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INTRODUCTION: Prophylactic pancreatic stent placement (PSP) is effective for preventing pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP) in high-risk cases, but the optimal technical approach to this intervention remains uncertain. METHODS: In this secondary analysis of 787 clinical trial patients who underwent successful stent placement, we studied the impact of (i) whether pancreatic wire access was achieved for the sole purpose of PSP or naturally during the conduct of the case, (ii) the amount of effort expended on PSP, (iii) stent length, (iv) stent diameter, and (v) guidewire caliber. We used logistic regression models to examine the adjusted association between each technical factor and post-ERCP pancreatitis (PEP). RESULTS: Ninety-one of the 787 patients experienced PEP. There was no clear association between PEP and whether pancreatic wire access was achieved for the sole purpose of PSP (vs occurring naturally; odds ratio [OR] 0.82, 95% confidence interval [CI] 0.37–1.84), whether substantial effort expended on stent placement (vs nonsubstantial effort; OR 1.58, 95% CI 0.73–3.45), stent length (>5 vs ≤5 cm; OR 1.01, 95% CI 0.63–1.61), stent diameter (≥5 vs <5 Fr; OR 1.13, 95% CI 0.65–1.96), or guidewire caliber (0.035 vs 0.025 in; 0.83, 95% CI 0.49–1.41). DISCUSSION: The 5 modifiable technical factors studied in this secondary analysis of large-scale randomized trial data did not appear to have a strong impact on the benefit of prophylactic PSP in preventing PEP after high-risk ERCP. Within the limitations of post hoc subgroup analysis, these findings may have important implications in procedural decision making and suggest that the benefit of PSP is robust to variations in technical approach.

OBJECTIVE Posterior lumbar interbody fusion (PLIF) and/or transforaminal lumbar interbody fusion (TLIF), referred to as "PLIF/TLIF," is a commonly performed operation for lumbar spondylolisthesis. Its long-term cost-effectiveness has not been well described. The aim of this study was to determine the 5-year cost-effectiveness of PLIF/TLIF for grade 1 degenerative lumbar spondylolisthesis using prospective data collected from the multicenter Quality Outcomes Database (QOD). METHODS Patients enrolled in the prospective, multicenter QOD grade 1 lumbar spondylolisthesis module were included if they underwent single-stage PLIF/TLIF. EQ-5D scores at baseline, 3 months, 12 months, 24 months, 36 months, and 60 months were used to calculate gains in quality-adjusted life years (QALYs) associated with surgery relative to preoperative baseline. Healthcare-related costs associated with the index surgery and related reoperations were calculated using Medicare reimbursement–based cost estimates and validated using price transparency diagnosis-related group (DRG) charges and Medicare charge-to-cost ratios (CCRs). Cost per QALY gained over 60 months postoperatively was assessed. RESULTS Across 12 surgical centers, 385 patients were identified. The mean patient age was 60.2 (95% CI 59.1–61.3) years, and 38% of patients were male. The reoperation rate was 5.7%. DRG 460 cost estimates were stable between our Medicare reimbursement–based models and the CCR-based model, validating the focus on Medicare reimbursement. Across the entire cohort, the mean QALY gain at 60 months postoperatively was 1.07 (95% CI 0.97–1.18), and the mean cost of PLIF/TLIF was $31,634. PLIF/TLIF was associated with a mean 60-month cost per QALY gained of $29,511. Among patients who did not undergo reoperation (n = 363), the mean 60-month QALY gain was 1.10 (95% CI 0.99–1.20), and cost per QALY gained was $27,591. Among those who underwent reoperation (n = 22), the mean 60-month QALY gain was 0.68 (95% CI 0.21–1.15), and the cost per QALY gained was $80,580. CONCLUSIONS PLIF/TLIF for degenerative grade 1 lumbar spondylolisthesis was associated with a mean 60-month cost per QALY gained of $29,511 with Medicare fees. This is far below the well-established societal willingness-to-pay threshold of $100,000, suggesting long-term cost-effectiveness. PLIF/TLIF remains cost-effective for patients who undergo reoperation.

The determination of an optimal treatment plan for an individual patient with rectal cancer is a complex process. In addition to decisions relating to the intent of rectal cancer surgery (ie, curative or palliative), consideration must also be given to the likely functional results of treatment, including the probability of maintaining or restoring normal bowel function/anal continence and preserving genitourinary functions. Particularly for patients with distal rectal cancer, finding a balance between curative-intent therapy while having minimal impact on quality of life can be challenging. Furthermore, the risk of pelvic recurrence is higher in patients with rectal cancer compared with those with colon cancer, and locally recurrent rectal cancer is associated with a poor prognosis. Careful patient selection and the use of sequenced multimodality therapy following a multidisciplinary approach is recommended. These NCCN Guidelines Insights detail recent updates to the NCCN Guidelines for Rectal Cancer, including the addition of endoscopic submucosal dissection as an option for early-stage rectal cancer, updates to the total neoadjuvant therapy approach based on the results of recent clinical trials, and the addition of a “watch-and-wait” nonoperative management approach for clinical complete responders to neoadjuvant therapy.

Background The optimal duration for dual antiplatelet therapy (DAPT) after stent-assisted coiling (SAC) of intracranial aneurysms is unclear. Longer-term therapy may reduce thrombotic complications but increase the risk of bleeding complications. Methods A retrospective review of prospectively maintained data at 12 institutions was conducted on patients with unruptured intracranial aneurysms who underwent SAC between January 1, 2016 and December 31, 2020, and were followed ≥6 months postprocedure. The type and duration of DAPT, stent(s) used, outcome, length of follow-up, complication rates, and incidence of significant in-stent stenosis (ISS) were collected. Results Of 556 patients reviewed, 450 met all inclusion criteria. Nine patients treated with DAPT <29 days after SAC and 11 treated for 43–89 days were excluded from the final analysis as none completed their prescribed duration of treatment. Eighty patients received short-term DAPT. There were no significant differences in the rate of thrombotic complications during predefined periods of risk in the short, medium, or long-term treatment groups (1/80, 1.3%; 2/188, 1.1%; and 0/162, 0%, respectively). Similarly, no differences were found in the rate of hemorrhagic complications during period of risk in any group (0/80, 0%; 3/188, 1.6%; and 1/162, 0.6%, respectively). Longer duration DAPT did not reduce ISS risk in any group. Conclusions Continuing DAPT >42 days after SAC did not reduce the risk of thrombotic complications or in-stent stenosis, although the risk of additional hemorrhagic complications remained low. It may be reasonable to discontinue DAPT after 42 days following non-flow diverting SAC of unruptured intracranial aneurysms.

Abstract Background This investigator-initiated phase II trial aimed to evaluate the efficacy of cabozantinib in combination with nivolumab and ipilimumab (CaboNivoIpi) in previously treated patients with radioactive iodine-refractory differentiated thyroid cancer. Methods Eligible patients with radioactive iodine-refractory differentiated thyroid cancer who progressed on 1 prior line of vascular endothelial growth factor receptor-targeted therapy received a 2-week run-in of cabozantinib monotherapy followed by CaboNivoIpi for 4 cycles (cycle length = 6 weeks), followed by cabozantinib plus nivolumab (cycle length = 4 weeks) until disease progression. The primary endpoint was objective response rate (ORR) within the first 6 months of treatment. A Simon optimal 2-stage design allowed for an interim analysis after accrual of 10 evaluable patients. At least 5 responses were needed to proceed to stage 2. Results Among 11 patients enrolled, the median age was 69 years. Prior vascular endothelial growth factor receptor-targeted therapies included lenvatinib, pazopanib, and sorafenib plus everolimus. Median follow-up was 13.4 months. Among 10 evaluable patients, ORR within the first 6 months of treatment was 10% (1 partial response). Median progression-free survival was 9 months (95% CI, 3.0–not reached) and median overall survival was 19.2 months (95% CI, 4.6–not reached). Grade 3/4 treatment-related adverse events (AEs) were noted in 55% (6/11) and grade 5 AEs in 18% (2/11) of patients. The most common treatment-related AE was hypertension. The study did not reach its prespecified efficacy threshold. Conclusion CaboNivoIpi had low ORRs and a high rate of grade ≥3 treatment-related AEs. Clinical Trial Registration NCT03914300

Bi-allelic disruptive variants (nonsense, frameshift, and splicing variants) in KDM5B have been identified as causative for autosomal recessive intellectual developmental disorder type 65. In contrast, dominant variants, usually disruptive as well, have been more difficult to implicate in a specific phenotype, since some of them have been found in unaffected controls or relatives. Here, we describe individuals with likely pathogenic variants in KDM5B, including eight individuals with dominant missense variants. This study is a retrospective case series of 21 individuals with variants in KDM5B. We performed deep phenotyping and collected the clinical information and molecular data of these individuals’ family members. We compared the phenotypes according to variant type and to those previously described in the literature. The most common features were developmental delay, impaired intellectual development, behavioral problems, autistic behaviors, sleep disorders, facial dysmorphism, and overgrowth. DD, ASD behaviors, and sleep disorders were more common in individuals with dominant disruptive KDM5B variants, while individuals with dominant missense variants presented more frequently with renal and skin anomalies. This study extends our understanding of the KDM5B-related neurodevelopmental disorder and suggests the pathogenicity of certain dominant KDM5B missense variants.

ImportanceThe prognosis of patients with adenocarcinoma of the esophagus and esophagogastric junction (AEG) is poor. From current evidence, it remains unclear to what extent preoperative chemoradiotherapy (CRT) or preoperative and/or perioperative chemotherapy achieve better outcomes than surgery alone.ObjectiveTo assess the association of preoperative CRT and preoperative and/or perioperative chemotherapy in patients with AEG with overall survival and other outcomes.Data SourcesLiterature search in PubMed, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, ClinicalTrials.gov, and International Clinical Trials Registry Platform was performed from inception to April 21, 2023.Study SelectionTwo blinded reviewers screened for randomized clinical trials comparing preoperative CRT plus surgery with preoperative and/or perioperative chemotherapy plus surgery, 1 intervention with surgery alone, or all 3 treatments. Only data from participants with AEG were included from trials that encompassed mixed histology or gastric cancer. Among 2768 initially identified studies, 17 (0.6%) met the selection criteria.Data Extraction and SynthesisThe Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines were followed for extracting data and assessing data quality by 2 independent extractors. A bayesian network meta-analysis was conducted using the 2-stage approach.Main Outcomes and MeasuresOverall and disease-free survival, postoperative morbidity, and mortality.ResultsThe analyses included 2549 patients (2206 [86.5%] male; mean [SD] age, 61.0 [9.4] years) from 17 trials (conducted from 1989-2016). Both preoperative CRT plus surgery (hazard ratio [HR], 0.75 [95% credible interval (CrI), 0.62-0.90]; 3-year difference, 105 deaths per 1000 patients) and preoperative and/or perioperative chemotherapy plus surgery (HR, 0.78 [95% CrI, 0.64-0.91]; 3-year difference, 90 deaths per 1000 patients) showed longer overall survival than surgery alone. Comparing the 2 modalities yielded similar overall survival (HR, 1.04 [95% CrI], 0.83-1.28]; 3-year difference, 15 deaths per 1000 patients fewer for CRT). Similarly, disease-free survival was longer for both modalities compared with surgery alone. Postoperative morbidity was more frequent after CRT plus surgery (odds ratio [OR], 2.94 [95% CrI, 1.01-8.59]) than surgery alone. Postoperative mortality was not significantly more frequent after CRT plus surgery than surgery alone (OR, 2.50 [95% CrI, 0.66-10.56]) or after chemotherapy plus surgery than CRT plus surgery (OR, 0.44 [95% CrI, 0.08-2.00]).Conclusions and RelevanceIn this meta-analysis of patients with AEG, both preoperative CRT and preoperative and/or perioperative chemotherapy were associated with longer survival without relevant differences between the 2 modalities. Thus, either of the 2 treatments may be recommended to patients.

Abstract This study explored the role of the ubiquitin-proteasome system (UPS) in dominantly inherited Alzheimer’s disease (DIAD) by examining changes in cerebrospinal fluid (CSF) levels of UPS proteins along with disease progression, AD imaging biomarkers (PiB PET, tau PET), neurodegeneration imaging measures (MRI, FDG PET), and Clinical Dementia Rating® (CDR®). Using the SOMAscan assay, we detected subtle increases in specific ubiquitin enzymes associated with proteostasis in mutation carriers (MCs) up to two decades before the estimated symptom onset. This was followed by more pronounced elevations of UPS-activating enzymes, including E2 and E3 proteins, and ubiquitin-related modifiers. Our findings also demonstrated consistent correlations between UPS proteins and CSF biomarkers such as Aβ42/40 ratio, total tau, various phosphorylated tau species to total tau ratios (ptau181/T181, ptauT205/T205, ptauS202/S202, ptauT217/T217), and MTBR-tau243, alongside Neurofilament light chain (NfL) and the CDR®. Notably, a positive association was observed with imaging markers (PiB PET, tau PET) and a negative correlation with markers of neurodegeneration (FDG PET, MRI), highlighting a significant link between UPS dysregulation and neurodegenerative processes. The correlations suggest that the increase in multiple UPS proteins with rising tau levels and tau-tangle associated markers, indicating a potential role for the UPS in relation to misfolded tau/neurofibrillary tangles (NFTs) and symptom onset. These findings indicate that elevated CSF UPS proteins in DIAD MCs could serve as early indicators of disease progression and suggest a link between UPS dysregulation and amyloid plaque, tau tangles formation, implicating the UPS as a potential therapeutic target in AD pathogenesis.

Importance The clinical effects of risankizumab (a monoclonal antibody that selectively targets the p19 subunit of IL-23) for the treatment of ulcerative colitis are unknown. Objective To evaluate the efficacy and safety of risankizumab when administered as an induction and a maintenance therapy for patients with ulcerative colitis. Design, Setting, and Participants Two phase 3 randomized clinical trials were conducted. The induction trial was conducted at 261 clinical centers (in 41 countries) and enrolled 977 patients from November 5, 2020, to August 4, 2022 (final follow-up on May 16, 2023). The maintenance trial was conducted at 238 clinical centers (in 37 countries) and enrolled 754 patients from August 28, 2018, to March 30, 2022 (final follow-up on April 11, 2023). Eligible patients had moderately to severely active ulcerative colitis; a history of intolerance or inadequate response to 1 or more conventional therapies, advanced therapies, or both types of therapies; and no prior exposure to risankizumab. Interventions For the induction trial, patients were randomized 2:1 to receive 1200 mg of risankizumab or placebo administered intravenously at weeks 0, 4, and 8. For the maintenance trial, patients with a clinical response (determined using the adapted Mayo score) after intravenous treatment with risankizumab were randomized 1:1:1 to receive subcutaneous treatment with 180 mg or 360 mg of risankizumab or placebo (no longer receiving risankizumab) every 8 weeks for 52 weeks. Main Outcomes and Measures The primary outcome was clinical remission (stool frequency score ≤1 and not greater than baseline, rectal bleeding score of 0, and endoscopic subscore ≤1 without friability) at week 12 for the induction trial and at week 52 for the maintenance trial. Results Among the 975 patients analyzed in the induction trial (aged 42.1 [SD, 13.8] years; 586/973 [60.1%] were male; and 677 [69.6%] were White), the clinical remission rates at week 12 were 132/650 (20.3%) for 1200 mg of risankizumab and 20/325 (6.2%) for placebo (adjusted between-group difference, 14.0% [95% CI, 10.0%-18.0%], P &amp;lt; .001). Among the 548 patients analyzed in the maintenance trial (aged 40.9 [SD, 14.0] years; 313 [57.1%] were male; and 407 [74.3%] were White), the clinical remission rates at week 52 were 72/179 (40.2%) for 180 mg of risankizumab, 70/186 (37.6%) for 360 mg of risankizumab, and 46/183 (25.1%) for placebo (adjusted between-group difference for 180 mg of risankizumab vs placebo, 16.3% [97.5% CI, 6.1%-26.6%], P &amp;lt; .001; adjusted between-group difference for 360 mg of risankizumab vs placebo, 14.2% [97.5% CI, 4.0%-24.5%], P = .002). No new safety risks were detected in the treatment groups. Conclusion and Relevance Compared with placebo, risankizumab improved clinical remission rates in an induction trial and in a maintenance trial for patients with moderately to severely active ulcerative colitis. Further study is needed to identify benefits beyond the 52-week follow-up. Trial Registration ClinicalTrials.gov Identifiers: NCT03398148 and NCT03398135

BACKGROUND: Transcatheter mitral valve-in-valve replacement offers a less-invasive alternative for high-risk patients with bioprosthetic valve failure. Limited experience exists in intermediate-risk patients. We aim to evaluate 1-year outcomes of the PARTNER 3 mitral valve-in-valve study. METHODS: This prospective, single-arm, multicenter study enrolled symptomatic patients with a failing mitral bioprosthesis demonstrating greater than or equal to moderate stenosis and regurgitation and Society of Thoracic Surgeons score ≥3% and <8%. A balloon-expandable transcatheter heart valve (SAPIEN 3, Edwards Lifesciences) was used via a transeptal approach. The primary end point was the composite of all-cause mortality and stroke at 1 year. RESULTS: A total of 50 patients from 12 sites underwent mitral valve-in-valve from 2018 to 2021. The mean age was 70.1±9.7 years, mean Society of Thoracic Surgeons score was 4.1%±1.6%, and 54% were female. There were no primary end point events (mortality or stroke) through 1 year, and no left-ventricular outflow tract obstruction, endocarditis, or mitral valve reintervention was reported. Six patients (12%) required rehospitalization, including heart failure (n=2), minor procedural side effects (n=2), and valve thrombosis (n=2; both resolved with anticoagulation). An additional valve thrombosis was associated with no significant clinical sequelae. From baseline to 1 year, all subjects with available data had none/trace or mild (grade 1+) mitral regurgitation and the New York Heart Association class improved in 87.2% (41/47) of patients. CONCLUSIONS: Mitral valve-in-valve with a balloon-expandable valve via transseptal approach in intermediate-risk patients was associated with improved symptoms and quality of life, adequate transcatheter valve performance, and no mortality or stroke at 1-year follow-up. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03193801.