Adam S. Brinkman

Multi-institutional analysis of pancreatic adenocarcinoma demonstrating the effect of diabetes status on survival after resection

BACKGROUND The effect of diabetes on survival after resection pancreatic ductal carcinoma (PDAC) is unclear. The present study was undertaken to determine whether pre-operative diabetes has any predictive value for survival. METHODS A retrospective review from seven centres was performed. Metabolic factors, tumour characteristics and outcomes of patients undergoing resection for PDAC were collected. Univariate and multivariable analyses were performed to determine factors associated with disease-free (DFS) and overall survival (OS). RESULTS Of the 509 patients in the present study, 31.2% had diabetes. Scoring systems were devised to predict OS and DFS based on a training set (n= 245) and were subsequently tested on an independent set (n= 264). Pre-operative diabetes (P < 0.001), tumour size >2 cm (P= 0.001), metastatic nodal ratio >0.1 (P < 0.001) and R1 margin (P < 0.001) all correlated with DFS and OS on univariate analysis. Scoring systems were devised based on multivariable analysis of the above factors. Diabetes and the metastatic nodal ratio were the most important factors in each system, earning two points for OS and four points for DFS. These scoring systems significantly correlated with both DFS (P < 0.001) and OS (P < 0.001). CONCLUSION Pre-operative diabetes status provides useful information that can help to stratify patients in terms of predicted post-operative OS and DFS.

Glycomacropeptide, a low-phenylalanine protein isolated from cheese whey, supports growth and attenuates metabolic stress in the murine model of phenylketonuria.

Phenylketonuria (PKU) is caused by a mutation in the phenylalanine (phe) hydroxylase gene and requires a low-phe diet plus amino acid (AA) formula to prevent cognitive impairment. Glycomacropeptide (GMP) contains minimal phe and provides a palatable alternative to AA formula. Our objective was to compare growth, body composition, and energy balance in Pah(enu2) (PKU) and wild-type mice fed low-phe GMP, low-phe AA, or high-phe casein diets from 3-23 wk of age. The 2 × 2 × 3 design included main effects of genotype, sex, and diet. Fat and lean mass were assessed by dual-energy X-ray absorptiometry, and acute energy balance was assessed by indirect calorimetry. PKU mice showed growth and lean mass similar to wild-type littermates fed the GMP or AA diets; however, they exhibited a 3-15% increase in energy expenditure, as reflected in oxygen consumption, and a 3-30% increase in food intake. The GMP diet significantly reduced energy expenditure, food intake, and plasma phe concentration in PKU mice compared with the casein diet. The high-phe casein diet or the low-phe AA diet induced metabolic stress in PKU mice, as reflected in increased energy expenditure and intake of food and water, increased renal and spleen mass, and elevated plasma cytokine concentrations consistent with systemic inflammation. The low-phe GMP diet significantly attenuated these adverse effects. Moreover, total fat mass, %body fat, and the respiratory exchange ratio (CO(2) produced/O(2) consumed) were significantly lower in PKU mice fed GMP compared with AA diets. In summary, GMP provides a physiological source of low-phe dietary protein that promotes growth and attenuates the metabolic stress induced by a high-phe casein or low-phe AA diet in PKU mice.

Enteral nutrients potentiate glucagon-like peptide-2 action and reduce dependence on parenteral nutrition in a rat model of human intestinal failure

Glucagon-like peptide-2 (GLP-2) is a nutrient-dependent, proglucagon-derived gut hormone that shows promise for the treatment of short bowel syndrome (SBS). Our objective was to investigate how combination GLP-2 + enteral nutrients (EN) affects intestinal adaption in a rat model that mimics severe human SBS and requires parenteral nutrition (PN). Male Sprague-Dawley rats were assigned to one of five groups and maintained with PN for 18 days: total parenteral nutrition (TPN) alone, TPN + GLP-2 (100 μg·kg(-1)·day(-1)), PN + EN + GLP-2(7 days), PN + EN + GLP-2(18 days), and a nonsurgical oral reference group. Animals underwent massive distal bowel resection followed by jejunocolic anastomosis and placement of jugular catheters. Starting on postoperative day 4, rats in the EN groups were allowed ad libitum access to EN. Groups provided PN + EN + GLP-2 had their rate of PN reduced by 0.25 ml/day starting on postoperative day 6. Groups provided PN + EN + GLP-2 demonstrated significantly greater body weight gain with similar energy intake and a safe 80% reduction in PN compared with TPN ± GLP-2. Groups provided PN + EN + GLP-2 for 7 or 18 days showed similar body weight gain, residual jejunal length, and digestive capacity. Groups provided PN + EN + GLP-2 showed increased jejunal GLP-2 receptor (GLP-2R), insulin-like growth factor-I (IGF-I), and IGF-binding protein-5 (IGFBP-5) expression. Treatment with TPN + GLP-2 demonstrated increased jejunal expression of epidermal growth factor. Cessation of GLP-2 after 7 days with continued EN sustained the majority of intestinal adaption and significantly increased expression of colonic proglucagon compared with PN + EN + GLP-2 for 18 days, and increased plasma GLP-2 concentrations compared with TPN alone. In summary, EN potentiate the intestinotrophic actions of GLP-2 by improving body weight gain allowing for a safe 80% reduction in PN with increased jejunal expression of GLP-2R, IGF-I, and IGFBP-5 following distal bowel resection in the rat.

Hirschsprung’s Associated Enterocolitis

Purpose of review Hirschsprungs disease (HSCR) is characterized by an absence of ganglion cells in the distal hindgut, extending from the rectum to a variable distance proximally, and results from a failure of cranial–caudal neural crest cell migration. Hirschsprungs-associated enterocolitis (HAEC) is a condition with classic manifestations that include abdominal distention, fever and foul-smelling stools, and is a significant and life-threatening complication of HSCR. The purpose of this review was to critically evaluate recent findings regarding the pathophysiology of HAEC. Recent findings Several recent studies have investigated the cause of HAEC in humans and mouse models. These studies suggest that alterations in the intestinal barrier, including goblet cell number and function, and Paneth cell function, impaired gastrointestinal mucosal immunity, including B-lymphocyte trafficking or function and secretory immunoglobulin A production, and dysbiosis of the intestinal microbiota may contribute to the development of HAEC. Summary Recent studies add to the body of literature, suggesting that the intestinal defects observed in HSCR are not restricted to the aganglionic segment but extend to the mucosal immune system within and beyond the gastrointestinal tract. Future studies further dissecting the mechanisms of HAEC and validating these findings in humans will allow for the development of directed therapeutic interventions.

Value of Primary Operative Drain Placement after Major Hepatectomy: A Multi-Institutional Analysis of 1,041 Patients

BACKGROUND The value of routine primary (intraoperative) drain placement after major hepatectomy remains unclear. We sought to determine if primary drainage led to decreased rates of complications, specifically, intra-abdominal biloma or infection requiring a secondary (postoperative) drainage procedure. STUDY DESIGN All patients who underwent major hepatectomy (≥3 hepatic segments) at 3 institutions, from 2000 to 2012, were identified. Patients with biliary anastomoses were excluded. Primary outcomes were any complication, rate of secondary drainage procedures, bile leak, and 30-day readmission. RESULTS There were 1,041 patients who underwent major hepatectomy without biliary anastomosis; 564 (54%) had primary drains placed at the surgeons discretion. Primary drain placement was associated with increased complications (56% vs 44%; p < 0.001), bile leaks (7.3% vs 4.2%; p = 0.048), and 30-day readmissions (16.4% vs 8.0%; p < 0.001), but was not associated with a decrease in secondary drainage procedures (8.0% vs 5.9%; p = 0.23). Patients with primary drains demonstrated higher American Society of Anesthesioloigsts (ASA) class, greater blood loss, more transfusions, and larger resections. After accounting for these significant clinicopathologic variables on multivariate analysis, primary drain placement was not associated with increased risk of any complications. Primary drainage was, however, independently associated with increased risk of bile leak (hazard ratio [HR] 2.04; 95% CI1.02 to 4.09; p = 0.044) and 30-day readmission (HR 1.79; 95% CI1.14 to 2.80; p = 0.011). There still was no reduction in the need for secondary drainage procedures (HR 0.98; p = 0.96). CONCLUSIONS Primary intraoperative drain placement after major hepatectomy does not decrease the need for secondary drainage procedures and may be associated with increased bile leaks and 30-day readmissions. Routine drain placement is not warranted.

Exogenous GLP-2 and IGF-I induce a differential intestinal response in IGF binding protein-3 and -5 double knockout mice.

Glucagon-like peptide-2 (GLP-2) action is dependent on intestinal expression of IGF-I, and IGF-I action is modulated by IGF binding proteins (IGFBP). Our objective was to evaluate whether the intestinal response to GLP-2 or IGF-I is dependent on expression of IGFBP-3 and -5. Male, adult mice in six treatment groups, three wild-type (WT) and three double IGFBP-3/-5 knockout (KO), received twice daily intraperitoneal injections of GLP-2 (0.5 μg/g body wt), IGF-I (4 μg/g body wt), or PBS (vehicle) for 7 days. IGFBP-3/-5 KO mice showed a phenotype of lower plasma IGF-I concentration, but greater body weight and relative mass of visceral organs, compared with WT mice (P < 0.001). WT mice showed jejunal growth with either IGF-I or GLP-2 treatment. In KO mice, IGF-I did not stimulate jejunal growth, crypt mitosis, sucrase activity, and IGF-I receptor (IGF-IR) expression, suggesting that the intestinotrophic actions of IGF-I are dependent on expression of IGFBP-3 and -5. In KO mice, GLP-2 induced significant increases in jejunal mucosal cellularity, crypt mitosis, villus height, and crypt depth that was associated with increased expression of the ErbB ligand epiregulin and decreased expression of IGF-I and IGF-IR. This suggests that in KO mice, GLP-2 action in jejunal mucosa is independent of the IGF-I system and linked with ErbB ligands. In summary, the intestinotrophic actions of IGF-I, but not GLP-2, in mucosa are dependent on IGFBP-3 and -5. These findings support the role of multiple downstream mediators for the mucosal growth induced by GLP-2.

Optimizing surgical resection of the bleeding Meckel diverticulum in children

PURPOSE Meckel diverticula containing gastric heterotopia predispose to local hyperacidity, mucosal ulceration, and gastrointestinal bleeding in children. Eradication of acid-producing oxyntic cells is performed by either of two surgical methods: segmental enterectomy including the diverticulum or diverticulectomy only. METHODS Retrospective review of all children having surgical resection of a Meckel diverticulum at a tertiary-referral childrens hospital from 2002 to 2016 was performed. Demographic data, surgical method, pathological specimens, and outcomes were evaluated. RESULTS 102 children underwent surgical resection of a Meckel diverticulum during the study period. 27 (26.5%) children presented with bleeding, of which 16 (59%) had diverticulectomy only, and 11 (41%) had segmental ileal resection. All Meckel diverticula in children presenting with bleeding contained gastric heterotopia, and resection margins were free of gastric mucosa. Histologically, 19 specimens showed microscopic features of ulceration, on average 2.95mm (SD 4.49) from the nearest gastric mucosa (range: 0-16mm). Mean length of hospitalization after ileal resection was 4.0days (SD 1.2) compared to 1.6days (SD 0.9) for diverticulectomy only (p<0.001), with no re-bleeding occurrences. CONCLUSION In the operative management of children having a bleeding Meckel diverticulum, diverticulectomy-only completely eradicates gastric heterotopia without increased risk of continued bleeding or complications and significantly shortens hospitalization. LEVEL OF EVIDENCE Treatment Study: Level III.

Computed tomography-related radiation exposure in children transferred to a Level i pediatric trauma center

PURPOSE Pediatric trauma patients presenting to referring facilities (RF) often undergo computed tomography (CT) scans to identify injuries before transfer to a Level I pediatric trauma center (PTC). The purpose of our study was to evaluate RF compliance with the American College of Radiology (ACR) guidelines to minimize ionizing radiation exposure in pediatric trauma patients and to determine the frequency of additional or repeat CT imaging after transfer to a PTC. METHODS After institutional review board approval, a retrospective review of all pediatric trauma admissions from January 2010 to December 2011 at our American College of Surgeons Level I PTC was performed. Patient demographics, means of arrival, Injury Severity Score, and disposition were analyzed. Patients who underwent CT were grouped by means of arrival: those who were transferred from an RF versus those who presented primarily to the PTC. Compliance with ACR guidelines and need for additional or repeat CT scans were assessed for both groups. RESULTS Six hundred ninety-seven children (aged <18 years) were identified, with a mean age of 10.6 years. Three hundred twenty-one (46%) patients presented primarily to the PTC. Three hundred seventy-six (54%) were transferred from an RF, of which 90 (24%) patients underwent CT imaging before transfer. CT radiation dosing information was available for 79 (88%) of 90 patients. After transfer, 8 (9%) of 90 of children imaged at an RF required additional CT scans. In comparison, 314 (98%) of 321 patients who presented primarily to the PTC and underwent CT received appropriate pediatric radiation dosing. Mean radiation dose at PTC was approximately half of that at RF for CT scans of the head, chest, and abdomen/pelvis (p < 0.01). CONCLUSION Pediatric trauma patients transferred from RF often undergo CT scanning with higher than recommended radiation doses, potentially placing them at an increased carcinogenic risk. Fortunately, few RF patients required additional CT scans after PTC transfer. Finally, compliance with ACR radiation dose limit guidelines is better achieved at a PTC. LEVEL OF EVIDENCE Care management study, level IV.

Evolution in management of adolescent blunt aortic injuries—a single institution 22-y experience

BACKGROUND In children, severe, life-threatening traumatic injuries of the thoracic aorta can be seen after motor vehicle collisions (MVCs) resulting in a sudden deceleration. Concurrent injuries in the thorax and abdomen can make treatment prioritization difficult and require early recognition and prompt intervention. With the increased utilization of minimally invasive endovascular approaches to traumatic aortic (TA) injuries, patients are often spared the increased surgical morbidity (spinal cord ischemia and renal insults) that can be seen with an open technique. The aim of this study was to evaluate a single American College of Surgeons level 1 pediatric trauma centers 22-y experience with TA injuries in children. METHODS After the Institutional Review Board approval, a 22-y (January 1990-April 2013) retrospective review of all pediatric trauma patients admitted with TA injuries was performed. Patient demographics including age, injury detail, treatment, and outcomes were recorded for analysis. RESULTS 17 children (<21-y old) were identified with ages ranging from 13-20 y old. The most common mechanism of injury was MVC with all 17 children sustaining TA injuries. The traumatic injuries included aortic transection (9), intimal flap (5), pseudoaneurysm (2), and contained thoracic rupture (1). All children were managed operatively with those before 2008 using an open technique. The endovascular approach was used in 7/17 (41%) cases with the median length of hospitalization 12 d versus 22.5 d using the open approach (P < 0.05). No child required conversion from an endovascular to an open technique for treatment of the aortic injury. There were no operative deaths, no procedure-related paraplegia and all children were discharged home from the hospital. Two children had mild mental deficits as a result of head trauma. CONCLUSIONS TA injuries are an uncommon injury in children and can result from MVCs or other sudden deceleration mechanisms. Surgical intervention is required in most of the cases and can be performed safely and effectively with low morbidity using an endovascular approach, which is the evolving approach of choice for thoracic aortic injuries. Lengthy follow-up care is recommended in children treated with an endovascular device to monitor for endoleaks and device complications.

Improving the value of care for appendectomy through an individual surgeon-specific approach

PURPOSE Standardized care via a unified surgeon preference card for pediatric appendectomy can result in significant cost reduction. The purpose of this study was to evaluate the impact of cost and outcome feedback to surgeons on value of care in an environment reluctant to adopt a standardized surgeon preference card. METHODS Prospective observational study comparing operating room (OR) supply costs and patient outcomes for appendectomy in children with 6-month observation periods both before and after intervention. The intervention was real-time feedback of OR supply cost data to individual surgeons via automated dashboards and monthly reports. RESULTS Two hundred sixteen children underwent laparoscopic appendectomy for non-perforated appendicitis (110 pre-intervention and 106 post-intervention). Median supply cost significantly decreased after intervention: