the Ataxia telangiectasia and Rad3-related (ATR) protein kinase, a critical component of the DNA damage repair response, have synergistic anti-cancer activity with platinum compounds in preclinical models. We therefore conducted a Phase 2 study of the ATR inhibitor berzosertib+carboplatin vs. docetaxel+carboplatin in metastatic castration-resistant prostate cancer. Patients and Methods: Patients previously treated with at least one androgen receptor pathway inhibitor and taxane underwent mandatory biopsy and were randomized 1:1 to receive Arm A (docetaxel 60 mg/m2+carboplatin AUC4 day 1; or carboplatin AUC5 if not a docetaxel candidate) or Arm B (berzosertib 90 mg/m2 days 2,9+carboplatin AUC5 day 1) every 21 days. The primary endpoint was overall response rate (ORR; ≥50% PSA decline or radiographic response). Results: Of 73 randomized patients, 65 received protocol treatment: 34 on Arm A (26 docetaxel+carboplatin; 8 carboplatin alone) and 31 on Arm B. Thirteen patients (38%) in Arm A and 20 (65%) in Arm B had ≥Grade 3 treatment-related adverse events (TrAEs). ORR was 15% in Arm A (5/34; 5/26[19%] with docetaxel+carboplatin) and 0% in Arm B (0/31). At interim analysis after 65 of planned 130 patients were treated, enrollment was halted due to futility. Homologous recombination repair deficiency status from tissue and blood did not correlate with clinical outcomes, but ATM-deficiency or high levels of phoshpo-KAP1 detected in tissue was associated with clinical benefit across both arms of the trial. Conclusions: Berzosertib+carboplatin demonstrated lower ORR and more frequent ≥grade 3 TrAEs compared to docetaxel+carboplatin in this heavily pre-treated, biomarker-unselected population. NCT03517969

Purpose To prospectively investigate subjective anterior groin pain, patient‐reported outcome measures, complications, reoperation rates, and hip flexion strength after arthroscopic iliopsoas fractional lengthening. Methods From 2023 to 2025, patients with persistent groin pain after total hip arthroplasty refractory to conservative management undergoing arthroscopic iliopsoas fractional lengthening were prospectively identified at 2 tertiary referral centers. Pre‐ and postoperative outcomes at a minimum 6‐month follow‐up including the Visual Analog Scale, Tegner activity scale, Single Assessment Numeric Evaluation, and subjective anterior groin pain and hip flexion strength were analyzed. Results Fifty‐nine hips in 56 patients were included (age: 64.9 ± 9.8 years, 59% women, body mass index: 30.0 ± 5.8 kg/m 2 ) and followed for 10.0 ± 6.9 months postoperatively (range: 4‐25 months). Patients experienced significant ( P < .001) postoperative improvements in the Visual Analog Scale at rest (1.4 ± 2.2 vs 2.8 ± 2.1), Visual Analog Scale with use (3.0 ± 2.9 vs 7.8 ± 1.8), Tegner activity scale (2.8 ± 1.2 vs 2.0 ± 1.0), and Single Assessment Numeric Evaluation score (73.8 ± 22.5 vs 47.7 ± 22.2). Postoperative surgical satisfaction was 8.0 ± 2.7 (scale: 0‐10). Nearly 90% of patients reported feeling much or slightly better regarding their anterior groin pain postoperatively at 2‐week (91%), 6‐week (88%), 3‐month (91%), and final follow‐up (92%). Regarding hip flexion strength, ≥66% reported feeling much or slightly better at 2‐week (73%), 6‐week (95%), 3‐month (89%), and final follow‐up (66%). Three hips (6%) underwent reoperation at the final follow‐up (1 acetabular screw removal with open revision release, 1 revision total hip arthroplasty for loosening, and 1 two‐stage exchange for nonacute periprosthetic joint infection). Conclusions Nearly 90% of patients who underwent arthroscopic iliopsoas fractional lengthening after primary total hip arthroplasty reported improved anterior groin pain, whereas two‐thirds reported increased subjective hip flexion strength throughout the follow‐up. Of note, clinically meaningful improvement in pain at rest was achieved by 50% of patients based on cohort‐specific minimal clinically important difference criteria. Level of Evidence Level IV, retrospective therapeutic case series.

Myeloproliferative neoplasm (MPN) patients are at risk of splanchnic vein thromboses (SVT). Prior studies have failed to demonstrate a benefit of hydroxyurea therapy in preventing recurrent thrombosis after SVT, but are limited by small sample sizes and inability to account for starting, stopping, or switching of cytoreductive therapies. To better assess the impact of cytoreductive therapy on thrombosis recurrence, we performed a retrospective cohort study of MPN-SVT patients from the international GASTRO-MPN Consortium, treating cytoreductive therapy as a time-dependent covariate. We identified 757 patients, of which 43% were treated with cytoreductive therapy. During a median follow-up of 7.4 years, 256 patients (34%) had thrombosis recurrence; 145 (19%) had SVT extension/recurrence/TIPS thrombosis, 138 (18%) an thrombosis recurrence outside the splanchnic bed (74% were venous). Additionally, 262 patients (35%) experienced clinically relevant bleeding and 170 (22%) died. After adjusting for age, sex, prior thrombosis, timing of MPN diagnosis relative to SVT, anticoagulation initiation within 30 days of SVT diagnosis, MPN type, JAK2 status, other cancers and cirrhosis, cytoreductive therapy was associated with a decreased risk of recurrent thrombosis (HR 0.67 95%CI 0.50-0.89, p=0.01). This was driven by a lower risk of SVT extension/recurrence (HR 0.62 95%CI 0.42-0.90, p=0.01) but not by extra-splanchnic thrombosis recurrence (HR 0.97 95%CI 0.72-1.30, p=0.82). In a subgroup of patients without erythrocytosis/thrombocytosis at initial SVT (n=275), cytoreductive therapy was associated with a HR 0.65 (95%CI 0.40-1.07, p=0.09) for recurrent thrombosis. These data support the use of cytoreductive therapy in MPN-SVT patients to prevent recurrent thrombosis, particularly SVT extension/recurrence.

Abstract. Introduction: Preterm birth drives adverse perinatal maternal and infant health outcomes through heterogeneous symptoms, severity, and etiologies. Delivery prior to reaching 37 weeks of gestation may result from medically indicated intervention for pregnancy complications or spontaneously in the absence of prior symptoms. Placental tissue collected following preterm birth exhibits differential DNA methylation compared to full-term placentas and may indicate pregnancy health during gestation. Placental DNA currently has limited utility for assessing health of ongoing pregnancy, as sampling placental tissue during gestation increases the risk of infection and miscarriage. Risks associated with placental sampling during pregnancy limit the use of DNA methylation in clinical preterm birth prediction. Assessing preterm birth risk during gestation requires non-invasive methods for characterizing placental DNA methylation. Results: We quantified genome-wide DNA methylation patterns of hypermethylated cell-free DNA in pregnant (n = 99) and non-pregnant (n = 93) plasma using cell-free methylated DNA immunoprecipitation sequencing (cfMeDIP-seq). In each sample, we assessed DNA methylation status in 300-bp genomic windows, examining both sequencing read counts and calculated absolute molar DNA amount. Known hypermethylated placental regions, including RASSF1, STAT5A, and ERG promoters showed significantly increased odds of detection in pregnant samples, suggesting enrichment of cell-free placental DNA. Of the 536,444 300-bp windows examined, 173,071 (32%) showed significant enrichment in pregnant plasma. Linear modeling identified 107,505 differentially methylated regions (DMRs) associated with pregnancies later diagnosed with intrauterine growth restriction (IUGR) (n = 22). Alu elements showed increased representation in these DMRs than expected, while other repetitive elements exhibited underrepresentation. Discussion: These results demonstrate cfMeDIP-seq's ability to enrich for cell-free placental DNA and characterize cell-free DNA methylation signatures of pregnancies complicated by IUGR. Enrichment of cell-free placental DNA enables non-invasive profiling of placental DNA methylation from maternal plasma. Detectable epigenetic signatures in maternal plasma may identify pregnancies at elevated risk for preterm birth before clinical symptoms appear. Our findings further highlight the potential of cell-free placental DNA for monitoring pregnancy health.

Abstract INTRODUCTION Plasma p‐tau217 and p‐tau217/Aβ42 reliably identify non‐Hispanic White individuals with symptomatic and pre‐clinical AD. However, performance across ethnoracially diverse groups remains unknown. METHODS Cognitively normal Black, Hispanic, and non‐Hispanic White participants completed cognitive evaluations, brain magnetic resonance imaging (MRI), amyloid and tau positron emission tomography (PET), and measures of kidney function. Plasma p‐tau217 and Aβ42 were measured using Fujirebio Lumipulse assays. Pre‐clinical AD detection was evaluated using symptomatic and cohort‐derived optimized cutoffs. RESULTS Among 191 participants (57 Black, 46 Hispanic White, 88 non‐Hispanic White), age‐adjusted plasma p‐tau217 and p‐tau217/Aβ42 performed similarly in detecting amyloid‐positive individuals (≥ 25 Centiloids), regardless of race/ethnicity. Both measures independently correlated with amyloid deposition, whereas estimated glomerular filtration rate (eGFR) correlated solely with p‐tau217. Pre‐clinical AD optimized cutoffs (p‐tau217 ≥ 0.132 pg/ml; p‐tau217/Aβ42 ≥ 0.0059) outperformed cutoffs established in symptomatic individuals (sensitivity: 83% vs. 57%; 77% vs. 63%; negative predictive value [NPV] > 93%). DISCUSSION Plasma biomarkers performed similarly across ethnoracially diverse cohorts. Optimized cutoffs may improve early detection and trial enrollment.

Background: Increased posterior tibial slope (PTS) has been associated with higher revision rates after anterior cruciate ligament reconstruction (ACLR). Whether the addition of lateral extra-articular tenodesis (LET) mitigates the risk associated with increased PTS is unclear. Purpose: To determine the prevalence of increased PTS (≥12°) in a young high-risk primary ACLR population and evaluate whether LET is associated with lower revision rates in patients with increased PTS. Study Design: Cohort study; Level of evidence, 3. Methods: This study included patients aged ≤25 years undergoing primary ACLR across 3 high-volume centers with ≥2 years between surgery and data collection. PTS was measured on lateral radiographs for medial and lateral plateaus. Primary analyses consisted of 4 prespecified multivariable logistic regression models with different PTS operationalizations as continuous predictors per 1° increase (medial PTS, lateral PTS, the maximum [PTSmax], and the lateral-medial difference), adjusted for patient and surgical covariates including graft type, with surgical center as a fixed effect. Secondary analyses used PTS dichotomized at 12°; revision rates were compared between isolated ACLR and ACLR with LET, with the treatment effect quantified as absolute risk reduction and number needed to treat. Results: A total of 780 patients were included; 84 (10.8%) underwent revision ACLR. Increased PTS (≥12°) was present in 28.2% of patients and more common in those requiring revision (38.6% vs 27.0%; P = .03). In patients with PTSmax ≥12°, revision occurred in 21.0% without LET and 9.2% with LET (absolute risk reduction, 11.8% [95% CI, 2.3%-21.3%]; number needed to treat, 9); in patients with PTSmax <12°, revision occurred in 13.2% without LET and 5.4% with LET (absolute risk reduction, 7.8% [95% CI, 3.0%-12.6%]; number needed to treat, 13). In the 4 prespecified multivariable models with PTS as a continuous predictor, LET was independently associated with substantially lower odds of revision ACLR (odds ratio [OR], 0.37; 95% CI, 0.22-0.62; P < .001). Lateral PTS (OR, 1.09 per 1° increase; 95% CI, 1.00-1.18; P = .04) and PTSmax (OR, 1.09; 95% CI, 1.00-1.19; P = .04) were independently associated with revision ACLR. The lateral-medial PTS difference was not associated with revision ACLR. Conclusion: In a young high-risk primary ACLR population, increased PTS was present in nearly 30% of patients. LET was associated with a lower risk of revision irrespective of PTS, while increased PTS was independently associated with revision ACLR.