Citations

Abstract Objective Autoimmune encephalitis is a cause of brain inflammation characterized by auto‐antibodies, which target cell surface neuronal proteins and lead to neuronal dysfunction. The most common form is associated with auto‐antibodies to leucine‐rich glioma‐inactivated 1 (LGI1) protein, the presentation of which includes frequent focal seizures. The exact cause of these auto‐antibodies remains unknown, but established predispositions include overrepresented human leukocyte antigen ( HLA ) alleles. Yet, these HLA alleles are themselves common in the healthy ancestry‐matched population. One potential etiological hypothesis is that an environmental trigger, such as the gut microbiome, interacts with a genetically predisposed individual. Methods To investigate this, we studied 42 patients with LGI1‐antibody encephalitis (LGI1‐Ab‐E) and 27 familial/environmentally matched controls, and performed metagenomic shotgun sequencing, to describe the compositional and functional differences in the gut microbiome. Results We observed that LGI1‐Ab‐E gut microbiomes exhibited a significant reduction in the ratio of Firmicutes (or Bacillota) and Bacteroidetes phyla, which is associated with the dosage of HLA susceptibility allele count in patients with LGI1‐Ab‐E. Furthermore, we identified differences in functional gene profiles in the gut microbiome that led to a reduction of neuroinflammatory protective short‐chain fatty acids (SCFAs) in LGI1‐Ab‐E patients. Significance Taken together, our results suggest that a compositional shift in the gut microbiome of LGI1‐Ab‐E associates with a neuroinflammatory state, possibly through the reduction of SCFA production. Our study highlights the potential of the gut microbiome to explain some of the complex condition and unravel etiological questions. Validation studies with greater sample sizes are recommended.

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 Objectives To investigate socio-economic and clinical disparities in the utilisation of robotic surgery for head and neck cancer. Methods Using the National Cancer Database (2010–2020), 212 449 surgically treated patients were analysed. Multivariate logistic regression identified predictors of robotic versus non-robotic surgery ( p < 0.05). Results Robotic surgery utilisation increased over time during the study period. The following characteristics positively correlated with the use of robotic surgery: male, aged 41–80 years, White race, insured (with private insurance, Medicaid and Medicare) and treatment at an Academic/Research centre. Metropolitan residency, higher income/education levels, lower comorbidity (Charlson–Deyo score of 0) and Stage I disease were also associated with increased robotic surgery utilisation. Conclusion Significant socio-economic disparities exist in robotic surgery access, potentially exacerbating outcome inequities. Targeted interventions are needed to improve equity in treatment access and standardise care protocols. Further research should validate trends and address systemic barriers.

PURPOSE Doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy is used commonly for pediatric Hodgkin lymphoma (pHL) in low- and middle-income countries. The role of radiotherapy (RT) after ABVD in pHL is uncertain. MATERIALS AND METHODS We conducted a systematic review to explore the use of ABVD with or without RT in pHL. Key clinical questions included the number of cycles of ABVD, indications for and dose of RT, and outcomes by risk group. A search was performed in PubMed. Articles reporting survival outcomes by risk group were included. RESULTS Of 97 articles identified in the literature search, nine met inclusion criteria. Chemotherapy consisted of four to six cycles in limited disease and mostly six cycles in advanced disease. Three studies used RT for all patients within a specified risk group. Six studies dictated an adapted RT approach, with 3%-43% of the patients receiving RT for bulky adenopathy, slow early response (SER), and/or incomplete response. Radiation doses ranged between 20 and 36 Gy. The progression-free survival and overall survival at 4-10 years ranged from 84% to 100% and 93%-100% in limited disease and 50%-84.4% and 75%-95.3% in advanced disease, respectively. Studies did not directly assess the impact of certain chemotherapy or RT strategies. Recommendations were made after reviewing outcomes with particular approaches. CONCLUSION Four cycles of ABVD are recommended for limited disease, and six cycles of ABVD are recommended for advanced disease. In both limited and advanced diseases, RT is recommended with a dose of 20-21 Gy only to sites of bulky and/or SER, with a boost of up to 36 Gy to sites of incomplete response. This approach could spare radiation for at least half of the patients with limited disease and one third of advanced disease.

Abstract Olfactory neuroblastoma (ONB) is a rare head and neck cancer arising from the upper nasal cavity, with limited systemic therapeutic options due to a poor understanding of its genomic landscape. This study aims to utilize a patient-level genomic repository to identify potential therapeutic targets and improve disease modeling in ONB. Retrospective genomic analysis. Data analysis was performed using the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database. Patients with confirmed ONB who have undergone targeted sequencing within GENIE. Data were analyzed for recurrent somatic mutations, along with their clinical and demographic correlations, with significance set at p < 0.05. A high prevalence of mutations in TP53 (tumor protein p53) and FRK (fibroblast growth factor receptor kinase) genes was identified. A moderate prevalence of mutations in NOTCH3 (notch receptor 3), SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4), RET (rearranged during transfection), and CTCF (CCCTC-binding factor) was also identified. The mutation patterns differed between pediatric and adult ONB cases. Specific mutations were enriched in metastatic tumors compared with primary tumors. This study provides a genomic profile for ONB, identifying key mutations and potential therapeutic targets. The identification of frequently mutated genes like TP53 and FRK suggests potential targets for novel therapies. The observation that certain genes are mutated in pediatric ONB but not adult ONB (and vice versa), and the presence of specific mutations in metastatic tumors that are absent in primary tumors, offers valuable insights for future precision medicine and the design of targeted therapeutic interventions for these distinct clinical presentations.

Importance Bilateral vocal cord paralysis is a challenging problem to manage in adults, and a known complication of thyroid surgery which is more common in resource-limited settings. Posterior graft laryngotracheal reconstruction is a management option that has not been studied in this population or setting. Objective To report the surgical outcomes of posterior graft laryngotracheal reconstruction for bilateral vocal cord paralysis in a resource-limited setting, and to evaluate the efficacy of a hybrid system for teaching this technique in Kenya. Design Retrospective cohort study. Setting Tertiary public referral hospital, Eldoret, Kenya Participants Adults >18 years with tracheostomy dependence secondary to bilateral vocal cord paralysis after thyroid surgery or other iatrogenesis. The hybrid training program included Kenyan surgeons and surgical trainees. Intervention or Exposures Posterior graft laryngotracheal reconstruction and hybrid training system included didactic lectures, simulation-based training, case discussion and planning, and live cases. Main Outcomes Measures One-year airway outcomes measured by achievement of tracheostomy decannulation, and self-reported surgeon knowledge and skill acquisition. Results Ten patients met criteria and were included in the analysis, with mean age 42 years (range 30-62 years) and had been tracheostomy dependent for an average of 6 years (range 1-12 years). Seven (70%) had open reconstruction, and 3 (30%) had endoscopic reconstruction. All were decannulated and remained tracheostomy-free at 1 year. Three surgeons and 7 trainees participated in the hybrid teaching methods. All reported increased comfort in laryngotracheal reconstruction, with all 3 surgeons reporting comfort performing the surgeries independently. Conclusion Posterior graft laryngotracheal reconstruction shows promise as a potential method of treating bilateral vocal cord paralysis and achieving decannulation in a resource-limited setting. Relevance The methods reported in this study lend themselves to replication and expansion to other similar settings. The authors plan to replicate this work in other centers in East Africa.

PURPOSE Neoadjuvant immunotherapy (IO) has become the standard of care for early-stage triple-negative breast cancer (TNBC), but not yet for other subtypes. We previously developed a clinical-grade mRNA-based immune classifier (ImPrint) predicting response to IO that is now being used in I-SPY2.2 as part of the response predictive subtypes. We report the performance of ImPrint in hormone receptor–positive and human epidermal growth factor receptor 2–negative (HR+HER2–) patients from five IO arms. METHODS A total of 204 HR+HER2– (MammaPrint high-risk) patients from five IO arms (anti–PD-1, anti–PD-L1/poly [ADP-ribose] polymerase inhibitor combination, anti–PD-1/toll-like receptor 9 dual-IO combination, and anti–PD-1 ± lymphocyte activation gene 3 dual-IO combination) and 191 patients from the chemotherapy-only control arm were included in this analysis. Patients were classified as ImPrint+ (likely sensitive) versus ImPrint– (likely resistant), using pretreatment mRNA. Performance of ImPrint for predicting pathologic complete response (pCR) to IO-containing arms was characterized and compared with tumor grade (III), MammaPrint (ultra) High2 risk (MP2), and estrogen receptor (ER)-low (ER ≤ 10%). RESULTS Overall, the pCR rate across the five IO arms was 33%. 26% of HR+HER2– patients were ImPrint+, and pCR rates with IO were 75% in ImPrint+ versus 17% in ImPrint–, with the highest pCR rate >90% in a dual-IO arm. In the control arm, pCR rates were 33% in ImPrint+ and 8% in ImPrint–. Tumor grade (III), MP2, and ER-low showed pCR rates in IO of 45%, 56%, and 63%, respectively, with lower pCR odds ratios (OR < 7.5) compared with ImPrint (OR = 14.5). CONCLUSION Using an accurate selection strategy, HR+HER2– patients could achieve pCR rates similar to what is seen with best neoadjuvant therapies in TNBC and HER2+ (ie, pCR rate >65%-70%). ImPrint, an Food and Drug Administration IDE-enabled assay, may represent a way to identify HR+HER2– patients for IO that best balances likely benefit versus risk of serious immune-related adverse events.

Background: Amid mounting pressure to reduce health care spending, strategies for identifying and eliminating unwarranted variation in costs have garnered significant attention. Previous studies have characterized intersurgeon variation in costs for common orthopaedic procedures, but such variation remains unexplored in the context of hip arthroscopic surgery. Purpose: To (1) characterize variation in the cost of hip arthroscopic surgery between surgeons using time-driven activity-based costing (TDABC) and (2) identify patient characteristics, intraoperative findings, and operative procedures underlying such intersurgeon variation in costs. Study Design: Cohort study; Level of evidence, 3. Methods: Employing TDABC, the authors determined the intraoperative cost of 890 outpatient hip arthroscopic surgery cases performed by 5 surgeons at 4 surgery centers from 2015 to 2022. All costs were calculated in United States dollars. Costs were normalized to protect the confidentiality of internal hospital cost data. Surgeon-specific mean costs were calculated with and without adjustment for patient characteristics, surgical personnel, operative factors, and surgery center. Finally, to elucidate the sources of surgeon-driven cost variation, the authors estimated the proportion of variation attributable to different cost subcategories, including labor, implant/allograft, and other supply costs. Results: The intraoperative cost per patient ranged from 38.2 to 212.8 normalized cost units (mean, 100.0 ± 26.5), with a 1.6-fold variation in the mean cost between the highest and lowest cost surgeons. Operating surgeon alone explained 53.4% of the observed variation in costs. Controlling for case-specific features significantly improved the explanatory power to 91.8% ( P < .001), but the adjusted variation in costs between surgeons remained essentially unchanged (decreased by <3%). Each of the 5 surgeons generated costs that deviated significantly from those predicted based on case-specific factors, with mean surgeon deviations ranging from −5.0% to 21.8% ( P < .001 for all). Drivers of cost variation differed substantially between surgeons but generally stemmed from labor or other supply costs rather than implant/allograft costs. Conclusion: The cost of outpatient hip arthroscopic surgery varied widely between surgeons; the cause of this deviation was multifactorial and surgeon specific. While within-surgeon cost variation was effectively explained by patient and operative characteristics, most between-surgeon variability remained unexplained by observable factors. These insights may support individual surgeons in cost reduction efforts and, more importantly, may enable the alignment of reimbursement rates with costs.

PURPOSE Tumor treating fields (TTFields) use alternating electric fields to disrupt cancer cell proliferation. Feasibility of TTFields therapy with gemcitabine/nab-paclitaxel was previously demonstrated in patients with advanced pancreatic adenocarcinoma. PANOVA-3 was designed to confirm safety and efficacy of TTFields in patients with unresectable locally advanced pancreatic adenocarcinoma (LA-PAC). METHODS In this global phase III trial, 571 patients with newly diagnosed LA-PAC were randomly assigned to receive gemcitabine 1,000 mg/m 2 and nab-paclitaxel 125 mg/m 2 by intravenous infusion once a day on days 1, 8, and 15 of a 28-day cycle with or without TTFields. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), local PFS, pain-free survival, and overall response rate (ORR). Distant PFS was analyzed post hoc. RESULTS OS was significantly prolonged using TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel (median, 16.2 months [95% CI, 15.0 to 18.0] v 14.2 months [95% CI, 12.8 to 15.4]; hazard ratio [HR], 0.82 [95% CI, 0.68 to 0.99]; P = .039). PFS, local PFS, and ORR were not improved. Pain-free survival was significantly prolonged with TTFields with gemcitabine/nab-paclitaxel (median, 15.2 months [95% CI, 10.3 to 22.8] v 9.1 months [95% CI, 7.4 to 12.7]; HR, 0.74 [95% CI, 0.56 to 0.97]; P = .027), as was distant PFS (median, 13.9 months [95% CI, 12.2 to 16.8] v 11.5 months [95% CI, 10.4 to 12.9]; HR, 0.74 [95% CI, 0.57 to 0.96]; P = .022). Device-related skin adverse events (AEs) were experienced by 76.3% of patients. Most device-related skin AEs were mild to moderate, with 7.7% of patients reporting a grade 3 AE. CONCLUSION This study demonstrated significant OS, pain-free survival, and distant PFS benefits for TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel in patients with unresectable LA-PAC, with no additive systemic toxicity.

Importance Nontraumatic subarachnoid hemorrhage (SAH) represents the third most common stroke type with unique etiologies, risk factors, diagnostics, and treatments. Nevertheless, epidemiological studies often cluster SAH with other stroke types leaving its distinct burden estimates obscure. Objective To estimate the worldwide burden of SAH. Design, Setting, and Participants Based on the repeated cross-sectional Global Burden of Disease (GBD) 2021 study, the global burden of SAH in 1990 to 2021 was estimated. Moreover, the SAH burden was compared with other diseases, and its associations with 14 individual risk factors were investigated with available data in the GBD 2021 study. The GBD study included the burden estimates of nontraumatic SAH among all ages in 204 countries and territories between 1990 and 2021. Exposures SAH and 14 modifiable risk factors. Main Outcomes and Measures Absolute numbers and age-standardized rates with 95% uncertainty intervals (UIs) of SAH incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) as well as risk factor–specific population attributable fractions (PAFs). Results In 2021, the global age-standardized SAH incidence was 8.3 (95% UI, 7.3-9.5), prevalence was 92.2 (95% UI, 84.1-100.6), mortality was 4.2 (95% UI, 3.7-4.8), and DALY rate was 125.2 (95% UI, 110.5-142.6) per 100 000 people. The highest burden estimates were found in Latin America, the Caribbean, Oceania, and high-income Asia Pacific. Although the absolute number of SAH cases increased, especially in regions with a low sociodemographic index, all age-standardized burden rates decreased between 1990 and 2021: the incidence by 28.8% (95% UI, 25.7%-31.6%), prevalence by 16.1% (95% UI, 14.8%-17.7%), mortality by 56.1% (95% UI, 40.7%-64.3%), and DALY rate by 54.6% (95% UI, 42.8%-61.9%). Of 300 diseases, SAH ranked as the 36th most common cause of death and 59th most common cause of DALY in the world. Of all worldwide SAH-related DALYs, 71.6% (95% UI, 63.8%-78.6%) were associated with the 14 modeled risk factors of which high systolic blood pressure (population attributable fraction [PAF] = 51.6%; 95% UI, 38.0%-62.6%) and smoking (PAF = 14.4%; 95% UI, 12.4%-16.5%) had the highest attribution. Conclusions and Relevance Although the global age-standardized burden rates of SAH more than halved over the last 3 decades, SAH remained one of the most common cardiovascular and neurological causes of death and disabilities in the world, with increasing absolute case numbers. These findings suggest evidence for the potential health benefits of proactive public health planning and resource allocation toward the prevention of SAH.