Citations

Study Design. Post hoc analysis of prospectively-collected data. Objective. To identify factors predicting the most (and least) satisfaction following surgery for cervical spondylotic myelopathy (CSM). Summary of Background Data. Patient satisfaction affects long-term outcomes after surgery but the preoperative factors that influence postoperative satisfaction have not been well studied in patients with CSM. Methods. We conducted a post hoc analysis of prospectively-collected data from the Quality Outcomes Database (QOD) CSM registry cohort. Baseline and surgical characteristics were compared for patients with CSM reporting the most [North American Spine Society Satisfaction Score (NASS) 1] and least (NASS 4) satisfaction 24 months postoperatively. A multivariable logistic regression model was constructed using backward stepwise elimination to determine significant predictors of most versus least satisfaction. Twenty-four-month patient-reported outcomes (PROs) were compared. Results. Overall, 1141 patients were prospectively enrolled with 948 (83.1%) reaching 24-month follow-up. Of these, 699 met prespecified inclusion criteria: 610 (87.3%) were most satisfied and 89 (12.7%) were least satisfied. Though there were mean improvements in all 24-month PROs for the most satisfied cohort ( P <0.001), there were no significant improvements in 24-month PROs for the least satisfied cohort ( P >0.05). Using multivariable logistic regression modeling, a preoperative symptom of upper extremity weakness (OR=2.5, P =0.003), subjective myelopathy (OR=2.0, P =0.04), absence of numbness complaints (OR=2.2, P =0.003), symptom duration under 12 months (OR=1.6, P =0.047), Caucasian race (OR=2.3, P =0.001), participation in activities outside of the home (OR=2.0, P =0.04), anterior approach (OR=2.3, P <0.001), and higher baseline quality of life (OR=4.0, P =0.01) were predictive of the most satisfaction. Conclusion. Compared with the least satisfied, those most satisfied following surgery for CSM more often had a preoperative symptom of arm weakness, subjective myelopathy, the absence of numbness complaints, symptom duration under 12 months, higher baseline quality of life, and participation in activities outside of the home. Compared with a posterior approach, an anterior approach was associated with the most satisfaction. Taken together, early surgical treatment--before myelopathic symptoms significantly impact one's quality of life--may be considered to optimize patient satisfaction following CSM surgery.

Patients with plasma cell leukemia (PCL) are generally excluded from pivotal T-cell redirecting bispecific antibody (BsAb) trials. We evaluated real-world outcomes in a multicenter retrospective study of 122 patients with primary or secondary PCL across 15 academic centers, categorized as 'active' (≥5% circulating plasma cells within 30 days of BsAb initiation) or 'historical'. In a heavily pretreated population, patients received teclistamab (37%), elranatamab (11%), talquetamab as a line of therapy (Tal LOT, 42%), or talquetamab as bridging therapy to CAR-T (Tal Bridge, 11%). Cytokine release syndrome (CRS) was grade 1-2 in 56% and grade 3-4 in 4%, whereas neurotoxicity was grade 1-2 in 16% and grade 3-4 in 5%. Among 110 evaluable patients, the overall response rate (ORR) was 55%, including 61% with Tal LOT, 58% with Tal Bridge, 46% with elranatamab, and 33% with teclistamab. With a median follow-up of 8.3 months, talquetamab demonstrated superior survival. Tal LOT showed a median progression-free survival (mPFS) of 5.5 months and a median overall survival (mOS) of 11.5 months, and both were unreached in the Tal Bridge cohort. In contrast, teclistamab and elranatamab showed a mPFS of 1.2 and 1.6 months and mOS of 8.1 and 3.6 months, respectively (P=0.007, P=0.023). In active PCL, Tal LOT achieved mPFS/mOS of 6.9/12.2 months versus 0.7/1.4 months with teclistamab and 1.0/3.1 months with elranatamab, respectively (P&lt;0.001, P=0.002). Multivariable analysis associated active PCL with worse survival and Tal LOT with improved outcomes. BsAbs were safe in PCL, with talquetamab showing superior outcomes compared with BCMA-directed BsAbs.

Abstract Background Oligodendrogliomas were previously defined by histology, but since 2016, the WHO has integrated molecular signatures to create the entity of IDH-mutant 1p/19q-codeleted oligodendroglioma. These tumors harbor recurrent genetic alterations—including IDH mutations, CIC and FUBP1 loss-of-function mutations, and PI3K-activating mutations—that collectively define a genetic profile distinct from IDH-mutant astrocytoma and IDH wild-type glioblastoma. The paucity of faithful model systems has impeded progress in advancing mechanistic insights and therapeutic development for oligodendroglioma. Results To test whether recurrent mutations found in oligodendroglioma patients would drive tumor formation in mice, we utilized in utero electroporation to introduce combinations of gain- and loss-of-function mutations into the developing cortex. Initial tests that included expression of IDH-and PIK3CA-mutants with Cic and Fubp1 loss (termed Oligo) were non-tumorigenic but biased cells towards glial lineages. Introducing Cdkn2a-loss, which is normally suppressed by IDH-associated epigenetic changes in human tumors, to the Oligo combination (termed Oligo-Cdkn2a) resulted in fully penetrant tumor formation. Histopathological review showed the Oligo Cdkn2a-loss mouse model resembled grade II/III oligodendroglioma with rounded nuclei and open chromatin. If Trp53-loss is used (termed Oligo-Trp53) in place of Cdkn2a-loss, tumor histology shifts to a more astrocytic phenotype with angulated nuclei with denser chromatin, demonstrating a direct impact of Trp53-loss on histological features. Bulk RNA-sequencing verifies metabolic alterations driven by the presence of IDH-mutations in Oligo-Cdkn2a mouse models compared to an IDH wild-type GBM model. Single-cell transcriptional profiling shows that Oligo-Cdkn2a tumors contain an increased population of tumor cells that resemble more differentiated oligodendrocytes. Examination of the tumor immune microenvironment within Oligo-Cdkn2a and IDHWT GBM mouse models is being performed to determine changes in immune cell infiltration and transcriptional programs. Conclusion We have created, to our knowledge, the first murine model of IDH-mutant 1p/19q-codeleted oligodendroglioma that incorporates Cic loss. This immune-competent mouse model of IDH-mutant 1p/19q-codeleted oligodendroglioma offers a powerful new tool for interrogating tumor biology and evaluating preclinical therapeutic strategies.

Abstract Background Cholangiocarcinoma (CCA) is an aggressive primary liver cancer with remarkable molecular heterogeneity. Mutations in SWI/SNF chromatin remodeling components occur in &gt; 20% of CCA cases, with ARID1A and PBRM1 being significantly co-mutated. However, how the dual loss of these subunits reshapes chromatin architecture and drives oncogenic programs remains unclear that we aimed to address by profiling SWI/SNF redistribution, chromatin accessibility, 3D chromatin structure, and transcriptome in a dual Arid1a/Pbrm1 knockout mouse model. Methods CCA was induced in Cas9 knock-in mice via biliary instillation of myr-AKT along with sgRNAs targeting Arid1a and Pbrm1, generating APAC cell line. AC cell line was derived from mice receiving myr-AKT alone. Isogenic dual knockout (AC-sgAP) and control (AC-NT) lines were then generated from AC cells. Multi-omics profiling included ChIP-seq for SMARCA4/BRG1 and DPF2, ATAC-seq, RNA-seq, and Hi-C. Results ChIP-seq revealed that AC-sgAP cells showed decreased BRG1 binding (9,217 vs. 20,769 peaks) but increased DPF2 binding (7,527 vs. 2,068 peaks) and co-occupancy (5,037 vs. 1,888 peaks) compared to AC-NT. In contrast, APAC cells exhibited depletion of both BRG1 (12,994 peaks) and particularly DPF2 (146 peaks) with minimal overlap (68 shared peaks). Genome-wide accessibility profiling demonstrated that APAC cells had 78,582 differentially accessible regions compared to AC-NT, the majority (&gt;70%) representing loss of accessibility, whereas AC-sgAP cells showed only 6,587 differentially accessible regions. Transcriptional profiling identified both unique and common significantly differentially expressed genes in APAC and AC-sgAP relative to AC-NT controls. Interestingly, topologically associating domains (TADs) calling revealed that AC-sgAP cells displayed approximately three-fold more differential TADs compared to AC-NT than APAC cells relative to controls. Conclusions Concurrent Arid1a/Pbrm1 loss drives extensive chromatin and transcriptional reprogramming through SWI/SNF redistribution. APAC cells achieving greater transcriptional dysregulation with fewer TAD disruptions might suggest that intra-TAD regulatory changes are critical events in SWI/SNF-mutant cholangiocarcinoma.

Multiple sclerosis is an immune-driven neurological disease that affects myelinated axons in the central nervous system. However, the trigger of the (dysregulated) immune reactions is not known. According to Wilkin’s primary lesion theory, myelin-reactive T cells present in the immune repertoire hyper-react to myelin antigens that are released from idiopathic lesions within the central nervous system. However, neither the cause of the primary lesion nor the cause of the immune hyper-reactivity is known. We investigated whether these unknown activation signals may be relayed by common herpesviruses. In this concept paper, we propose the novel paradigm that the trigger of autoimmunity in MS comprises a conspiracy of three common herpesviruses: human herpesvirus-6A as a potential trigger of primary lesions due to its proven capacity to cause oligodendrogliopathy, cytomegalovirus as a trigger for the formation of effector memory cytotoxic T cells with proven capacity to induce multiple sclerosis pathology in a non-human primate MS model and Epstein-Barr Virus due to its capacity to render B cells capable to effectively present a critical myelin antigen to these effector memory cytotoxic T cells.

ABSTRACT Purpose Substantial endothelial cell loss (∼80%) occurs after keratoplasty. Corneal rigid and scleral lenses are frequently prescribed to manage irregular astigmatism and high refractive error, but lens wear may contribute to hypoxic stress. The relationship between various lens wear and corneal stress after penetrating keratoplasty remains unclear. This study characterizes cell density distribution in post‐keratoplasty corneas and evaluates its influence on swelling during lens wear. Methods Participants ≥5 years post‐surgery, with or without habitual lens wear, were enrolled. Specular microscopy measured endothelial cell density in central, superior, inferior, superotemporal, and superonasal corneal quadrants (@3 mm). Baseline corneal thickness maps (>2 h after waking without lens wear) were acquired using Scheimpflug imaging (Pentacam). Wearers applied habitual lenses and all participants returned 6–8 h later for imaging. Nonparametric tests assessed cell density variation by quadrant and lens designs. Linear mixed models evaluated associations between endothelial parameters and corneal swelling while accounting for within‐subject correlation, repeated measures, lens type, location, and interactions. Results Twenty‐five participants (31 eyes) from three centers were included; 90% had keratoconus preoperatively. Four wore large‐diameter scleral lenses (13%), nine wore small‐diameter scleral lenses (29%), 12 wore corneal rigid lenses (39%), and six did not wear lenses (19%). Cell density across quadrants averaged 780 ± 240 cells/mm 2 . Central thickness decreased slightly in non‐lens‐wearing eyes (−0.3%) but increased in lens‐wearing eyes (1.9% ± 3.1%). Central cell density showed a weak negative correlation with swelling ( r = −0.39, p = 0.03). Compared with non‐lens wearers, corneal rigid ( p = 0.02) and large diameter scleral lenses ( p = 0.05) generated greater swelling; smaller diameter scleral lenses did not. Conclusions Although all eyes fitted with various lens designs were clear, lower central cell density correlated with increased swelling during lens wear, except when smaller diameter scleral lenses were worn. Clinically, however, cell density does not seem to be a robust predictor of corneal swelling induced by lens wear post‐keratoplasty.

Abstract Purpose This study evaluates associations with suicidal ideation (SI) of impact of work on personal relationships (IWPR), self-valuation (SV), and imposter phenomenon and compares the SI point prevalence in physicians vs other workers. Method This study used American Medical Association Physician Professional Data to sample US physicians across different specialties between November 2020-March 2021. Of 7360 survey respondents, 6497 (88.3%) completed the SI question. A probability-based sample included 2508 nonphysician individuals from the US population employed at the time of survey administration, with 2501 workers (99.7%) completing the SI item. Logistic regression was used to evaluate the associations of occupational distress factors, including IWPR, SV, imposter phenomenon, and other factors, with SI before and after adjusting for depression and compare the risk of SI among physicians with other US workers. Results The study included 6497 physicians and 2501 workers in other fields. Adjusting for sex, age, relationship status, parenting status, and depression, each 1-point higher IWPR score (range, 0-10) was associated with 10% increased SI odds (odds ratio [OR], 1.10; 95% confidence interval [CI], 1.05-1.15). Adjusting for the same variables, each 1-point higher SV score (range, 0-10) was associated with 10% lower SI odds (OR, 0.90; 95% CI, 0.85-0.95). The association between imposter phenomenon scores (range, 4-20) and SI was not statistically significant (OR, 1.03; 95% CI, 0.99-1.08). The unadjusted 1-year SI point prevalence was 6.6% (95% CI, 6.0%-7.4%) in physicians vs 5.6% (95% CI, 4.7%-6.6%) among workers in other fields (P = .09). In a multivariable model, workers in other fields with a bachelor’s or master’s degree had lower SI odds compared with physicians (OR, 0.64; 95% CI, 0.46-0.87). Conclusions IWPR and low SV are associated with SI among physicians, independent of depression. Development and evaluation of interventions designed to mitigate these factors in physicians may be warranted.