Citations

Abstract Objectives: Radiologist participation in multidisciplinary tumor board can be time-consuming and demanding, requiring substantial preparation. Anecdotally radiologist participation is felt to help identify discrepancies in previous interpretations; however, there are limited data assessing the actual impact of their tumor board review on patient management. This prospective study aims to evaluate how the reinterpretation of outside imaging and review at hepatobiliary tumor board (HBTB) affects the diagnosis and management of patients with hepatobiliary neoplasms. Methods: This prospective analysis included all patients presented at the weekly HBTB between 6/13/2023 - 6/25/2024. One radiologist reviewed the available reports of outside imaging, the local reinterpretation of outside imaging, the updated local imaging, and documented conclusions from discussion of the case at HBTB. HBTB included 4 radiologists who had reviewed each case. Discrepancies (presence/absence, number, and reasons for) were recorded. When discrepancies occurred, the impact on patient management (5-point Likert scale) was determined by two of the radiologists present at the HBTB in consensus, with input from clinicians if needed. A six-month follow-up was performed to confirm suspected diagnoses. Results: 208 cases (128 males, 104 chronic liver disease patients) were presented at HBTB. Disagreements in the detection or characterization of lesions were found in 59/208 (28.4%) of cases. A change in management occurred in 38/59 (64.6%) of these discrepant cases. In cases with recorded discrepancies in which follow-up confirmation was available, the final interpretation was confirmed in 34/41 (82.9%) of cases. Conclusion: Our study found a discrepant interpretation in nearly one-third of cases presented at a weekly HBTB and a resultant change in management in 65% of those cases. These findings highlight the importance of reinterpretation of prior imaging studies and the presence of radiologists at HBTB to guide optimal patient management.

OBJECTIVE The purpose of this study was to determine risk factors for distal junctional failure (DJF) following three-column osteotomy (3CO) for the correction of cervical deformity. METHODS A retrospective review was performed of patients who underwent a cervical or upper thoracic 3CO for cervical deformity correction by the senior author from 2008 to 2023. The main outcome of interest was DJF, defined as revision surgery with extension of the distal end of the fusion construct. Patients were excluded if the lowest instrumented vertebra (LIV) was the sacrum/pelvis, and if patients had prior autofusion throughout the distal part of the spine to the sacrum (e.g., ankylosing spondylitis). The minimum follow-up duration was 1 year. RESULTS One hundred fourteen patients were identified who underwent a cervical or upper thoracic 3CO for cervical deformity correction, 41 of whom met inclusion criteria for this study. The median patient age was 66 years, median BMI was 27, and 61% were male. Ten patients (24%) experienced DJF, requiring reoperation and distal extension of the construct to the pelvis in 9 cases and to L1 in 1 case. On univariable analysis, patients who experienced DJF compared with those who did not were more likely to be female (80% vs 35%, p = 0.007), had lower LIV Hounsfield units (HUs; 127 vs 167, p = 0.041), were less likely to have an LIV in a small autofused segment (10% vs 45%, p = 0.02), had an LIV that was closer to the first lordotic level (one level above vs three, p = 0.043), and had a longer length of fusion (17 vs 13 levels, p = 0.033). A stepwise multivariable regression model showed that having an LIV closer to the first lordotic vertebra was the only statistically significant predictor of DJF (OR 0.49, p = 0.013) and low LIV HUs did not reach statistical significance (OR 0.97, p = 0.09). CONCLUSIONS Patients with cervical deformity undergoing a 3CO are at higher risk for DJF with constructs terminating near the first lordotic vertebra. While LIV selection is complex and patient specific, choosing an LIV at least two levels above the first lordotic vertebra may help prevent DJF.

Abstract Oligodendrogliomas are initially slow-growing brain tumors that are prone to malignant transformation despite surgery and cytotoxic therapy. Understanding of oligodendroglioma evolution and new treatments for patients have been encumbered by a paucity of patient-matched newly diagnosed and recurrent tumor samples for multiplatform analyses, and by a lack of preclinical models for interrogation of therapeutic vulnerabilities that drive oligodendroglioma growth. Here we integrate spatial and functional analyses of tumor samples and patient-derived organoid co-cultures to show that synaptic connectivity is a hallmark of oligodendroglioma evolution and recurrence. We find that patient-matched recurrent oligodendrogliomas are enriched in synaptic gene expression programs irrespective of previous therapy or histologic grade. Analyses of spatial, single-cell, and clinical data reveal epigenetic misactivation of synaptic genes that are concentrated in regions of cortical infiltration and can be used to predict eventual oligodendroglioma recurrence. To translate these findings to patients, we show that local field potentials from tumor-infiltrated cortex at the time of resection and neuronal hyperexcitability and synchrony in patient-derived organoid co-cultures are associated with oligodendroglioma proliferation and recurrence. In preclinical models, we find that neurophysiologic drugs block oligodendroglioma growth and pathologic electrophysiology. These results elucidate mechanisms underlying oligodendroglioma evolution from an indolent tumor to a fatal disease and shed light on new biomarkers and new treatments for patients.

Abstract Chronically elevated circulating excess free fatty acids (ie, lipotoxicity) is a pathological process implicated in several metabolic disorders, including obesity-driven type 2 diabetes (T2D). Lipotoxicity exerts detrimental effects on pancreatic islet β-cells by reducing glucose-stimulated insulin secretion (GSIS), altering β-cell transcriptional identity, and promoting apoptosis. While β-cell-derived small extracellular vesicles (sEV) have been shown to contribute to β-cell failure in T2D, their specific role in lipotoxicity-mediated β-cell failure remains to be elucidated. In this work, we demonstrate that lipotoxicity enhances the release of sEVs from β-cells, which exhibit altered proteomic and lipidomic profiles. These palmitate (PAL)-exposed extracellular vesicles (EVs) induce β-cell dysfunction in healthy mouse and human islets and trigger significant islet transcriptional changes, including the upregulation of genes associated with the TGFβ/Smad3 pathway, as noted by RNA sequencing. Importantly, pharmacological inhibition of the TGFβI/II receptor improved PAL EV-induced β-cell dysfunction, underscoring their involvement in activating the TGFβ/Smad3 pathway during this process. We have comprehensively characterized lipotoxic β-cell sEVs and implicated their role in inducing β-cell functional failure in T2D. These findings highlight potential avenues for therapeutic interventions targeting sEV-mediated pathways to preserve β-cell health in metabolic disorders.

Introduction Targeted immunomodulators (eg, advanced therapies) effectively achieve symptomatic remission in patients with inflammatory bowel disease (IBD). However, ~25%–50% of patients with IBD achieving symptomatic remission with an advanced therapy may have continued endoscopically/radiologically active bowel inflammation, and it is uncertain whether changing alternative advanced therapies in asymptomatic patients with IBD will reduce bowel inflammation and achieve durable deep remission. Methods and analysis The QUality Outcomes Treating IBD to Target (QUOTIENT) study is an open-label, multicentre, pragmatic, randomised, controlled trial that aims to compare the efficacy and safety of switching to an alternative advanced therapy targeting endoscopic/radiological remission (treat-to-target) versus continuing the initial, or index, advanced therapy, in asymptomatic patients with IBD with moderate-to-severe endoscopic/radiological bowel inflammation. Enrolment is planned for ~250 participants in Canada/USA, randomised 1:1 to switching to alternative advanced therapy or continuing index advanced therapy, and then followed 104 weeks within routine clinical practice. Patient-reported outcomes measure efficacy and quality of life/treatment burden/safety. Primary endpoint is the time from randomisation to treatment failure. Ethics and dissemination The study is conducted in compliance with the protocol, ICH Good Clinical Practice, applicable regulatory requirements and appropriate review boards/independent ethics committees (approval numbers: Pro00077486; Pro00061437; STUDY00002062; 22-004171; i22-01269; IRB22-0890; IRB_00154397; 2000032384; SHIRB#2022.095-2; STUDY00007146; MMC#2024-18; REB#125290; 17784; Pro00142214; 20240660-01H), with documented written informed consent. Findings will be disseminated through peer-reviewed journals, scientific presentations, and publicly available Patient-Centered Outcomes Research Institute (PCORI) websites, including lay summaries. The Crohn’s & Colitis Foundation Education, Support, and Advocacy Department, and our patient advocacy stakeholder, will develop educational and marketing resources to communicate findings to a broad audience (>250 000 patients/caregivers/healthcare professionals). Trial registration number NCT05230173 .

Importance Neoadjuvant systemic therapy (NST) has been associated with pathologic complete response (pCR) in up to 60% of breast cancers (BCs). The findings of this trial question the necessity of surgery. Objective To report preplanned 5-year efficacy outcomes evaluating radiotherapy alone without breast surgery in patients selected with image-guided vacuum assisted biopsy (VAB). Design, Setting, and Participants This single-arm, prospective, phase 2 nonrandomized clinical trial was conducted at 7 US medical centers and included women 40 years or older with cT1-2N0-1M0 ERBB2 -positive (formerly HER2 -positive) or triple-negative invasive BC who showed residual breast lesions after NST of less than 2 cm on imaging. Enrollment was from March 6, 2017, to November 9, 2021. Data analysis was from October to December 2024. Intervention Image-guided VAB of the tumor bed (9G with a minimum of 12 cores) was performed after standard NST. Patients with clinically node-negative disease at diagnosis and no residual cancer in the breast on post-NST VAB underwent whole-breast radiotherapy with a boost without breast or axillary surgery. Patients with initial documented nodal disease and a breast pCR on VAB underwent targeted axillary dissection, while those with residual cancer when undergoing VAB had standard breast and axillary surgery. Patients were monitored with physical examinations and mammography every 6 months. Main Outcome Measures The primary outcome was ipsilateral breast tumor recurrence. Results Fifty patients (median [IQR] age, 62 [55-77] years) were enrolled and underwent post-NST VAB. Twenty-nine (58%) and 21 (42%) patients had ERBB2 -positive and triple-negative invasive BC, respectively. Breast pCR on VAB was identified in 31 patients (62%; 95% CI, 47.2%-75.34%), and axillary pCR was identified among all 8 patients with initial nodal metastases and breast pCR on VAB who underwent targeted axillary dissection. At a median follow-up of 55.4 (IQR, 44.0-63.5) months, the ipsilateral breast tumor recurrence rate was 0%, and disease-free and overall survival rates were 100% for patients without breast surgery. Conclusions and Relevance The results of this nonrandomized clinical trial that reported preplanned 5-year outcomes suggest that omission of breast surgery in select patients after NST may be feasible, with no recurrences seen. More confirmatory studies are necessary before this new approach alters surgical practice. Trial Registration ClinicalTrials.gov Identifier: NCT02945579