Citations

ABSTRACT Background The COVID‐19 pandemic presented unprecedented challenges to hospital system and critical care resources, leading to significant changes to operations and patient care. There are limited national data on these changes and instances of unsanctioned deviations from patient care, yet understanding the COVID response is key to future preparedness efforts. We sought to understand how hospitals and states navigated scarcity during COVID‐19, particularly in the absence of a declaration of crisis standards of care. Methods Between February 2022 and September 2022 we conducted 34 interviews with 36 leaders of U.S. states' COVID‐19 planning and response efforts. Interviews were transcribed verbatim and verified. We analyzed interviews using iterative inductive thematic analysis for descriptions of resource scarcity and changes to policies and procedures to prevent rationing lifesaving care. Results Nearly all participants described equipment and personnel scarcity in their home institution or state during COVID‐19. Hospitals across regions and states developed formal and informal coordination processes for load and resource sharing in response to influxes of high‐acuity patients, avoiding formal rationing of lifesaving resources in many regions. Participants also described unsanctioned patient triage, early discharge, and patients counseled to accept less aggressive care (e.g., premature transition to hospice) in states that had not declared crisis standards of care. Conclusions Extending limited resources and inter‐institutional collaboration helped avoid formal rationing. Yet, patient care was unquestionably impacted due to scarcity, both real and perceived. Reports of using hospital triage protocols to deny patients lifesaving care outside of formally recognized crisis conditions and attempts to nudge patients to accept less‐resource‐intensive care are concerning. This may have had disproportionate effects on older adults, individuals with disabilities, and racial and ethnic minoritized groups. To avoid unsanctioned deviations from standard practice in future health emergencies, we recommend that transparent and equitable triage protocols are implemented with robust oversight.

Abstract Background Intracranial mesenchymal tumors, FET::CREB fusion-positive (ICMT), show fusions involving FET RNA-binding protein family genes (EWSR1 or FUS) and CREB family of transcription factors (ATF1, CREB1, or CREM). The methylation signature(s), gene expression characteristics, and clinical behavior of this important tumor type require further characterization. Methods We study the methylation profiles of 81 ICMT cases (61 newly profiled cases and 20 cases from publicly available sources). Clinicopathologic and genomic data were recorded for each case when available. Results ICMT showed a relatively distinct methylation signature compared to related tumors. Among the 65 cases where fusion types were documented, the identified fusions included EWSR1::ATF1 (25 cases), EWSR1::CREB1 (12 cases), EWSR1::CREM (21 cases), FUS::CREM (3 cases), and SMARCA2::CREM (4 cases). We confirmed the prior description of 2 distinct subgroups of ICMT (subclasses A and B). The majority of the cases belonged to subclass A (n = 69; 85%), which showed a higher median age compared to subclass B patients (26 years vs. 15 years). Subclass B cases (n = 12; 15%) showed shorter progression-free survival (P < 0.01). Gene expression analysis of ICMT showed key overexpressed markers in ICMT, with significant CREM overexpression regardless of fusion type, when compared to either meningioma alone or a larger group of CNS tumors. Conclusions This work provides further characterization of ICMT as an important CNS mesenchymal neoplasm that is prone to tumor recurrence, showing 2 prognostically relevant methylation subclasses and warranting diagnostic distinction from other epigenetically and histologically related tumors. ICMTs show substantial overexpression of the CREM gene, independent of fusion type.

Abstract Isolated/idiopathic rapid eye movement sleep behavior disorder (iRBD) is a usually prodromal manifestation of neurodegenerative disorders with α-synuclein pathology: Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Clinical trials in the iRBD population face substantial barriers: limited access to well-characterized cohorts, inconsistent assessment protocols across centers, and the absence of validated biomarkers of disease burden. The North American Prodromal Synucleinopathy (NAPS) Consortium was established to address these challenges and facilitate clinical trials for neuroprotective therapies targeting synucleinopathy at the earliest known stages. In this multi-site, longitudinal, observational study, nine academic centers across North America will enroll and follow over 500 individuals with iRBD from existing sleep centers. Sixty control participants, matched for age, sex, and race will also be recruited. A harmonized protocol—including a standardized clinical battery assessing motor, cognitive, autonomic, psychiatric, sensory, and sleep function; structured diagnostic adjudication; biospecimen collection; and centralized analysis of both polysomnography and neuroimaging data—is outlined herein and reflects NAPS Stage 2. Each participants completes these assessments annually, and are replaced in the event of phenoconversion. By unifying assessments and expanding geographic reach, NAPS lays the groundwork for efficient, well-powered clinical trials designed to delay or prevent progression of iRBD to overt PD, DLB, or MSA—ultimately enabling earlier, more effective therapeutic intervention for neurodegenerative disease. Registered at clinicaltrials.gov (NCT05826457).

Bone scintigraphy is a valuable adjunct to cross-sectional imaging and can be used to evaluate disease extent in multifocal processes such as blastic osseous metastatic disease, provide diagnostic information to aid in problem solving in challenging cases, and serve as the primary diagnostic modality for diseases that manifest with pathognomonic scintigraphic appearances.

837 Background: A recent randomized trial suggested that CR may influence ICI activity in patients with lung cancer. However, the same has not been established in GI cancers, where reports have shown mixed results with variable definitions of 'early' vs 'late' IT. We evaluated multiple approaches to assess the impact of CR on first-line ICI in GI malignancies. Methods: This retrospective study included patients from three Mayo Clinic sites (N=455). Both previously reported IT cutoffs and a new cutoff derived from ROC analysis were evaluated. Patients were categorized by the median of all ITs, the median of the first four ITs, and whether ≥20% of ITs occurred before the identified cutoff. Univariate and multivariate Cox regression (adjusting for age, MSI status, type of cancer, metastasis status, number of cycles, and receipt of chemotherapy with ICI) assessed associations with OS. KM analyses were performed to illustrate survival differences. The primary endpoint was OS. Results: When patients were categorized based on whether ≥20% of infusions occurred before 14:00 (ROC-derived cutoff), a significant association with OS was observed. On univariate analysis, early infusion timing was associated with improved survival (HR 2.30, 95% CI 1.58–3.32, p <0.001). This remained significant after multivariable adjustment (HR 2.11, 95% CI 1.41–3.16, p < 0.001). Median OS was 14.2 months in the early group vs 3.8 months in the late group (log-rank p < 0.001). Using previously defined cutoffs, categorization by the median IT of all infusions or the median of the first four infusions did not demonstrate a significant association with OS in either univariate or multivariate Cox regression analyses. Conclusions: These findings highlight the potential role of infusion timing as a chronotherapy factor in GI cancers. Given the retrospective design and heterogeneous population, prospective studies are warranted to validate this signal and clarify its clinical relevance. Baseline demographics of patients by infusion timing (early vs late). Variables Early N=412 (%) LateN=43(%) Total N=455(%) p-value Age <70 249(60.4) 21(48.8) 270 (59.3) 0.1 >70 163(39.6) 22(51.2) 185 (40.7) Gender F 118(28.6) 16(37.2) 134 (29.5) 0.3 M 294(71.4) 27(62.8) 321 (70.5) Cancer Type Gastroesophageal 109 (26.5) 8 (18.6) 117 (25.7) 0.1 Hepatocellular 159 (38.6) 24 (55.8) 183 (40.2) Biliary 86 (20.9) 4 (9.3) 90 (19.8) MSI-H 58 (14.1) 7 (16.3) 65 (14.3) Metastasis No 150 (36.4) 22 (51.2) 172 (37.8) 0.1 Yes 262 (63.6) 21 (48.8) 283 (62.2) Immunotherapy Cycle Number <6 189 (45.9) 33 (76.7) 222 (48.8) <0.001 >6 223 (54.1) 10 (23.3) 233 (51.2)

593 Background: TP53 and CDKN2A are the most frequently mutated tumor suppressors in BTC, each linked to poor outcomes. Their co-alteration remains unexplored due to the current single-gene classification. Methods: This is an international multicenter study involving 35 institutions across 3 continents (North America, Asia, South America). Genomic profiling was performed on tissue or blood samples using NGS. Patients (pts) were categorized as wild-type (wt) TP53/ wt CDKN2A (WT/WT) (42%), mutated (mut) TP53 /wt CDKN2A (45%), wt TP53 /mut CDKN2A (5%), mut TP53 /mut CDKN2A (8%). Associations between TP53 / CDKN2A status , clinical and genomic features were evaluated using Chi-squared/Kruskal-Wallis tests adjusted for multiple comparisons. Overall survival (OS) from start of first-line systemic therapy was analyzed by Kaplan–Meier and multivariate Cox regression (covariates: age, sex, stage, primary site, first-line treatment, TP53/CDKN2A status), p or q<0.05. Results: We included 1079 pts with BTC. Median age 66 years with intrahepatic BTC (46%), gallbladder cancer (25%), extrahepatic BTC (22%), undefined (6%), ampullary cancer (< 1%). Most had de novo metastatic disease (54%), followed by recurrent (38%) and locally advanced disease (8%). Treatment regimens included chemotherapy (87%), chemo-immunotherapy (12%) and immunotherapy alone (<1%). The most frequently actionable genes were HER2 (8%), IDH1 (7%), BRAF (6%), FGFR2 fusions (4%), MSI-High (H) (3%). HER2 alterations were prevalent in mut TP53 /wt CDKN2A vs WT/WT (11 vs 4%, q = 0.002). IDH1 alterations were more frequent in WT/WT vs TP53 mut/wt CDKN2A (10 vs 4%, q < 0.001). FGFR2 fusions were more common in wt TP53 /mut CDKN2A vs WT/WT (17 vs 6%, q < 0.001), mut TP53 /mut CDKN2A (17 vs 3%, q = 0.001) and mut TP53 /wt CDKN2A (17 vs 1%, q < 0.001). MSI-H was enriched in mut TP53 /mut CDKN2A vs wt TP53 /mut CDKN2A (11 vs 2%, q = 0.035), mut TP53 /wt CDKN2A (11 vs 3%, q = 0.002) and WT/WT (11 vs 2%, q < 0.001). TMB-H was more prevalent in mut TP53 /mut CDKN2A vs mut TP53 /wt CDKN2A (16 vs 8%, q < 0.001) and WT/WT (16 vs 3%, q < 0.024). There was no significant difference in ORR, DCR and PFS among the four groups. mut TP53 /mut CDKN2A had the shortest median OS, while WT/WT had the longest (Table). Only 14% of mut TP53 /mut CDKN2A received regimens including immunotherapy. Conclusions: mut TP53 /mut CDKN2A represents a high-risk subset enriched with MSI-H and TMB-H pts, underscoring the need to prioritize the development of immunotherapy strategies. TP53 / CDKN2A status is prognostic, stratifying patients into distinct survival groups and supporting NGS use in the first-line setting. mOS (months) (95% CI) HR (95% CI) P-value WT/WT 21.4 (19.0-24.4) reference wt TP53 /mut CDKN2A 17.3 (12.4-25.9) 1.16 (0.79-1.71) 0.442 mut TP53 /wt CDKN2A 17.4 (16.0-19.2) 1.21 (1.01-1.45) 0.040 mut TP53 /mut CDKN2A 13.8 (11.5-18.1) 1.54 (1.13-2.09) <0.001

567 Background: IDH2 mutation is rare (1%) in patients (pts) with cholangiocarcinoma and there are no data on prognosis in these pts and response to first line (1L) chemotherapy or off-label IDH2 inhibitor enasidenib. Methods: This IRB approved retrospective study included consecutive pts 18 years or older with IDH2 mutated biliary cancer identified between 2010-2024 at 4 large academic centers. Pt characteristics, systemic therapy(ies), next-generation sequencing (NGS) and survival data were obtained via review of electronic medical records. Survival probabilities were estimated using the product-limit method of Kaplan-Meier using SAS (v9.4, Cary, NC). Results: In 40 pts who met criteria, 9 (22.5%) underwent curative intent resection/ ablation, 34 (85%) had recurrent or de novo locally advanced or metastatic stage and of them 33 (82.5%) received any therapy for advanced cancer. Of these 33 pts, 25 (75.7%) were female, 29 (87.9%) non-Hispanic White and 32 (97%) had intrahepatic subtype with a median (range) age of 65 (28-82) years. NGS on tissue (51.5%), plasma (21.2%) or both tissue and plasma (27.3%) identified IDH2 R172* in 28 (84.8%), I98T in 1 (3%), F278fs in 1 (3%) pts and not reported/missing in 1 (3%) pt. Most common co-altered genes included TP53 (27.5%), ARID1A (17.5%), PBRM1 (12.5%), CDKN2A (10%), BAP1 (10%). FGFR2 fusion or N/KRAS mutation was present in 2 (5%) pts each. Of 33 pts with advanced stage, 1L therapy was gemcitabine/platinum +/- devimistat or durvalumab in 84.9%. Median (95% CI) progression-free survival (PFS) on 1L chemotherapy and overall survival were 6.6 (4.1-7.8) and 16.3 (12.1-28.9) months, respectively. Eight of 33 (24.2%) pts with advanced stage received off label enasidenib as Nth line therapy with median PFS (95% CI) 3.9 (1.1-5.1) months. Conclusions: Most pts with IDH2 mutation had advanced ds with median survival similar to those with IDH1 mutated advanced cholangiocarcinoma. Off label enasidenib had modest benefit in this rare subset of pts and should be investigated further.

561 Background: For patients with aHCC, second-line treatment options are not well established. The primary aim of this study was to evaluate the efficacy of Futi, an FGFR 1-4 inhibitor, in combination with Pem as a second line therapy in patients with FGF19-expressing aHCC. Methods: Patients aged ≥ 18 years, with histological/cytological diagnosis or radiological diagnosis of HCC, Child-Pugh (CP) class A-B7, Barcelona Clinic Liver Cancer (BCLC) A, B or C, ECOG performance status of 0-2, and FGF19+, by in-situ hybridization or immunohistochemistry, received Futi 20 mg once daily plus i.v. Pem 200mg every 3 weeks. The primary endpoint was progression-free survival at 6 months (PFS6). Secondary endpoints include overall survival (OS). The study was designed to enroll 22 evaluable patients to detect PFS6 from 25% (historical control) to 47%, assuming a 1-sided alpha of 0.1 with 80% power. All patients provided written consent. Eligible patients with consent who started treatment are considered evaluable. Results: The study was closed to enrollment early at the request of funding agency due to poor accrual. Between 8/2021 and 3/2024, 14 patients enrolled with 1 patient withdrawing consent before beginning protocol treatment. Among 13 evaluable patients, median age was 72 (range: 60-87) years, 7 (53.8%) were male, 12 CP A (92.3%), 7 BCLC C (53.8%), with 7 (53.8%) having received prior liver directed therapy. Median PFS was 15 weeks (95% confidence interval [CI]: 9.0-Not Estimable) and PFS6 was 23.1% (95% CI: 8.6%, 62.3%). Objective response rate was 0% (95% CI: 0%, 24.71%) and stable disease occurred in 7 (53.9%) of patients. Median OS was 55.7 weeks (95% CI: 47.3-NE). Nine (69.2%) patients experienced at least 1 grade 3+ adverse event (AE), and 2 (15.4%) patients experienced at least a grade 4+ AE. One patient had a grade 5 AE unrelated to study treatment (acute kidney injury). Most commonly reported AEs (occurring in more than 31% of patients) were hyperphosphatemia (76.9%), fatigue (69.3%), diarrhea (61.6%), AST (53.9%) and ALT (46.2%), dry eye (38.5%), nail changes (38.5%), rash-maculo-papular (38.5%), and mucositis oral (38.5%). Conclusions: This prospective study evaluated the use of a targeted treatment in combination with immunotherapy following first line immune-based therapy. This combination had modest activity as a second line therapy for patients with aHCC but did not meet the primary endpoint. The safety profile was acceptable and consistent with prior reports. An optimal second-line regimen remains a critical need. Clinical trial information: NCT04828486 .

554 Background: Atezo/Bev is the 1 st -line standard for advanced hepatocellular carcinoma (aHCC). Optimal 2 nd -line therapy post-Atezo/Bev remains undefined. This study evaluates continuation of atezolizumab with a MKI versus MKI alone in the 2 nd -line setting. Methods: This multicenter, randomized phase II trial enrolled patients with unresectable aHCC who progressed on Atezo/Bev. Patients were randomized 2:1 to atezolizumab plus MKI (cabozantinib or lenvatinib; Arm A) or MKI alone (Arm B). Stratification factors included MKI choice, viral etiology, and alpha-fetoprotein levels. Dual primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), duration of response (DOR), and safety. With 84 death and 89 PFS events, from 122 patients, this trial had 80% power to detect a hazard ratio (HR) of 0.556 in OS and HR of 0.571 in PFS with a one-sided type I error (alpha) of 0.05 for each endpoint. Results: Twenty patients were accrued across 5 U.S. centers, between 01/2022 and 03/2025, before early closure due to slow accrual. Eighteen received treatment (Arm A: n=13; Arm B: n=5). Baseline characteristics: median age 68 yr, extrahepatic 56%, Hep B+ 0%, Hep C+ 33%, NASH 33% and CP A (5 to 6) 100%. MKIs used were cabozantinib (Arm A: 6/13; Arm B: 4/5) and lenvatinib (Arm A: 7/13; Arm B: 1/5). Median follow-up was 28.0 months (mo), with 14 deaths reported. Median (95% CI) OS were 13.9 (7.1-Not Estimable [NE]) and 6.2 (5.1-NE) mo (Arm A and B respectively); and that of PFS 4.3 (2.3-NE) and 4.1 (3.7-NE) mo. ORR was 7.7% (1/13) in Arm A (responder received lenvatinib) and 0% (0/5) in Arm B. Grade ≥3 adverse events (at least possibly related) occurred in 46.2% of Arm A and 60.0% of Arm B patients. G3+ events occurring in >10% of patients included hypertension, fatigue, anorexia, and ALT elevation in Arm A; and hypertension, hallucination, nausea, hypomagnesemia, hypokalemia, mucositis, AST increased and colitis in Arm B. Conclusions: In this limited cohort, continuation of atezolizumab with MKI showed relative activity and manageable safety in aHCC post-Atezo/Bev. The AE profile for atezo/MKI is consistent with the known profile of respective agents. These findings support further investigation of immunotherapy-based combinations in the 2nd-line setting. Clinical trial information: NCT05168163 .

BACKGROUND: Patients with cervical artery dissection (CeAD) may experience a recurrent dissection, but its frequency, risk factors, and clinical implications are not well defined. We aimed to determine the risk, associated factors, and clinical impact of recurrent CeAD. METHODS: The STOP-CAD study (Antithrombotic Treatment for Stroke Prevention in Cervical Artery Dissection) was a multicenter international retrospective observational study of patients with CeAD treated between January 2015 and June 2022. Recurrent dissection was defined as a CeAD occurring at least 7 days after the diagnosis of the index event that affects a different artery or a different segment of the same artery. Patients were followed from day 7 up to 2 years. The absolute risk of recurrent CeAD over time was calculated using Kaplan-Meier survival estimates. Multivariable logistic and Cox regression models were used to assess predictors of CeAD recurrence. RESULTS: Of the 4023 patients included in STOP-CAD, 3836 (median age 46 years, 45% women) were eligible for this analysis. During a median (interquartile range) follow-up of 295 (97–720) days, 88 (2.29%) patients had a CeAD recurrence. Median time-to-recurrent CeAD was 53 (interquartile range, 18–157) days. The estimated risk of recurrent CeAD at 2 years was 3.22% (95% CI, 2.59%–4.00%). In multivariable analyses, younger age (adjusted odds ratios, 0.98 [95% CI, 0.96–0.99]), migraine (adjusted odds ratio, 1.88 [95% CI, 1.14–3.07]), and fibromuscular dysplasia (adjusted odds ratio, 2.90 [95% CI, 1.66–5.06]) were associated with CeAD recurrence, while presenting with an ischemic stroke was associated with a lower likelihood of recurrence (adjusted odds ratio, 0.47 [95% CI, 0.29–0.75]). These associations with CeAD recurrence over time were confirmed by Cox regression analyses. Among the 88 patients with recurrent CeAD, only 5 had accompanying ischemic events (3 strokes, 2 transient ischemic attacks). CONCLUSIONS: In this retrospective study, recurrent CeAD was uncommon, approximately half of the events were diagnosed within the first 2 months of the index event, and recurrent events rarely caused new ischemic events. Younger age, migraine, absence of ischemic stroke at presentation, and signs of fibromuscular dysplasia may help identify high-risk patients.