Bryan Dicken

Gastric Adenocarcinoma: Review and Considerations for Future Directions

Objective:This update reviews the epidemiology and surgical management, and the controversies of gastric adenocarcinoma. We provide the relevance of outcome data to surgical decision-making and discuss the application of gene-expression analysis to clinical practice. Summary Background Data:Gastric cancer mortality rates have remained relatively unchanged over the past 30 years, and gastric cancer continues to be one of the leading causes of cancer-related death. Well-conducted studies have stimulated changes to surgical decision-making and technique. Microarray studies linked to predictive outcome models are poised to advance our understanding of the biologic behavior of gastric cancer and improve surgical management and outcome. Methods:We performed a review of the English gastric adenocarcinoma medical literature (1980–2003). This review included epidemiology, pathology and staging, surgical management, issues and controversies in management, prognostic variables, and the application of outcome models to gastric cancer. The results of DNA microarray analysis in various cancers and its predictive abilities in gastric cancer are considered. Results:Prognostic studies have provided valuable data to better the understanding of gastric cancer. These studies have contributed to improved surgical technique, more accurate pathologic characterization, and the identification of clinically useful prognostic markers. The application of microarray analysis linked to predictive models will provide a molecular understanding of the biology driving gastric cancer. Conclusions:Predictive models generate important information allowing a logical evolution in the surgical and pathologic understanding and therapy for gastric cancer. However, a greater understanding of the molecular changes associated with gastric cancer is needed to guide surgical and medical therapy.

Lymphovascular Invasion Is Associated With Poor Survival in Gastric Cancer: An Application of Gene-Expression and Tissue Array Techniques

Objectives:To examine a population-based cohort for the association between clinicopathologic predictors of survival and immunohistochemical markers (IHC), and to assess changes in gene expression that are associated with lymphovascular invasion (LVI). Summary Background Data:LVI has been associated with poor survival and aggressive tumor behavior. The molecular changes responsible for the behavior of gastric cancer have yet to be determined. Characterization of IHC markers and gene expression profiles may identify molecular alterations governing tumor behavior. Methods:Clinicopathologic and survival data of 114 patients were reviewed. Archival specimens were used to construct a multitumor tissue array that was subjected to IHC of selected protein targets. Correlation of IHC with tumor thickness (T status), LVI and prognosis was studied. Microarray analysis of fresh gastric cancer tissue was conducted to examine the gene expression profile with respect to LVI. Results:In a multivariate analysis, nodal status (N), metastasis (M), and LVI were independent predictors of survival. LVI was associated with a 5-year survival of 13.9% versus 55.9% in patients in whom it was absent. LVI correlated with advancing T status (P = 0.001) and N status (P < 0.001). IHC staining of cyclooxygenase-2 (COX-2) correlated with T status, tumor grade, lymph node positivity, and IHC staining of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). Microarray analyses suggested differential expression of oligophrenin-1 (OPHN1) and ribophorin-II (RPNII) with respect to LVI. Conclusion:LVI was an independent predictor of survival in gastric cancer. Expression of COX-2 may facilitate tumor invasion through MMP-2 and MMP-9 activation. OPHN1 and RPN II appeared to be differentially expressed in gastric cancers exhibiting LVI. The reported function of OPHN1 and RPN II makes these gene products promising candidates for future studies involving LVI in gastric cancer.

Heterotaxy syndrome and intestinal rotation abnormalities: A survey of institutional practice

PURPOSE Abnormalities of intestinal rotation (IRA) are commonly associated with heterotaxy syndrome (HS). There is controversy whether asymptomatic infants with HS require screening for IRA and if present, whether a prophylactic Ladd procedure is indicated. The objective of this study is to determine institutional practice across North America in the management of asymptomatic infants with HS and IRA. METHODS We performed an international, multi-institutional web based survey to examine current practice and opinions in the management of IRA in HS patients. RESULTS Overall response rate was 30%. Of physicians surveyed, 84% believe that HS patients should be screened for IRA in the neonatal period. 61% of general surgeons, 50% of cardiovascular surgeons and 45% of cardiologists feel that all patients with HS and an asymptomatic IRA should have a prophylactic Ladd procedure. 55% of physicians stated they would be comfortable with conservative management for patients with HS and asymptomatic IRA. CONCLUSIONS The risk of midgut volvulus, morbidity and mortality from elective procedures and cardiovascular prognosis must be considered prior to an elective Ladd procedure on asymptomatic HS patients. There are practice variance among sub-specialists caring for these patients, a lack of expert consensus, and a paucity of evidence-based data for IRA in this population.

A Safety and Dosing Study of Glucagon-Like Peptide 2 in Children With Intestinal Failure

Background and Aims: A glucagon-like peptide 2 (GLP-2) analogue is approved for adults with intestinal failure, but no studies of GLP-2 have included children. This study examined the pharmacokinetics, safety, and nutritional effects of GLP-2 in children with intestinal failure. Methods: Native human GLP-2(1-33) was synthesized following good manufacturing practices. In an open-label trial, with parental consent, 7 parenteral nutrition–dependent pediatric patients were treated with subcutaneous GLP-2 (20 µg/kg/d) for 3 days (phase 1) and, if tolerated, continued for 42 days (phase 2). Nutritional treatment was directed by the primary caregivers. Patients were followed to 1 year. Results: Seven patients were enrolled (age: 4.0 ± 0.8 years; bowel length, mean ± SEM: 24% ± 4% of predicted). All were parenteral nutrition dependent since birth, receiving 44% ± 5% of calories by parenteral nutrition. GLP-2 treatment had no effect on vital signs (blood pressure, heart rate, and temperature) and caused no significant adverse events. Peak GLP-2 levels were 380 pM (day 3) and 295 pM (day 42), with no change in half-life or endogenous GLP-2 levels. Nutritional indices showed a numeric improvement in z scores and citrulline levels; the z score was maintained while citrulline levels returned to baseline once GLP-2 was discontinued. Conclusions: GLP-2 was well tolerated in children, with a pharmacokinetic profile similar to that of adults. There were no changes in endogenous GLP-2 release or metabolism. These results suggest that GLP-2 ligands may be safely used in pediatric patients; larger trials are suggested to investigate nutritional effects.

Central venous catheter repair is not associated with an increased risk of central line infection or colonization in intestinal failure pediatric patients

PURPOSE The intestinal failure (IF) population is dependent upon central venous catheters (CVC) to maintain minimal energy requirements for growth. Central venous catheter infections (CVCI) are frequent and an independent predictor of intestinal failure associated liver disease. A common complication in children with long-term CVC is the risk of line breakage. Given the often-limited usable vascular access sites in this population, it has been the standard of practice to perform repair of the broken line. Although widely practiced, it is unknown if this practice is associated with increased line colonization rates and subsequent line loss. METHODS A retrospective review of our institutional IF population over the past 8years (2006-2014) was performed. Utilizing a prospectively constructed database, all pediatric patients (n=13, ages 0-17 years) with CVC dependency enrolled in the Childrens Intestinal Rehabilitation Program with IF were included who underwent a repair and/or replacement procedure of their line. The control replacement group was CVCs that were replaced without being repaired (36), the experimental repair group was CVCs that were repaired (8). The primary outcome of interest was the mean number of days in each group from the intervention (replacement or repair) to line infection/colonization. Mann-Whitney tests for significance were performed with p-values <0.05 being the threshold value for significance. RESULTS There were no catheter repair associated CVCI. The mean number of days from the replacement or repair of a CVC to its removal owing to infection/colonization was 210.0 and 162.8days respectively. There was no statistically significant difference between these groups in time to removal owing to line infection (p=0.55). CONCLUSION Repair of central venous catheters in the pediatric population with intestinal failure does not lead to an increased rate of central venous catheter infection and should be performed when possible.

Bedside to Bench: The Risk of Bleeding with Parenteral Omega-3 Lipid Emulsion Therapy

Our clinical experience led us to reassess the effect of sole omega-3 lipid therapy on hemostasis. We compared thromboelastography platelet mapping in neonatal piglets given sole omega-3 lipid. We identified abnormalities in reaction time (P = .025) and the arachidonic acid pathway (P = .025). The potential for bleeding complications from parenteral omega-3 lipid emulsion therapy in high-risk infants with liver disease has been dismissed but, on the basis of this data, should be reconsidered.

Surveillance after initial surgery for Stage I pediatric and adolescent boys with malignant testicular germ cell tumors: Report from the Children’s Oncology Group

PURPOSE The purpose of this study was to determine prognostic factors correlating with outcome in boys with Stage I malignant testicular germ cell tumors (MTGCT) initially managed with surveillance after surgical resection. METHODS Between November 2003 and July 2011, 80 boys 0-15 years with Stage I MTGCT were enrolled in Childrens Oncology Group Study AGCT0132. Those with residual or recurrent disease were treated with chemotherapy. RESULTS Characteristics include: age (65, 0-5 years and 15, 11+years), pure YST (93.9%, 0-5 years and 0%, 11+years); and lymphovascular invasion (LVI) (50.6% present vs. 49.4% absent). At median follow-up of 4.94 years, 19 had persistent or recurrent disease, all detected by elevated AFP at a median of 87 days after study enrollment. The outcome from enrollment was 4-year EFS 74% (95% CI: 63%-83%) and 4-year OS 100%. 4-year EFS was improved with younger age (<11 years, 80% vs. 11+years, 48%, p<0.01); pure YST vs. mixed histology (81% vs. 45%, p<0.01), and lack of LVI (84% vs. 62%, p=0.03). CONCLUSIONS Boys with Stage I MTGCT have excellent overall survival when treated with surgery alone. Age greater than 10 years, mixed histology and presence of LVI are each associated with relapse and may allow identification of high risk boys at time of enrollment.

Platelet Arachidonic Acid Deficiency May Contribute to Abnormal Platelet Function During Parenteral Fish Oil Monotherapy in a Piglet Model

BACKGROUND Fish oil monotherapy has been an advance for treating intestinal failure-associated liver disease (IFALD). However, such patients are at risk of bleeding complications from liver disease and because fish oil can inhibit thrombosis. We have previously reported abnormal platelet function in neonatal piglets given fish oil monotherapy during parenteral nutrition (PN). The purpose of this study was to determine if abnormal fatty acid composition of the platelets could explain the prior observed antiplatelet effect. METHODS Neonatal piglets were assigned to 2 treatments: PN with fish oil monotherapy (FO; n = 4) or PN with soy oil (SO; n = 5). On day 14, plasma was collected and platelets isolated by centrifuging. The fatty acid content in plasma and platelet plug were measured using gas liquid chromatography and compared with controls (CON; n = 5). RESULTS The arachidonic acid (AA) content in the FO group was on average half that of the SO group, in both the platelets (FO, 3.5% vs SO, 7.6%; P = .021; CON, 4.5%-11%) and the plasma (FO, 3.8% vs SO, 9.2%; P = .002; CON, 6.1%-9.5%). No bleeding complications were observed for any piglets during PN treatment. CONCLUSIONS Using platelet mapping, we have previously shown that neonatal piglets given fish oil monotherapy have abnormal platelet function in the AA pathway. This report demonstrates that such an abnormality can be explained by platelet AA deficiency. Platelet mapping and platelet fatty acid analysis should be undertaken in human infants treated with fish oil monotherapy during PN.

Fecal Microbial Transplant After Ileocolic Resection Reduces Ileitis but Restores Colitis in IL-10-/- Mice.

Background:Ileocolic resection (ICR) is frequently performed for Crohns disease; however, disease commonly recurs early in the neoterminal ileum. The aim of this study was to use the IL-10−/− mouse to determine the effects of ICR on gut microbiome and immune function and if postoperative fecal microbial transplant (FMT) would improve disease. Methods:ICR was performed in 129S1/SvlmJ IL10−/− mice followed by FMT using stool from wild-type mice. Sham-transplant mice received their own stool. Stool samples were collected on day 0, day 13 (after ICR), and day 27 (after FMT) for whole metagenome shot-gun sequencing. Mucosal-associated bacteria were quantified with quantitative PCR and visualized by fluorescent in situ hybridization. Tissue cytokines were measured with multiplex arrays and mononuclear phagocyte populations by flow cytometry. Results:Surgery induced microbial functional and taxonomic shifts, decreased diversity, and depleted Bacteroidia and Clostridia. ICR mice had reduced colitis but worse ileitis with bacterial overgrowth, increased translocation, and reduction in tissue macrophages. FMT prevented ileitis but restored colitis and allowed for a bloom of &ggr;-proteobacteria. In the colon, ICR and sham transplant were associated with recruitment of tolerogenic dendritic cells, whereas FMT shifted these immune cell subsets to control profiles along with increasing cytokine levels. Conclusions:This study suggests that surgical-induced immune dysfunction and microbial dysbiosis with impaired clearance may be the underlying cause of the early ulcerations found in the ileum of patients with Crohns disease after ICR. FMT has an immunostimulatory effect on the postoperative intestine, which was beneficial in preventing ileitis, but detrimental in restoring colonic injury after surgery.

Low-dose vasopressin improves cardiac function in newborn piglets with acute hypoxia-reoxygenation.

ABSTRACT Cardiovascular dysfunction in asphyxiated neonates contributes significantly to their morbidity and mortality. We have recently shown that a low-dose vasopressin infusion (0.005 – 0.01 units/kg per hour) may improve myocardial oxygen transport balance in a swine model of neonatal hypoxia-reoxygenation. We aimed to compare the systemic and regional hemodynamic effects of low-dose vasopressin to dobutamine, a synthetic beta-adrenoreceptor agonist. Piglets (1 – 5 days old, 1.6 – 2.2 kg) were anesthetized and instrumented to continuously monitor systemic hemodynamic parameters, including cardiac output and mesenteric flow indices. After 2 h of hypoxia (10% – 15% O2), piglets had normoxic reoxygenation for 4 h. In a blinded randomized fashion, piglets received infusion of either vasopressin (0.01 units/kg per hour started at 30 min of reoxygenation) or dobutamine (20 &mgr;g/kg per minute started at 2 h of reoxygenation) (n = 8 per group). Hypoxia-reoxygenation controls (placebo, n = 8) and sham-operated (n = 5) piglets were also studied. Tissue lactate, glutathione, glutathione disulfide, and lipid hydroperoxides levels and histology of the left ventricle and the small bowel were analyzed. Plasma was also analyzed for troponin-I and intestinal fatty acid–binding protein levels. Piglets subjected to hypoxia-reoxygenation had cardiogenic shock and metabolic acidosis, which improved on reoxygenation. During recovery, cardiac output and mesenteric flows gradually deteriorated and were increased similarly in vasopressin- and dobutamine-treated piglets (P < 0.05 vs. controls). Plasma troponin-I and left ventricular lactate levels were lower in the vasopressin and dobutamine groups (P < 0.05 vs. controls), with no difference in the histological analysis among groups. The intestinal GSSG/GSH ratio and lipid hydroperoxides level were lower in the vasopressin and dobutamine groups (P < 0.05 vs. controls). This study is the first to demonstrate that a low-dose vasopressin infusion used in the setting of neonatal swine model of hypoxia-reoxygenation is associated with an improvement in cardiac output and mesenteric perfusion.