Vascular Endothelial Growth Factor secretion and immunosuppression are distinct potency mechanisms of Human Bone Marrow Mesenchymal Stromal Cells.

Mesenchymal Stromal Cells (MSCs) are investigated as cellular therapeutics for Inflammatory Bowel Diseases and associated Perianal Fistula, although consistent efficacy remains a concern. Determining host factors that modulate MSCs' potency including their secretion of angiogenic & wound healing factors, immunosuppression and anti-inflammatory properties are important determinants of their functionality. We investigated the mechanisms that regulate the secretion of angiogenic & wound healing factors and immune suppression of human bone marrow MSCs. Secretory analysis of MSCs focusing on eighteen angiogenic & wound healing secretory molecules identified the most abundancy of Vascular Endothelial Growth Factor-A(VEGF-A). MSC viability and secretion of other angiogenic factors are not dependent on VEGF-A secretion which exclude the autocrine role of VEGF-A on MSC's fitness. However, combination of inflammatory cytokines IFNγand TNFαreduces MSC's VEGF-A secretion. To identify the effect of intestinal microvasculature on MSCs' potency, coculture analysis was performed between Human Large Intestine Microvascular Endothelial Cells(HLMVECs) and human bone marrow derived MSCs. HLMVECs do not attenuate MSCs' viability despite blocking their VEGF-A secretion. In addition, HLMVECs neither attenuate MSC's IFNγmediated upregulation of immunosuppressive enzyme Indoleamine 2,3-dioxygenase(IDO) nor abrogate suppression of T cell proliferation despite the attenuation of VEGF-A secretion. We found that HLMVECs express copious amounts of endothelial nitric oxide synthase (eNOS) and mechanistic analysis showed that pharmacological blocking reverses HLMVEC mediated attenuation of MSC's VEGF-A secretion. Together these results suggest that secretion of VEGF-A and immunosuppression are separable functions of MSCs which are regulated by distinct mechanisms in the host.

Indications for Contralateral Prophylactic Mastectomy: A Consensus Statement Using Modified Delphi Methodology.

OBJECTIVE: To reach a consensus about contralateral prophylactic mastectomy in unilateral breast cancer. SUMMARY BACKGROUND DATA: There has been a substantial increase in the number of North American women with unilateral breast cancer undergoing a therapeutic mastectomy and a contralateral prophylactic mastectomy (CPM) either simultaneously or sequentially. The purpose of this project was to create a nationally endorsed consensus statement for CPM in women with unilateral breast cancer using modified Delphi consensus methodology. METHODS: A nationally representative expert panel of 19 general surgeons, 2 plastic surgeons, 2 medical oncologists, 2 radiation oncologists, and 1 psychologist was invited to participate in the generation of a consensus statement. Thirty-nine statements were created in 5 topic domains: predisposing risk factors for breast cancer, tumor factors, reconstruction/symmetry issues, patient factors, and miscellaneous factors. Panelists were asked to rate statements on a 7-point Likert scale. Two electronic rounds of iterative rating and feedback were anonymously completed, followed by an in-person meeting. Consensus was reached when there was at least 80% agreement. RESULTS: Our panelists did not recommend for average risk women with unilateral breast cancer. The panel recommended CPM for women with a unilateral breast cancer and previous Mantle field radiation or a BrCa1/2 gene mutation. The panel agreed that CPM could be considered by the surgeon on an individual basis for: women with unilateral breast cancer and a genetic mutation in the CHEK2/PTEN/p53/PALB2/CDH1 gene, and in women who may have significant difficulty achieving symmetry after unilateral mastectomy. CONCLUSION: Contralateral prophylactic mastectomy is rarely recommended for women with unilateral breast cancer.

Aberrant right hepatic artery in pancreaticoduodenectomy for adenocarcinoma: impact on resectability and postoperative outcomes.

OBJECTIVES: An aberrant right hepatic artery (aRHA) may pose technical and oncologic challenges during pancreaticoduodenectomy (PD) for pancreatic adenocarcinoma (PA) as a result of its proximity to the head of the pancreas. The aim of this study was to assess the impact of an aRHA on resectability, and perioperative and oncologic outcomes after PD for PA. METHODS: An 11-year retrospective cohort study was conducted. A total of 289 patients with PA scheduled for PD with intent for resection were included in the study. RESULTS: Of 289 patients, 249 underwent PD and 40 were found to have unresectable tumours. Incidences of aRHA in the resectable (14.9%) and unresectable (7.5%) groups were similar (P = 0.2); the main reasons for aborting PD were not directly related to the presence of an aRHA. In patients who underwent resection, complications occurred more frequently in the standard PD group (41.5% versus 24.3%; P = 0.04), but there was no difference in rates of positive margin (R1) resection (10.8% versus 16.0%; P = 0.4) or median overall survival (17 months versus 23 months; P = 0.1) between patients with and without an aRHA. CONCLUSIONS: The presence of an aRHA in patients with PA does not affect resectability. In patients with resectable tumours, the presence of an aRHA does not increase morbidity or R1 resection rates and does not impact on overall survival.

Combined pancreaticoduodenectomy and colon resection for locally advanced peri-ampullary tumours: analysis of peri-operative morbidity and mortality.

BACKGROUND: Combined pancreaticoduodenectomy (PD) and colonic resection may be necessary to achieve an R0 resection of peri-ampullary tumours. The aim of this study was to examine the morbidity and mortality associated with this procedure. METHODS: A retrospective cohort study was performed comparing 607 patients who underwent a standard pancreaticoduodenectomy (S-PD) to 28 patients who had a concomitant colon resection and PD (PD-colon) over a 10-year period at an academic centre. RESULTS: Patients in the PD-colon group were more likely to have received neoadjuvant chemotherapy ± radiation (3/28, 11% versus 14/607, 2%, P = 0.024). Operative time was also longer (530 versus 410 min, P < 0.001) and they were more likely to have had portal vein resections (9/28, 32% versus 76/607, 13%, P = 0.007). There was no difference in the intra-operative blood loss, length of stay, or overall complication rates. The PD-colon group had a higher rate of severe post-operative bleeding (4/28, 11% versus 8/607, 1%, P = 0.002). The post-operative mortality rates for the PD-colon and PD groups were 2/28 (7%) and 8/607 (1%), respectively (P = 0.068). CONCLUSIONS: PD-colon has an acceptable risk of peri-operative morbidity compared with S-PD in well-selected patients.

Hormone profiling, WHO 2010 grading, and AJCC/UICC staging in pancreatic neuroendocrine tumor behavior.

Pancreatic neuroendocrine tumors (pNETs) are the second most common pancreatic neoplasms, exhibiting a complex spectrum of clinical behaviors. To examine the clinico-pathological characteristics associated with long-term prognosis we reviewed 119 patients with pNETs treated in a tertiary referral center using the WHO 2010 grading and the American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC) staging systems, with a median follow-up of 38 months. Tumor size, immunohistochemistry (IHC) profiling and patient characteristics-determining stage were analyzed. Primary clinical outcomes were disease progression or death. The mean age at presentation was 52 years; 55% were female patients, 11% were associated with MEN1 (multiple endocrine neoplasia 1) or VHL (Von Hippel-Lindau); mean tumor diameter was 3.3 cm (standard deviation, SD) (2.92). The clinical presentation was incidental in 39% with endocrine hypersecretion syndromes in only 24% of cases. Nevertheless, endocrine hormone tissue immunoreactivity was identified in 67 (56.3%) cases. According to WHO 2010 grading, 50 (42%), 38 (31.9%), and 3 (2.5%) of tumors were low grade (G1), intermediate grade (G2), and high grade (G3), respectively. Disease progression occurred more frequently in higher WHO grades (G1: 6%, G2: 10.5%, G3: 67%, P = 0.026) and in more advanced AJCC stages (I: 2%, IV: 63%, P = 0.033). Shorter progression free survival (PFS) was noted in higher grades (G3 vs. G2; 21 vs. 144 months; P = 0.015) and in more advanced AJCC stages (stage I: 218 months, IV: 24 months, P < 0.001). Liver involvement (20 vs. 173 months, P < 0.001) or histologically positive lymph nodes (33 vs. 208 months, P < 0.001) were independently associated with shorter PFS. Conversely, tissue endocrine hormone immunoreactivity, independent of circulating levels was significantly associated with less aggressive disease. Age, gender, number of primary tumors, and heredity were not significantly associated with prognosis. Although the AJCC staging and WHO 2010 grading systems are useful in predicting disease progression, tissue endocrine hormone profiling provides additional information of potentially important prognostic value.

Is daily dilatation by parents necessary after surgery for Hirschsprung disease and anorectal malformations?

BACKGROUND/PURPOSE: Most surgeons recommend daily dilatation after surgery for Hirschsprung disease and anorectal malformations. Our goal was to critically evaluate the potential risks and benefits of this practice. METHODS: A retrospective chart review was carried out of all children undergoing repair of Hirschsprung disease or anorectal malformation over 5 years. Patients with long segment Hirschsprung disease or anal stenosis were excluded. RESULTS: There were 95 patients, of which 34 had Hirschsprung disease and 61 had an anorectal malformation. Postoperatively, 65 underwent routine dilatation by parents; and 30 underwent weekly calibration by the surgeon, with daily dilatation by the parents only if the anastomosis was felt to be narrow. Of the 30 children undergoing weekly calibration, only 5 (17%) developed late narrowing that required conversion to the daily parental dilatation approach. There were no significant differences between the 2 approaches with respect to stricture development, anastomotic disruption, perineal excoriation, or enterocolitis. CONCLUSION: Weekly calibration by the surgeon is associated with similar outcomes to daily dilatation by the parents. Because this approach is kinder to the parents and the child, it should be seriously considered for the postoperative management of children with Hirschsprung disease or anorectal malformations.

Comparison of DPPC and DPPG environments in pulmonary surfactant models.

Deuterium nuclear magnetic resonance was used to monitor lipid acyl-chain orientational order in suspensions of dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylglycerol (DPPG) containing Ca(2+) and the lung surfactant proteins SP-A and SP-B separately and together. To distinguish between protein-lipid interactions involving the PC and PG lipid headgroups and to examine whether such interactions might influence spatial distribution of lipids within the bilayer, acyl chains on either the DPPC or the DPPG component of the mixture were deuterated. The lipid components of the resulting mixtures were thus either DPPC-d(62)/DPPG (7:3) or DPPC/DPPG-d(62) (7:3), respectively. SP-A had little effect on DPPC-d(62) chain order but did narrow the temperature range over which DPPG-d(62) ordered at the liquid-crystal-to-gel transition. No segregation of lipid components was seen for temperatures above or below the transition. Near the transition, though, there was evidence that SP-A promoted preferential depletion of DPPG from liquid crystalline domains in the temperature range over which gel and liquid crystal domains coexist. SP-B lowered average chain order of both lipids both above and below the main transition. The perturbations of chain order by SP-A and SP-B together were smaller than by SP-B alone. This reduction in perturbation of the lipids by the additional presence of SP-A likely indicated a strong interaction between SP-A and SP-B. The competitive lipid-lipid, lipid-protein, and protein-protein interactions suggested by these observations presumably facilitate the reorganization of surfactant material inherent in the transformation from lamellar bodies to a functional surfactant layer.

Increasing the range of unambiguity in step-height measurement with multiple-wavelength interferometry--application to absolute long gauge block measurement.

An instrument for step-height measurement by multiple-wavelength interferometry is described. The addition of a 1152-nm wavelength to a multiple-wavelength scheme applying wavelengths of 633, 612, and 543 nm relaxes the tolerance range of the required preliminary measurement to +/- 140 microm, if the total uncertainty in the fringe fraction measurement can be kept below 2%. For larger fringe fraction measurement uncertainty, numerical simulations show that the integer number of interference orders can still be determined unambiguously if the range in the preliminary knowledge of the length has been correspondingly reduced. The interferometer instrument is described, and experimental data are presented in the context of long gauge block calibration at the National Research Council of Canada.