Citations

Abstract Glioblastoma (GBM) remains one of the most therapy-resistant malignancies with frequent local failures despite aggressive surgery, chemotherapy, and ionizing radiation (IR). Small molecule inhibitors of DNA-dependent protein kinase (DNA-PKi) are potent radiosensitizers currently in clinical trials. Determining which patients may benefit from radiosensitization with DNA-PKi is critical to avoid unnecessary increased risk of normal tissue toxicity. In this study, we used GBM patient-derived xenografts (PDX) in orthotopic murine models to study the relationship between molecular features, pharmacokinetics, and the radiosensitizing potential of the DNA-PKi peposertib. We show that peposertib radiosensitizes established and PDX GBM lines in vitro at 300 nmol/L and above, with a significant increase in radiosensitization by maintaining post-IR exposure for >12 hours. Radiosensitization by peposertib is mediated by catalytic inhibition of DNA-PK, and knockdown of DNA-PK by short hairpin RNA (shRNA) largely abolished the radiosensitizing effect. Peposertib decreased auto-phosphorylation of DNA-PKcs after IR in a dose-dependent manner with a delay in resolution of γH2AX foci at 24 hours. The addition of peposertib to IR significantly increased survival in GBM120 orthotopic xenografts, but not in GBM10. There was no difference in plasma or average tumor concentrations of peposertib in the two cohorts. Although the mechanism underpinning this discordant effect in vitro versus in vivo is not clear, there was an association for greater sensitization in TP53 mutant lines. Transfection of a dominant-negative TP53 mutant in baseline TP53 wild-type GBM lines significantly delayed growth and decreased nonhomologous end joining efficiency (but not homologous recombination), after peposertib exposure. See related commentary by Buchsbaum, p. 840

Abstract Background: Despite the proven effectiveness of endovascular therapy (EVT) in acute ischemic strokes (AIS) involving anterior circulation large vessel occlusions, isolated posterior cerebral artery (PCA) occlusions (iPCAo) remain underexplored in clinical trials. This study investigates the comparative effectiveness and safety of EVT against medical management (MM) in patients with iPCAo. Methods: This multinational, multicenter propensity score-weighted study analyzed data from the Multicenter Analysis of primary Distal medium vessel occlusions: effect of Mechanical Thrombectomy (MAD-MT) registry, involving 37 centers across North America, Asia, and Europe. We included iPCAo patients treated with either EVT or MM. The primary outcome was the modified Rankin Scale (mRS) at 90 days, with secondary outcomes including functional independence, mortality, and safety profiles such as hemorrhagic complications. Results: A total of 177 patients were analyzed (88 MM and 89 EVT). EVT showed a statistically significant improvement in 90-day mRS scores (OR = 0.55, 95% CI = 0.30–1.00, p = 0.048), functional independence (OR = 2.52, 95% CI = 1.02–6.20, p = 0.045), and a reduction in 90-day mortality (OR = 0.12, 95% CI = 0.03–0.54, p = 0.006) compared to MM. Hemorrhagic complications were not significantly different between the groups. Conclusion: EVT for iPCAo is associated with better neurological outcomes and lower mortality compared to MM, without an increased risk of hemorrhagic complications. Nevertheless, these results should be interpreted with caution due to the study’s observational design. The findings are hypothesis-generating and highlight the need for future randomized controlled trials to confirm these observations and establish definitive treatment guidelines for this patient population.

AbstractBackgroundThe clinical relevance of cardiac troponin (cTn) elevation in takotsubo syndrome (TTS) remains uncertain. The present study sought to investigate the role of cardiac troponin (cTn) elevations in mortality prediction of patients with Takotsubo syndrome (TTS).MethodsPatients enrolled in the International Takotsubo (InterTAK) Registry from January 2011 to February 2020 with available data on peak cTn levels were included in the analysis. Peak cTn levels during the index hospitalization were used to define clinically relevant myocardial injury. The threshold at which clinically relevant myocardial injury drives mortality at 1 year was identified using restricted cubic spline analysis.ResultsOut of 2′938 patients, 222 (7.6%) patients died during 1‐year follow‐up. A more than 28.8‐fold increase of cTn above the upper reference limit was identified as threshold for clinically relevant myocardial injury. The presence of clinically relevant myocardial injury was significantly associated with an increased risk of mortality at 5 years (adjusted HR 1.58, 95% CI 1.18–2.12, p =.002). Clinically relevant myocardial injury was related to an increased 5‐year mortality risk in patients with apical TTS (adjusted HR 1.57, 95% CI 1.21–2.03, p =.001), in presence of physical stressors (adjusted HR 1.60, 95% CI 1.22–2.11, p =.001), and in absence of emotional stressors (adjusted HR 1.49, 95% CI, 1.17–1.89, p =.001).ConclusionThis study for the first time determined a troponin threshold for the identification of TTS patients at excess risk of mortality. These findings advance risk stratification in TTS and assist in identifying patients in need for close monitoring and follow‐up.

OBJECTIVE Some patients treated surgically for grade 1 spondylolisthesis require revision surgery. Outcomes after revision surgery are not well studied. The objective of this study was to determine how revision surgery impacts patient-reported outcomes (PROs) in patients undergoing decompression only or decompression and fusion (D+F) for grade 1 spondylolisthesis within 5 years of the index surgery. METHODS Patients in the 12 highest Quality Outcomes Database (QOD) enrolling sites with a diagnosis of grade 1 spondylolisthesis were identified and the incidence of revision surgery between the decompression-only and D+F patients were compared. PROs were compared between cohorts requiring revision surgery versus a single index procedure. RESULTS Of 608 patients enrolled, 409 had complete 5-year data available for this study. Eleven (13.3%) of 83 patients underwent revision in the decompression-only group as well as 32 (9.8%) of 326 in the D+F group. For the entire cohort, patients requiring revision had significantly worse PROs at 5 years: Oswestry Disability Index (ODI) 27.4 versus 19.4, p = 0.008; numeric rating scale for back pain (NRS-BP) 4.1 versus 3.0, p = 0.013; and NRS for leg pain (NRS-LP) 3.4 versus 2.1, p = 0.029. In the decompression-only group, the change in 5-year PROs was not impacted by revision status: ODI 31.9 versus 24.2, p = 0.287; NRS-BP 1.9 versus 2.9, p = 0.325; and NRS-LP 6.2 versus 3.7, p = 0.011. In the D+F group, the change in 5-year PROs was diminished if patients required revision: ODI 19.1 versus 29.1, p = 0.001; NRS-BP 3.0 versus 4.0, p = 0.170; and NRS-LP 2.3 versus 4.6, p = 0.001. CONCLUSIONS The most common reasons for reoperation within 5 years in the decompression-only group were repeat decompression and instability, whereas in the D+F group the most common reason was adjacent-segment disease. The need for revision resulted in modestly diminished benefit compared with patients with no revisions. These differences were greater in the fusion cohort compared with the decompression-only cohort. The mean PRO improvement still far exceeded minimal clinically important difference thresholds for all measures for patients who underwent a revision surgery.

OBJECTIVE The Woven EndoBridge (WEB) device was approved to treat wide-necked bifurcation aneurysms. The device is designed as an intrasaccular flow disruptor covering aneurysm widths up to 10 mm. Although prior studies combined all aneurysm sizes, it is known that aneurysms behave differently in response to endovascular treatment based on their size. Therefore, the authors’ objective was to identify ideal middle cerebral artery (MCA) aneurysm width and neck sizes most suitable for WEB treatment. METHODS The WorldWideWEB consortium is a large multicenter retrospective database that analyzes intracranial aneurysms treated with the WEB device. In this study, all unruptured MCA bifurcation aneurysms with available measurements were included. Cutoff values based on aneurysm width and neck in relation to aneurysm occlusion status were measured using the receiver operating characteristic (ROC) curve. Propensity score matching (PSM) was then used to compare treatment outcomes between aneurysms smaller and larger than the cutoff value for both width and neck size. RESULTS The ideal cutoff values for MCA bifurcation aneurysm width and neck were 6.1 mm and 4.6 mm, respectively. On PSM, 87 matched pairs were compared based on width size (≤ 6.1 mm and > 6.1 mm), and 77 matched pairs were compared based on neck size (≤ 4.6 mm and > 4.6 mm). There was a significant difference in adequate aneurysm occlusion between aneurysms smaller and larger than those cutoff values for both widths (93% vs 76%, p = 0.0017) and neck sizes (90% vs 70%, p = 0.0026). The retreatment rate was also significantly higher for larger aneurysms in both parameters. CONCLUSIONS This study shows that MCA bifurcation aneurysms ≤ 6.1 mm in width and ≤ 4.6 mm in neck size are significantly better candidates for WEB treatment, leading to improved occlusion status and reduced retreatment rate, which are important considerations when using WEB devices.

Abstract Purpose: Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating toxicity of many drugs used in cancer treatment. There are numerous available strategies for preventing or treating CIPN, but few are guideline-recommended, due to limited evidence of their effectiveness. The primary objective of this survey was to understand what strategies patients used to prevent or treat CIPN, and to understand their perceptions around CIPN prevention and treatment. Methods: The Multinational Association of Supportive Care in Cancer (MASCC) Neurological Complications Study Group created a cross-sectional online survey to recruit individuals who are currently or had previously received neurotoxic chemotherapy treatment and self-reported peripheral neuropathy. Descriptive statistics were reported. Results: Most of the 447 survey participants did not use any CIPN prevention strategy (71%), though given options of any strategy the plurality preferred a prescribed medication or supplement (30%). The most common treatment strategy used was exercise (47%), with some patients trying prescription medications including non-guideline recommended gabapentin (33%) or guideline-recommended duloxetine (8%) options. Nearly half of participants (49%) used at least one non-prescribed medication for treating CIPN. Patient’s often followed suggestions of their medical oncology clinical team, but sometimes relied on the internet or other patients to recommend non-prescription strategies. Conclusion: In the absence of many guideline-recommended strategies for CIPN prevention and treatment, some patients use options with minimal evidence of effectiveness. Additional research is needed to determine which strategies are effective for prevention and treatment so these can be implemented in practice to improve treatment outcomes in patients with cancer.

Abstract Many patients in the emergency department present with signs and symptoms that arouse concern for sepsis; however, other explanations are also possible. There are currently no rapid tests used in clinical practice that reliably distinguish the presence of a bacterial or viral infection vs. a non-infectious etiology and can predict a patient’s likelihood to decompensate. The diagnostic and prognostic uncertainty in “gray zone” patients complicates the decision to begin therapy as clinicians need to balance the risk of withholding therapy vs. the risk of the therapy itself (e.g., overtreatment with antibiotics and hospitalization, which is costly, potentially harmful, and contributes to antibiotic resistance). The TriVerity™ Test uses isothermal amplification and machine-learning algorithms to quantify and interpret mRNA expression levels to determine both likelihood of bacterial infection, viral infection, or no infection, and whether the patient will likely require one or more critical interventions within 7 days. The three scores each fall into one of five interpretation bands ranging from Very high to Very low. Testing takes approximately 30 minutes using the proprietary Myrna™ Instrument with an operator hands-on-time of under one minute. We enrolled 1,222 patients from 22 emergency departments (ED) to validate the performance of the TriVerity Test. Patients were treated as per local standard of care and were followed for 28 days. Bacterial and viral TriVerity results were validated against clinically adjudicated infection status; the illness severity TriVerity result was validated against the need for at least one critical interventions within 7 days. The bacterial TriVerity result had high AUROC for the diagnosis of bacterial infection (0.83; 80% CI 0.81–0.85) and divided bacterial infection likelihood scores into five interpretation bands with increasing likelihood ratios of infection ranging from Very low (LR- 0.08, 80% CI 0.06–0.11) to Very high (LR + 8.04, 80% CI 5.72–11.78). The AUROC for the bacterial TriVerity result was significantly higher compared to AUROCs for C-reactive protein, procalcitonin or white blood cell count. Similarly, the viral TriVerity score showed high AUROC for the diagnosis of viral infection (0.91; 80% CI 0.90–0.93) and likelihood ratios from Very low (LR- 0.09, 80% CI 0.05–0.14) to Very high (LR + 40.93; 80% CI 29.11–79.23). The TriVerity Illness Severity score showed a high AUROC for the prediction of illness severity (0.77; 80% CI 0.77–0.81) with scores divided into five interpretation bands with increasing likelihood ratios ranging from Very low (LR- 0.22; 80% CI 0.14–0.33) to Very high (LR + 11.33; 80% CI 7.31–17.00). TriVerity illness severity results allowed marked re-classification of the risk for “ICU-level care” as compared to clinical assessment (qSOFA scores) alone. In conclusion, TriVerity provides rapid, highly accurate and actionable results for the diagnosis and prognosis of patients with suspected acute infection and/or sepsis, supporting a major unmet medical need. TriVerity may improve personalized management of patients with suspected acute infections and suspected sepsis for improved overall healthcare outcomes.

Abstract Disclosure: R.J. Auchus: Consulting Fee; Self; Neurocrine Biosciences, Inc., Crinetics Pharmaceuticals, OMass Therapeutics, H Lundbeck A/S, Adrenas Therapeutics. Research Investigator; Self; Neurocrine Biosciences, Inc., Diurnal, Crinetics Pharmaceuticals, Spruce Biosciences. O. Hamidi: Advisory Board Member; Self; Corcept Therapeutics, Recordati Rare Diseases, Amryt Pharma, Neurocrine Biosciences, Inc., Xeris, Lantheus. R. Pivonello: Advisory Board Member; Self; Corcept Therapeutics, Recordati AG, Crinetics Pharmaceuticals, H. Lundbeck A/S. Research Investigator; Self; Corcept Therapeutics, Recordati AG, Strongbridge Biopharma, Neurocrine Biosciences, Inc. I. Bancos: Consulting Fee; Self; Corcept Therapeutics, Recordati Rare Diseases, HRA Pharmaceuticals, Neurocrine Biosciences, Inc., Diurnal, Spruce Biosciences, Sparrow Pharmaceuticals, Adrenas Therapeutics. Research Investigator; Self; Recordati Rare Diseases. G. Russo: Advisory Board Member; Self; Novartis Pharmaceuticals, Sandoz, Diurnal. Speaker; Self; Novartis Pharmaceuticals, Sandoz, Diurnal. S.F. Witchel: Research Investigator; Self; Neurocrine Biosciences, Inc. A.M. Isidori: Research Investigator; Self; Pfizer, Inc., Merck Serono, HRA Pharmaceuticals, Recordati AG, Corcept. P. Rodien: Consulting Fee; Self; Pfizer, Inc., Novo Nordisk, Lilly USA, LLC, Ipsen, HRA Pharmaceuticals, IBSA Pharma, Recordati Rare Diseases. U. Srirangalingam: Advisory Board Member; Self; Diurnal. Speaker; Self; Diurnal. F.W. Kiefer: Advisory Board Member; Self; AstraZeneca, Boehringer Ingelheim, Eli Lilly & Company, Novartis Pharmaceuticals, Novo Nordisk, Pfizer, Inc., Sanofi. Speaker; Self; AstraZeneca, Boehringer Ingelheim, Eli Lilly & Company, Novartis Pharmaceuticals, Novo Nordisk, Pfizer, Inc., Sanofi. H. Falhammar: Consulting Fee; Self; Diurnal, Roche Diagnostics, Neurocrine Biosciences, Inc., H Lundbeck A/S, Adrenas Therapeutics. D.P. Merke: Research Investigator; Self; Diurnal, Adrenas Therapeutics, Neurocrine Biosciences, Inc. N. Reisch: Consulting Fee; Self; Diurnal, Crinetics Pharmaceuticals, Neurocrine Biosciences, Inc., Spruce Biosciences, H Lundbeck A/S. J. Sturgeon: Employee; Self; Neurocrine Biosciences, Inc. E. Roberts: Employee; Self; Neurocrine Biosciences, Inc. V.H. Lin: Employee; Self; Neurocrine Biosciences, Inc. J.L. Chan: Employee; Self; Neurocrine Biosciences, Inc. R. Farber: Employee; Self; Neurocrine Biosciences, Inc.. Introduction: Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), a genetic disorder characterized by cortisol deficiency and excess adrenal androgens, typically requires management with supraphysiological glucocorticoid (GC) doses. Crinecerfont is a novel oral CRF1 antagonist that reduced elevated adrenocorticotropic hormone and adrenal androgens in patients with 21OHD in 14-day open-label Phase 2 studies. This Phase 3 study (CAHtalyst: NCT04490915) evaluated whether crinecerfont can reduce daily GC dose while maintaining androgen control in adults with 21OHD. Methods: Adults (≥18 years) with 21OHD, stable GC regimens at doses >13 mg/m2/d in hydrocortisone equivalents (HCe), and normal or elevated androstenedione (A4) were randomized (2:1) to crinecerfont 100 mg BID or placebo for 24 weeks. GC dosing was maintained stable for 4 weeks, followed by a planned GC down-titration over 8 weeks to achieve a GC dose of 8-10 mg/m2/d. GC doses were adjusted as needed during the last 12 weeks to maintain A4 control (≤120% of baseline or ≤upper limit of normal [ULN]) by week 24. Results: In the 182 randomized participants (51% male, mean age 31 years), demographics and baseline characteristics were similar between treatment arms (122 crinecerfont, 60 placebo). Mean GC dose at baseline was 17.6 mg/m2/d HCe (32 mg/d), with 58% on HC alone, 29% taking predniso[lo]ne, and 13% taking dexamethasone; mean pre-GC A4 (620 ng/dL) was elevated >2-3-fold the ULN. Over 95% of participants completed the double-blind treatment period. At week 24, the crinecerfont arm had a significantly greater percent reduction in GC dose while maintaining A4 control vs placebo (-27% vs -10%; least squares mean difference [LSMD]: -17%; p<0.0001) (primary endpoint). At week 4 (end of GC-stable period), a greater reduction in A4 prior to the morning GC dose was observed with crinecerfont vs placebo (LSMD: -345 ng/dL; p<0.0001) (key secondary endpoint). At week 24, a higher percentage of participants reached a protocol-defined physiological GC dose (≤11 mg/m2/d) while maintaining A4 control with crinecerfont (63% vs 18% for placebo; p<0.0001) (key secondary endpoint). The most common treatment-emergent adverse events (AEs) in the crinecerfont arm were fatigue (25% vs 15% for placebo), headache (16% vs 15%), and COVID-19 (14% vs 9%). There were few serious AEs (3% overall), with none assessed as related to the study drug. Conclusions: Crinecerfont, an oral CRF1 antagonist, represents a novel treatment option to improve androgen control for patients with 21OHD. In the largest interventional Phase 3 study conducted to date in adults with 21OHD, crinecerfont led to a significant reduction in A4 while GC dose was stable, enabling a significant percent reduction in GC dose while maintaining A4 control at 24 weeks. Crinecerfont was overall well tolerated. Presentation: 6/1/2024

Stenosis of the left main coronary artery (LM stenosis) is associated with significant mortality and morbidity due to the large area of affected myocardium. Evidence on the use of percutaneous coronary intervention (PCI) for the treatment of LM stenosis is growing. However, the role of Western guidelines on patients in the Asian-Pacific region is unclear due to anatomical variations, substantial heterogeneity in healthcare resources and infrastructure, and the lack of consensus on the optimal management of LM stenosis in the Asia-Pacific region. Hence, an Asian Pacific Society of Cardiology (APSC) working group developed consensus recommendations on the use of PCI in the management of LM stenosis in the Asia-Pacific region. The APSC expert panel reviewed and appraised the available evidence using the Grading of Recommendations Assessment, Development, and Evaluation system. Consensus recommendations were developed and put to an online vote. Consensus was reached when 80% of votes for a given recommendation were in support of ‘agree’ or ‘neutral’. The resulting 12 statements provide guidance for clinical practitioners in the region on the use of PCI in the treatment of patients with LM stenosis.

Importance In 2022, the US House of Representatives passed a bipartisan resolution (House of Representatives Resolution 1118 at the 117th Congress [2021-2022]) calling for meaningful nutrition education for medical trainees. This was prompted by increasing health care spending attributed to the growing prevalence of nutrition-related diseases and the substantial federal funding via Medicare that supports graduate medical education. In March 2023, medical education professional organizations agreed to identify nutrition competencies for medical education. Objective To recommend nutrition competencies for inclusion in medical education to improve patient and population health. Evidence Review The research team conducted a rapid literature review to identify existing nutrition-related competencies published between July 2013 and July 2023. Additional competencies were identified from learning objectives in selected nutrition, culinary medicine, and teaching kitchen curricula; dietetic core competencies; and research team–generated de novo competencies. An expert panel of 22 nutrition subject matter experts and 15 residency program directors participated in a modified Delphi process and completed 4 rounds of voting to reach consensus on recommended nutrition competencies, the level of medical education at which they should be included, and recommendations for monitoring implementation and evaluation of these competencies. Findings A total of 15 articles met inclusion criteria for competency extraction and yielded 187 competencies. Through review of gray literature and other sources, researchers identified 167 additional competencies for a total of 354 competencies. These competencies were compiled and refined prior to voting. After 4 rounds of voting, 36 competencies were identified for recommendation: 30 at both undergraduate and graduate levels, 2 at the undergraduate level only, and 4 at the graduate level only. Competencies fell into the following nutrition-related themes: foundational nutrition knowledge, assessment and diagnosis, communication skills, public health, collaborative support and treatment for specific conditions, and indications for referral. A total of 36 panelists (97%) recommended nutrition competencies be assessed as part of licensing and board certification examinations. Conclusions and Relevance These competencies represent a US-based effort to use a modified Delphi process to establish consensus on nutrition competencies for medical students and physician trainees. These competencies will require an iterative process of institutional prioritization, refinement, and inclusion in current and future educational curricula as well as licensure and certification examinations.