Nikiforos Ballian

Islet Vasculature as a Regulator of Endocrine Pancreas Function

The islets of Langerhans consist of endocrine cells embedded in a network of specialized capillaries that regulate islet blood flow. Despite evidence for a critical role of islet perfusion in endocrine pancreas function, there is information to support no fewer than three models of endocrine cell perfusion, emphasizing the lack of a universally accepted physiological theory. Islet blood flow is regulated by signals, such as hormones and nutrients that reach the islet vasculature from distant tissues via the bloodstream. In addition, islet perfusion determines communication between endocrine and exocrine cells and between different types of endocrine cells within islets. Interest in islet microcirculation has increased after improvements in islet transplantation, a therapy for diabetes mellitus that requires revascularization of grafted islets in a new host organ. Abnormal revascularization is thought to be partly responsible for differences in graft and native islet function. Similarly, angiogenesis has been shown to be a critical step in the transformation of islet hyperplasia to neoplasia.

PDX-1 acts as a potential molecular target for treatment of human pancreatic cancer.

Objectives: The purpose of this study was to investigate whether pancreatic and duodenal homeobox factor 1 (PDX-1) could serve as a potential molecular target for the treatment of pancreatic cancer. Methods: Cell proliferation, invasion capacity, and protein levels of cell cycle mediators were determined in human pancreatic cancer cells transfected with mouse PDX-1 (mPDX-1) alone or with mPDX-1 short hairpin RNA (shRNA) and/or human PDX-1 shRNA (huPDX-1 shRNA). Tumor cell growth and apoptosis were also evaluated in vivo in PANC-1 tumor-bearing severe combined immunodeficient mice receiving multiple treatments of intravenous liposomal huPDX-1 shRNA. Results: mPDX-1 overexpression resulted in the significant increase of cell proliferation and invasion in MIA PaCa2, but not PANC-1 cells. This effect was blocked by knocking down mPDX-1 expression with mPDX-1 shRNA. Silencing of huPDX-1 expression in PANC-1 cells inhibited cell proliferation in vitro and suppressed tumor growth in vivo which was associated with increased tumor cell apoptosis. PDX-1 overexpression resulted in dysregulation of the cell cycle with up-regulation of cyclin D, cyclin E, and Cdk2 and down-regulation of p27. Conclusions: PDX-1 regulates cell proliferation and invasion in human pancreatic cancer cells. Down-regulation of PDX-1 expression inhibits pancreatic cancer cell growth in vitro and in vivo, implying its use as a potential therapeutic target for the treatment of pancreatic cancer.

Visceral obesity is associated with outcomes of total mesorectal excision for rectal adenocarcinoma

General obesity, measured by the body mass index (BMI), increases the technical difficulty of total mesorectal excision (TME) but does not affect oncologic outcomes. The purpose of this study is to compare visceral and general obesity as predictors of outcomes of TME for rectal adenocarcinoma.

A simplified prognostic system for resected pancreatic neuroendocrine neoplasms

BACKGROUND A number of prognostically relevant clinicopathological variables have been proposed for pancreatic neuroendocrine neoplasms. However, a standardized prognostication system has yet to be established for patients undergoing potentially curative tumour resection. METHODS We examined a prospectively maintained, single-institution database to identify patients who underwent potentially curative resection of non-metastatic primary pancreatic neuroendocrine neoplasms. Patient, operative and pathological characteristics were analysed to identify variables associated with disease-specific and disease-free survival. RESULTS Between 1991 and 2007, 43 patients met inclusion criteria. After a median follow-up of 68 months, 5-year disease-specific survival was 94% and 5-year disease-free survival was 72%. Tumours sized > or = 5 cm and vascular invasion were associated with worse disease-specific survival. Tumours sized > or = 5 cm, nodal metastases, positive resection margins and perineural invasion were associated with worse disease-free survival. A scoring system consisting of tumour size > or = 5 cm, histological grade, nodal metastases and resection margin positivity (SGNM) permitted stratification of disease-specific (P= 0.006) and disease-free (P= 0.0004) survival. This proposed scoring system demonstrated excellent discrimination of individual disease-specific and disease-free survival outcomes as reflected by concordance indices of 0.814 and 0.794, respectively. CONCLUSIONS A simple scoring system utilizing tumour size, histological grade, nodal metastases and resection margin status can be used to stratify outcomes in patients undergoing resection of primary pancreatic neuroendocrine neoplasms.

Somatostatin and its receptors in the development of the endocrine pancreas.

Abstract: The development of the endocrine pancreas is regulated by numerous transcription and growth factors. Somatostatin (SST) is present in many tissues and acts as a neurotransmitter and autocrine/paracrine/endocrine regulator in response to ions, nutrients, peptides, and hormones as well as neurotransmitters. In the pancreas, there is evidence that SST acts an inhibitory paracrine regulator of hormone secretion. Somatostatin receptors (SSTRs) are a family of 5 transmembrane G protein-coupled receptors, which are widely expressed in mammals including humans. SSTRs regulate multiple downstream signal transduction pathways that mediate inhibitory effects. These receptors also exhibit age- and tissue-specific expression patterns. Interactions of SST and SSTRs are not only important during normal pancreas development, but have also been implicated in many pancreatic diseases such as diabetes mellitus and pancreatic cancer. In this review article, we use evidence from recently published animal studies to present the critical roles of SST and SSTRs proteins in the development of the endocrine pancreas.

Glucose metabolism in burn patients: The role of insulin and other endocrine hormones

Severe burn causes a catabolic response with profound effects on glucose and muscle protein metabolism. This response is characterized by hyperglycemia and loss of muscle mass, both of which have been associated with significantly increased morbidity and mortality. In critically ill surgical patients, obtaining tight glycemic control with intensive insulin therapy was shown to reduce morbidity and mortality and has increasingly become the standard of care. In addition to its well-known anti-hyperglycemic action and reduction in infections, insulin promotes muscle anabolism and regulates the systemic inflammatory response. Despite a demonstrated benefit of insulin administration on the maintenance of skeletal muscle mass, it is unknown if this effect translates to improved clinical outcomes in the thermally injured. Further, insulin therapy has the potential to cause hypoglycemia and requires frequent monitoring of blood glucose levels. A better understanding of the clinical benefit associated with tight glycemic control in the burned patient, as well as newer strategies to achieve and maintain that control, may provide improved methods to reduce the clinical morbidity and mortality in the thermally injured patient.

Predictors of mortality after emergent surgery for acute colonic diverticulitis: Analysis of National Surgical Quality Improvement Project data

BACKGROUND The surgical treatment of acute colonic diverticulitis is associated with significant morbidity and mortality. However, patient and operative characteristics associated with mortality in this patient population are unclear. We hypothesize that demographic and perioperative variables can be used to predict postoperative mortality. The purpose of this study was to identify perioperative variables predictive of postoperative mortality after emergent surgery for acute diverticulitis. METHODS Patients with diverticulitis undergoing colostomy and/or partial colectomy with or without primary anastomosis were retrieved from the American College of Surgeons National Surgical Quality Improvement Program database for years 2005 to 2008 inclusive. Only patients undergoing emergent surgery for acute diverticulitis were included. Univariate analyses were performed to compare demographic characteristics, preoperative laboratory values, comorbidities, and intraoperative variables. Variables with a significant (p < 0.10) difference between survivors and nonsurvivors were included in a stepwise logistic regression model to determine predictors of 30-day mortality. Concordance indices (c indices) for postoperative mortality were calculated using 2005 to 2008 data to determine predictive accuracy and validated on 2009 data. RESULTS A total of 2,214 patients met inclusion criteria. Mean age was 61 years, and 50% of patients were male. Thirty-day mortality was 5.1%. Nine preoperative variables were significantly associated with postoperative mortality on multivariable analysis. The c index of this nine-variable model was 0.901. Renal dysfunction, hypoalbuminemia, American Society of Anesthesiologists class, and age were chosen to create a simpler model, with a c index of 0.886 for 2005 to 2008 data and 0.893 for 2009 data. CONCLUSION Four readily available perioperative variables can be used to predict 30-day mortality after emergent surgery for acute diverticulitis. LEVEL OF EVIDENCE Prognostic study, level II.

Proliferation, Hyperplasia, Neogenesis, and Neoplasia in the Islets of Langerhans

Pancreatic disease is responsible for significant morbidity and mortality as a result of pancreatic carcinoma and diabetes mellitus. Regulation of endocrine cell mass is thought to have a central role in the pathogenesis of both these diseases. Islet cell proliferation, hypertrophy, neogenesis, and apoptosis are the main determinants of endocrine cell mass in the pancreas, and their understanding has been improved by new clues of their genetic and molecular basis. &bgr; Cells have attracted most research interest because of potential implications in the treatment of diabetes mellitus and hypoglycemic disorders. The processes that operate during pancreatic adaptation to a changing hormonal milieu are important in pancreatic carcinogenesis. There is evidence that somatostatin and its receptors are fundamental regulators of endocrine cell mass and are involved in islet tumorigenesis.

Multiple treatment cycles of liposome-encapsulated adenoviral RIP-TK gene therapy effectively ablate human pancreatic cancer cells in SCID mice

BACKGROUND Adenoviral gene therapy has been applied widely for cancer therapy; however, transient gene expression as result of humoral immunoneutralization response to adenovirus limits its effect. The purpose of this study is to determine whether DOTAP:cholesterol liposome could shield adenovirus from neutralizing antibody and permit the use of multiple cycles of intravenous liposome encapsulated serotype 5 adenoviral rat insulin promoter directed thymidine kinase (L-A-5-RIP-TK) with ganciclovir (GCV) to enhance its effect. METHODS The effect of multiple cycles of systemic L-A-5-RIP-TK/GCV therapy was evaluated in grouped PANC-1 SCID mice treated with different numbers of cycles. Humoral immune response to A-5-RIP-TK or L-A-5-RIP-TK was assessed using C57/B6J mice challenged with adenovirus or liposome adenovirus complex. RESULTS The minimal residual tumor burden (3.2 ± 0.6 mm(3)) and greatest survival time (153.0 ± 6 days) were obtained in the mice receiving 4 and 3 cycles of therapy, respectively. Toxicity to islet cells associated with RIP-TK/GCV therapy was observed after 4 cycles. DOTAP:chol-encapsulated adenovectors were able to protect adenovectors from the neutralization of high titer of anti-adenoviral antibodies induced by itself. CONCLUSION Multiple treatment cycles of L-A-5-RIP-TK/GCV ablate human PANC-1 cells effectively in SCID mice; however, the mice become diabetic and have substantial mortality after the 4th cycle. Liposome-encapsulated adenovirus is functionally resistant to the neutralizing effects of anti-adenoviral antibodies, suggesting feasibility of multiple cycles of therapy. Liposome encapsulation of the adenovirus may be a promising strategy for repeated delivery of systemic adenoviral gene therapy.

Colonoscopic Findings and Tumor Site Do Not Predict Bowel Obstruction During Medical Treatment of Stage IV Colorectal Cancer

BACKGROUND In the absence of symptoms related to their primary tumor, patients with stage IV colorectal cancer can undergo medical treatment with their primary tumor in situ. In these patients, bowel obstruction is the most common primary tumor-related complication. We hypothesized that left-sided, circumferential, near-obstructing lesions and/or inability to advance the colonoscope beyond the primary tumor are associated with symptomatic bowel obstruction and are indications for prophylactic primary tumor resection (PTR) or colonic diversion. PATIENTS AND METHODS The medical oncology database of the University of Wisconsin Hospital was retrospectively reviewed. Inclusion criteria were presentation with stage IV colorectal cancer without previous treatment. Students t-test and Fishers exact test were used to compare continuous and noncontinuous variables, respectively. RESULTS Forty-nine patients met the inclusion criteria. None underwent colonic diversion or stenting during the course of their disease. At presentation, nine patients underwent PTR for obstructive symptoms. Forty percent of patients with high-risk colonoscopic lesions required PTR at presentation, compared with 3% of patients without high-risk findings. No patients with high-risk colonoscopic findings and/or left-sided lesions who did not undergo PTR at presentation developed symptoms of obstruction during medical therapy. CONCLUSION In stage IV colorectal cancer, circumferential, near-obstructing lesions and inability to advance the colonoscope beyond the primary tumor are common colonoscopic findings and are associated with obstructive symptoms at the time of diagnosis. Left-sided lesions and/or high-risk colonoscopic findings do not predict bowel obstruction during medical treatment and should not be indications for prophylactic PTR or colonic diversion in asymptomatic patients.