Citations

89 Background: Enterocolitis is a potentially fatal toxicity of CAPE. The safety of infusional 5-FU-based regimens in patients developing severe enterocolitis with CAPE is not well established in the literature. Methods: After institutional review board approval, a database search identified patients who received infusional 5-FU-based regimens between January 2015 and July 2022 in a tertiary care cancer center after experiencing severe CAPE-induced enterocolitis, defined as the presence of grade 3 or higher diarrhea and features of enterocolitis on computed tomography (CT) scan. Data on patient characteristics, grade of CAPE-induced diarrhea, clinical course, details of 5-FU-based regimens administered after recovery, and outcomes were collected by retrospective electronic chart review. Results: Among the 791 patients treated with CAPE during the study period, 27 (3.4%) developed grade 3 or higher diarrhea, and 15 of these 27 patients (1.9%) had evidence of enterocolitis on CT scan. All patients were treated with supportive measures. All but 1 patient recovered fully; 1 patient died due to a condition unrelated to CAPE toxicity. After complete recovery, 7 patients aged 46 to 69 years (median, 68 years) received FOLFOX (oxaliplatin and infusional 5-FU). The time interval between recovery from CAPE-induced enterocolitis and the start of infusional 5-FU ranged from 4 to 20 weeks (median, 12 weeks), with 3 patients starting 5-FU within 4-5 weeks of recovery. Standard dose 5-FU (2400 mg/m2 over 46 hours) was given to 2 of the 7 patients; the remaining 5 patients received 50% to 80% of the standard dose at the beginning of treatment, but eventually tolerated the standard dose. All patients tolerated 5-FU infusion without experiencing any grade 2 or higher 5-FU induced GI toxicity. Conclusions: Most patients developing severe enterocolitis with CAPE recover fully with appropriate supportive measures. Infusional 5-FU-based regimens appear to be safe in this patient group. Severe CAPE-induced enterocolitis should not preclude the use of infusional 5-FU-based regimens, especially in curative-intent settings such as adjuvant therapy.

Abstract Objective The Financial Capacity Instrument-Short Form (FCI-SF) is a performance-based measure of everyday financial skills that takes 15 min to administer. Although the FCI-SF has demonstrated excellent psychometric properties, advanced psychometric methods such as item response theory (IRT) can provide important information on the performance of individual test items in measuring financial capacity and in distinguishing between healthy and cognitively impaired individuals. Method Participants were 272 older adults diagnosed with mild cognitive impairment (MCI) and 1,344 cognitively healthy controls recruited from the Mayo Clinic Study of Aging at the Mayo Clinic in Rochester, Minnesota and also from the Cognitive Observations in Seniors study at the University of Alabama at Birmingham. Participants in each study were administered the FCI-SF, which evaluates coin/currency calculation, financial conceptual knowledge, use of a checkbook/register, and use of a bank statement. Results A unidimensional two-parameter logistic model best fit the 37 FCI-SF Test items, and most FCI-SF items fit the unidimensional two-parameter model well. The results indicated that all FCI-SF items robustly distinguished cognitively healthy controls from persons with MCI. Conclusions The study results showed that the FCI-SF performed well under IRT analysis, further highlighted the psychometric properties of the FCI-SF as a valid and reliable measure of financial capacity, and demonstrated the clinical utility of the FCI-SF in distinguishing between cognitively normal and cognitively impaired individuals.

NAFLD will soon be the most common indication for liver transplantation (LT). In NAFLD, HCC may occur at earlier stages of fibrosis and present with more advanced tumor stage, raising concern for aggressive disease. Thus, adult LT recipients with HCC from 20 US centers transplanted between 2002 and 2013 were analyzed to determine whether NAFLD impacts recurrence-free post-LT survival. Five hundred and thirty-eight (10.8%) of 4981 total patients had NAFLD. Patients with NAFLD were significantly older (63 vs. 58, p<0.001), had higher body mass index (30.5 vs. 27.4, p<0.001), and were more likely to have diabetes (57.3% vs. 28.8%, p<0.001). Patients with NAFLD were less likely to receive pre-LT locoregional therapy (63.6% vs. 72.9%, p<0.001), had higher median lab MELD (15 vs. 13, p<0.001) and neutrophil-lymphocyte ratio (3.8 vs. 2.9, p<0.001), and were more likely to have their maximum pre-LT alpha fetoprotein at time of LT (44.1% vs. 36.1%, p<0.001). NAFLD patients were more likely to have an incidental HCC on explant (19.4% vs. 10.4%, p<0.001); however, explant characteristics including tumor differentiation and vascular invasion were not different between groups. Comparing NAFLD and non-NAFLD patients, the 1, 3, and 5-year cumulative incidence of recurrence (3.1%, 9.1%, 11.5% vs. 4.9%, 10.1%, 12.6%, p=0.36) and recurrence-free survival rates (87%, 76%, and 67% vs. 87%, 75%, and 67%, p=0.97) were not different. In competing risks analysis, NAFLD did not significantly impact recurrence in univariable (HR: 0.88, p=0.36) nor in adjusted analysis (HR: 0.91, p=0.49). With NAFLD among the most common causes of HCC and poised to become the leading indication for LT, a better understanding of disease-specific models to predict recurrence is needed. In this NAFLD cohort, incidental HCCs were common, raising concerns about early detection. However, despite less locoregional therapy and high neutrophil-lymphocyte ratio, explant tumor characteristics and post-transplant recurrence-free survival were not different compared to non-NAFLD patients.

Abstract Mixed model repeated measures (MMRM) is the most common analysis approach used in clinical trials for Alzheimer's disease and other progressive diseases measured with continuous outcomes over time. The model treats time as a categorical variable, which allows an unconstrained estimate of the mean for each study visit in each randomized group. Categorizing time in this way can be problematic when assessments occur off‐schedule, as including off‐schedule visits can induce bias, and excluding them ignores valuable information and violates the intention to treat principle. This problem has been exacerbated by clinical trial visits which have been delayed due to the COVID19 pandemic. As an alternative to MMRM, we propose a constrained longitudinal data analysis with natural cubic splines that treats time as continuous and uses test version effects to model the mean over time. Compared to categorical‐time models like MMRM and models that assume a proportional treatment effect, the spline model is shown to be more parsimonious and precise in real clinical trial datasets, and has better power and Type I error in a variety of simulation scenarios.

AbstractWell‐selected patients with kidney disease and diabetes mellitus who undergo simultaneous kidney‐pancreas transplantation often experience dramatic improvements in quality of life and long‐term survival compared to those who remain on medical therapy. Over the past several years the importance of frailty in the pancreas transplant candidate and recipient populations has grown. More patients with advanced age have entered the waitlist, and complications from prolonged diabetes, even in younger patients, have created increased evidence of risk for frailty. Given these concerns, and the broad challenges facing pancreas transplantation volumes overall, we generated this review to help establish the impact and implications. We summarize the interplay of immunological factors, aging, environmental factors, diabetes mellitus, and chronic kidney disease that put these patients at risk for frailty. We discuss its measurement and recommend a combination of two instruments (both well‐validated and one entirely objective). We describe the outcomes for patients before and after pancreas transplantation who may have frailty, and what interventions can be taken to mitigate its effects. Broader investigation into frailty in the pancreas transplant population is needed to better understand how to select patients for pancreas transplantation and to how manage its consequences thereafter.

Abstract Mesenchymal stem/progenitor cells (MSPCs) have immunomodulatory activity. We previously observed that osteoprogenitors and CD8+T cells are increased in the bone marrow (BM) of mice lacking the transcription factor Nmp4. Transcriptome analysis of MSPCs from Nmp4−/− and wild type (WT) mice revealed significant changes in genes related to innate immune responses, including reduced expression of Tlr3 and Mda5 in the null MSPCs. Loss of Nmp4 increased mRNA translation, ribosomal biogenesis, and Gadd34 expression in MSPCs; collectively, these processes likely promote the unfolded protein response (UPR), expanding the processing capacity of the endoplasmic reticulum. Therefore, we hypothesized that disabling Nmp4 would improve innate immune cell function. To test this, Nmp4−/− mice (C57BL6) were infected intranasally with influenza A/PR8 (H1N1; 150pfu). Despite having similar virus load in the lung, H1N1-infected Nmp4−/− mice lost less body weight than WT mice post infection and had improved survival. Infected Nmp4−/− mice had fewer infiltrating neutrophils (PMNs; CD11b+/Ly6G+) and monocytes (CD11b+/SiglecFNeg/Ly6GNeg/Ly6C+) in bronchoalveolar lavage (BAL) but more BAL macrophages (CD11c+/SiglecF+); CD4+ and CD8+ T cells were not different between genotypes. Ex vivo, Nmp4-deficiency did not alter the differentiation of BM marrow-derived macrophages; however, Chil3/Ym1 and Alox15 mRNA expression was reduced in Nmp4−/− macrophages polarized with IL-4/IL-13, suggesting cell-autonomous regulation of M2 macrophage activation by Nmp4. Our data point to Nmp4 as a novel regulator of innate immunity and influenza response in mice.

Abstract A segment of the murine immune response-associated (Ia) antigen A beta chain mRNA has been cloned, and this cDNA clone has been used to examine the organization of the genes encoding these highly polymorphic cell surface proteins. To isolate this clone, pIA beta-1, we screened 5000 cDNA clones by a filter hybridization-selection assay using a rabbit heteroantiserum to identify the A beta chain produced in in vitro translation reactions. This clone corresponds to a segment of the mRNA encoding the beta chain of the murine I-A antigen. The 464 bp nucleotide sequence of the insert is consistent with a cDNA clone encoding the carboxyl end of the murine A beta chain. Comparison of this nucleotide sequence to a human Ia beta chain-derived cDNA clone suggests that the two clones could encode proteins that are about 90% homologous in this region. Southern blot analysis using pIA beta-1 as a probe to investigate the structure of the A beta chain gene in inbred strains of mice allows two conclusions. First, there is only one A beta chain gene homologous to this cDNA clone in each haploid mouse genome. Second, the restriction fragments encoding this gene are highly polymorphic. We postulate that the mechanism which generates polymorphic variation of the A beta chain may be involved in generating the restriction site polymorphism within or near the A beta chain gene.

Abstract Introduction We aimed to define a Mayo Preclinical Alzheimer's disease Cognitive Composite (Mayo‐PACC) that prioritizes parsimony and use of public domain measures to facilitate clinical translation. Methods Cognitively unimpaired participants aged 65 to 85 at baseline with amyloid PET imaging were included, yielding 428 amyloid negative (A‐) and 186 amyloid positive (A+) individuals with 7 years mean follow‐up. Sensitivity to amyloid‐related cognitive decline was examined using slope estimates derived from linear mixed models (difference in annualized change across A+ and A‐ groups). We compared differences in rates of change between Mayo‐PACC and other composites (A+ > A‐ indicating more significant decline in A+). Results All composites showed sensitivity to amyloid‐related longitudinal cognitive decline (A+ > A‐ annualized change p < 0.05). Comparisons revealed that Mayo‐PACC (AVLT sum of trials 1‐5+6+delay, Trails B, animal fluency) showed comparable longitudinal sensitivity to other composites. Discussion Mayo‐PACC performs similarly to other composites and can be directly translated to the clinic.