Citations

AbstractBackgroundEnergy balance-related biomarkers are associated with risk and prognosis of various malignancies. Their relationship to survival in metastatic colorectal cancer (mCRC) requires further study.MethodsBaseline plasma insulin-like growth factor (IGF)-1, IGF-binding protein (IGFBP)-3, IGFBP-7, C-peptide, and adiponectin were measured at time of trial registration in a prospective cohort of patients with mCRC participating in a National Cancer Institute–sponsored trial of first-line systemic therapy. We used Cox proportional hazards regression to adjust for confounders and examine associations of each biomarker with overall survival (OS) and progression-free survival (PFS). P values are 2-sided.ResultsMedian follow-up for 1086 patients was 6.2 years. Compared with patients in the lowest IGFBP-3 quintile, patients in the highest IGFBP-3 quintile experienced an adjusted hazard ratio (HR) for OS of 0.57 (95% confidence interval [CI] = 0.42 to 0.78; Pnonlinearity < .001) and for PFS of 0.61 (95% CI = 0.45 to 0.82; Ptrend = .003). Compared with patients in the lowest IGFBP-7 quintile, patients in the highest IGFBP-7 quintile experienced an adjusted hazard ratio for OS of 1.60 (95% CI = 1.30 to 1.97; Ptrend < .001) and for PFS of 1.38 (95% CI = 1.13 to 1.69; Ptrend < .001). Plasma C-peptide and IGF-1 were not associated with patient outcomes. Adiponectin was not associated with OS; there was a nonlinear U-shaped association between adiponectin and PFS (Pnonlinearity = .03).ConclusionsAmong patients with mCRC, high plasma IGFBP-3 and low IGFBP-7 were associated with longer OS and PFS. Extreme levels of adiponectin were associated with shorter PFS. These findings suggest potential avenues for prognostic and therapeutic innovation.

Abstract Asparagine‐linked glycosylation 13 homolog ( ALG13 ) encodes a nonredundant, highly conserved, X‐linked uridine diphosphate (UDP)‐ N ‐acetylglucosaminyltransferase required for the synthesis of lipid linked oligosaccharide precursor and proper N‐linked glycosylation. De novo variants in ALG13 underlie a form of early infantile epileptic encephalopathy known as EIEE36, but given its essential role in glycosylation, it is also considered a congenital disorder of glycosylation (CDG), ALG13‐CDG. Twenty‐four previously reported ALG13‐CDG cases had de novo variants, but surprisingly, unlike most forms of CDG, ALG13‐CDG did not show the anticipated glycosylation defects, typically detected by altered transferrin glycosylation. Structural homology modeling of two recurrent de novo variants, p.A81T and p.N107S, suggests both are likely to impact the function of ALG13. Using a corresponding ALG13‐deficient yeast strain, we show that expressing yeast ALG13 with either of the highly conserved hotspot variants rescues the observed growth defect, but not its glycosylation abnormality. We present molecular and clinical data on 29 previously unreported individuals with de novo variants in ALG13 . This more than doubles the number of known cases. A key finding is that a vast majority of the individuals presents with West syndrome, a feature shared with other CDG types. Among these, the initial epileptic spasms best responded to adrenocorticotropic hormone or prednisolone, while clobazam and felbamate showed promise for continued epilepsy treatment. A ketogenic diet seems to play an important role in the treatment of these individuals.

TPS4661 Background: Liposomal irinotecan administered with 5-fluorouracil/leucovorin (5-FU/LV) is approved in the USA for metastatic pancreatic ductal adenocarcinoma (mPDAC) following progression with gemcitabine-based therapy. A phase 1/2 study in previously untreated locally advanced/metastatic PDAC showed promising anti-tumor activity with liposomal irinotecan 50 mg/m2 free base + 5-FU 2400 mg/m2 + LV 400 mg/m2 + oxaliplatin (OX) 60 mg/m2 on days 1 and 15 of a 28-day cycle (Wainberg et al. Ann Oncol 2019;30 Suppl 4: SO-005). Herein, we present the design of the phase 3 NAPOLI-3 study investigating the efficacy and safety of this regimen as first-line therapy in patients with mPDAC. Methods: NAPOLI-3 (NCT04083235) is a phase 3, open-label, randomized, global study in adults with histologically/cytologically confirmed pancreatic adenocarcinoma not previously treated in the metastatic setting. Patients are required to have one or more metastatic tumors measurable with computed tomography/magnetic resonance imaging and an Eastern Cooperative Oncology Group performance status score of 0–1. Site activation began in Dec 2019 and enrollment is ongoing. Random allocation (1:1) of 750 patients is planned to liposomal irinotecan + 5-FU/LV + OX (regimen as per phase 1/2 study) or nab-paclitaxel 125 mg/m2 + gemcitabine 1000 mg/m2 on days 1, 8 and 15 in a 28-day cycle. The primary endpoint is overall survival (OS). Secondary endpoints (progression-free survival [PFS] and overall response rate assessed with Response Evaluation Criteria in Solid Tumors v1.1 criteria) will be compared only if the primary endpoint shows superiority for liposomal irinotecan + 5-FU/ LV + OX over nab-paclitaxel + gemcitabine. Safety assessments include adverse-event monitoring. Patients will continue treatment until disease progression, unacceptable toxicity or study withdrawal, and will then be followed for survival every 2 months until death or study end (when all patients have died, withdrawn consent or are lost to follow-up). Clinical trial information: NCT04083235 .

e16076 Background: Median overall survival (mOS) of patients (pt) with metastatic colorectal cancer (mCRC) has improved steadily over the past two decades. However, epidemiological data suggest that cancer outcomes for rural compared to urban dwelling pts are worse. In this study, we retrospectively compared progression free survival (PFS) and OS among mCRC pts residing in urban versus rural areas enrolled in N9741 (1997-2004) and CALGB 80405 (2005-2012) clinical trials. Methods: Zip code data from the Centers for Disease Control (CDC) were used to classify pts into rural or urban dwellers. Chi-square and Kruskal Wallis analyses were used to compare the groups. Survival outcomes were evaluated using Kaplan-Meier estimates, compared by stratified log rank and cox proportional hazards models. Results: In N9741 and 80405 respectively, 217 (35%) and 521 (21%) pts resided in rural areas. Median age of mCRC pts at diagnosis was 60.5 yrs. (rural) compared to 58.6 yrs. (urban) in 80405 (P < 0.01) and 59.6 yrs. to 60.2 yrs. in N9741 (P = 0.4). In 80405, pts in rural areas were less likely to be female (35% vs 43%, P < 0.01) black (6.6% vs 15.1%, P < 0.01), unmarried (51% vs 62%, P < 0.01), and to have private insurance (PI) (45% vs 50%, P = 0.03) when compared to pts in urban areas. In N9741, gender (P = 0.8) and PI (P = 0.3) distribution was similar; pts in rural areas were less likely to be black (1.4% vs 9.1%, P < 0.01). Rural vs urban pt PFS was no different in either trial. MOS was worse in pts in rural areas when compared to urban dwellers in 80405 (Table). OS outcomes stratified based on the use of cetuximab based regimen in 80405 showed worse outcomes for pts in rural compared to urban dwellers (21.9 vs 26.3 mo. HR: 1.22 (1.03-1.44), P = 0.02). Conclusions: MCRC pts from rural areas had a significantly worse mOS when compared to pts in urban areas in 80405. Furthermore, mOS with cetuximab based regimens was 4.4 months shorter in rural pts. The observed rural vs urban dweller mOS disparities in 80405 pts justifies additional research searching for causal factors and the necessity to identify actionable approaches in order to improve pt outcomes in rural areas. Support: U10CA180821, U10CA180882, U10CA180888, UG1CA180830; Pfizer, Sanofi, BMS, Genentech, https://acknowledgments.alliancefound.org . ClinicalTrials.gov Identifier: NCT00003594, NCT00265850. [Table: see text]

Abstract Background The incidence of very early onset inflammatory bowel disease (VEOIBD) is increasing, yet the phenotype and natural history of VEOIBD are not well described. Methods We performed a retrospective cohort study of patients diagnosed with VEOIBD (6 years of age and younger) between 2008 and 2013 at 25 North American centers. Eligible patients at each center were randomly selected for chart review. We abstracted data at diagnosis and at 1, 3, and 5 years after diagnosis. We compared the clinical features and outcomes with VEOIBD diagnosed younger than 3 years of age with children diagnosed with VEOIBD at age 3 to 6 years. Results The study population included 269 children (105 [39%] Crohn’s disease, 106 [39%] ulcerative colitis, and 58 [22%] IBD unclassified). The median age of diagnosis was 4.2 years (interquartile range 2.9–5.2). Most (94%) Crohn’s disease patients had inflammatory disease behavior (B1). Isolated colitis (L2) was the most common disease location (70% of children diagnosed younger than 3 years vs 43% of children diagnosed 3 years and older; P = 0.10). By the end of follow-up, stricturing/penetrating occurred in 7 (6.6%) children. The risk of any bowel surgery in Crohn’s disease was 3% by 1 year, 12% by 3 years, and 15% by 5 years and did not differ by age at diagnosis. Most ulcerative colitis patients had pancolitis (57% of children diagnosed younger than 3 years vs 45% of children diagnosed 3 years and older; P = 0.18). The risk of colectomy in ulcerative colitis/IBD unclassified was 0% by 1 year, 3% by 3 years, and 14% by 5 years and did not differ by age of diagnosis. Conclusions Very early onset inflammatory bowel disease has a distinct phenotype with predominantly colonic involvement and infrequent stricturing/penetrating disease. The cumulative risk of bowel surgery in children with VEOIBD was approximately 14%–15% by 5 years. These data can be used to provide anticipatory guidance in this emerging patient population.

Abstract How medical inter-professional (IP) education should be introduced to students is still a matter of research. We evaluated IP student attitudes before and after a busy “hands-on” clinical experience. During 3 separate trips, first/second year medical and physician assistant students and third/fourth year nursing students traveled to Central America to work together for 1 week in an underserved clinical setting. Student opinions on inter-professional education were obtained before and after Brigade-1 using the Readiness for Inter-professional Learning Scale validated questionnaire. From these results, a modified version of the survey was developed that included quantitative and qualitative responses. For brigades-2 and -3, students received this modified version of the survey pre and post brigade. Quantitative data was analyzed via paired student t test, and qualitative data was analyzed to identify emerging themes using constant comparative methodology by three separate investigators. No significant quantitative differences between IP student groups were observed in their evaluation of the importance of inter-professional education either before or after the brigades. Qualitative data noted pre-brigade expectations of positive IP, experiential and patient-centered cultural learning. Pre- and post-brigade student perspectives maintained a strong belief that high functioning IP care benefited the patient. Post-brigade perspectives revealed a shift in attitude from purely positive expectations to more practical aspects of teamwork, respect, and interpersonal relationships. Students believe that patient care benefits from IP collaboration. After a busy clinical experience requiring collaboration, students realized that functional teams require appropriate skills, roles, and respectful interpersonal relationships.

Coronin‐1a is an evolutionarily conserved protein involved in rearrangements of the actin cytoskeleton. The expression of coronin‐1a is restricted to cells of the hematopoietic lineage. Microglia are resident immune cells of the central nervous system thought to have hematopoietic origins. The aim of this study was to determine if coronin‐1a could be used as a marker for detecting microglia in mammalian species. Using a polyclonal antibody and immunohistochemistry, we show that coronin‐1a is an effective marker for microglia in tissue culture and archival formalin fixed, paraffin embedded tissue, including a range of neurodegenerative and neuroinflammatory conditions and transgenic mice. In human, monkey, horse, rat and mouse tissue coronin‐1a immunoreactivity was present in cells with the morphology and distribution of microglia, even in sections that had been stored for long periods of time. The identity of coronin‐1a positive cells as microglia was confirmed with double immunolabeling for HLA‐DR and Iba‐1. Coronin‐1a immunoreactivity was also detected in T‐ and B‐lymphocytes in lymphoid tissue and neuroinflammatory conditions, but it was not expressed by astrocytes or oligodendrocytes. The results demonstrate that coronin‐1a is a novel marker for microglia in routinely processed tissue from normal and neurodegenerative conditions in both humans and animals.