Citations

BackgroundFocally enlarged sulci (FES) are areas of proposed extraventricular fluid entrapment that may occur within idiopathic normal pressure hydrocephalus (iNPH) with radiographic evidence of disproportionately enlarged subarachnoid‐space hydrocephalus (DESH), and should be differentiated from atrophy.PurposeTo evaluate for change in FES size and pituitary height after shunt placement in iNPH.Study typeRetrospective.SubjectsA total of 125 iNPH patients who underwent shunt surgery and 40 age‐matched controls.Field Strength/Sequence1.5 T and 3 T. Axial T2w FLAIR, 3D T1w MPRAGE, 2D sagittal T1w.AssessmentFES were measured in three dimensions and volume was estimated by assuming an ellipsoid shape. Pituitary gland height was measured in the mid third of the gland in iNPH patients and controls.Statistical testsWilcoxon signed‐rank test for comparisons between MRI measurements; Wilcoxon rank sum test for comparison of cases/controls. Significance level was P < 0.05.ResultsFifty percent of the patients had FES. FES volume significantly decreased between the pre and first postshunt MRI by a median of 303 mm3 or 30.0%. Pituitary gland size significantly increased by 0.48 mm or 14.4%. FES decreased significantly by 190 mm3 or 23.1% and pituitary gland size increased significantly by 0.25 mm or 6% between the first and last postshunt MRI.Data ConclusionDecrease in size of FES after shunt placement provides further evidence that these regions are due to disordered cerebrospinal fluid (CSF) dynamics and should not be misinterpreted as atrophy. A relatively smaller pituitary gland in iNPH patients that normalizes after shunt is a less‐well recognized feature of altered CSF dynamics.Evidence Level3Technical EfficacyStage 2

AbstractBackgroundTwo studies that examined the interaction between HLA‐DRB1 and smoking in Parkinson's disease (PD) yielded findings in opposite directions.ObjectiveTo perform a large‐scale independent replication of the HLA‐DRB1 × smoking interaction.MethodsWe genotyped 182 single nucleotide polymorphism (SNPs) associated with smoking initiation in 12 424 cases and 9480 controls to perform a Mendelian randomization (MR) analysis in strata defined by HLA‐DRB1.ResultsAt the amino acid level, a valine at position 11 (V11) in HLA‐DRB1 displayed the strongest association with PD. MR showed an inverse association between genetically predicted smoking initiation and PD only in absence of V11 (odds ratio, 0.74, 95% confidence interval, 0.59–0.93, PInteraction = 0.028). In silico predictions of the influence of V11 and smoking‐induced modifications of α‐synuclein on binding affinity showed findings consistent with this interaction pattern.ConclusionsDespite being one of the most robust findings in PD research, the mechanisms underlying the inverse association between smoking and PD remain unknown. Our findings may help better understand this association. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Background and Objectives: Early allograft dysfunction (EAD) is considered a surrogate marker for adverse post-liver transplant (LT) outcomes. With the increasing use of nonconventional donors, EAD has become a more frequent occurrence. Given this background, we aimed to assess the prevalence and impact of EAD in an updated cohort inclusive of both conventional and nonconventional liver allografts. Materials and Methods: Perioperative and one-year outcomes were assessed for a total of 611 LT recipients with and without EAD from Mayo Clinic Arizona. EAD was defined as the presence of one or more of the following: bilirubin > 10 mg/dL on day 7, INR > 1.6 on day 7, or ALT and/or AST > 2000 IU/L within the first 7 days of LT. Results: Within this cohort, 31.8% of grafts (n = 194) came from donation after circulatory death (DCD) donors, 17.7% (n = 108) were nationally shared, 16.4% (n = 100) were allocated as post-cross clamp, and 8.7% contained moderate steatosis. EAD was observed in 52.2% (n = 321) of grafts in the study cohort (79% in DCD grafts and 40% in DBD grafts). EAD grafts had higher donor risk index (DRI) scores (1.9 vs. 1.6, p < 0.0001), were more likely to come from DCD donors (48% vs. 13.8%, p < 0.0001), were regionally allocated (p = 0.003), and had higher cold ischemia times (median 6.0 vs. 5.5 h, p = 0.001). Primary nonfunction events were rare in both groups (1.3% vs. 0.3%, p = 0.22). Post-LT acute kidney injury occurred at a similar frequency in recipients with and without EAD (43.6% vs. 30.3%, p = 0.41), and there were no differences in ICU (median 2 vs. 1 day, p = 0.60) or hospital (6 vs. 5 days, p = 0.24) length of stay. For DCD grafts, the rate of ischemic cholangiopathy was similar in the two groups (14.9% EAD vs. 17.5% no EAD, p = 0.69). One-year patient survival for grafts with and without EAD was 96.0% and 94.1% (HR 1.2, 95% CI 0.7–1.8; p = 0.54); one-year graft survival was 92.5% and 92.1% (HR 1.0, 95% CI 0.7–1.5; p = 0.88). Conclusions: In this cohort, EAD occurred in 52% of grafts. The occurrence of EAD, however, did not portend inferior outcomes. Compared to those without EAD, recipients with EAD had similar post-operative outcomes, as well as one-year patient and graft survival. EAD should be managed supportively and should not be viewed as a deterrent to utilization of non-ideal grafts.

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by stromal fibrosis, hypoxia, and nutritional deprivation. PDAC tumors grow aggressively, diagnosis is typically made after metastasis and the disease remains associated with poor outcomes. The triplet chemotherapy regimen of gemcitabine, nab-paclitaxel with cisplatin was associated with a median overall survival of 16.4 months in patients with metastatic pancreatic cancer in the first-line setting (Jameson et al., 2020). Nutritional, metabolic interventions offer an opportunity to fundamentally change the tumor microenvironment and improve outcomes for patients. A medically supervised ketogenic diet (MSKD) defined as lower carbohydrate, lower protein, and higher fat can significantly reduce glucose and insulin and increase metabolically active ketone bodies. A ketogenic diet combined with triplet chemotherapy (gemcitabine, nab-paclitaxel, cisplatin) was shown to inhibit murine pancreatic KPC tumor growth and to triple the survival benefit of chemotherapy alone. The ketogenic diet combined with triple chemotherapy was associated with glucose depletion, altered TCA substrate usage, and NADH elevation. Methods: In this Phase II randomized clinical trial (NCT04631445), we are evaluating a medically supervised ketogenic diet (MSKD) versus a standard diet when combined with the triplet therapy in patients with treatment-naive advanced pancreatic cancer. The primary endpoint is progression free survival for triplet therapy while on MSKD or non-MSKD. Secondary endpoints include disease control rate (PR+ CR+ SD for at least 9 weeks), change in CA 19-9 (or CA125, or CEA if not expressers of CA 19-9), average insulin levels, HbA1c, body weight, a comparison of gut microbial diversity, changes in serum metabolites and quality of life via the EORTC QLQ-C30 assessment. Unlike prior ketogenic intervention studies, the MSKD is being supported by a continuous care nutrition intervention through Virta Health Corp, that offers tracking of daily ketone and glucose levels, a web-based software application, education, and communication with a remote care team to ensure sustained nutritional ketosis. A total of 40 patients with untreated metastatic PDAC are planned for enrollment, 20 randomized to each arm. The trial opened for accrual November 2020. Citation Format: Diana Hanna, Gayle S. Jameson, Drew W. Rasco, Angela Alistar, Richard C. Frank, Anthony B. El-Khoueiry, Julia E. Wiedmeier, Caroline Roberts, Brandon Fell, Sarah Hallberg, Denise Roe, Derek Cridebring, Joshua Rabinowitz, Stephen Thomas Gately, Daniel D. Von Hoff. Randomized Phase II trial of two different nutritional approaches for patients receiving treatment for their advanced pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT549.

ObjectivePatients with myelin oligodendrocyte glycoprotein antibody (MOG‐IgG)‐associated disease (MOGAD) suffer from severe optic neuritis (ON) leading to retinal neuro‐axonal loss, which can be quantified by optical coherence tomography (OCT). We assessed whether ON‐independent retinal atrophy can be detected in MOGAD.MethodsEighty patients with MOGAD and 139 healthy controls (HCs) were included. OCT data was acquired with (1) Spectralis spectral domain OCT (MOGAD: N = 66 and HCs: N = 103) and (2) Cirrus high‐definition OCT (MOGAD: N = 14 and HCs: N = 36). Macular combined ganglion cell and inner plexiform layer (GCIPL) and peripapillary retinal nerve fiber layer (pRNFL) were quantified.ResultsAt baseline, GCIPL and pRNFL were lower in MOGAD eyes with a history of ON (MOGAD‐ON) compared with MOGAD eyes without a history of ON (MOGAD‐NON) and HCs (p < 0.001). MOGAD‐NON eyes had lower GCIPL volume compared to HCs (p < 0.001) in the Spectralis, but not in the Cirrus cohort. Longitudinally (follow‐up up to 3 years), MOGAD‐ON with ON within the last 6–12 months before baseline exhibited greater pRNFL thinning than MOGAD‐ON with an ON greater than 12 months ago (p < 0.001). The overall MOGAD cohort did not exhibit faster GCIPL thinning compared with the HC cohort.InterpretationOur study suggests the absence of attack‐independent retinal damage in patients with MOGAD. Yet, ongoing neuroaxonal damage or edema resolution seems to occur for up to 12 months after ON, which is longer than what has been reported with other ON forms. These findings support that the pathomechanisms underlying optic nerve involvement and the evolution of OCT retinal changes after ON is distinct in patients with MOGAD. ANN NEUROL 2022;92:476–485

Background: This study aimed to better characterize morbidly obese kidney transplant recipients, their clinical characteristics, and outcomes by using an unsupervised machine learning approach. Methods: Consensus cluster analysis was applied to OPTN/UNOS data from 2010 to 2019 based on recipient, donor, and transplant characteristics in kidney transplant recipients with a pre-transplant BMI ≥ 40 kg/m2. Key cluster characteristics were identified using the standardized mean difference. Post-transplant outcomes, including death-censored graft failure, patient death, and acute allograft rejection, were compared among the clusters. Results: Consensus clustering analysis identified 3204 kidney transplant recipients with a BMI ≥ 40 kg/m2. In this cohort, five clinically distinct clusters were identified. Cluster 1 recipients were predominantly white and non-sensitized, had a short dialysis time or were preemptive, and were more likely to receive living donor kidney transplants. Cluster 2 recipients were older and diabetic. They were likely to have been on dialysis >3 years and receive a standard KDPI deceased donor kidney. Cluster 3 recipients were young, black, and had kidney disease secondary to hypertension or glomerular disease. Cluster 3 recipients had >3 years of dialysis and received non-ECD, young, deceased donor kidney transplants with a KDPI < 85%. Cluster 4 recipients were diabetic with variable dialysis duration who either received non-ECD standard KDPI kidneys or living donor kidney transplants. Cluster 5 recipients were young retransplants that were sensitized. One-year patient survival in clusters 1, 2, 3, 4, and 5 was 98.0%, 94.4%, 98.5%, 98.7%, and 97%, and one-year death-censored graft survival was 98.1%, 93.0%, 96.1%, 98.8%, and 93.0%, respectively. Cluster 2 had the worst one-year patient survival. Clusters 2 and 5 had the worst one-year death-censored graft survival. Conclusions: With the application of unsupervised machine learning, variable post-transplant outcomes are observed among morbidly obese kidney transplant recipients. Recipients with earlier access to transplant and living donation show superior outcomes. Unexpectedly, reduced graft survival in cluster 3 recipients perhaps underscores socioeconomic access to post-transplant support and minorities being disadvantaged in access to preemptive and living donor transplants. Despite obesity-related concerns, one-year patient and graft survival were favorable in all clusters, and obesity itself should be reconsidered as a hard barrier to kidney transplantation.

Abstract Rationale The leading cause of death in coronavirus disease 2019 (COVID-19) is severe pneumonia, with many patients developing acute respiratory distress syndrome (ARDS) and diffuse alveolar damage (DAD). Whether DAD in fatal COVID-19 is distinct from other causes of DAD remains unknown. Objective To compare lung parenchymal and vascular alterations between patients with fatal COVID-19 pneumonia and other DAD-causing etiologies using a multidimensional approach. Methods This autopsy cohort consisted of consecutive patients with COVID-19 pneumonia (n = 20) and with respiratory failure and histologic DAD (n = 21; non–COVID-19 viral and nonviral etiologies). Premortem chest computed tomography (CT) scans were evaluated for vascular changes. Postmortem lung tissues were compared using histopathological and computational analyses. Machine-learning-derived morphometric analysis of the microvasculature was performed, with a random forest classifier quantifying vascular congestion (CVasc) in different microscopic compartments. Respiratory mechanics and gas-exchange parameters were evaluated longitudinally in patients with ARDS. Measurements and Main Results In premortem CT, patients with COVID-19 showed more dilated vasculature when all lung segments were evaluated (P = 0.001) compared with controls with DAD. Histopathology revealed vasculopathic changes, including hemangiomatosis-like changes (P = 0.043), thromboemboli (P = 0.0038), pulmonary infarcts (P = 0.047), and perivascular inflammation (P &lt; 0.001). Generalized estimating equations revealed significant regional differences in the lung microarchitecture among all DAD-causing entities. COVID-19 showed a larger overall CVasc range (P = 0.002). Alveolar-septal congestion was associated with a significantly shorter time to death from symptom onset (P = 0.03), length of hospital stay (P = 0.02), and increased ventilatory ratio [an estimate for pulmonary dead space fraction (Vd); p = 0.043] in all cases of ARDS. Conclusions Severe COVID-19 pneumonia is characterized by significant vasculopathy and aberrant alveolar-septal congestion. Our findings also highlight the role that vascular alterations may play in Vd and clinical outcomes in ARDS in general.

3601 Background: Two cfDNA assays are FDA-approved for use in advanced cancer pts across solid tumors. While several NCCN guidelines recommend cfDNA as a valid and useful method for molecular testing, the utility varies by cancer type. Despite the growing number of molecular alterations pertinent to first-line treatment in mCRC, current guidelines offer little guidance on the use of cfDNA in mCRC. Here we assess the ability of cfDNA to detect guideline-relevant actionable biomarkers informative for first-line therapy selection and beyond in patients with mCRC. Methods: We queried consecutive samples from advanced cancer pts with a diagnosis of CRC who underwent testing via a commercially available cfDNA assay (Guardant360) from September 2018 to January 2022. Validation and content of this assay has been previously described. To enrich for less heavily treated pts, we limited analysis to those whose first cfDNA test was done during the study period and only included the pt’s first test. The maximum variant allele fraction (maxVAF) for each test was used as a proxy for tumor shed and was compared between cancers with a Mann-Whitney test. The frequency of suspected germline alterations was assessed only in pts who received testing via a panel version with expanded mismatch repair (MMR) gene coverage. Tissue frequencies for select biomarkers were obtained from the MSK-IMPACT Clinical Sequencing Cohort in cBioPortal. Results: In total, 14,345 pts with mCRC received their first cfDNA test during the study period, with 92% of pts (13,190) having >1 cfDNA alteration detected. Median age was 62 and 44% of pts were female. The frequencies of key biomarkers are listed in Table 1. The median maxVAF was 5.6%, compared to 2.5% and 1.8% for pts with advanced gastric and NSCLC, respectively (p = < 0.0001 for both). The average turnaround time (TAT) for tests was 7 calendar days. Conclusions: cfDNA results from pts with mCRC demonstrated detection of biomarkers essential to first-line treatment decisions at a frequency comparable to what has been reported via tissue genotyping. mCRC pts had significantly higher tumor shed compared to other cancer types with guidelines that recommend cfDNA as an option for molecular testing, suggesting a potential gap in coverage. Tissue availability in mCRC does not guarantee comprehensive testing is completed quickly (compared to the 7-day TAT seen for cfDNA here), making it an attractive alternative strategy for first-line therapy selection in mCRC. [Table: see text]

TPS3172 Background: Ulixertinib (BVD-523) is a small molecule inhibitor of extracellular signal-regulated kinases 1/2 (ERK1/2) in development as a novel anti-cancer drug. Early clinical data demonstrated anti-tumor activity, especially for patients with tumors harboring atypical BRAF or MEK1/2 alterations (Sullivan et al., Cancer Discov. 2018;8(2):184-195). Atypical BRAF (non-V600) alterations can be categorized according to characteristics of molecular signaling (Class II or III), are seen in approximately 3% of all human cancers, and there are currently no approved therapies for this indication. Similar to atypical BRAF alterations, the incidence of MEK1/2 alterations are rare in human tumors (< 1 %). Preclinical data have demonstrated activity of ulixertinib in MEK mutant models. Ulixertinib has FDA fast-track designation for patients with solid tumors, other than CRC, with specific BRAF mutations (G469A, L485W, or L597Q). Designed with intent to register, the BVD-523-ABC clinical trial will continue evaluation of ulixertinib in patients with tumors harboring any atypical BRAF or MEK1/2 alteration (NCT04488003). Methods: This multi-center, phase II study, will be conducted in two parts and assess the clinical benefit, safety, pharmacokinetics, and pharmacodynamics of ulixertinib in patients with advanced malignancies. Ulixertinib will be administered at the RP2D of 600 mg BID for 28-day treatment cycles. Eligible patients will have locally advanced or metastatic cancer which progressed following standard systemic therapies, or for which the patient is not a candidate or refused systemic therapy. Planned correlative analyses include reverse phase protein array and transcriptomics of tumor tissue. Part A is open-label and tumor agnostic, except for group 4 and 6 (CRC patients only). Patients will enroll into one of six groups based on BRAF (groups 1-4) or MEK1/2 (groups 5-6) tumor alteration (38 patients per group). Overall response rate (ORR) is the primary endpoint for Part A, with secondary endpoints including duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Part B is tumor histology specific. Patients will be randomized to receive either ulixertinib or physician's choice of treatment in a 2:1 ratio. Up to three specified tumor histologies will be defined, guided by available Part A data (n = 80-100 per histology). The primary endpoint of Part B is PFS, and secondary endpoints include OS, ORR, and DOR. This study has enrolled 43 patients of the planned 228 in Part A at the time of abstract submission. Clinical trial information: NCT04488003.