Citations

Abstract Purpose: Head and neck (HN) radiotherapy contour quality directly impacts local control (LC) and survival; however, few departments peer review (PR) contours prior to radiotherapy planning (RTP). This study reports outcomes of a single institution’s formal HN contour PR process. Methods: A formal HN contour PR process was implemented. Prior to RTP, HN radiation oncologists reviewed contours, provided feedback and assigned contour grades as follows: R0 (no change), R1 (minor revision, not high risk) or R2 (major revision; high risk). The PR task was completed and the contour grade was recorded. Cochran-Armitage trend test was performed. Results: Pilot PR process was performed over a 7-month period for 88 patients, followed by a maintenance phase. Contours were graded as follows: R0 ( N = 51), R1 ( N = 20) and R2 ( N = 17). Over time, the number of R2 revisions decreased ( p = 0.0001); month 1 ( N = 7), month 2 ( N = 3), month 3 ( N = 5), month 4 ( N = 2) and months 5–7 ( N = 0). Conversely, the number of R0 revisions improved over time ( p = 0.0203); month 1 ( N = 5), months 2–3 ( N = 9), month 4 ( N = 5), month 5 ( N = 8), month 6 ( N = 12) and month 7 ( N = 3). Each radiation oncologist demonstrated reduction in R2 revisions during the pilot. During maintenance, all 3 radiation oncologists demonstrated low rates of R2 revisions of less than 3 cases per year. Conclusion: Incorporation of HN contour PR into routine clinical workflow is feasible. The collective experience of multiple high-volume HN radiation oncologists led to improved contour quality in the pilot for each radiation oncologist and continued to ensure high quality in the maintenance phase.

566 Background: FGFR inhibitors (FGFRi) have an established role in treating FGFR2-altered (alt) cholangiocarcinoma (CCA). Tinengotinib, a novel FGFRi, has shown promising activity overcoming acquired resistance to prior FGFRi. We present biomarker analyses evaluating tinengotinib’s ability to overcome prior FGFRi resistance and to elucidate mechanism of resistance to tinengotinib. Methods: Eligible patients (pts) with advanced/metastatic CCA who had received ≥ 1 prior systemic chemotherapy were treated with tinengotinib 10 mg daily across 4 Cohorts: A1: FGFR2 fusion (fus) with primary progressive disease (PD) on prior FGFRi; A2: FGFR2 fus with PD after prior response to FGFRi; B: FGFR alt without FGFR2 fus; C: FGFR wild-type. Efficacy was assessed by RECIST v1.1. All pts underwent liquid biopsy for circulating tumor DNA (ctDNA) at baseline; additional timepoints include cycle 3 day 1 (C3D1), time of PD, and end of treatment (EOT). Samples were analyzed using FoundationOne Liquid panel. Results: 27 out of 55 enrolled pts had biomarker samples collected at baseline and C3D1. Among them, pts in A1 (n=10, 107 mutations (mut)), B (n=8, 90 mut) and C (n=5, 74 mut) showed a significant decrease in short variant allele frequencies (VAF) from baseline to C3D1 by a median relative VAF reduction of 100% (p<0.0001) for each of the three cohorts. Although a median relative VAF reduction of 33.3% was seen in A2 (n=4, 15 mut), this was not significant (p=0.6093) likely due to low baseline mutation burden. A ≥50% reduction in ctDNA was associated with improved progression free survival (p<0.0014). Additionally, 100% of median relative reductions in FGFR2 kinase domain (KD) mut were seen in A1 and B (p<0.0001, 95% CI 100-100% and p=0.0156, 95% CI 83.6-100%, respectively), with 92% and 57% clearance of initial FGFR2 KD mut by C3D1. In a subgroup of 10 pts with biomarker sampling at baseline and EOT, 3 pts in A1 with acquired resistance showed emergence of novel FGFR2 mut, loss of FGFR-sensitive mut and new mut in alternate pathways (e.g., AKT, EGFR, RAS/MAPK) while retaining the original FGFR2 fus. 1 pt from B developed resistance due to new FGFR2 rearrangements and FGFR2 mut. 4 FGFR wild-type pts from C developed resistance involving mut in TP53, KRAS, and other oncogenic drivers. Conclusions: These findings provide genomic evidence that tinengotinib may overcome resistance to prior FGFRi treatment in FGFR2 fus-positive CCA, as reflected by significantly reductions in ctDNA VAFs and frequent clearance of FGFR2 KD mutations. The emergence of resistance alterations including de novo FGFR2 mutations and bypass pathways activations indicates acquired resistance that may limit long-term benefit. These results support further investigation with expanded biomarker sampling to better characterize resistance evolution and guide therapy optimization in an ongoing Phase 3 trial. Clinical trial information: NCT04919642 .

Abstract Background Isolated REM sleep behavior disorder (iRBD) is a parasomnia that reflects an evolving α‐synucleinopathy disorder, providing an opportunity to study early pathological changes. While diffusion tensor imaging (DTI) studies have shown white matter changes in iRBD, Neurite Orientation Dispersion and Density Imaging (NODDI) may offer better biological specificity in characterizing microstructural alterations through measures of Neurite Density Index (NDI), Orientation Dispersion Index (ODI), and Free Water Fraction (FWF). Method We included 77 participants with polysomnography‐confirmed iRBD from the North American Prodromal Synucleinopathy (NAPS) Consortium and 154 age‐ and sex‐matched cognitively unimpaired controls from the Mayo Clinic Study of Aging. White matter microstructure was evaluated using standardized multi‐shell diffusion on 3T MRI, quantifying DTI metrics (fractional anisotropy, FA; and mean diffusivity, MD) and NODDI parameters across bilateral white matter tracts defined by the JHU “Eve” WM atlas. Group differences were assessed using conditional logistic regression, with correlations to motor performance evaluated using the Purdue Pegboard and Alternating Finger Tapping tests. Result Compared to controls, iRBD participants demonstrated widespread and bidirectional white matter changes across major white matter pathways (see Figure 1 for glass brain visualizations). While predominantly showing decreases, FA exhibited some increases, particularly in the corticospinal tract. MD showed a largely opposite pattern with predominantly increased values across tracts. NODDI metrics revealed complex bidirectional patterns: ODI was broadly increased across multiple tracts with focal decreases, while NDI showed a pattern of predominantly decreased values alongside localized increases. FWF demonstrated a mixed pattern with predominant decreases across most tracts. In addition, both DTI and NODDI metrics showed extensive, moderate correlations with the Purdue Pegboard Test and Alternating Finger Tapping performance ( T = 2.0, p < 0.05, Figure 2). Conclusion Our study highlighted widespread and complex bidirectional white matter microstructural alterations in individuals with iRBD, demonstrating significant correlations with dexterity and motor performance even during the prodromal stage. These results suggest that extensive white matter abnormalities occur early in prodromal α‐synucleinopathies and highlight the value of advanced diffusion imaging techniques in characterizing iRBD and its potential prediction of phenoconversion to overt neurodegenerative disorders.

Abstract Secondary central nervous system (CNS) large B-cell lymphoma (SCNSL) occurs in the de novo setting, as a CNS-isolated relapse, or synchronous (concomitant CNS and systemic) relapse. SCNSL is a devastating event without therapeutic consensus. Thus, we aimed to evaluate treatment outcomes in an international cohort. Progression-free survival (PFS), overall survival (OS), and cumulative incidence of relapse (CIR, estimated using competing-risk models) were reported. Prognostic factors were identified in a 6-month landmark multivariate analysis. Outcomes after thiotepa autologous stem cell transplant (ASCT) and chimeric antigen receptor (CAR) T-cell therapy (CAR-T) delivered at relapse were compared after propensity score matching (PSM). A total of 1139 patients were included in the analysis (de novo: 537; relapsed SCNSL: 602). Two-year PFS estimates were 40.4%, 43.9%, and 16.2% for de novo SCNSL, CNS-isolated relapse, and synchronous relapse, respectively. Patients with CNS-isolated relapse demonstrated low rates of systemic recurrence (24-month CIR, 6%). Thiotepa-ASCT correlated with longer survival in de novo SCNSL (PFS: hazard ratio [HR], 0.57; P = .005; and OS: HR, 0.62; P = .023) and CNS-isolated relapses (PFS: HR, 0.55; P = .002; and OS: HR, 0.39; P&lt; .0001). ASCT (thiotepa or no thiotepa) also associated with improved survival in synchronous relapses (PFS: HR, 0.57; P = .023; and OS: HR, 0.48; P = .019). Higher survival with thiotepa-ASCT than CAR-T was observed after PSM (PFS: HR, 0.45; P = .005 and OS: HR, 0.41; P = .014). These data support thiotepa-ASCT in eligible patients, particularly de novo disease and CNS-isolated relapses. CNS-isolated relapse was infrequently associated with systemic recurrence, supporting treatment regimens adopted from primary CNS lymphoma.

ABSTRACT A prevailing model holds that human cytomegalovirus (HCMV) spreads cell-to-cell spread upon initial culturing from clinical specimens and that de novo mutations in the UL128-131 genes reduce expression of glycoprotein complex gH/gL/UL128-131 (pentamer) relative to gH/gL/gO (trimer), which in turn enhances virion infectivity and favors cell-free spread. The clone Merlin-BAC (ME) expresses far more pentamer than trimer and is highly cell-associated, whereas clone TB40-BAC4 (TB) expresses mostly trimer and spreads predominantly cell-free. A single G>T polymorphism in TB relative to ME was shown to impair UL128 mRNA splicing, reducing pentamer expression and enhancing infectivity and cell-free spread. However, enhanced cell-free spread of ME due to pentamer suppression did not come at the expense of efficient cell-to-cell spread, and cell-to-cell spread of TB was especially poor despite highly infectious intracellular virus. Most of the nucleotide diversity in the HCMV genome is due to 17 genes that have up to 14 alleles each, and TB and ME match at only two of the 17. Here, we report a set of recombinant HCMV generated by coinfecting cells with TB and ME. Trimer:pentamer ratio and virion infectivity largely aligned with the TB or ME UL128, with “TB-like” recombinants displaying more trimer and higher infectivity and “ME-like” recombinants displaying more pentamer and lower infectivity. Strikingly, some recombinants had shifts in preference for cell-free vs cell-to-cell spread without predicted changes to trimer:pentamer ratio or virion infectivity, demonstrating uncoupling of these phenotypes. IMPORTANCE The emerging picture of HCMV genetic diversity in vivo prompts a reevaluation of how in vitro -characterized phenotypes, such as the abundance of different viral envelope glycoproteins, virion infectivity, and tendency toward cell-free or direct cell-to-cell spread, reflect viral characteristics in vivo . Laboratory examination of HCMV phenotypes has included a limited sampling of the apparent in vivo genetic diversity. A widely held model that directly links cell-free and cell-to-cell spread characteristics to glycoprotein display and virion infectivity also presumes that HCMV is predominantly cell-associated in vivo . These have implications for intervention strategies, such as calling into question the therapeutic benefit of neutralizing antibodies. Our finding that spread characteristics can be uncoupled from glycoprotein display and virion infectivity suggests a model that includes both cell-free and cell-associated spread as bona fide wild-type phenotypes for different allelic haplotypes. This model would allow a broader examination of neutralizing antibodies as correlates of protection.

Abstract Background African Americans (AA) are twice as likely to develop dementia than non‐Hispanic Whites but remain underrepresented in Alzheimer's Disease (AD) research. Recent studies have identified AA specific risk factors for AD. Therefore, targeted biomarkers and/or therapies may be needed to effectively treat AD in AA. In this study, we aimed to determine if genetic variants that show association with AD‐risk, plasma transcript or protein levels in AA, may serve as accurate and accessible AD biomarkers. Method In 189 clinically diagnosed AA AD cases and 183 AA cognitively unimpaired (CU) controls, we performed targeted DNA sequencing of 10 AD‐associated loci. Genetic variants at these loci were tested for association with corresponding plasma transcripts and total tau protein levels previously measured in this cohort using a custom nanoString panel and Simoa assays, respectively. Utilizing phased haplotypes (SHAPEIT4) from target sequencing, we inferred local ancestry (RFMix v2) using five superpopulations from the 1000 Genomes Project as anchors. Subsequently, we tested the association of each ancestry specific allelic dosages with endophenotypes using Tractor. In receiver operating characteristic (ROC) analyses, the most significant e/pQTLs were added sequentially to a base model that included age and sex to identify e/pQTLs that improved the accuracy to correctly classify AD cases and CU controls. Result Of the 5,112 variants that were tested, 70 were nominally associated with AD‐risk and with plasma transcript or protein levels. Seven of these 70 variants also showed nominally significant associations of AD‐risk and transcript levels with either African or East Asian local ancestry. ROC analysis of age, sex, 33 e/pQTLs in APOE , SORL1 , TLR4 , EPHA1 , ABCA7 , CLU , and CR1 , and plasma levels of APP, ABCA7, AKAP9, CD14, CLU, and APOE ‐ɛ4 dosage achieved 88.2% area under the curve to discriminate AD vs. CU, a 30.4% improvement over the base model that only included age and sex. Conclusion Plasma transcript levels and e/pQTLs are promising diagnostic biomarkers for AD that may improve accessibility and reduce costs for a more accurate diagnosis of AD.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cervical Cancer provide diagnostic workup, staging, and various treatment recommendations for cervical cancer based on clinical and surgical staging. This selection from the NCCN Guidelines for cervical cancer specifically focuses on diagnosis and workup, principles of staging and surgery, and primary treatment recommendations for early-stage and advanced disease and provides a detailed overview of systemic therapy recommendations for cervical cancer.

Abstract Background Small vessel vasculitides (SVV) comprise a heterogeneous group of cutaneous SVV (CSVV) that can be skin‐limited or systemic. Given their diverse forms and symptoms and the lack of a standardized diagnostic approach, it is crucial to establish clear and consensus‐driven recommendations for diagnosis. Objectives To standardize diagnosis for the detection of the type, extent, potential causes or underlying conditions of CSVV. Methods International experts comprised the panel. The Delphi panel data was collected through two rounds of questionnaires. Agreement was measured using an 11‐point Likert scale (0 = strongly disagree, 10 = strongly agree). A 7‐vote minimum was required for agreement on each statement. Delphi panel statements scoring 3–7 were discussed during the meeting. Results 20 experts participated in the first round of the Delphi panel, while 17 experts took part in the second. They agreed that the diagnosis of CSVV relies on a combination of clinical manifestations, laboratory findings and histopathology. Palpable purpura on the lower extremities is recognized as the most reliable hallmark for most SVV and a sign of immune complex vasculitis. When the latter is suspected, a skin biopsy for direct immunofluorescence (DIF) should be obtained from an early, partially blanchable macule because the type of perivascular immunoglobulin is important for further diagnosis. The proper selection of biopsy sites for routine HE biopsy depends on the morphology of lesions. A comprehensive medical history and selected laboratory testing should be conducted to investigate organ involvement, potential causes and associated conditions. The extent of diagnostic procedures should be based on the severity, duration, systemic symptoms and recurrence of SVV. Conclusions Experts reached a strong consensus on the management of CSVV patients, culminating in the first International Consensus Statement for adult CSVV. This statement proposes a practical management algorithm and underscores the importance of collaboration in rare diseases management.

Importance The choice of induction agent during rapid sequence intubation (RSI) of critically ill adults may affect clinical outcomes. Although ketamine and etomidate are frequently used for RSI, their comparative effectiveness remains controversial. Objective To compare the safety of etomidate vs ketamine for emergency RSI in critically ill adults. Design, Setting, and Participants This cohort study used a target trial emulation with observational data collected between March 1, 2022, and April 30, 2024, from 18 emergency departments across Brazil, with data from the Brazilian Airway Registry Cooperation. Adults who underwent RSI and received either etomidate or ketamine as a sole hypnotic agent were included; those with preintubation cardiac arrest or immediate postintubation transfer were excluded. Exposure Administration of etomidate or ketamine as the induction agent for RSI. Main Outcomes and Measures The primary outcome was 28-day in-hospital mortality. Secondary outcomes included 7-day in-hospital mortality, first-attempt intubation success, and major adverse events (new hemodynamic instability, severe hypoxemia, and cardiac arrest) within 30 minutes after intubation. Inverse probability of treatment weighting was used to adjust for confounding. Risk ratios (RRs) and risk differences (RDs) with 95% CIs were used to compare outcomes between groups. Results Among 1810 patients (median age, 64 years [IQR, 50-74 years]; 1048 men [57.9%]), 514 received ketamine and 1296 received etomidate. The median shock index was higher in the ketamine group than the etomidate group (0.81 [IQR, 0.65-1.01] vs 0.76 [IQR, 0.59-0.99]), and preintubation vasopressor use was more common in the ketamine group than the etomidate group (191 of 514 [37.2%] vs 391 of 1296 [30.2%]). Weighted 28-day mortality was higher with etomidate than ketamine (60.5% [95% CI, 57.2%-63.8%] vs 54.4% [95% CI, 45.0%-63.9%]; RR, 1.14 [95% CI, 1.03-1.27]; RD, 7.6% [95% CI, 2.0%-13.3%]). Seven-day mortality was also higher with etomidate than ketamine (35.2% [95% CI, 32.0%-38.3%] vs 30.1% [95% CI, 23.5%-36.7%]; RR, 1.19 [95% CI, 1.04-1.35]). New hemodynamic instability within 30 minutes after intubation was more frequent with ketamine (24.2% [95% CI, 20.4%-28.0%] vs 18.9% [95% CI, 16.7%-21.0%]; RR, 0.78 [0.64-0.95]). There were no statistically significant differences in the other secondary outcomes. Conclusions and Relevance In this cohort study of critically ill adults undergoing RSI, etomidate use was associated with higher in-hospital mortality at 7 and 28 days compared with ketamine. These findings highlight the need for definitive randomized clinical trials to compare both agents.