Citations

ABSTRACT The microvasculature of peripheral nerve not only is important for the understanding of the development of compression syndromes, but it plays a critical role in the evolution of other nerve pathologies, including, for example, the distribution of intraneural ganglion cysts and lymphoma. We investigated the anatomical course of vessels around the human sciatic nerve and its bifurcation in eight human cadavers. Specifically, the presence of fenestrations on the epineurium and paraneurium's thickness in relation to the intraneural vessels was investigated. The sciatic, tibial, peroneal and sural nerves at the level of the bifurcation are surrounded by different layers, including the epineurium and paraneurial layers. Multiple fenestrations were observed in all membranes surrounding these nerves, which formed openings for the transfer of adipocytes and vessels from one compartment to the neighboring one. The openings were relatively large compared to the size of the vessels. In conclusion, vessels always travel through a natural opening in the paraneurial and epineurium. These vessels are important connections between the extrinsic and intrinsic nerve vasculature. In addition, the fenestration provides an important anatomical explanation for the possibility of transfer of anesthetic agents or different nerve pathologies, including intraneural ganglion cyst and tumors.

Abstract The cumulative impact of baseline comorbidities on outcomes of chimeric antigen receptor T-cell (CAR-T) therapy is not well established. Therefore, we developed and validated a Cellular Therapy Comorbidity Index (CT-CI) to predict outcomes following CD19-directed CAR-T therapy for large B-cell lymphoma (LBCL). Patients aged 18 or older receiving commercial CAR-T therapy for LBCL during 2017 to 2020 were selected from the Center for International Blood and Marrow Transplant Research registry. Patients were randomly assigned to training or validation cohorts. Comorbidities given weighted scores comprised the CT-CI, which was then validated for overall survival (OS) prognostication. A total of 1916 patients from 97 medical centers were included, with a median age of 64 years (19-91 years). About 70% of patients had comorbidities, such as cardiac disease (12%); diabetes (14%); hepatic dysfunction (mild, 8%; moderate to severe, 2%); psychiatric disturbance (18%); and pulmonary dysfunction (moderate, 15%; severe, 12%). The CT-CI was calculated, stratified patients in 3 categories, and was associated with increased mortality. Patients with higher CT-CI scores had worse OS (CT-CI 1: hazard ratio [HR], 1.37 [95% confidence interval [CI], 1.16-1.62; P< .001]; CT-CI 2: HR, 1.49 [95% CI, 1.17-1.89; P = .001]; CT-CI ≥ 3: HR, 2.55 [95% CI, 1.90-3.42; P< .001]). Higher CT-CI scores predicted treatment-related mortality and relapse. There was no correlation between the CT-CI score and CAR-T–related toxicities. The novel CT-CI score stratifies the effect of patient comorbidities on survival after CAR-T therapy and can be used for clinical decision-making and treatment selection in high-risk populations. However, comorbidities and fear of increased toxicity should not preclude patients from this effective therapy.

Abstract Background: Responsiveness to mood-stabilizing pharmacotherapy varies in bipolar disorder (BD). We investigated clinical correlates of second-generation antipsychotic (SGA) treatment response and conducted the first genome-wide association study (GWAS), including exploratory polygenic scores (PGS), of SGA pharmacogenomic treatment response in BD. Methods: Treatment response was quantified using the Alda scale, and GWAS was performed using Alda-A score, controlling for sex, genotyping batch, and the genomic principal components. Results: The cohort included 2,159 adults with BD (1,416 BD-I, 691 BD-II, 51 schizoaffective BD), mean age 41.8 years, 62% female, 84% white, and 14% Hispanic. Nearly half (48%) were treated with SGAs. Current SGA users were younger (41.2±14.7 vs. 42.5±15.3 years, p =0.040), more likely to be Hispanic (14% vs. 11%, p =0.047), had a higher body mass index (BMI; 30.4±7.6 vs. 29.5±7.1 kg/m 2 , p =0.005). Lifetime comorbidity patterns for current SGA users include higher rates of manic psychosis (29% vs. 17%, p <0.001) and eating disorders — Anorexia Nervosa (7% vs. 4%, p =0.003), Bulimia Nervosa (7% vs. 4%, p =0.003), and Binge Eating Disorder (14% vs. 11%, p =0.030). We detected a genome-wide significant association between SGA Alda-A scores and GAS7 variants (top variant: rs202127418, β =-2.998, p =4.96E-08). However, SGA response was not significantly associated with PGS for schizophrenia, BD, and major depression (FDR>0.05). Conclusions: SGAs are frequently utilized as mood stabilizers in patients with BD and are associated with manic psychosis and eating disorders. GAS7 variants may predict SGA response, but larger, more diverse cohorts are needed for validation.

Abstract Tisagenlecleucel (tisa-cel) is a CD19-directed chimeric antigen receptor T-cell therapy for relapsed/refractory precursor B-cell acute lymphoblastic leukemia (R/R B-ALL). We report infectious complications for 100 days (D100) following tisa-cel therapy in 471 pediatric and young adults (median age 13.8 years) with R/R B-ALL reported from September 2017 to June 2022. By D100, 137 (29%) patients had an infectious event, with an infection density of 0.542 per 100 person-days at risk. D100 cumulative incidences of bacterial, viral, and fungal infections were 14.1%, 11.6%, and 1.3%, corresponding to infection density scores of 0.296, 0.213, and 0.033 per 100 person-days at risk, respectively. In a multivariable analysis, receipt of ≥3 lines of therapy before tisa-cel (hazard ratio [HR], 1.86; 95% confidence interval [CI], 1.13-3.08; P = .015), any-grade cytokine release syndrome (HR, 1.78; 95% CI, 1.17-2.71; P = .007), and lack of neutrophil recovery (HR, 2.63; 95% CI, 1.47-4.69; P = .001) were associated with an increased risk for any infection. Similar associations were observed for bacterial infections, with the addition of younger age as an adverse risk (&lt;6 vs 6-15 years; HR, 2.38; 95% CI, 1.23-4.61; P = .01). Risk factors for viral infections included increasing age (1-year increase; HR, 1.05; 95% CI, 1.01-1.09; P = .016), prior history of any infection (HR, 2.76, 95% CI, 1.40-5.46; P = .004), and prior hematopoietic cell transplant (HR, 2.10; 95% CI, 1.18-3.71; P = .011). D100 infection-related mortality (IRM) rate was low at 0.2% (95% CI, 0.0-0.8). In this multicenter real-world study, we observed a high incidence of infectious complications but a low IRM following tisa-cel for R/R B-ALL.

Abstract Background and Aims The long-term efficacy and safety of upadacitinib in patients with moderate to severe Crohn’s disease (CD) were evaluated in the U-ENDURE Long-Term Extension (LTE) study. Here we report the results after 2 years of total maintenance treatment. Methods U-ENDURE is an ongoing 240-week LTE study conducted at 243 sites across 43 countries (first patient enrolled in LTE 21 March 2019). Patients who completed the 52-week maintenance study continued their previously assigned treatment, once-daily upadacitinib 15 mg or upadacitinib 30 mg. Efficacy was analyzed at week 48 of the LTE; safety was analyzed in the cumulative study population (combined 52 week maintenance and 48 week LTE) and the LTE study population only (cutoff date: 19 December 2023). Results From LTE week 0 to week 48, as-observed efficacy rates for clinical remission (per stool frequency/abdominal pain score, upadacitinib 15 mg: 78.3% to 82.9%; upadacitinib 30 mg: 84.7% to 76.6%; per CD Activity Index, upadacitinib 15 mg: 81.3% to 83.1%; upadacitinib 30 mg: 86.1% to 86.8%), endoscopic response (upadacitinib 15 mg: 59.6% to 67.1%; upadacitinib 30 mg: 71.2% to 69.6%), inflammatory biomarkers, and quality-of-life outcomes remained stable. The safety profile of the cumulative maintenance population observed through LTE week 48 was consistent with previous trials in the upadacitinib CD program. Treatment-emergent adverse event rates for the cumulative maintenance population were 283.1 and 273.4 events/100 patient-years for upadacitinib 15 mg and upadacitinib 30 mg, respectively. Event rates of serious treatment-­emergent adverse events were 16.0 events/100 patient-years for upadacitinib 15 mg and 14.6 events/100 patient-years for upadacitinib 30 mg. The most common adverse events of special interest (≥ 5.0 events/100 patient-years) were hepatic disorder, lymphopenia, creatine phosphokinase elevation, herpes zoster, and anemia. There was 1 treatment-emergent adverse event of suicide leading to death. Conclusion Sustained clinical, endoscopic, quality-of-life, and biomarker outcomes were observed in patients who were initial responders to upadacitinib and completed 2 years of maintenance therapy, with no new safety signals identified. Clinical trial identifier U-ENDURE; ClinicalTrials.gov number, NCT03345823.

Abstract Checkpoint inhibitors (CPIs) have shown remarkable efficacy in Hodgkin lymphoma (HL), and are now used routinely. While allogeneic hematopoietic cell transplantation (allo-HCT) remains a curative option for HL, there are concerns prior CPIs may exacerbate post–allo-HCT complications, particularly graft-versus-host disease (GVHD), and lead to worse outcomes. Given the relative paucity of data, we performed a Center for International Blood and Marrow Transplant Research/European Society for Blood and Marrow Transplantation study to examine the impact of prior CPIs in allo-HCT. We included 2186 adult patients aged &gt;18 years who received a first allo-HCT using a matched related, unrelated, or haploidentical donor from 2008 to 2023. Twenty-seven percent of patients received prior CPIs. GVHD prophylaxis was posttransplant cyclophosphamide (PTCy) in 55.8% of patients in the CPI cohort, and 35% in the non-CPI cohort. Median follow-up among survivors was longer for the non-CPI (39 months) than CPI cohort (16.5 months). In multivariate analysis, prior CPI exposure did not affect overall survival (OS) or nonrelapse mortality, but resulted in improved progression-free survival (non-CPI vs CPI hazard ratio [HR], 0.81; 0.67-0.98; P = .03) and lower relapse incidence (HR, 0.58; 0.45-0.76; P &lt; 001). While grade 2 to 4 (HR, 1.26; 1.04-1.53; P = .02) and 3 to 4 (HR, 1.41; 1.04-1.92; P = .03) acute GVHD (aGVHD) were increased, differences in chronic GVHD (cGVHD) were not significant. PTCy–based GVHD prophylaxis resulted in improved OS, lower grade 2 to 4 aGVHD, and cGVHD in patients with prior CPI exposure. In summary, allo-HCT should still be considered a curative option for patients with HL in the era of CPIs.

OBJECTIVE The formation and propagation of intraneural ganglion cysts (INGCs) is being elucidated by the unified articular theory. Its principles include a connection for joint fluid to egress from a synovial joint via an articular branch to a parent nerve and cyst following the path of least resistance, dependent on pressures and pressure fluxes. The occurrence of so-called extreme peroneal or tibial INGCs in the popliteal fossa extending to the sciatic nerve has been reported. One rarely described variant with a circumferential cyst within the subparaneurial compartment outside the epineurium of nerve(s) has been previously illustrated, but its mechanism and morphology have not been clarified. In this study, the authors aimed to investigate this type of cyst to challenge the principles of the unified articular theory. METHODS Four novel cases of patients with peroneal INGCs and "extreme subparaneurial cyst(s)" of the sciatic nerve and its distal branches were investigated: 3 arose from the superior tibiofibular joint (STFJ) and 1 from the knee joint. Three other cases of recognized extreme subparaneurial cyst (2 peroneal and 1 tibial from the STFJ) and 1 case of a peroneal subparaneurial cyst in the literature were reinterpreted. Data on clinical presentation, MR images, and surgical results were analyzed. RESULTS In all 8 cases, subparaneurial extension was observed to different degrees along the sciatic, tibial, common peroneal, sural, and deep and superficial peroneal nerves, as was subparaneurial-to-subparaneurial communication at the sciatic nerve bifurcation (i.e., crossover). Sequential MRI performed in 7 patients showed variable dynamic changes, including extreme ascent and descent. Extraneural rupture of the subparaneurial cyst, with spread into the surrounding tissue, was present at the sciatic nerve bifurcation in 6 cases. CONCLUSIONS The authors provide pathoanatomical and pathophysiological evidence supporting that extreme subparaneurial cysts follow the principles of the articular theory. They propose a distribution pattern that explains the occurrence and evolution of extreme subparaneurial cysts along the sciatic nerve and its distal branches in patients with peroneal or tibial INGCs and subepineurial cysts. Crossover in the subparaneurial compartment allows potentially extensive circumferential distribution within connected nerves. Also, dynamic factors can lead to dramatic changes in cyst size and appearance from reabsorption or extraneural rupture. In Part 2 of this study, the authors provide evidence showing that a fenestration in the epineurium allows cysts to pass from the subepineurial-to-subparaneurial, subparaneurial-to-subparaneurial, and subparaneurial-to-subepimyseal compartments.

OBJECTIVE Extreme subparaneurial ganglion cysts are poorly understood. In Part 1, the authors demonstrated that patterns of distribution in the subparaneurial space are consistent with the principles of the articular theory for intraneural ganglion cysts (INGCs). How a cyst transfers from the subepineurial to the subparaneurial compartment remains to be determined. In this part, the authors provide evidence supporting that cyst transfer occurs at the sciatic nerve bifurcation based on MRI and histological analysis, and introduce the geyser theory as an explanation for the redistribution of cysts. METHODS The authors analyze MR images obtained in patients with extreme subparaneurial cysts as well as newly identified cases of nearly extreme subparaneurial cysts (i.e., cysts visible in the subparaneurial compartment but not to the extreme degree as defined in Part 1) for potential crossover sites. They also analyze histological sections from 10 cadavers around the sciatic nerve bifurcation for the presence of openings in the epineurium and paraneurium. RESULTS MRI studies performed in 8 patients in Part 1 and 8 newly identified examples with nearly extreme subparaneurial INGCs showed evidence to support communication between different compartments at the sciatic nerve bifurcation (subepineurial-to-subparaneurial and subparaneurial-to-neighboring soft tissues). Openings in the epineurium of the common peroneal and tibial nerves at the sciatic nerve bifurcation were consistently found in all 10 cadaver specimens, as were openings in the paraneurium. CONCLUSIONS The authors expand on the evidence to support cyst redistribution at the sciatic nerve bifurcation for INGCs in the knee region. They put forth a logical explanation for the development of a spectrum of extreme INGCs (ranging from a faint amount of cyst around the epineurium [wedding ring sign] to extreme subparaneurial INGCs [owl eyes]) based on principles seen in a geyser. The authors believe that radiological occurrence of crossover can be explained by the presence of fenestrations in both the epineurium and paraneurium at the sciatic nerve bifurcation, allowing cyst crossover in two steps: from the subepineurial to the subparaneurial space ("cross") and between a shared subparaneurial space of different nerves ("over"). Finally, the frequent occurrence of extraneural rupture ("cross-out") is due to cyst transfer into the soft tissue compartment via an opening in the outermost circumneurial layer.

OBJECTIVE Mechanical thrombectomy (MT) is well established for large-vessel occlusion (LVO) strokes, but its safety in distal and medium-vessel occlusions (DMVOs) requires further investigation. This study analyzed the relationship between procedural approaches, petechial hemorrhage (PetH), and clinical outcomes in DMVO thrombectomy, with particular attention to technical considerations and the complex interplay between tissue injury and hemorrhagic complications. METHODS A retrospective cohort study was conducted on DMVO stroke patients treated with MT at 37 stroke centers worldwide from 2016 to 2024. Patients were categorized based on follow-up imaging into those with or without PetH. Four logistic regression models analyzed the association of PetH with favorable functional outcomes (modified Rankin Scale score ≤ 2) at 90 days, early neurological improvement (≥ 4-point National Institutes of Health Stroke Scale score decrease at 24 hours), all-cause mortality, and independent determinants of PetH. Adjusted odds ratios (aORs), 95% confidence intervals, and p values were reported. RESULTS Of 1428 patients, 439 (30.7%) developed PetH. Factors independently associated with PetH were multiple thrombectomy passes (aOR 1.58, 95% CI 1.21–2.06; p = 0.001), IV thrombolysis (aOR 1.31, 95% CI 1.01–1.69; p = 0.04), and the combined use of a stent retriever with aspiration as the first-line method compared with aspiration alone (aOR 1.66, 95% CI 1.15–2.38; p = 0.007). Conversely, general anesthesia (aOR 0.55, 95% CI 0.40–0.77; p < 0.001), higher Alberta Stroke Program Early CT Scores (aOR 0.76, 95% CI 0.69–0.83; p < 0.001), and successful recanalization (aOR 0.56, 95% CI 0.39–0.80; p = 0.002) were significantly associated with a lower odds of PetH. PetH was associated with a decreased odds of favorable functional outcomes (aOR 0.51, 95% CI 0.36–0.73; p < 0.001), reduced early neurological improvement (aOR 0.59, 95% CI 0.44–0.79; p < 0.001), and increased all-cause mortality (aOR 1.84, 95% CI 1.23–2.76; p < 0.001). CONCLUSIONS PetH is a frequent sequela following MT in DMVO strokes and is associated with poorer outcomes, likely reflecting underlying ischemic injury rather than direct causation. Procedural factors influence PetH risk, suggesting medical treatment as first-line therapy for DMVOs, with MT reserved for refractory cases using less aggressive approaches.