Citations

ABSTRACT Background Abdominal‐based free flaps are the mainstay in autologous breast reconstruction. Their safety and consistency in outcomes are well‐documented. When flap compromise occurs, operative salvage is the gold standard. However, when—and if—to place these patients on heparin infusions is unclear. The goal of this study was to investigate abdominal‐based free flap compromise and compare outcomes with and without heparin infusion. Materials and Methods This was a single‐institution, multiple‐surgeon, retrospective chart review of patients undergoing autologous, abdominal‐based free flap breast reconstruction who experienced anastomotic compromise within a 6‐year period. Treatment and outcomes data collected include flap salvage, hematoma, seroma, surgical site infection (SSI), transfusion requirement, and length of hospital stay. Results Fifty‐one flaps had evidence of compromise. A total of 31 (60.8%) patients were placed on heparin infusions after experiencing anastomotic compromise, compared to 20 who did not receive heparin infusion. Thirty‐five patients (68.6%) underwent deep inferior epigastric perforator flaps. Twenty‐six patients (51%) experienced venous congestion, 22 patients (43.1%) experienced arterial compromise, and three (5.9%) experienced both. Twenty‐eight patients (54.9%) received tissue plasminogen activator; in the heparin infusion group, 21 patients (67.7%) received tissue plasminogen activator. The total salvage rate of compromised flaps was 94.1% (48/51). There was no significant difference between heparin infusion and standard cares in length of hospital stay, length of drains in‐place, successful salvage (93.5% vs. 95%), hematoma (19.4% vs. 15%), fat necrosis, SSI, hospital readmission (19.4% vs. 15%), and return rates to the operating room (48.4% vs. 50%). However, there was a significantly higher transfusion rate in patients receiving heparin infusion (38.7% vs. 10%). Of the 25 flaps with evidence of thrombosis, 72% were placed on heparin infusions while 28% were not; there was no significant difference in salvage rate in this sub‐group. Conclusions This review of autologous breast reconstruction free flap compromise provides evidence of similar safety profiles, with similar salvage rates, when comparing salvage with and without heparin infusion; there is a higher transfusion requirement when treating with heparin infusion.

ABSTRACTIntroductionThe diagnosis of antibody‐mediated rejection (AMR) requires input from several transplant professionals. Bringing clinical and laboratory experts together may help standardize care. Yet, little is known about current global practices of multidisciplinary meetings for AMR management.MethodsThe Banff Antibody‐Mediated Injury Working Group approached professional societies worldwide to distribute a survey on the availability, content, participants, perceived value, and barriers to the implementation of multidisciplinary meetings.ResultsFour hundred two transplant professionals from six continents caring for kidney (90.55%), liver (21.14%), pancreas (20.65%), heart (15.17%), and lung (14.18%) transplant recipients participated in the survey, and 302 (75.12%) reported attending multidisciplinary meetings. Multidisciplinary meetings were more prevalent in academic centers, in high‐ versus low‐to‐middle‐income regions (81.03% and 65.99%, respectively; p < 0.001), and in mid‐to‐large size transplant programs compared to smaller programs. Perceived value included continued professional development (97.68%) and trainee education (95.70%). AMR was reported to be discussed at these meetings by 217 respondents with case presentations reviewing patient characteristics, histology, and HLA antibody data. A third of the respondents reviewed non‐HLA/pathogenic autoantibodies and/or molecular diagnostics, with the latter being more frequently applied in high‐ versus low‐to‐middle‐income regions (46.71% and 12.31%, respectively; p < 0.001). AMR case presentations allowed diagnosis revision, actionable management plans and were perceived as improving care. The primary barrier to the implementation of multidisciplinary meetings (63.27%) was the unavailability of transplant professionals (e.g., transplant immunologists).ConclusionFacilitating multidisciplinary meetings through the remote participation of pertinent experts and incentivizing participation through remuneration, protected time, or continued medical education may help standardize AMR diagnosis and harmonize its management.

Background Bruton tyrosine kinase (BTK) is a protein-coding gene crucial for B cell development. It is found on Xq21.3-Xq22 of the long arm of the X chromosome and belongs to the Tec family of cytoplasmic protein tyrosine kinases consisting of 5 structural domains: PH, TH, Src3, Src2, and TK. Pathogenic variants in the BTK gene can fully or partially block B cell development. BTK has been linked to various antibody deficiencies beyond agammaglobulinemia, including CVID. In hypomorphic BTK variants, there are detectable B cells in the periphery that may result in variable levels of serum immunoglobulins and clinical phenotype. Objective Investigate the impact of a missense pathogenic hypomorphic BTK variant (p.Arg525Gln) observed in a large kindred. Results We plan to assess by flow cytometry BTK protein expression in specific B cell subsets in hypomorphic XLA patients in this kindred. The flow cytometry revealed a uniformly reduced BTK expression in B cells (B cells evaluation is limited by low cell counts). BTK expression was decreased with an unexpected bimodal distribution in monocytes. Since both patients were male, XXY syndrome was initially considered but deemed less likely. The unexpected monocyte expression pattern in the current patient suggests possible somatic mosaicism or other genetic factors, or the two peaks are related to BTK protein degradation, and this may differ in specific cellular compartments or change with age, warranting further investigation. Conclusions This highlights the challenges of diagnosing hypomorphic XLA, especially in patients with detectable B cell counts and atypical BTK expression. Flow cytometric analysis of two patients with BTK mutations identified bimodal mosaic patterns of BTK expression in monocytes. This bimodal expression pattern may reflect cellular mosaicism like in mothers who are obligate carriers of XLA. BTK biology with hypomorphic variants remains incompletely understood, particularly how these variants affect B cell development and result in milder antibody deficiency phenotypes, warranting further investigation. This emphasizes the importance of genetic screening in kindreds with XLA and the need for increased awareness of partial XLA among healthcare providers to ensure timely diagnosis and treatment.

ImportanceMyeloperoxidase is one of the most abundant peroxidase enzymes in activated myeloid cells. Myeloperoxidase inhibitors may have a clinical benefit in amyotrophic lateral sclerosis (ALS) by slowing neurodegeneration via reduced neuroinflammation and oxidative stress.ObjectiveTo determine the safety, tolerability, and efficacy of verdiperstat, a selective myeloperoxidase inhibitor, in ALS.Design, Settings, and ParticipantsVerdiperstat was tested as a regimen of the HEALEY ALS Platform Trial, a multicenter, double-blind, perpetual platform design, randomized clinical trial, with sharing of trial infrastructure and placebo data across multiple regimens. The study was conducted at 54 ALS referral centers across the US from July 2020 to April 2022. Adult participants with a diagnosis of clinically possible, probable, laboratory-supported probable, or definite ALS defined by the revised El Escorial criteria were randomized to verdiperstat or regimen-specific placebo. An additional group of participants concurrently randomized to placebo from other regimens was included in the analyses.InterventionsEligible participants were randomized in a 3:1 ratio to receive oral verdiperstat, 600 mg, twice daily or matching placebo for a planned placebo-controlled duration of 24 weeks.Main Outcomes and MeasuresThe primary efficacy outcome was change from baseline through week 24 in disease severity, as measured by a joint model of ALS Functional Rating Scale–Revised and survival, with the treatment effect quantified by the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression of verdiperstat relative to placebo.ResultsA total of 167 participants (mean [SD] age, 58.5 [11.4] years; 59 [35.3%] female; 108 [64.6%] male) were randomized to either verdiperstat (126 [75.4%]) or to placebo (41 [25.6%]). Among the participants randomized to the verdiperstat regimen, 130 (78%) completed the trial. The estimated DRR was 0.98 (95% credible interval, 0.77-1.24; posterior probability = 0.57 for slowing of disease progression [DRR &amp;lt;1]). Verdiperstat was estimated to slow progression by 2% vs placebo (95% credible interval, −23% to 24%; posterior probability 0.57). Verdiperstat was overall safe and well tolerated. Common adverse events in the verdiperstat group were nausea, insomnia, and elevated thyrotropin levels.Conclusions and RelevanceResults demonstrate that treatment with verdiperstat was unlikely to alter disease progression in ALS.Trial RegistrationClinical Trial Identifiers: NCT04297683 and NCT04436510

ImportanceAmyotrophic lateral sclerosis (ALS) is a fatal disease. The sigma-1 (σ1) receptor emerged as a target for intervention.ObjectiveTo determine the effects of pridopidine, a σ1-receptor agonist, in ALS.Design, Settings, and ParticipantsPridopidine was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind, platform trial. The study was conducted at 54 sites in the US from January 2021 to July 2022 (final follow-up, July 14, 2022). A total of 163 participants with ALS were randomized to receive pridopidine or placebo. An additional 122 concurrently randomized participants were assigned to receive placebo in other regimens and included in the analyses.InterventionsEligible participants were randomized 3:1 to receive oral pridopidine 45 mg twice daily (n = 121) or matching oral placebo (n = 42) for a planned duration of 24 weeks.Main Outcomes and MeasuresThe primary efficacy outcome was change from baseline through week 24 in ALS disease severity, analyzed using a bayesian shared parameter model, which has components for function (Revised Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS-R]) and survival that were linked through an integrated estimate of treatment-dependent disease slowing across these 2 components. This was denoted as the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression on pridopidine relative to placebo. There were 5 key secondary end points: time to 2-point or greater reduction in ALSFRS-R total score among participants with bulbar dysfunction at baseline, rate of decline in slow vital capacity among participants with bulbar dysfunction at baseline, percentage of participants with no worsening in the ALSFRS-R bulbar domain score, time to 1-point or greater change in the ALSFRS-R bulbar domain score, and time to death or permanent assisted ventilation.ResultsAmong 162 patients (mean age, 57.5 years; 35% female) who were randomized to receive the pridopidine regimen and included in the primary efficacy analysis, 136 (84%) completed the trial. In the primary analysis comparing pridopidine vs the combined placebo groups, there was no significant difference between pridopidine and placebo in the primary end point (DRR, 0.99 [95% credible interval, 0.80-1.21]; probability of DRR &amp;lt;1, 0.55) and no differences were seen in the components of ALSFRS-R or survival. There was no benefit of pridopidine on the secondary end points. In the safety dataset (pridopidine, n = 121; placebo, n = 163), the most common adverse events were falls (28.1% vs 29.3%, respectively) and muscular weakness (24.0% vs 31.7%, respectively).Conclusions and RelevanceIn this 24-week study, pridopidine did not impact the progression of ALS.Trial RegistrationClinicalTrials.gov Identifiers: NCT04297683, NCT04615923

Importance The etiology of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, is unknown. However, neuroinflammation and complement activation may play a role in disease progression. Objective To determine the effects of zilucoplan, an inhibitor of complement C5, in individuals with ALS. Design, Setting, and Participants Zilucoplan was tested as regimen A of the HEALEY ALS Platform Trial, a phase 2 to 3 multicenter, randomized, double-blind, placebo-controlled perpetual platform clinical trial with sharing of trial infrastructure and placebo data across multiple regimens. Regimen A was conducted from August 17, 2020, to May 4, 2022. A total of 162 participants were randomized to receive zilucoplan (122 [75.3%]) or regimen-specific placebo (40 [24.7%]). An additional 124 concurrently randomized participants were randomized to receive placebo in other regimens. Interventions Eligible participants were randomized in a 3:1 ratio to receive zilucoplan or matching placebo within strata of edaravone and/or riluzole use for a planned duration of 24 weeks. Active drug (zilucoplan, 0.3 mg/kg) and placebo were provided for daily subcutaneous dosing. Main Outcomes and Measures The primary end point was change in disease severity from baseline through 24 weeks as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) total score and survival, analyzed using a bayesian shared-parameter model and reported as disease rate ratio (DRR; &amp;lt;1 indicating treatment benefit). The study included prespecified rules for early stopping for futility. Outcome analyses were performed in the full analysis set comparing the zilucoplan group with the total shared placebo group (n = 164). Results Among the 162 participants who were randomized (mean [SD] age, 59.6 [11.3]; 99 [61.1%] male), 115 (71.0%) completed the trial. The estimated DRR common to ALSFRS-R and survival was 1.08 (95% credible interval, 0.87-1.31; posterior probability of superiority, 0.24). The trial was stopped early for futility. No unexpected treatment-related risks were identified. Conclusions and Relevance In this randomized clinical trial of zilucoplan in ALS, treatment did not alter disease progression. The adaptive platform design of the HEALEY ALS Platform Trial made it possible to test a new investigational product with efficient use of time and resources. Trial Registration ClinicalTrials.gov Identifier: NCT04297683

Importance Bioenergetic failure has been proposed as a driver of amyotrophic lateral sclerosis (ALS). CNM-Au8 is a suspension of gold nanocrystals that catalyzes the conversion of nicotinamide adenine dinucleotide hydride into NAD + , resulting in an increase of cellular adenosine triphosphate production. Objective To determine the effects of CNM-Au8 on ALS disease progression. Design, Setting, and Participants CNM-Au8 was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind platform trial. The study was conducted at 54 sites in the US from July 2020 to March 2022 (final follow-up, March 17, 2022). A total of 161 participants with ALS were randomized to receive CNM-Au8 (n = 120) or regimen-specific placebo (n = 41). Data from 123 concurrently randomized placebo participants in other regimens were combined for analyses. Interventions Eligible participants were randomized in a 3:3:2 ratio to receive CNM-Au8 60 mg daily (n = 61), CNM-Au8 30 mg daily (n = 59), or matching placebo (n = 41) for 24 weeks. Main Outcomes and Measures The primary efficacy outcome was change from baseline through week 24 in ALS disease severity measured by a bayesian shared parameter model of function (based on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale) and survival, which provided an estimate of the rate of disease progression measured by the disease rate ratio (DRR), with a DRR of less than 1 indicating treatment benefit. Secondary end points included a Combined Assessment of Function and Survival using a joint-rank test, rate of decline in slow vital capacity (percent predicted), and survival free of permanent assisted ventilation. Results Among 161 participants who were randomized within the CNM-Au8 regimen (mean age, 58.4 years; 61 [37.9%] female), 145 (90%) completed the trial. In the primary analysis comparing the combined CNM-Au8 dosage groups vs the combined placebo groups, the primary end point (DRR, 0.97 [95% credible interval, 0.783-1.175]; posterior probability of DRR &amp;lt;1, 0.65) and the 3 secondary end points suggested no benefit or harm of CNM-Au8. In the active (n = 120) vs placebo (n = 163) groups, the most common adverse events were diarrhea (23 [19%] vs 12 [7%]), nausea (17 [14.2%] vs 14 [8.6%]), fatigue (12 [10.8%] vs 30 [18.4%]), and muscular weakness (24 [20%] vs 45 [27.6%]). Conclusions and Relevance No benefit of CNM-Au8 on ALS disease progression was observed at 24 weeks. Trial Registration ClinicalTrials.gov Identifiers: NCT04297683 , NCT04414345

Introduction and Hypothesis: New bleeding in cerebral cavernous malformations (CCM) heralds increased risk of future hemorrhage for several years, yet conventional imaging only detects new bleeding that occurred in the prior weeks. A biomarker of hemorrhage could help identifying high risk lesions. An increase of mean lesional quantitative susceptibility mapping (QSM) ≥6% on MRI has been adjudicated as reflecting new bleeding in CCM during longitudinal follow-up. However, mean lesional QSM from a single acquisition could not diagnose or prognosticate a bleed. We hypothesize that machine learning (ML) may identify diagnostic and prognostic features of bleeding within QSM maps at a single point in time. Material and Methods: Two hundred and sixty-five QSM maps of CCM lesions were acquired in 120 patients enrolled in National Institute of Health (NIH) multisite trial readiness project (NCT03652181). Each map was classified (Yes/No) in association with symptomatic hemorrhage (SH) and/or biomarker event with QSM increase ≥6% in the prior (diagnostic association) and subsequent (prognostic association) year. Twenty-eight features were extracted including 14 texture, 5 first-order statistical, as well as 3 size, shape, and morphological. Five-fold cross-validation was conducted on a support-vector machine (SVM) with linear stepwise kernel for both diagnostic and prognostic associations. Performance of individual features and composite classifiers was evaluated using student t-test ( p <0.05) with Bonferroni-correction and receiver operating characteristic (ROC) analysis, area under the curve (AUC). Results: Lesions with SH in the prior year had lower average values for sum variance (AUC=0.79, p<0.001), variance (AUC=0.79, p<0.001), and correlation (AUC=0.71, p=0.004) as compared to lesions without SH. The SVM classification method tasked with distinguishing lesions with mean QSM increase ≥6% in the prior year included recurrent selection of sum average, mean, sphericity and margin sharpness, yielding an AUC of 0.61 (p=0.02). In the prognostic cohort, no individual feature nor any SVM classification model was able to distinguish cases with a subsequent clinical bleed or biomarker event. Conclusion: This proof-of-concept suggests that ML may assist in deriving features on QSM maps acquired at a single timepoint, which reflect prior hemorrhagic activity in CCM. Further investigation is planned in larger cohorts and in conjunction with clinical trials of bleeding in CCM.

Background: Positron emission tomography (PET) scan is the imaging modality of choice for initial staging and response assessment of follicular lymphoma (FL). Quantitative parameters such as standardized uptake value (SUV) have been investigated as putative prognosticators in FL, with high baseline SUVmax predicting aggressive disease. To date, there is no data to guide treatment choices in patients (pts) with high SUVmax but with no documented evidence of histologic transformation (HT). Specifically, it remains unclear whether anthracycline-containing regimens, such as R-CHOP, are more beneficial than R-Bendamustine (BR) in these pts. Therefore, we aimed to compare the efficacy of frontline R-CHOP and BR in newly diagnosed FL pts based on the SUVmax at baseline PET (bPET). Patients and Methods: Pts with newly diagnosed, biopsy-proven FL1-2 and FL3A who had a bPET scan and who received either first-line R-CHOP or BR within 6 months of diagnosis between 2002 and 2022 were evaluated. Analysis was restricted to pts with age &lt; 70 years to reduce confounding of age with treatment selection. Cohorts included were the FOLL12 (n=562, Luminari et al JCO 2022) and the R-chemotherapy arm of the RELEVANCE (n=216, Morschhauser et al NEJM 2018) clinical trials, the prospectively enrolled Molecular Epidemiology Resource (MER) and the Lymphoma Epidemiology of Outcomes (LEO) cohorts (n=288) and a retrospective cohort from 13 Australian centers (n=219). Choice of chemotherapy regimen was per treating physician. Maintenance was per protocol (FOLL12/RELEVANCE) or per treating physician (MER/LEO/Australia). Event-free survival (EFS) and overall survival (OS) were defined as time from treatment initiation to progression, relapse, retreatment or death; both were censored at 72 months due to varying follow-up across cohorts. SUVmax was grouped by tertile within each cohort to account for potential differences in SUVmax distributions and patient populations across cohorts. Kaplan Meier curves and multivariable Cox models cohort-stratified and adjusted for clinical factors (FLIPI, ECOG PS, age, grade 3A) were used to evaluate outcomes. Results: The median age at diagnosis was 57 years (IQR 49-64). 651 (51%) pts were treated with R-CHOP and 634 (49%) with BR. Within the study cohorts, there was a prevalence of cases receiving BR compared to R-CHOP in the Australian (90% vs 10%) and MER/LEO (68% vs 32%) cohorts, while the opposite was observed in the RELEVANCE (16% vs 84%) and FOLL12 (37% vs 63; p&lt;0.001) trials. Pts receiving R-CHOP were slightly younger (median 56 vs 58 years, p=0.005), more frequently had grade 3A (17% vs 7%, p&lt;0.001), elevated LDH (27% vs 22%, p=0.029), bulky disease &gt; 7 cm (44% vs 37%, p=0.019), lower ECOG PS (PS &gt;1 7% vs 13%, p&lt;0.001), and higher rate of high risk FLIPI (37% vs 30%, p=0.005). Baseline SUVmax was slightly lower in R-CHOP (median 10.7, IQR 7.9-14.9) vs BR (median 11.0, IQR 8.2-14.2) treated pts (p=0.0045). At a median follow-up of 56 months (range, 1-72 months), 415 pts (32%) had an event and 103 (8%) died. Higher SUVmax was not associated with EFS (middle tertile HR=0.96, 95% CI 0.76-1.22; upper tertile HR=0.86, 95% CI 0.68-1.09; p=0.45) or OS (middle tertile HR=1.28, 95% CI 0.80-2.05; upper tertile HR=0.97, 95% CI 0.59-1.59; p=0.44) in multivariable models stratified on cohort and adjusted for treatment and clinical factors. We then compared outcomes by treatment within tertiles of SUVmax. In multivariable models, R-CHOP had modestly inferior EFS to BR in low (HR=1.27, 95% CI 0.84-1.93) and middle tertiles (HR=1.49, 95% CI 0.99-2.25), and modestly superior OS to BR in low (HR=0.59, 95% CI 0.23-1.47) and middle (HR=0.79, 95% CI 0.37-1.71) tertiles. Both EFS (HR=1.06, 95% CI 0.71-1.58) and OS (HR=1.02, 95% CI 0.45-2.30) for R-CHOP were similar to BR in the highest tertile. No comparisons identified a statistically significant benefit for either therapy in multivariable models when evaluating SUVmax tertile subsets. Conclusions: In this large multicenter study of newly diagnosed FL pts with bPET who received frontline immunochemotherapy, higher baseline SUVmax was not associated with inferior outcomes after adjusting for treatment and clinical factors. Within the caveats of retrospective studies and confounding of treatment selection, these data provide no clear insights for SUVmax-based therapy selection in first-line follicular lymphoma pts treated with immunochemotherapy.