Citations

SUMMARY Ewing sarcoma (EwS) is a group of bone and soft tissue cancers in children and young adults. Since EwS cells have pronounced sensitivity to radiation and chemotherapy-induced DNA damage, the role of the oncoprotein, EWS-FLI1, in DNA repair is likely. Here, we demonstrate that EWS-FLI1 causes a defect in microhomology-mediated end-joining (MMEJ) repair. EWSR1 is a splicing factor that promotes the faithful splicing of the POLQ pre-mRNA, required for the expression of POLΘ, a critical protein in the MMEJ pathway. Expression of EWS-FLI1, or loss of EWSR1, causes exon 25 skipping of the POLQ transcript, decreased POLΘ expression, impaired MMEJ, and cellular sensitivity to inhibitors of the Fanconi Anemia (FA), NHEJ, or HR pathways, through the mechanism of synthetic lethality. Knockdown of EWS-FLI1 expression restores POL0 mitotic foci and increases MMEJ activity. Inhibitors of the FA, NHEJ, or HR therefore may provide a targeted therapy for patients with EwS. Highlights - Ewing sarcoma tumors have a deficiency in POLθ expression and a corresponding loss of MMEJ activity - EWSR1 is a splicing factor that interacts with other splicing factors such as FUBP1 and KHSRP/FUBP2 to accurately splice the POLQ mRNA. - The EWS-FLI1 fusion oncoprotein, or loss of EWSR1, causes a splicing defect, leading to exon25 skipping of the POLQ pre-mRNA and loss of POLθ expression - The MMEJ deficiency of EwS cells results in cellular sensitivity to inhibitors of Fanconi Anemia, Homologous Recombination or Non-Homologous End-Joining - Exon 25 skipping of POLQ mRNA is a predictive biomarker for HR inhibitors in human cancers

Abstract Electrical stimulation is increasingly used to modulate brain networks for clinical purposes. The basic unit of neurostimulation, a single electrical pulse, can travel through white matter to influence connected neuronal populations. However, the mechanisms by which it influences connected populations is not well understood: stimulation may excite, inhibit, or add noise to neuronal population activity. In this study, we investigated how single pulses modulate the neuronal processing of images in a well-controlled visual paradigm. In two human subjects implanted with iEEG electrodes for clinical purposes, single pulses were delivered to electrodes in white matter tracts connected to measurement electrodes in visual cortex. Images appeared on-screen at 0, 100, or 200 ms after each pulse. Using finite impulse response modeling, we decomposed the broadband and evoked potential responses into separate components induced by electrical stimulation and by visual processing. Single pulses induced transient broadband increases followed by suppression, but they did not modulate the visual broadband responses (i.e., stimulation response was additive to visual response). In contrast, single pulses elicited prominent brain stimulation evoked potentials and they modulated the visual evoked potentials. Specifically, visual evoked potentials were larger when stimulation occurred closer to visual onset. This indicates that a single electrical pulse can increase the strength or synchrony of visual inputs. Overall, these findings suggest that the effects of electrical stimulation in the visual system are two-fold: stimulation induces additive effects on broadband power, possibly by adding noise, and it interacts with synchronous visual inputs to amplify them.

OBJECTIVE Pelvic incidence (PI) is a key parameter of sagittal alignment. While conventionally held to be fixed, increasing evidence suggests PI may be variable. This study aimed to identify predictors of change in PI with patient position and to assess the association of preoperative radiographic characteristics and intraoperative maneuvers with postoperative PI. METHODS Patients who underwent thoracolumbosacral fusion were identified, and data were gathered on preoperative spinopelvic parameters, patient demographic characteristics, and operative details. Preoperative spinopelvic parameters were measured on upright, supine, and prone radiographs. Univariable comparisons of PI between the different patient positions were performed. Multivariable analysis was performed to identify variables independently correlated with PI on 6-week postoperative radiographs. Change in PI was defined as ≥ 5° change between positions. RESULTS In total, 138 patients were identified (mean ± SD age 66.0 ± 8.7 years; 38.4% male). Statistically significant differences in PI were noted between preoperative standing and supine (mean −3.2° ± 4.2°, p < 0.001), preoperative supine and prone (3.5° ± 4.7°, p < 0.001), preoperative and 6-week postoperative standing (1.5° ± 6.2°, p = 0.01), and immediate and 6-week upright (1.1° ± 3.9°, p = 0.007) radiographs. Univariable comparisons showed PI decrease from standing to supine was predicted only by weight (87.0 ± 15.0 vs 81.1 ± 19.3 kg, p = 0.04); there were no significant predictors of increase in PI from standing to prone. Increase in PI from preoperative to 6-week standing radiographs was predicted by lower preoperative PI class (p < 0.001), L5/S1 interbody placement (74.4% vs 52.0%, p = 0.02), and change in PI from preoperative standing to supine (12.8% vs 39.8%, p = 0.002) and from standing to prone (51.3% vs 13.3%, p < 0.001). Multivariable analysis showed that 6-week postoperative PI was associated with only preoperative supine PI (B = 0.293, 95% CI 0.10–0.48, p = 0.003) and prone PI (B = 0.647, 95% CI 0.44–0.85, p < 0.001). CONCLUSIONS There are position-dependent changes in PI among patients without prior pelvic fixation. Statistically significant changes in PI are seen even after pelvic fixation with a single S2-alar-iliac screw bilaterally. Postoperative PI was best predicted by preoperative PI on supine and prone radiographs rather than upright radiographs, suggesting that preoperative prone and supine radiographs may provide surgeons with the best information for achieving PI–lumbar lordosis mismatch < 10°.

OBJECTIVE Transforaminal lumbar interbody fusion (TLIF) offers both indirect decompression and segmental correction through restoration of disc height. However, stresses exerted on the vertebral endplates by the interbody device can result in implant subsidence and loss of correction. The present time-to-event analysis aimed to identify predictors of interbody subsidence. METHODS Patients who underwent 1- or 2-level TLIF were identified. Data on demographics, surgical details, preoperative bone quality using CT-based Hounsfield units (HU), and pre- and postoperative lumbopelvic parameters were collected. Univariable analyses were conducted to identify predictors of subsidence (≥ 2-mm intrusion of interbody into cranial or caudal vertebrae) and significant subsidence (≥ 4-mm intrusion). Multivariable Cox regression was performed to identify independent predictors of subsidence, expressed as hazard ratios with 95% confidence intervals. RESULTS A total of 198 patients treated at 241 levels were included (median age 66.6 years, IQR 59.5, 73.7 years; 56.6% were women). In 92 levels (38.2%) there was some subsidence and in 25 (10.4%) there was significant subsidence. Implanted levels demonstrating subsidence (≥ 2 mm) were associated with lower HU in cranial and caudal vertebrae; had interbodies positioned farther from the anterior apophyseal ring; were implanted with taller, more lordotic interbodies; and underwent greater disc height restoration. Those showing significant subsidence (≥ 4 mm) were similarly associated with lower HU in the cranial and caudal vertebrae; had interbodies positioned farther from the anterior apophyseal ring of the caudal vertebrae; and underwent greater disc height restoration. Multivariable Cox regression showed that time to subsidence was predicted by greater implant height (HR 1.20/mm, 95% CI 1.05–1.38; p = 0.009), greater postoperative disc height (HR 1.21/mm, 95% CI 1.09–1.34; p < 0.001), and greater disc height restoration (HR 1.11/mm, 95% CI 1.04–1.19; p = 0.002). The time-to-subsidence analysis for significant (≥ 4 mm) subsidence showed that it was predicted by lower HU in the cranial vertebrae (HR 0.98/unit, 95% CI 0.97–0.99; p = 0.001); increasing number of levels instrumented (HR 1.26, 95% CI 1.04–1.52; p = 0.016); and greater disc height restoration (HR 1.33/mm, 95% CI 1.18–1.51; p < 0.001). CONCLUSIONS This time-to-event analysis suggests that interbody subsidence following TLIF is best predicted by implantation of a taller interbody and aggressive disc height restoration. Significant subsidence is similarly predicted by aggressive disc height restoration along with poor baseline bone quality. The results suggest the need to balance aggressive correction at the time of surgery against the increased risk of subsequent interbody subsidence.

ASCO Guidelines provide recommendations with comprehensive review and analyses of the relevant literature for each recommendation, following the guideline development process as outlined in the ASCO Guidelines Methodology Manual . ASCO Guidelines follow the ASCO Conflict of Interest Policy for Clinical Practice Guidelines . Clinical Practice Guidelines and other guidance (“Guidance”) provided by ASCO is not a comprehensive or definitive guide to treatment options. It is intended for voluntary use by clinicians and should be used in conjunction with independent professional judgment. Guidance may not be applicable to all patients, interventions, diseases or stages of diseases. Guidance is based on review and analysis of relevant literature and is not intended as a statement of the standard of care. ASCO does not endorse third-party drugs, devices, services, or therapies and assumes no responsibility for any harm arising from or related to the use of this information. See complete disclaimer in Appendix 1 and 2 (online only) for more. PURPOSE To develop a clinical practice guideline and recommendations for symptom management of patients with well-differentiated grade 1 to grade 3 metastatic gastroenteropancreatic neuroendocrine tumors. METHODS ASCO convened an Expert Panel to develop a clinical practice guideline by reviewing the literature for relevant guidelines, systematic reviews, randomized controlled trials (RCTs), and observational studies to develop recommendations for clinical practice. RESULTS The literature review identified eight guidelines, 19 systematic reviews, and three RCTs that informed the development of guideline recommendations. RECOMMENDATIONS Recommendations are included for carcinoid syndrome, carcinoid heart disease and carcinoid crisis, and functional pancreatic neuroendocrine tumor syndromes. Recommendations are provided for surgical management, liver-directed therapy, and systemic therapy options, as well as palliative care. Limited guidance is provided for sequencing of interventions. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

We have developed a cost-effective method to study the fate of stents, particularly flow diverter stents placed in the abdominal aorta, in a rat model. This technique utilizes (caudal) tail artery access,1–5 thereby avoiding the need for surgical exposure of the femoral or carotid arteries and reducing procedural invasiveness,6 7 aligning with the principles of refinement and reduction in animal research.7 This approach may be particularly beneficial for studies requiring multiple or iterative vascular access. The use of ultrasound guidance further reduces costs and infrastructure requirements by eliminating the need for specialized angiography suites.8 This makes this technique accessible to a broader range of research settings, promoting wider adoption and collaboration in the field of endovascular research. A detailed demonstration of this method is provided in the accompanying educational video (video 1). Video 1 -Technical video describing the tail artery access and flow diverter deployment using ultrasound guidance.

Importance Many older adults with advanced cancer never communicate goals of care or treatment preferences to their clinicians, raising the risk that care received will not match their values. Scalable models of care may help surmount this barrier. Objective To test whether a combined patient and clinician intervention increased the rate of advance care planning (ACP) documentation in large health care systems. Design, Setting, and Participants This stepped-wedge cluster randomized clinical trial using an open cohort design included patients aged 65 years or older with advanced cancer seen at oncology clinics in 3 health care systems located in the US South, Midwest, and Mid-Atlantic regions from April 1, 2020, to November 30, 2022. Data collection ended in 2024. Intervention The intervention involved delivering brief evidence-based patient-facing video decision aids available in 25 languages as well as goals-of-care communication training to oncology clinicians. Patients in the control period received usual care. Main Outcomes and Measures The primary outcome was ACP documentation, which included any electronic health record documentation of a goals-of-care conversation, palliative care, hospice, or limitation of life-sustaining treatments, identified via a validated natural language processing program. Analysis was performed on an intention-to-treat basis. Results Twenty-nine practices, comprising 13 800 unique eligible patients with a total of 29 357 repeated measurements, were included (mean [SD] age, 74.5 [6.6] years; 52.3% men [15 344 of 29 357 measurements]). The proportion of patients with ACP documentation was greater in the intervention phase compared with the usual care phase (adjusted rate difference, 6.8% [95% CI, 2.8%-10.8%]; P &amp;lt; .001). ACP documentation in the intervention phase occurred among 3980 of 15 754 patients (25.3%) (goals-of-care conversation, 21.4% [3377 of 15 754]; palliative care, 9.6% [1517 of 15 754]; hospice, 5.4% [847 of 15 754]; and limitation of life-sustaining treatments, 7.2% [1128 of 15 754]). In comparison, ACP documentation in the usual care phase occurred among 2834 of 13 603 patients (20.8%) (goals-of-care conversation, 16.8% [2281 of 13 603]; palliative care, 9.5% [1287 of 13 603]; hospice, 5.3% [724 of 13 603]; and limitation of life-sustaining treatments, 8.4% [1149 of 13 603]). Conclusions and Relevance In this stepped-wedge cluster randomized clinical trial for older adults with advanced cancer, a bundled evidence-based decision aid and communication training intervention increased the proportion of older patients with ACP documentation. This approach offers an innovative paradigm with a clinically meaningful increase in ACP documentation, a widely used quality metric that reflects high-quality patient-centered care delivery. Trial Registration ClinicalTrials.gov Identifier: NCT03609177

Importance Few studies have assessed whether factors outside the workplace, such as support from a spouse or partner, are associated with work-life integration (WLI) satisfaction and burnout among physicians. Evaluating such an association may help with developing novel strategies to address burnout and improve WLI satisfaction among this group. Objectives To compare spousal support among female and male physicians and explore associations of spousal support with WLI satisfaction and burnout. Design, Setting, and Participants This cross-sectional, multispecialty survey study was conducted among 661 faculty physicians employed at an academic medical center from March 26 to May 22, 2024. Main Outcomes and Measures Survey items measured spousal support (5 items), WLI satisfaction (1 item), and burnout (2 Maslach Burnout Inventory items). Associations of spousal support and gender with WLI and burnout were assessed using logistic regression analyses adjusting for age, race and ethnicity, weekly work hours, and weekly hours spent on household or childcare duties. Results Overall, 739 of 2103 faculty physicians (response rate, 35.1%) completed the survey, of whom 661 (89.4%) were currently married or partnered (359 of 661 men [54.3%]). In this subset, 322 of 351 male physicians (91.7%) and 276 of 298 of female physicians (92.6%) reported frequent career support (defined as often, most of the time, or always) over the last year from their spouse or partner. Physicians reporting high levels of career support from their spouse or partner had higher odds of WLI satisfaction (odds ratio [OR], 1.50 [95% CI, 1.22-1.86]; P &amp;lt; .001) and lower odds of burnout (OR, 0.73 [95% CI, 0.61-0.87]; P &amp;lt; .001), independent of gender and adjusted for age, race and ethnicity, weekly work hours, and weekly hours spent on household or childcare duties. Male physicians had higher odds of WLI satisfaction than female physicians (OR, 1.95 [95% CI, 1.32-2.90]; P &amp;lt; .001), even after adjusting for spousal career support and other covariates listed, whereas odds of burnout did not significantly differ by gender (OR, 0.84 [95% CI, 0.57-1.23]; P = .37). Conclusions and Relevance This study suggests that the level of career support from a spouse or partner is associated with WLI satisfaction and burnout among physicians, independent of gender. Future studies should explore whether interventions designed to enhance career support can improve WLI and well-being among physicians.