Western Diet-induced Transcriptional Changes in Anastomotic Tissue Is Associated With Early Local Recurrence in a Mouse Model of Colorectal Surgery.

OBJECTIVE: To determine the timeframe and associated changes in the microenvironment that promote the development of a diet-induced local-regional recurrence in a mouse model of colorectal surgery. BACKGROUND: Postoperative recurrence and metastasis occur in up to 30% of patients undergoing attempted resection for colorectal cancer (CRC). The underlying mechanisms that drive the development of postoperative recurrences are poorly understood. Preclinical studies have demonstrated a diet and microbial-driven pathogenesis of local-regional recurrence, yet the precise mechanisms remain undefined. METHODS: BALB/C mice were fed a western diet (WD) or standard diet (SD), underwent a colon resection and anastomosis, given an Enterococcus faecalis enema on postoperative day (POD) 1, and subjected to a CT26 cancer cell enema (mimicking shed cancer cells) on POD2. Mice were sacrificed between POD3 and POD7 and cancer cell migration was tracked. Dynamic changes in gene expression of anastomotic tissue that were associated with cancer cell migration was assessed. RESULTS: Tumor cells were identified in mice fed either a SD or WD in both anastomotic and lymphatic tissue as early as on POD3. Histology demonstrated that these tumor cells were viable and replicating. In WD-fed mice, the number of tumor cells increased over the early perioperative period and was significantly higher than in mice fed a SD. Microarray analysis of anastomotic tissue found that WD-fed mice had 11 dysregulated genes associated with tumorigenesis. CONCLUSIONS: A WD promotes cancer cells to permeate a healing anastomosis and migrate into anastomotic and lymphatic tissue forming viable tumor nodules. These data offer a novel recurrence pathogenesis by which the intestinal microenvironment promotes a CRC local-regional recurrence.

Novel Trauma Composite Score is superior to Injury Severity Score in predicting mortality across all ages.

BACKGROUND: Injury Severity Score (ISS) is a widely used metric for trauma research and center verification; however, it does not account for age-related physiologic parameters. We hypothesized that a novel age-based injury severity metric would better predict mortality. METHODS: Adult patients (≥18 years) sustaining blunt trauma (BT) or penetrating trauma (PT) were abstracted from the 2010 to 2016 National Trauma Data Bank. Admission vitals, Glasgow Coma Scale, ISS, mechanism, and outcomes were analyzed. Patients with incomplete/non-physiologic vital signs were excluded. For each age: (1) a cut point analysis was used to determine the ISS with the highest specificity and sensitivity for predicting mortality and (2) a linear discriminant analysis was performed using ISS, ISS greater than 16, Trauma and Injury Severity Score, and Revised Trauma Scale to compare each scoring system's mortality prediction. A novel injury severity metric, the trauma component score (TCS), was developed for each age using significant (p < 0.05) variables selected from Abbreviated Injury Scale scores, Glasgow Coma Scale, vital signs, and gender. Receiver operator curves were developed and the areas under the curve were compared between the TCS and other systems. RESULTS: There 777,794 patients studied (BT, 91.1%; PT, 8.9%). Blunt trauma patients were older (53.6 ± 21.3 years vs. 34.4 ± 13.8 years), had higher ISS scores (11.1 ± 8.5 vs. 8.5 ± 8.9), and lower mortality (2.9% vs. 3.4%) than PT patients (p < 0.05). When assessing the entire PT and BT cohort the optimal ISS cut point was 16. The optimal ISS was between 20 and 25 for BT younger than 70 years. For those older than 70 years, the optimal BT ISS steadily declined as age increased PT's cut point was 16 or less for all ages assessed. When the injury metrics were compared by area under the curve, our novel TCS more accurately predicted mortality across all ages in both BT and PT (p < 0.001). CONCLUSION: Injury Severity Score is a poor mortality predictor in older patients and those sustaining penetrating trauma. The age-based TCS is a superior metric for mortality prediction across all ages. LEVEL OF EVIDENCE: Clinical outcomes, Level IV.

Novel Trauma Composite Score is a more reliable predictor of mortality than Injury Severity Score in pediatric trauma.

BACKGROUND: The equivalent Injury Severity Score (ISS) cutoffs for severe trauma vary between adult (ISS, >16) and pediatric (ISS, >25) trauma. We hypothesized that a novel injury severity prediction model incorporating age and mechanism of injury would outperform standard ISS cutoffs. METHODS: The 2010 to 2016 National Trauma Data Bank was queried for pediatric trauma patients. Cut point analysis was used to determine the optimal ISS for predicting mortality for age and mechanism of injury. Linear discriminant analysis was implemented to determine prediction accuracy, based on area under the curve (AUC), of ISS cutoff of 25 (ISS, 25), shock index pediatric adjusted (SIPA), an age-adjusted ISS/abbreviated Trauma Composite Score (aTCS), and our novel Trauma Composite Score (TCS) in blunt trauma. The TCS consisted of significant variables (Abbreviated Injury Scale, Glasgow Coma Scale, sex, and SIPA) selected a priori for each age. RESULTS: There were 109,459 blunt trauma and 9,292 penetrating trauma patients studied. There was a significant difference in ISS (blunt trauma, 9.3 ± 8.0 vs. penetrating trauma, 8.0 ± 8.6; p < 0.01) and mortality (blunt trauma, 0.7% vs. penetrating trauma, 2.7%; p < 0.01). Analysis of the entire cohort revealed an optimal ISS cut point of 25 (AUC, 0.95; sensitivity, 0.86; specificity, 0.95); however, the optimal ISS ranged from 18 to 25 when evaluated by age and mechanism. Linear discriminant analysis model AUCs varied significantly for each injury metric when assessed for blunt trauma and penetrating trauma (penetrating trauma-adjusted ISS, 0.94 ± 0.02 vs. ISS 25, 0.88 ± 0.02 vs. SIPA, 0.62 ± 0.03; p < 0.001; blunt trauma-adjusted ISS, 0.96 ± 0.01 vs. ISS 25, 0.89 ± 0.02 vs. SIPA, 0.70 ± 0.02; p < 0.001). When injury metrics were assessed across age groups in blunt trauma, TCS and aTCS performed the best. CONCLUSION: Current use of ISS in pediatric trauma may not accurately reflect injury severity. The TCS and aTCS incorporate both age and mechanism and outperform standard metrics in mortality prediction in blunt trauma. LEVEL OF EVIDENCE: Retrospective review, level IV.

Cost-effectiveness Analysis of Contralateral Prophylactic Mastectomy Compared to Unilateral Mastectomy with Routine Surveillance for Unilateral, Sporadic Breast Cancer.

BACKGROUND: Contralateral prophylactic mastectomy (CPM) rates in younger women with unilateral breast cancer have more than doubled. Studies of cost and quality of life of the procedure remain inconclusive. METHODS: A cost-effectiveness analysis using a decision-tree model in TreeAge Pro 2015 was used to compare long-term costs and quality of life following unilateral mastectomy (UM) with routine surveillance versus CPM for sporadic breast cancer in women aged 45 years. A 10-year risk period for contralateral breast cancer (CBC), reconstruction, wound complications, cost of routine surveillance, and treatment for CBC were used to estimate accrued costs. In addition, a societal perspective was used to estimate quality-adjusted life years (QALYs) following either treatment for a period of 30 years. Medical costs were obtained from the 2014 Medicare physician fee schedule and event probabilities were taken from recent literature. RESULTS: The mean cost of UM with surveillance was $14,141 and CPM was $20,319. Treatment with CPM resulted in $6178 more in costs but equivalent QALYs (17.93) compared with UM over 30 years of follow-up. Even with worst-case scenario and varying assumptions, CPM is dominated by UM in terms of cost and quality. CONCLUSIONS: From this refined model, UM with routine surveillance costs less and provides an equivalent quality of life. Patients undergoing CPM may eliminate the anxiety of routine surveillance, but they face the burden of higher lifetime medical costs.

Large-bowel disease presenting as small-bowel obstruction is associated with a poor prognosis.

INTRODUCTION: Small-bowel obstruction (SBO) is a common cause of admission to the surgical service. On rare occasions, a diagnosed SBO is actually due to large-bowel pathology combined with an incompetent ileocecal valve. The purpose of this study was to investigate this phenomenon. METHODS: We performed a retrospective medical record review of patients that were admitted with a diagnosis of SBO at University of Louisville hospital and the Veterans Affairs hospitals in Louisville, KY, from 2006 until 2014. RESULTS: A total of 498 patients were admitted with SBO during this time period. Forty-one patients were found to have an underlying large-bowel disease. The most common large-bowel pathologies included malignancy (51%), inflammation (15%), and infection (15%). Fifteen (43%) of these patients died during admission; 93% of these were due to either their bowel obstruction or the underlying disease state. This was significantly higher than the general population (9.4% mortality, 6% due to underlying disease). CONCLUSIONS: Patients that present with SBO due to a large-bowel source have a much higher mortality rate than those that present with other causes. Rapid identification of these patients will allow for more timely and appropriate treatment.

Anti-inflammatory effects of miR-21 in the macrophage response to peritonitis.

We investigated the role of microRNA-21 in the macrophage response to peritonitis; microRNA-21 expression increases in peritoneal macrophages after lipopolysaccharide stimulation but is delayed until 48 hours after cecal ligation and puncture. MicroRNA-21-null mice and bone marrow-derived cell lines were exposed to cecal ligation and puncture or lipopolysaccharide, and survival, microRNA-21 levels, target messenger RNAs and proteins, and cytokines were assayed. Macrophages were also transfected with microRNA-21 mimics and antagomirs, and similar endpoints were measured. Survival in microRNA-21-null mice was significantly decreased after lipopolysaccharide-induced peritonitis but unchanged after cecal ligation and puncture compared with similarly treated wild-type mice. MicroRNA-21 expression, tumor necrosis factor-α, interleukin 6, and programmed cell death protein 4 levels were increased after lipopolysaccharide addition in peritoneal cells. Pelino1 and sprouty (SPRY) messenger RNAs were similarly increased early, whereas programmed cell death protein 4 messenger RNA was decreased after lipopolysaccharide, and all microR-21 target messenger RNAs were subsequently decreased by 24 hours after lipopolysaccharide. Transfection with mimics and antagomirs led to appropriate responses in microRNA-21 and tumor necrosis factor-α. Knockdown of microRNA-21 in bone marrow-derived cells showed increased tumor necrosis factor-α and decreased interleukin 10 in response to lipopolysaccharide. Target proteins were unaffected by knockdown as was extracellular signal-regulated kinase; however, the nuclear factor κB p65 subunit was increased after lipopolysaccharide in the microRNA-21 knockout cells. In contrast, there was little change in these parameters after cecal ligation and puncture induction between null and wild-type mice. MicroRNA-21 is beneficial to survival in mice following lipopolysaccharide peritonitis. Overexpression of microRNA-21 decreased tumor necrosis factor-α secretion, whereas suppression of microRNA-21 expression increased tumor necrosis factor-α and interleukin 6, and decreased interleukin 10 levels after lipopolysaccharide. Protein targets of microRNA-21 were not different following suppression of microRNA-21. Nuclear factor κB was increased by suppression of microRNA-21. These findings demonstrate microRNA-21 is beneficial in modulating the macrophage response to lipopolysaccharide peritonitis and an improved understanding of the anti-inflammatory effects of microRNA-21 may result in novel, targeted therapy against peritonitis and sepsis.

Extraintestinal manifestations of inflammatory bowel disease and the influence of smoking.

AIMS: To define the number/frequency of organ systems affected by extraintestinal manifestations (EIMs), to identify factors affecting the clinical course of inflammatory bowel disease (IBD) and EIM development, and to determine the impact of smoking, disease duration and location on the diagnosis of EIMs in Crohn's disease (CD) and ulcerative colitis (UC). METHODS: IBD patients were derived from a single university colorectal surgery practice. Smoking data were obtained through a modified Behavioral Risk Factor Surveillance System survey. The frequencies of arthritis/arthralgia, primary sclerosing cholangitis (PSC), ocular and cutaneous EIMs were determined. RESULTS: Of the 757 patients evaluated (CD 488, UC 269), 50% had ≥1 EIM. Arthritis/arthralgia, cutaneous and ocular EIMs were significantly higher in frequency in CD compared to UC patients. Prolonged disease duration was associated with increased prevalence of arthritis/arthralgia in IBD (p ≤ 0.001) as well as PSC (p = 0.049), ocular (p = 0.030) and cutaneous (p = 0.009) EIMs in CD. Disease location affected the occurrence of EIMs in CD. Smoking appeared to increase the prevalence of ocular EIMs in UC (p = 0.026). CONCLUSION: Arthritis/arthralgia, cutaneous and ocular EIMs occurred in a significantly higher proportion of CD patients. CD patients with longer disease duration had a significantly higher prevalence of PSC, ocular and cutaneous EIMs. Smoking was found to increase ocular EIMs in UC.

Poor outcome in bacterial peritonitis is associated with dysregulated microRNAs and an increased inflammatory response.

BACKGROUND: Peritonitis is a common cause of surgical sepsis. The failure of the host to mount an appropriate immune response contributes to persistence of the infection. We investigated the role microRNAs may play in this failed immune response. METHODS: Klebsiella pneumoniae was injected intraperitoneally in mice. Weight loss was used to predict clinical outcome. Peritoneal exudate cells (PECs) and supernatant were collected. RNA from PECs was run on screening microRNA array cards to determine gene expression, and validated by single assay analysis. Cytokine levels in supernatant were assayed by enzyme-linked immunosorbent assay. RESULTS: Despite similar bacterial levels, PEC counts were higher in the predicted death group. The predicted deaths had higher levels of proinflammatory tumor necrosis factor-α/IL-6 and significantly lower levels of interleukin-10. MiR-221 was up-regulated in both the predicted death and predicted survivor groups. Five miRNAs were up-regulated in the predicted survivor group compared with normal controls. CONCLUSION: Higher PEC counts and proinflammatory cytokines in the predicted death group indicates an exaggerated inflammatory response, with lower IL-10 levels despite similar bacterial counts. There were two dysregulated miRNAs with transcriptional targets that may explain our results. A more balanced immune response with an appropriate counter inflammatory response may be important for improving survival.

Accuracy of computed tomography in small bowel obstruction.

Small bowel obstruction is a common clinical occurrence, primarily caused by adhesions. The diagnosis is usually made on the clinical findings and the presence of dilated bowel loops on plain abdominal radiograph. Computed tomography (CT) is increasingly used to diagnose the cause and location of the obstruction to aid in the timing of surgical intervention. We used a retrospective chart review to identify patients with a diagnosis of small bowel obstruction between 2009 and 2012. We compared the findings on CT with the findings at operative intervention. Sixty patients had abdominal CT and subsequent surgical intervention. Eighty-three per cent of CTs were correct for small intestine involvement and 80 per cent for colon involvement. The presence of adhesions or perforation was correctly identified in 21 and 50 per cent, respectively. Sixty-four per cent correctly identified a transition point. The presence of a mass was correctly identified in 69 per cent. Twenty per cent of the patients who had ischemic small bowel at surgery were identified on CT. CT has a role in the clinical assessment of patients with small bowel obstruction, identifying with reasonable accuracy the extent of bowel involvement and the presence of masses and transition points. It is less reliable at identifying adhesions, perforations, or ischemic bowel.