Surgical Decision-Making in Familial Adenomatous Polyposis.

Familial adenomatous polyposis (FAP) is an autosomal dominant disorder affecting patients with germline mutations of the adenomatous polyposis coli (APC) tumor suppressor gene. The surgical treatment of colorectal disease in FAP, which has the goal of colorectal cancer prevention, varies based on both patient and disease factors but can include the following: total colectomy with ileorectal anastomosis, proctocolectomy with stapled or hand-sewn ileal pouch-anal anastomosis, or total proctocolectomy with end ileostomy. The operative options and extent of resection, as well as the use of endoscopy and chemoprevention for the management of polyposis, will be discussed in detail in this article. In addition, commonly debated management decisions related to the treatment of patients with FAP, including the timing of prophylactic colorectal resections for patients with FAP and management of the polyp burden in the rectum, will be discussed. Finally, genotype considerations and the impact of desmoid disease on operative decisions in the setting of FAP will also be reviewed.

Roles for Bile Acid Signaling and Nonsense-Mediated Ribonucleic Acid Decay in Small Bowel Resection-Associated Liver Injury.

INTRODUCTION: Massive intestinal loss resulting in short bowel syndrome has been linked to intestinal failure associated liver disease. Efforts to elucidate the driving force behind the observed hepatic injury have identified inflammatory mediators, alterations in the microbiome, extent of structural and functional intestinal adaptation, and toxic shifts in the bile acid pool. In the present study, we posit that ileocecal resection interrupts the delivery of these hepatotoxic substances to the liver by physically disrupting the enterohepatic circulation, thereby shielding the liver from exposure to the aforementioned noxious stimuli. METHODS: Mice underwent sham, 50% proximal, or 50% distal small bowel resection (SBR), with or without tauroursodeoxycolic acid supplementation. Enterohepatic signaling and nonsense-mediated ribonucleic acid (RNA) decay were evaluated and correlated with hepatic injury. RESULTS: When compared to 50% proximal SBR, mice that underwent ileocecal resection exhibited reduced hepatic oxidative stress and exhibited a more physiological bile acid profile with increased de novo bile acid synthesis, enhanced colonic bile acid signaling, and reduced hepatic proliferation. Distal intestinal resection promoted an adaptive response including via the nonsense-mediated RNA decay pathway to satisfactorily process injurious messenger RNA and successfully maintain homeostasis. By contrast, this adaptive response was not observed in the proximal SBR group and hepatic injury persisted. CONCLUSIONS: In summary, interruption of enterohepatic circulation via ileocecal resection abrogates the liver's exposure to toxic and inflammatory mediators while promoting physiological adaptations in bile acid metabolism and maintaining existing homeostatic pathways.

Disruption of Enterohepatic Circulation of Bile Acids Ameliorates Small Bowel Resection Associated Hepatic Injury.

BACKGROUND: Massive small bowel resection (SBR) is associated with liver injury and fibrosis. Efforts to elucidate the driving force behind hepatic injury have identified multiple factors, including the generation of toxic bile acid metabolites. METHODS: Sham, 50% proximal, and 50% distal SBR were carried out in C57BL/6 mice to determine the effect of jejunal (proximal SBR) versus ileocecal resection (distal SBR) on bile acid metabolism and liver injury. Tissues were harvested at 2 and 10-week postoperative timepoints. RESULTS: When compared with 50% proximal SBR, mice that underwent distal SBR exhibited less hepatic oxidative stress as verified by decreased mRNA expression of tumor necrosis factor-α (TNFα, p ≤ 0.0001), nicotinamide adenine dinucleotide phosphate oxidase (NOX, p ≤ 0.0001), and glutathione synthetase (GSS, p ≤ 0.05). Distal SBR mice also exhibited a more hydrophilic bile acid profile with reduced abundance of insoluble bile acids (cholic acid (CA), taurodeoxycholic acid (TCA), and taurolithocholic acid (TLCA)), and increased abundance of soluble bile acids (tauroursodeoxycholic acid (TUDCA)). In contrast with proximal SBR, ileocecal resection alters enterohepatic circulation leading to reduced oxidative stress and promotes physiological bile acid metabolism. CONCLUSION: These findings challenge the notion that preservation of the ileocecal region is beneficial in patients with short bowel syndrome. Administration of selected bile acids may present potential therapy to mitigate resection-associated liver injury. LEVEL OF EVIDENCE: III-Case-Control Study.

Intestinal Knockout of Peroxisome Proliferator-Activated Receptor-Alpha Affects Structural Adaptation but not Liver Injury Following Massive Enterectomy.

BACKGROUND: Resection-associated liver steatosis, injury, and fibrosis is a devastating complication associated with massive small bowel resection (SBR). Peroxisome proliferator-activated receptor-alpha (PPARα) is a key regulator of intestinal lipid transport and metabolism whose expression is selectively increased after SBR. Here we asked if attenuating intestinal PPARα signaling would prevent steatosis and liver injury after SBR. METHODS: Pparα was deleted selectively in adult mouse intestine using a tamoxifen-inducible Cre-LoxP breeding schema. Mice underwent 50% SBR. At 10 weeks post-operatively, metabolic phenotyping, body composition analysis, in vivo assessment of lipid absorption and intestinal permeability, and assessment of adaptation and liver injury was completed. RESULTS: Pparα intestinal knockout and littermate control mice were phenotypically similar in terms of weight trends and body composition after SBR. All mice demonstrated intestinal adaptation with increased villus height and crypt depth; however, Pparα intestinal knockout mice exhibited decreased villus growth at 10 weeks compared to littermate controls. Liver injury and fibrosis were similar between groups as assessed by serum AST and ALT levels, Sirius Red staining, and hepatic expression of Col1a1 and Acta2. CONCLUSIONS: Inducible intestinal deletion of Pparα influences structural adaptation but does not mitigate liver injury after SBR. These findings suggest that enterocyte PPARα signaling in adult mice is dispensable for resection-induced liver injury. The results are critical for understanding the contribution of intestinal lipid metabolic signaling pathways to the pathogenesis of hepatic injury associated with short bowel syndrome.

National Trends in Pediatric Metabolic and Bariatric Surgery: 2010-2017.

BACKGROUND: The childhood obesity epidemic has grown exponentially and is known to disproportionately affect minority groups. Successful treatment of this complex health issue requires a multidisciplinary approach including metabolic and bariatric surgery (MBS) for qualifying pediatric patients. This study examines current national trends in pediatric bariatric surgery from 2010 to 2017 using the National Inpatient Sample. METHODS: This study analyzed MBS among pediatric patients <19 years old using weighted discharge data from 2010 to 2017. The primary outcome was national procedure rates. Secondary analyses included procedure type, demographics, BMI, comorbidities, length of stay, and complication rates. RESULTS: From 2010 to 2017, annual bariatric procedure rates increased from 2.29 to 4.62 per 100 000 (P < .001). Laparoscopic sleeve gastrectomy outpaced Roux-en-Y gastric bypass and laparoscopic adjustable gastric band over time (0.31-3.99 per 100 000, P < .0001). The mean age was stable over time 18.10-17.96 (P = .78). The cohort was primarily female (76.5% to 75.4%), white (54.0% to 45.0%), and privately-insured (59.9% to 53.4%). Preoperative BMI increased from 2010 to 2017 (P < .001), whereas number of obesity-related comorbidities was stable (P > .05). Length of stay was <2 days (2.02-1.75, P = .04) and in-hospital complication rates were low (7.2% to 6.45%, P = .88). CONCLUSIONS: Pediatric MBS is underutilized nationally with disproportionately lower rates among minority groups. Despite incremental progress, further investigation into the racial and social determinants that limit access to pediatric weight loss surgery is critical.

A novel maladaptive unfolded protein response as a mechanism for small bowel resection-induced liver injury.

The unfolded protein response (UPR) is a complex adaptive signaling pathway activated by the accumulation of misfolded proteins in the endoplasmic reticulum (ER). ER stress (ERS) triggers a cascade of responses that converge upon C/EBP homologous protein (CHOP) to drive inflammation and apoptosis. Herein, we sought to determine whether liver injury and fibrosis after small bowel resection (SBR) were mediated by a maladaptive hepatic ERS/UPR. C57BL/6 mice underwent 50% proximal SBR or sham operation. Markers of liver injury and UPR/ERS pathways were analyzed. These were compared with experimental groups including dietary fat manipulation, tauroursodeoxycholic acid (TUDCA) treatment, distal SBR, and global CHOP knockout (KO). At 10 wk, proximal SBR had elevated alanine aminotransferase/aspartate aminotransferase (ALT/AST) (P < 0.005) and greater hepatic tumor necrosis factor-α (TNFα) (P = 0.001) and collagen type 1 α1 (COL1A1) (P = 0.02) than shams. SBR livers had increased CHOP and p-eIF2α, but were absent in activating transcription factor 4 (ATF4) protein expression. Low-fat diet (LFD), TUDCA, and distal SBR groups had decreased liver enzymes, inflammation, and fibrosis (P < 0.05). Importantly, they demonstrated reversal of hepatic UPR with diminished CHOP and robust ATF4 signal. CHOP KO-SBR had decreased ALT but not AST compared with wild-type (WT)-SBR (P = 0.01, P = 0.12). There were no differences in TNFα and COL1A1 (P = 0.09, P = 0.50). SBR-induced liver injury, fibrosis is associated with a novel hepatic UPR/ERS response characterized by increased CHOP and decreased ATF4. LFD, TUDCA, and ileocecal resection rescued the hepatic phenotype and reversed the UPR pattern. Global CHOP KO only partially attenuated liver injury. This underscores the significance of disruptions to the gut/liver axis after SBR and potentiates targets to mitigate the progression of intestinal failure-associated liver disease.NEW & NOTEWORTHY The unfolded protein response (UPR) is a complex signaling cascade that converges upon C/EBP-homologous protein (CHOP). Under conditions of chronic cellular stress, the UPR shifts from homeostatic to proapoptotic leading to inflammation and cell death. Here, we provide evidence that small bowel resection-induced liver injury and fibrosis are mediated by a maladaptive hepatic UPR. Low-fat diet, TUDCA treatment, and ileocecal resection rescued the hepatic phenotype and reversed the UPR pattern.

Distal Small Bowel Resection Yields Enhanced Intestinal and Colonic Adaptation.

BACKGROUND: Murine ileocecal resection (ICR) has been used to investigate intestinal adaptation. The established model often includes the sacrifice of significant length of the proximal colon. Here, we optimized a highly selective vascular approach to the ICR, with primary jejunal-colic anastomosis yielding maximal colonic preservation. MATERIALS AND METHODS: Forty C57BL/6 mice underwent a highly vascularly selective ICR. The terminal branches of the ileocecal artery are isolated apart from the mesenteric branches supplying the small bowel to be resected. The distal 50% of small bowel and cecum are resected; a primary jejuno-colonic anastomosis is performed. Animals were sacrificed at postoperative weeks 2 (n = 10) and 10 (n = 29). Proximal 50% small bowel resection (SBR) with jejuno-ileal anastomosis was also performed for comparison. RESULTS: The entire colon (with exception of the cecum) was preserved in 100% of animals. Ninety-seven percent of animals survived to postoperative week 10, and all exhibited structural adaptation in the remnant small intestine epithelium. Crypts deepened by 175%, and villi lengthened by 106%, versus 39% and 29% in the proximal SBR cohort, respectively. Colonic proliferation, structural adaptation, and functional adaptation (measured by p-histone 3, luminal-facing apical crypt border size, and sucrase isomaltase, respectively) were increased in ICR compared with proximal SBR. CONCLUSIONS: Highly selective isolation of the cecal vasculature allows for greater colon preservation and yields enhanced remnant intestine epithelial adaptation. ICR is also associated with greater colonic adaptation and unique plasticity toward an intestinal phenotype. These findings underscore major differences between resection sites and offer insights into the critical adaptive mechanisms in response to massive intestinal loss.

Implementation of a clinical guideline for nonoperative management of isolated blunt renal injury in children.

BACKGROUND: The aim was to evaluate the impact of a standardized nonoperative management protocol by comparing patients with isolated blunt renal injury before and after implementation. METHODS: We retrospectively reviewed the trauma registry at our Level 1 pediatric trauma center. We compared consecutive patients (≤ 18 years) managed nonoperatively for blunt renal injury Pre (1/2010-9/2014) and Post (10/2014-3/2020) implementation of a clinical guideline. Outcomes included length of stay, intensive care unit admission, urinary catheter use, and imaging studies. RESULTS: We included 48 patients with isolated blunt renal injuries (29 Pre, 19 Post). There were no differences in age, sex, injury grade, or mechanism (P > .05). Postprotocol had decreased length of stay (P = .040), intensive care unit admissions (P = .015), urinary catheter use (P = .031), and ionizing radiation imaging (P < .001). CONCLUSION: These data suggest improved outcomes and resource utilization following implementation of a nonoperative management protocol of pediatric isolated blunt renal injuries.

Adolescent Bariatric Surgery: Racial Disparities in 30-Day Outcomes Using the MBSAQIP from 2015 to 2018.

INTRODUCTION: Racial disparities exist in obesity prevalence and obesity-related comorbid conditions among youth. We hypothesized that non-White adolescents would have poorer 30-day outcomes after adolescent bariatric surgery. METHODS: Adolescent patients 19 years or younger who had bariatric surgery from January 2015 to December 2018 were identified in the Metabolic and Bariatric Surgery Accreditation and Quality Initiative Program datafiles. Patient characteristics and 30-day perioperative outcomes were compared across racial groups. Trends in utilization of adolescent bariatric surgery were evaluated by race and procedure. RESULTS: Bariatric surgery was performed in 3177 adolescents with a mean age of 17.9 years [standard deviation (SD) 1.1 years]. The majority of patients were White 71.5% (2,271), while only 16.4% (520) were Black, and 12.1% (386) were other. Black adolescents 42.7% (222) more commonly presented with a BMI >50kg/m2 compared to 28.4% (645) White and 27.2% (105) other. Baseline hypertension and sleep apnea were more common among Black adolescents than other racial groups (P< 0.05). Black adolescents with LRYGB comprised 4.6% (48) of procedures in 2015 and only 1.5% (11) in 2018. Clavien-Dindo complications and all-cause readmission rates were similar among racial groups. Mean BMI decrease after 30 days was greatest for Black patients after Roux-en-Y gastric bypass, with a loss of 3.1 BMI points (SD 1.5). CONCLUSIONS: Despite similar short-term outcomes, significant disparities exist for Black adolescents who qualify for bariatric surgery. Further investigation is warranted to better understand the racial differences that limit access and utilization of this safe and effective intervention.

Small Bowel Resection Increases Paracellular Gut Barrier Permeability via Alterations of Tight Junction Complexes Mediated by Intestinal TLR4.

BACKGROUND: Short bowel syndrome resulting from small bowel resection (SBR) is associated with significant morbidity and mortality. Many adverse sequelae including steatohepatitis and bacterial overgrowth are thought to be related to increased bacterial translocation, suggesting alterations in gut permeability. We hypothesized that after intestinal resection, the intestinal barrier is altered via toll-like receptor 4 (TLR4) signaling at the intestinal level. METHODS: B6 and intestinal-specific TLR4 knockout (iTLR4 KO) mice underwent 50% SBR or sham operation. Transcellular permeability was evaluated by measuring goblet cell associated antigen passages via two-photon microscopy. Fluorimetry and electron microscopy evaluation of tight junctions (TJ) were used to assess paracellular permeability. In parallel experiments, single-cell RNA sequencing measured expression of intestinal integral TJ proteins. Western blot and immunohistochemistry confirmed the results of the single-cell RNA sequencing. RESULTS: There were similar number of goblet cell associated antigen passages after both SBR and sham operation (4.5 versus 5.0, P > 0.05). Fluorescein isothiocyanate-dextran uptake into the serum after massive SBR was significantly increased compared with sham mice (2.13 ± 0.39 ng/µL versus 1.62 ± 0.23 ng/µL, P < 0.001). SBR mice demonstrated obscured TJ complexes on electron microscopy. Single-cell RNA sequencing revealed a decrease in TJ protein occludin (21%) after SBR (P < 0.05), confirmed with immunostaining and western blot analysis. The KO of iTLR4 mitigated the alterations in permeability after SBR. CONCLUSIONS: Permeability after SBR is increased via changes at the paracellular level. However, these alterations were prevented in iTLR4 mice. These findings suggest potential protein targets for restoring the intestinal barrier and obviating the adverse sequelae of short bowel syndrome.

Alterations in pancreatic islet cell function in response to small bowel resection.

After 50% proximal small bowel resection (SBR) in mice, we have demonstrated hepatic steatosis, impaired glucose metabolism without insulin resistance, and increased pancreatic islet area. We sought to determine the consequences of SBR on pancreatic ß-cell morphology, proliferation, and expression of a key regulatory hormone, glucagon-like peptide-1 (GLP-1). C57BL/6 mice underwent 50% SBR or sham operation. At 10 wk, pancreatic insulin content and secretion was measured by ELISA. Immunohistochemistry was performed to determine structural alterations in pancreatic α-and ß-cells. Western blot analysis was used to measure GLP-1R expression, and immunoassay was used to measure plasma insulin and GLP-1. Experiments were repeated by administering a GLP-1 agonist (exendin-4) to a cohort of mice following SBR. After SBR, there was pancreatic islet hypertrophy and impaired glucose tolerance. The proportion of α and ß cells was not grossly altered. Whole pancreas and pancreatic islet insulin content was not significantly different; however, SBR mice demonstrated decreased insulin secretion in both static incubation and islet perfusion experiments. The expression of pancreatic GLP-1R was decreased approximately twofold after SBR, compared with sham and serum GLP-1, was decreased. These metabolic derangements were mitigated after administration of the GLP-1 agonist. Following massive SBR, there is significant hypertrophy of pancreatic islet cells with morphologically intact α- and ß-cells. Significantly reduced pancreatic insulin release in both static and dynamic conditions demonstrate a perturbed second phase of insulin secretion. GLP-1 is a key mediator of this amplification pathway. Decreased expression of serum GLP-1 and pancreatic GLP-1R in face of no change in insulin content presents a novel pathway for enteropancreatic glucose regulation following SBR.NEW & NOTEWORTHY Metabolic changes occur following intestinal resection; however, the effects on pancreatic function are unknown. Prior studies have demonstrated that glucagon-like protein-1 (GLP-1) signaling is a crucial player in the improved insulin sensitivity after bariatric surgery. In this study, we explore the effect of massive small bowel resection on gut hormone physiology and provide novel insights into the enteropancreatic axis.

Nutrition in Necrotizing Enterocolitis and Following Intestinal Resection.

This review aims to discuss the role of nutrition and feeding practices in necrotizing enterocolitis (NEC), NEC prevention, and its complications, including surgical treatment. A thorough PubMed search was performed with a focus on meta-analyses and randomized controlled trials when available. There are several variables in nutrition and the feeding of preterm infants with the intention of preventing necrotizing enterocolitis (NEC). Starting feeds later rather than earlier, advancing feeds slowly and continuous feeds have not been shown to prevent NEC and breast milk remains the only effective prevention strategy. The lack of medical treatment options for NEC often leads to disease progression requiring surgical resection. Following resection, intestinal adaptation occurs, during which villi lengthen and crypts deepen to increase the functional capacity of remaining bowel. The effect of macronutrients on intestinal adaptation has been extensively studied in animal models. Clinically, the length and portion of intestine that is resected may lead to patients requiring parenteral nutrition, which is also reviewed here. There remain significant gaps in knowledge surrounding many of the nutritional aspects of NEC and more research is needed to determine optimal feeding approaches to prevent NEC, particularly in infants younger than 28 weeks and <1000 grams. Additional research is also needed to identify biomarkers reflecting intestinal recovery following NEC diagnosis individualize when feedings should be safely resumed for each patient.

Radium-223 Use in Clinical Practice and Variables Associated With Completion of Therapy.

BACKGROUND: Radium-223 has shown clinical efficacy in metastatic castration-resistant prostate cancer. Despite improvement in quality of life and survival, practice patterns and utility of this agent outside the context of clinical trials have not been fully characterized. The primary objective in this study was to evaluate variables associated with completion of 5 to 6 radium-223 doses. PATIENTS AND METHODS: We conducted retrospective analyses of patients who received radium-223 (n = 135). Patients were classified into 3 cohorts: 1 to 2, 3 to 4, or 5 to 6 radium-223 doses. We evaluated the association of clinical and laboratory variables with the number of cycles administered (5-6 vs. 1-4 doses). RESULTS: Twenty-five patients (18.5%) received 1 to 2 radium-223 doses, 27 (20.0%) received 3 to 4, and 83 (61.5%) received 5 to 6. The most common reasons for treatment discontinuation included disease progression (61.5%, n = 40), patient preference (15.4%, n = 10), and toxicity (10.8%, n = 7). Factors associated with therapy completion in univariate analysis included previous sipuleucel-T treatment (P = .068), no previous abiraterone or enzalutamide treatment (P = .007), hemoglobin ≥ lower limit of normal (LLN; P = .006), white blood cell count ≥ LLN (P = .045), absolute neutrophil count (ANC) ≥ LLN (P = .049), lower alkaline phosphatase (P = .029), and lower lactate dehydrogenase levels (P = .014). Factors associated with therapy completion in multivariable analysis included previous sipuleucel-T treatment (P = .009), hemoglobin ≥ LLN (P = .037), and ANC ≥ LLN (P = .029). CONCLUSION: Several clinical parameters are associated with radium-223 therapy completion. In general, these parameters reflect earlier disease stage. These data are hypothesis-generating and prospective testing of the optimal number of radium-223 doses is warranted.

Characterizations of Clinical and Therapeutic Histories for Men With Prostate Cancer-Specific Mortality.

BACKGROUND: Careful descriptions of men with prostate cancer (PCa)-specific mortality are scant in nontrial settings. The present retrospective review describes the clinical characteristics, timelines, and treatment histories from initial presentation to death in a cohort of men with metastatic, castrate-resistant PCa (mCRPC). Unique to the present study is the unequivocal attribution of PCa death by a single experienced clinician. PATIENTS AND METHODS: A total of 119 patients who had been treated at Tulane Cancer Center and had died of mCRPC from 2008 to 2015 were studied through a retrospective review of the medical records. RESULTS: The median age at diagnosis was 65 years (range, 40-85 years), and 34.4% of the patients presented with metastatic disease (stage M1). Of these patients, 56% had received definitive primary therapy, all had received androgen-deprivation therapy, and 52% had received docetaxel. The patients had received a median of 7 (1-14) systemic therapies before death. Most were secondary hormonal manipulations after the diagnosis of mCRPC (median, 4; range, 0-9). The median survival was 69 months (range, 5-270 months) after diagnosis, and the median age at death was 73 years (range, 47-95 years). The presence of metastases at diagnosis was a significant predictor of early death (hazard ratio, 4.33; P < .001), and definitive primary therapy was a significant predictor of longer survival (P < .001). The median survival for patients presenting with metastases was 39 months (range, 5-235 months) compared with 100 months (range, 6-270 months) for those with localized disease (P < .001). The median age at diagnosis between the docetaxel- and non-docetaxel-treated patients was significantly different at 62 and 71 years, respectively (P = .002). CONCLUSION: The present retrospective analysis provides initial views clarifying the clinical characteristics of men dying of mCRPC and the therapies they received before death. Additional data are needed in multi-institutional settings to confirm these findings.