Citations

Abstract Purpose: Metastatic castration-resistant prostate cancer (mCRPC) resistant to androgen receptor signaling inhibitors (ARSI) is often lethal. Liquid biopsy biomarkers for this deadly form of disease remain under investigation, and underpinning mechanisms remain ill-understood. Experimental Design: We applied targeted cell-free DNA (cfDNA) sequencing to 126 patients with mCRPC from three academic cancer centers and separately performed genome-wide cfDNA methylation sequencing on 43 plasma samples collected prior to the initiation of first-line ARSI treatment. To analyze the genome-wide sequencing data, we performed nucleosome positioning and differential methylated region analysis. We additionally analyzed single-cell and bulk RNA sequencing data from 14 and 80 patients with mCRPC, respectively, to develop and validate a stem-like signature, which we inferred from cfDNA. Results: Targeted cfDNA sequencing detected AR/enhancer alterations prior to first-line ARSIs that correlated with significantly worse progression-free survival (P = 0.01; HR = 2.12) and overall survival (P = 0.02; HR = 2.48). Plasma methylome analysis revealed that AR/enhancer lethal mCRPC patients have significantly higher promoter-level hypomethylation than AR/enhancer wild-type mCRPC patients (P < 0.0001). Moreover, gene ontology and CytoTRACE analysis of nucleosomally more accessible transcription factors in cfDNA revealed enrichment for stemness-associated transcription factors in patients with lethal mCRPC. The resulting stemness signature was then validated in a completely held-out cohort of 80 patients with mCRPC profiled by tumor RNA sequencing. Conclusions: We analyzed a total of 220 patients with mCRPC, validated the importance of cell-free AR/enhancer alterations as a prognostic biomarker in lethal mCRPC, and showed that the underlying mechanism for lethality involves reprogramming developmental states toward increased stemness. See related commentary by Nawfal et al., p. 7

ImportanceTranexamic acid reduces bleeding and blood transfusion in many types of surgery, but its effect in patients undergoing liver resection for a cancer-related indication remains unclear.ObjectiveTo determine whether tranexamic acid reduces red blood cell transfusion within 7 days of liver resection.Design, Setting, and ParticipantsMulticenter randomized clinical trial of tranexamic acid vs placebo conducted from December 1, 2014, to November 8, 2022, at 10 hepatopancreaticobiliary sites in Canada and 1 site in the United States, with 90-day follow-up. Participants, clinicians, and data collectors were blinded to allocation. A volunteer sample of 1384 patients undergoing liver resection for a cancer-related indication met eligibility criteria and consented to randomization.InterventionsTranexamic acid (1-g bolus followed by 1-g infusion over 8 hours; n = 619) or matching placebo (n = 626) beginning at induction of anesthesia.Main Outcomes and MeasuresThe primary outcome was receipt of red blood cell transfusion within 7 days of surgery.ResultsThe primary analysis included 1245 participants (mean age, 63.2 years; 39.8% female; 56.1% with a diagnosis of colorectal liver metastases). Perioperative characteristics were similar between groups. Red blood cell transfusion occurred in 16.3% of participants (n = 101) in the tranexamic acid group and 14.5% (n = 91) in the placebo group (odds ratio, 1.15 [95% CI, 0.84-1.56]; P = .38; absolute difference, 2% [95% CI, −2% to 6%]). Measured intraoperative blood loss (tranexamic acid, 817.3 mL; placebo, 836.7 mL; P = .75) and total estimated blood loss over 7 days (tranexamic acid, 1504.0 mL; placebo, 1551.2 mL; P = .38) were similar between groups. Participants receiving tranexamic acid experienced significantly more complications compared with placebo (odds ratio, 1.28 [95% CI, 1.02-1.60]; P = .03), with no significant difference in venous thromboembolism (odds ratio, 1.68 [95% CI, 0.95-3.07]; P = .08).Conclusions and RelevanceAmong patients undergoing liver resection for a cancer-related indication, tranexamic acid did not reduce bleeding or blood transfusion but increased perioperative complications.Trial RegistrationClinicalTrials.gov Identifier: NCT02261415

Abstract Artificial intelligence (AI)–enabled interpretation of electrocardiogram (ECG) images (AI-ECGs) can identify patterns predictive of future adverse cardiac events. We hypothesized that such an approach would provide prognostic information for the risk of cardiac complications and mortality in patients undergoing hematopoietic cell transplantation (HCT). We retrospectively subjected ECGs obtained before HCT to an externally trained, deep-learning model designed to predict the risk of atrial fibrillation (AF). Included were 1377 patients (849 autologous [auto] HCT and 528 allogeneic [allo] HCT recipients). The median follow-up was 2.9 years. The 3-year cumulative incidence of AF was 9% (95% confidence interval [CI], 7-12) in patients who underwent auto HCT and 13% (10%-16%) in patients who underwent allo HCT. In the entire cohort, pre-HCT AI-ECG estimate of AF risk correlated highly with the development of clinical AF (hazard ratio [HR], 7.37; 95% CI, 3.53-15.4; P < .001), inferior survival (HR, 2.4; 95% CI, 1.3-4.5; P = .004), and greater risk of nonrelapse mortality (NRM; HR, 95% CI, 3.36; 1.39-8.13; P = .007), without increased risk of relapse. Association with mortality was only noted in allo HCT recipients, where the risk of NRM was greater. The use of cyclophosphamide after transplantation resulted in greater 90-day incidence of AF (13% vs 5%; P = .01) compared to calcineurin inhibitor–based graft-versus-host disease prophylaxis, corresponding to temporal changes in AI-ECG AF prediction after HCT. In summary, AI-ECG can inform risk of posttransplant cardiac outcomes and survival in HCT patients and represents a novel strategy for personalized risk assessment.

Objectives: Radial tears of the meniscus are increasingly treated with repair instead of partial meniscectomy, with satisfactory short-term clinical outcomes. There remains a paucity of mid- and long-term outcomes data for this preservation technique. The purpose of this study was to 1) evaluate the mid- to long-term clinical outcomes and reoperation rate of radial meniscal repair versus bucket-handle meniscal repair and 2) evaluate the outcomes of both surgeries overtime. We hypothesized that radial repair would provide similar outcomes and reoperation rates to that of bucket-handle meniscal repair in this propensity-matched cohort. Methods: A previously identified cohort of radial meniscal tears without concurrent root injuries undergoing surgical repair at a single institution between 2011 and 2015 were reviewed. Inclusion criteria was patients undergoing repair of full-thickness radial tears. Exclusion criteria were patients who had 1) not consented for research follow-up, 2) <2 year of follow-up, 3) high-grade (Outerbridge grade 3 or 4) chondromalacia, 4) knee dislocations or combined anterior cruciate ligament and posterior cruciate ligament injuries, 5) repair of posterior meniscal root tears, and 6) repair of partial radial tears. Propensity matching was performed based on age at surgery, sex, laterality, body mass index (BMI), and concomitant anterior cruciate ligament reconstruction (ACLR) using a comparison pool of 70 bucket-handle meniscal repairs (BHMR). Reoperation-free survival rates, Tegner Activity Score, visual analog scale (VAS) for pain, and International Knee Documentation Committee (IKDC) scores were analyzed. Results: Twenty-four patients (18 males, 6 females, age 22.8 ± 11.9 years, BMI 26.5 ± 5.8) with radial meniscal repair were included in this study. Eighteen of these patients were successfully propensity matched to 18 bucket-handle meniscal tears for an overall mean follow-up of 10.2 ± 1.7 years (range, 7.3-13.5) (Table 1). The 24 radial tear repairs demonstrated significant and durable postoperative improvements at mean 10.2 years across VAS at rest (3.0 ± 2.5 vs 0.5 ± 1.0, p < 0.001), VAS for pain at use (5.8 ± 2.9 vs 1.4 ± 1.9, p < 0.001) Tegner (2.6 ± 1.4 vs 6.8 ± 2.0, p < 0.001) and IKDC (39.8 ± 12.3 vs 84.1 ± 16.5, p < 0.001) (Table 1). Of patients not undergoing reoperation (19), 100% reported being “Satisfied” 4/19 (21%) or “Very Satisfied” 15/19 (79%). When the 18 radial tear repairs were compared to the 18 BHMT repairs, there was no significant difference across VAS for pain at rest (0.6 ± 1.2 vs 0.3 ± 0.7, p = 0.48), VAS for pain at use (1.6 ± 2.1 vs 1.1 ± 1.3, p = 0.48) Tegner (6.9 ± 2.2 vs 6.4 ± 2.1, p = 0.51) and IKDC (83.4 ± 17.4 vs 82.1 ± 14.1, p = 0.83) (Table 2). Importantly, survival without reoperation rates were not statistically different between the 2 groups at 10-year follow-up (14/18 (78%) vs 16/18 (89%), p = 0.37) (Figure 1). There was no significant difference between clinical outcomes (Tegner and IKDC) at final follow-up in the radial repair group as compared to the 4-year mid-term outcomes (p = 0.58 and 0.19 respectively). For the BHMR group, Tegner scores were not significantly different (p = 0.60) compared with their 4-year timepoint; however, IKDC scores at the final timepoint were significantly lower 93.4 ± 3.4 vs 82.1 ± 14.1 (p = 0.01). Notably, both the radial repair and bucket-handle repairs groups reported final follow-up Tegner scores that were not significantly different from their preinjury Tegner scores (p = 0.70 for the radial group and p = 0.62 for the bucket-handle group). Conclusions: At mean 10-year follow-up, significant clinical improvements and high rates of satisfaction were observed for radial meniscal tear repair. When propensity matched, radial and BHMR demonstrated durable improvements in postoperative VAS for pain, IKDC, and Tegner scores, as well as similar, acceptable reoperation rates. [Figure: see text]

Objectives: Medial meniscus posterior root tears (MMPRTs) render the meniscus essentially non-functional, resulting in increased peak contact pressures, reduced forced dissipation, and increased risk of early osteoarthritis. Transtibial root repair has shown promise at restoring meniscus function and improving clinical outcomes; however, a paucity of literature exists evaluating the prognostic clinical and radiographic factors for poor outcomes following isolated meniscus root repair. The purpose of this study was to 1) describe the patient reported clinical outcomes after isolated MMPRT repair at minimum 2-year follow-up, 2) determine the retear and conversion to arthroplasty rates, and 3) identify prognostic factors for clinical outcomes and International Knee Documentation Committee (IKDC) Patient Acceptable Symptom State (PASS) achievement. Methods: Isolated MMPRT repairs from 2010-2020 at three institutions in Rochester, MN; Jacksonville, FL; and Phoenix, AZ were followed prospectively for postoperative Tegner Activity Scale, Visual Analog Scale (VAS) for pain, IKDC, Forgotten Joint Score (FJS), subjective improvement and knee preference, and subsequent surgeries at minimum 2-year follow up. PASS for IKDC was set at 69. Demographics, injury characteristics, and surgical details were collected. Results: Eighty-four patients were included in this study (age: 49.7 ± 11.0 years [range: 13-76]; sex: 75.0% female; BMI: 31.6 ± 6.9 kg/m 2 [MH1] ). Forty-five patients (53.6%) had BMI >30 kg/m 2 , and 14 patients (16.7%) reported a history of active smoking (Table 1). Mean medial compartment Outerbridge grade was 2.0 ± 1.1, with 73.8% of patients having grade ≥2 changes. Mean preinjury Tegner score, preoperative VAS at rest, and preoperative VAS with use were 4.6 ± 2.4, 3.6 ± 2.7, and 6.5 ± 2.5, respectively. At final follow-up (mean 3.9 ± 2.0 years), mean Tegner score was 4.3 ± 1.8, mean VAS at rest was 1.2 ± 2.0, and mean VAS with use was 2.3 ± 2.2. There was no significant difference in preinjury vs. postoperative Tegner scores (p = 0.208), and preinjury Tegner was significantly positively correlated with postoperative Tegner (p < 0.001). Significant (p < 0.001) postoperative improvements in both VAS at rest and with use were observed. Mean postoperative IKDC score was 73.3 ± 17.0, and mean FJS was 59.6 ± 27.9 at final follow-up. When asked to rate their knee at final follow-up compared to before surgery on a scale from 0-5 (0 = “significantly worse”, 1 = “mildly worse”, 3 = “unchanged”, 4 = “mildly improved”, 5 = “significantly improved”), the mean score 4.6 ± 0.8. Forty-one patients (74.5%) reported significant improvement, 8 (14.5%) reported mild improvement, 3 (5.5%) reported no change, and 3 (5.5%) reported mild worsening. No patients reported significant worsening. When asked which knee they preferred, 13 patients (26.0%) reported preferring their operated knee, compared to 18 (36.0%) who preferred their nonoperated knee. The remaining 19 patients (38.0%) had no preference for one knee over the other. A summary of all patient reported outcomes is reported in Table 2. At the time of final follow-up, 16 (19.0%) of patients had reached a clinical endpoint. Twenty-nine patients (34.5%) underwent postoperative MRIs at an average of 1.5 ± 1.7 years (range: 0.3-5.9 years) after surgery[MH1] . Twelve of the MRIs (41.4%) were ordered for evaluation of continued pain, while 7 (24.1%) were ordered for new pain or injury, and 10 (34.5%) were ordered for research purposes. Five patients (6.0%) had MRI-confirmed retears of the MMPRT repair at an average of 1.1 ± 1.3 years (range: 0.3-3.4) after surgery[HMMP2] , one of which was in an asymptomatic patient who received a follow-up MRI for research purposes. No patients underwent revision MMPRT repair surgery, and 7 patients (8.3%) progressed to arthroplasty (6 TKA, 1 UKA) at an average of 3.4 ± 4.3 years (range 0.6-12.6), one of whom also sustained a root retear. Therefore, the surgical failure was noted in 11 patients, corresponding to a surgical failure rate of 13.1% in this cohort. Of note, three of the five patients with MRI-confirmed retears had not received any further surgical intervention[MH3] [BA(M4] at the time of final follow-up 2.7, 3.8, and 8.5 years after surgery. Additionally, there were six non-MMPRT revision, non-arthroplasty subsequent surgeries in five patients, and there were three patients (3.6%) who sustained new medial meniscus tears 2.8-, 3.6-, and 5.9-years postoperatively, respectively. A concise summary of clinical endpoints can be found in Table 3 and Table 4. Significantly more females experienced surgical failures than males (17.5% vs. 0%, p = 0.040), and significantly more patients with medial compartment Outerbridge grades ≥2 experienced surgical failure than those with grades <2 (17.7% vs. 0%, p = 0.034). Additionally, patients who failed did have significantly higher mean KL grades than those who did not (1.4 ± 0.9 vs. 0.7 ± 0.7, p = 0.012). There were no other significant differences in the demographic or pathologic characteristics of patients who experienced surgical failure and those who did not. Of note, 37% of patients failed to achieve IKDC PASS, with smoking status associated with a 15-point reduction in IKDC (p=0.010) Conclusions: Patients undergoing transtibial root repair demonstrate restoration of pre-injury activity levels, significant clinical improvements in pain and function, and low surgical failure rates at minimum 2-year follow-up, with 89% of patients reporting subjective improvement after surgery. However, only 63% of patients were able to achieve PASS thresholds, suggesting that while effective, additional research on root repair technical and clinical optimization is warranted.

Objectives: Hip arthroscopy is rapidly advancing, with literature increasingly reporting positive outcomes at short- and mid-term follow-up; however, available long-term data remains limited. The purpose of this study is to evaluate long-term outcomes of primary hip arthroscopy at minimum 10-year follow-up at two academic centers by describing patient-reported outcomes (PROs) and determining reoperation, revision, and total hip arthroplasty (THA) rates. Methods: Primary hip arthroscopies performed between January 1988 and April 2013 at 2 academic centers were evaluated for postoperative PROs including Visual Analogue Scale (VAS), Tegner Activity Scale score, Hip Outcome Score Activities of Daily Living and Sport Scale (HOS-ADL/HOS-SS), modified Harris Hip Score (mHHS), Nonarthritic Hip Score (NAHS), 12-item International Hip Outcome Tool (iHOT-12), surgery satisfaction, function, and reoperations. Results: Two-hundred ninety-four primary hip arthroscopies with a mean age of 40±14 years; 66% female; and a mean body mass index (BMI) of 27±6 kg/m 2 were followed for mean 12±3 years (range: 10-24). Labral debridement and repair were performed in 41% and 59% of patients, respectively. All patients underwent interportal capsulotomy and 2% underwent T-capsulotomy. Eleven percent of patients underwent capsular repair. At final follow-up, patients reported mean VAS at rest of 2±2, with use of 3±3, iHOT-12 of 68±27, NAHS of 81±18, mHHS of 79±17, HOS-ADL of 82±19, and HOS-SS of 74±25. Mean surgical satisfaction was 8.4±2.4 (Table 1). Sixty-five hips (23%) underwent THA and 33 (11%) underwent revision arthroscopy (Table 2). Risk factors for THA included older age (p<0.001), higher BMI (p<0.001), lower lateral center-edge angle (p=0.039), larger alpha angle (p=0.001), higher Tönnis grade (p=0.011), labral debridement (p=0.004), and capsular nonrepair (p=0.030). Patients undergoing combined labral and capsular repair demonstrated a THA conversion rate of 3% compared to 31% for patients undergoing combined labral debridement and capsular nonrepair (p=0.006) (Table 3). Labral repair trended towards increased 10-year THA-free survival (84% vs. 77%, p=0.085) while capsular repair demonstrated significantly increased 10-year THA-free survival (97% vs 79%, p=0.032) (Figure 1). Conclusions: At minimum 10-year follow-up, patients undergoing primary hip arthroscopy demonstrated high rates of satisfaction and acceptable outcome scores. In total, 11% of patients underwent revision hip arthroscopic surgery with a THA conversion rate of 23%. Conversion to THA was associated with patient factors including older age and higher Tönnis grade as well as potentially modifiable surgical factors including labral debridement and capsular nonrepair.

AbstractPrior studies have suggested that immune thrombotic thrombocytopenic purpura (iTTP) may display seasonal variation; however, methodologic limitations and sample sizes have diminished the ability to perform a rigorous assessment. This 5‐year retrospective study assessed the epidemiology of iTTP and determined whether it displays a seasonal pattern. Patients with both initial and relapsed iTTP (defined as a disintegrin and metalloprotease with thrombospondin type motifs 13 activity <10%) from 24 tertiary centers in Australia, Canada, France, Greece, Italy, Spain, and the US were included. Seasons were defined as: Northern Hemisphere—winter (December–February); spring (March–May); summer (June–August); autumn (September–November) and Southern Hemisphere—winter (June–August); spring (September–November); summer (December–February); autumn (March–May). Additional outcomes included the mean temperature in months with and without an iTTP episode at each site. A total of 583 patients experienced 719 iTTP episodes. The observed proportion of iTTP episodes during the winter was significantly greater than expected if equally distributed across seasons (28.5%, 205/719, 25.3%–31.9%; p = .03). Distance from the equator and mean temperature deviation both positively correlated with the proportion of iTTP episodes during winter. Acute iTTP episodes were associated with the winter season and colder temperatures, with a second peak during summer. Occurrence during winter was most pronounced at sites further from the equator and/or with greater annual temperature deviations. Understanding the etiologies underlying seasonal patterns of disease may assist in discovery and development of future preventative therapies and inform models for resource utilization.

Background: Little is known about the relationship between neighborhood disadvantage and neuromyelitis optica spectrum disorder (NMOSD) outcomes. Objective: The objective is to determine the impact of neighborhood disadvantage on time from symptom onset to diagnosis and annualized relapse rate (ARR). Methods: Neighborhood disadvantage were captured with the Area Deprivation Index (ADI), a validated measure of neighborhood-level disadvantage. Negative binomial regression models assessed the impact of ADI on diagnostic delay (⩾3 months between symptom onset and diagnosis) and ARR. Results: A total of 158 NMOSD patients were identified, a majority of whom were White (56.3%) and female (89.9%) with a mean age of 46 years at diagnosis. The ADI did not significantly affect odds of diagnostic delay (odds ratio (OR) = 0.99, p = 0.26). In univariable models, the ADI was not significantly associated with ARR (OR = 1.004, p = 0.29), but non-White race (OR = 1.541, p = 0.02) and time on immunosuppressive therapies (ISTs; OR = 0.994, p = 0.03) were. White patients used IST for an average of 81% of the follow-up period, compared to an average of 65% for non-White patients ( p < 0.01). Conclusion: No significant relationship between neighborhood-level disadvantage and diagnostic delay or ARR in NMOSD patients was observed. Non-White patients had a higher ARR, which may be related to less IST use.

Abstract The effect of prior inotuzumab ozogamicin (InO) treatment on brexucabtagene autoleucel (brexu-cel) outcomes remains unclear in adults with acute lymphoblastic leukemia (ALL). We conducted a retrospective multicenter analysis of 189 patients with relapsed/refractory ALL treated with brexu-cel. Over half of the patients received InO before brexu-cel (InO exposed). InO-exposed patients were more heavily pretreated (P = .02) and frequently had active marrow disease before apheresis (P = .03). Response rate and toxicity profile after brexu-cel were comparable for InO-exposed and InO-naïve patients; however, consolidation therapy after brexu-cel response was used at a higher rate in InO-naïve patients (P = .005). With a median follow-up of 11.4 months, InO-exposed patients had inferior progression-free survival (PFS; P = .013) and overall survival (OS; P = .006) in univariate analyses; however, prior InO exposure did not influence PFS (hazard ratio, 1.20; 95% confidence interval, 0.71-2.03) in multivariate models. Within InO-exposed patients, InO responders had superior PFS (P = .002) and OS (P &lt; .0001) relative to InO-refractory patients. The timing of administering InO did not affect brexu-cel outcomes, with comparable PFS (P = .51) and OS (P = .86) for patients receiving InO as bridging therapy or before apheresis. In conclusion, although InO exposure was associated with inferior survival outcomes after brexu-cel in unadjusted analyses, these associations were no longer significant in multivariate analyses, suggesting it is unlikely that InO negatively affects brexu-cel efficacy. Our data instead imply that InO-exposed recipients of brexu-cel tend to be higher-risk patients with intrinsic adverse leukemia biology.

Because proton beam therapy (PBT) can lower the dose of radiation to the heart, lungs, and breast, it is an established radiation modality for patients with Hodgkin lymphoma (HL). Pencil beam scanning (PBS) PBT facilitates the treatment of more extensive targets. This may be especially of value for lymphoma patients who require RT to both mediastinal and axillary targets, defined here as extended target RT (ETRT), given the target distribution and need to minimize the lung, heart, and breast dose. Using the Proton Collaborative Group registry, we identified patients with HL treated with PBT to both their mediastinum and axilla, for which DICOM-RT was available. All patients were treated with PBS. To evaluate the dosimetric impact of PBS, we compared delivered PBS plans with VMAT butterfly photon plans optimized to have the same target volume coverage, when feasible. Between 2016 and 2021, twelve patients (median 26 years) received PBS ETRT (median 30.6 Gy (RBE)). Despite the large superior/inferior (SI, median 22.2 cm) and left/right (LR, median 22.8 cm) extent of the ETRT targets, all patients were treated with one isocenter except for two patients (both with SI and LR > 30 cm). Most commonly, anterior beams, with or without posterior beams, were used. Compared to photons, PBS had greater target coverage, better conformity, and lower dose heterogeneity while achieving lower doses to the lungs and heart, but not to the breast. No acute grade 3+ toxicities were reported, including pneumonitis. Proton ETRT in this small cohort was safely delivered with PBS and was associated with an improved sparing of the heart and lungs compared to VMAT.