Surgical Interventions, Malignancies, and Causes of Death in a FAP Patient Registry.

BACKGROUND: Familial adenomatous polyposis (FAP) patients are at risk for numerous malignancies. Multiple surgeries exist to mitigate the risk of colorectal cancer. Surgeons must weigh future quality of life versus the risk of dysplasia. As FAP patient longevity increases, there remains a risk of other malignancies. This study examines surgical interventions, development of cancers, and causes of mortality in a FAP registry. METHODS: Patients with FAP or attenuated FAP (aFAP) were identified by linking the Hereditary Gastrointestinal Cancer Registry with University of Utah's medical records. Patients without sufficient information were excluded. Patient demographics, surgical histories, cancer diagnoses, and causes of death were extracted. Logrank and Fisher's exact tests were employed to detect significant differences between groups. RESULTS: After exclusion criteria, 140 patients were analyzed. Sixty patients (42.9%) underwent total proctocolectomy with ileal pouch-anal anastomosis (IPAA) followed by 50 (35.7%) having total colectomy with ileorectal anastomosis (IRA). IPAA patients were more likely female (p = 0.01) and have FAP (p < 0.01) versus IRA patients. Nineteen patients (15.0%) required additional colorectal surgeries; however, no differences were based on initial surgery. Colorectal cancer was diagnosed in 22 patients (15.7%), while 7 (5.0%) developed gastric cancer. Of the 15 deceased patients, 6 (40%) died due to gastric adenocarcinoma. DISCUSSION: This study suggests that aFAP and FAP patients are undergoing appropriate colorectal interventions to reduce colorectal cancer mortality; however, repeat interventions are frequent. Gastric malignancy is common and represents the leading cause of death. Further studies are needed to determine appropriate surveillance protocols to reduce this risk of malignancy.

Differential methylation of G-protein coupled receptor signaling genes in gastrointestinal neuroendocrine tumors.

Neuroendocrine tumors (NETs) of the small intestine undergo large chromosomal and methylation changes. The objective of this study was to identify methylation differences in NETs and consider how the differentially methylated genes may impact patient survival. Genome-wide methylation and chromosomal copy number variation (CNV) of NETs from the small intestine and appendix were measured. Tumors were divided into three molecular subtypes according to CNV results: chromosome 18 loss (18LOH), Multiple CNV, and No CNV. Comparison of 18LOH tumors with MultiCNV and NoCNV tumors identified 901 differentially methylated genes. Genes from the G-protein coupled receptor (GPCR) pathways are statistically overrepresented in the differentially methylated genes. One of the highlighted genes from the GPCR pathway is somatostatin (SST), a clinical target for NETs. Patient survival based on low versus high methylation in all samples identified four significant genes (p < 0.05) OR2S2, SMILR, RNU6-653P, and AC010543.1. Within the 18LOH molecular subtype tumors, survival differences were identified in high versus low methylation of 24 genes. The most significant is TRHR (p < 0.01), a GPCR with multiple FDA-approved drugs. By separating NETs into different molecular subtypes based on chromosomal changes, we find that multiple GPCRs and their ligands appear to be regulated through methylation and correlated with survival. These results suggest opportunities for better treatment strategies for NETs based on molecular features.

Contributors to Increased Mortality Associated With Care Fragmentation After Emergency General Surgery.

Importance: Care fragmentation at time of readmission after emergency general surgery (EGS) is associated with high mortality; however, the factors underlying this finding remain unclear. Objective: To identify patient and hospital factors associated with increased mortality among patients after EGS readmitted within 30 days of discharge to a nonindex hospital. Design, Setting, and Participants: Retrospective cohort study using the 2014 Healthcare Cost and Utilization Project Nationwide Readmissions Database. Participants were all adult patients (18 years or older) who underwent 1 of the 15 most common EGS procedures in the United States from January 1 to November 30, 2014, and survived to discharge. The dates of analysis were October through December 2019. Exposures: Thirty-day readmission to a hospital other than that of the index surgical procedure. The study examined the association of interventions during readmission, change in hospital resource level, and severity of patient illness during readmission. Main Outcomes and Measures: Ninety-day inpatient mortality. Results: In total, 71 944 patients who underwent EGS (mean [SD] age, 59.0 [18.3] years; 53.5% [38 487 of 71 944] female) were readmitted within 30 days of discharge, of whom 10 495 (14.6%) were readmitted to a nonindex hospital. Compared with patients readmitted to index hospitals, patients readmitted to nonindex hospitals were more likely to be readmitted to hospitals with low annual EGS volume (33.5% vs 25.6%, P < .001) and be in the top half of illness severity profile (37.2% vs 31.2%, P < .001). Overall 90-day mortality was higher in the patients readmitted to nonindex hospitals (6.1% vs 4.3%, P < .001). When adjusted for baseline patient and hospital characteristics, care fragmentation was independently associated with increased mortality (adjusted odds ratio [aOR], 1.36; 95% CI, 1.17-1.58; P < .001). After adjustment for interventions performed during readmission, change in EGS hospital volume level, and severity of patient illness, care fragmentation was no longer independently associated with mortality (aOR, 1.05; 95% CI, 0.88-1.26; P = .58). In this complete model, severity of illness was the strongest risk factor of mortality during readmission. Conclusions and Relevance: In this cohort study of adult patients who require rehospitalization after EGS, 14.6% are readmitted to a hospital other than where the index procedure was performed. Although the overall mortality rate is higher for this population, the excess mortality appears to be primarily associated with severity of patient illness at time of readmission. These data underscore the need to develop systems of care to rapidly triage patients to hospitals best equipped to manage their condition.

Palladin expression is a conserved characteristic of the desmoplastic tumor microenvironment and contributes to altered gene expression.

The stroma surrounding solid tumors contributes in complex ways to tumor progression. Cancer-associated fibroblasts (CAFs) are the predominant cell type in the tumor stroma. Previous studies have shown that the actin-binding protein palladin is highly expressed in the stroma of pancreas tumors, but the interpretation of these results is complicated by the fact that palladin exists as multiple isoforms. In the current study, the expression and localization of palladin isoform 4 was examined in normal specimens and adenocarcinomas of human pancreas, lung, colon, and stomach samples. Immunohistochemistry with isoform-selective antibodies revealed that expression of palladin isoform 4 was higher in adenocarcinomas versus normal tissues, and highest in CAFs. Immunohistochemistry staining revealed that palladin was present in both the cytoplasm and the nucleus of CAFs, and this was confirmed using immunofluorescence staining and subcellular fractionation of a pancreatic CAF cell line. To investigate the functional significance of nuclear palladin, RNA Seq analysis of palladin knockdown CAFs versus control CAFs was performed, and the results showed that palladin regulates the expression of genes involved in the biosynthesis and assembly of collagen, and organization of the extracellular matrix. These results suggested that palladin isoform 4 may play a conserved role in establishing the phenotype of CAFs in multiple tumor types.

Use of prehospital 12-lead electrocardiography and treatment times among ST-elevation myocardial infarction patients with atypical symptoms.

OBJECTIVES: Guidelines advise that a prehospital electrocardiogram (ECG) should be obtained in any patients with chest pain, yet up to 20% of patients with ST-elevation myocardial infarction (STEMI) do not present with chest pain. The objective was to determine the association of atypical presentations in the prehospital setting on the likelihood of receiving a prehospital ECG and subsequent time to reperfusion therapy. METHODS: This study used a data set that linked prehospital medical information from a statewide EMS data system with a clinical registry of treatment and outcomes data for patients with STEMI. Among 2,639 STEMI patients from 2008 to 2010, the association between non-chest pain presentations, prehospital ECG use, and reperfusion times among patients undergoing primary percutaneous coronary intervention (PCI) were examined. Inverse probability weights were used to account for observed baseline confounders. RESULTS: Overall, 318 of 2,639 patients (12.1%) presented without chest pain. A prehospital ECG was obtained in 2,021 of 2,321 (87.1%) patients with chest pain compared with only 230 of 318 (72.3%) without chest pain (odds ratio [OR] = 2.24, 95% confidence interval [CI] = 1.69 to 2.98). Among patients without chest pain, those who received a prehospital ECG had significantly shorter first medical contact (FMC) to device times (30.9% < 90 minutes vs. 11.4% > 90 minutes, adjusted OR = 2.81, 95% CI = 1.29 to 6.11, p < 0.01). CONCLUSIONS: Over one-quarter of STEMI patients presenting without chest pain did not receive prehospital ECGs and had significantly longer FMC to device times. Future efforts are needed to promote the use of prehospital ECGs to achieve more rapid identification of STEMI patients with atypical presentations in the prehospital setting.