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

BACKGROUND AND OBJECTIVES: 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. METHODS: Adult patients undergoing TME for rectal adenocarcinoma were retrospectively identified. Preoperative computed tomography scans were used to measure abdominal circumference (AC), visceral (VFA), and subcutaneous fat area (SFA). BMI, AC, VFA, SFA, total fat area (TFA, sum of VFA and SFA), and VFA/SFA ratio were examined for association with operative, postoperative, oncologic, and survival outcomes in a univariate analysis model. RESULTS: Between 1999 and 2009, 113 patients met inclusion criteria. Increasing VFA and VFA/SFA ratio were associated with reduced lymph node retrieval (P = 0.03 and P = 0.009, respectively). The association between increasing VFA/SFA ratio with delayed resumption of oral intake (P = 0.05) and prolonged overall survival (P = 0.003) were also significant. Increasing BMI was associated with improved overall (P = 0.02) but not disease-free survival (P = 0.14). CONCLUSION: Visceral obesity, measured by VFA/SFA ratio, is a better predictor of postoperative, oncologic, and survival outcomes after TME for rectal adenocarcinoma than general obesity measured by the BMI.

Comparable postoperative morbidity and mortality after laparoscopic and open emergent restorative colectomy: outcomes from the ACS NSQIP.

BACKGROUND: Laparoscopic surgery is safe and effective in the management of common abdominal emergencies. However, there is currently a lack of data about its use for emergency colorectal surgery. We hypothesized that laparoscopy can improve the postoperative outcomes of emergency restorative colon resection. METHODS: Adult patients undergoing emergent open and laparoscopic colon resection with primary anastomosis were retrieved from the American College of Surgeons National Surgical Quality Improvement Program database for the years 2005 to 2008 inclusive. Demographic and operative characteristics, laboratory values, and postoperative outcomes were compared between patients undergoing laparoscopic and open colon resection using univariate analyses, multivariate logistic regression, and propensity score analyses. RESULTS: A total of 341 laparoscopic (9.6 %) and 3211 (90.4 %) open colon resections were included. Patients undergoing laparoscopic surgery had a significantly lower prevalence of co-morbidities and better postoperative outcomes. On multivariate analysis, laparoscopic surgery was an independent predictor of a longer operating time (p < 0.001) and shorter total (p = 0.013) and postoperative (p = 0.004) hospital stays, but it did not affect the need for intraoperative blood transfusion (p = 0.488), the 30-day reoperation rates (p = 0.969), or mortality (p = 0.417). After adjusted propensity score analysis, postoperative morbidity (p = 0.833) and mortality (p = 0.568) were comparable in patients undergoing laparoscopic and open surgery. CONCLUSIONS: On a national scale, laparoscopic emergent colon resections are being performed in a small number of patients, who have favorable co-morbidity characteristics and improved postoperative outcomes. Laparoscopic emergent colon resection with primary anastomosis has postoperative morbidity and mortality rates comparable to those seen with the open approach, and it reduces the total and postoperative length of hospital stay.

Aorta to proper hepatic artery bypass with total pancreatectomy and celiac axis resection (TP-CAR) in a patient with locally advanced pancreas adenocarcinoma.

INTRODUCTION: Total pancreatectomy with en-bloc celiac axis resection (TP-CAR) and interposition graft placement between the aorta and the proper hepatic artery is a technically demanding, very uncommonly performed operation, even in high-volume pancreatic centers. PRESENTATION OF CASE: We present, in clinical and technical detail, a patient with locally advanced adenocarcinoma of the pancreatic body and neck involving the celiac and common hepatic arteries and portal vein, who underwent neoadjuvant chemotherapy and radiation with very good response, followed by TP-CAR and aorto-proper hepatic artery bypass using saphenous vein graft. The patient had an uneventful intraoperative and postoperative course, short hospital stay, and histology consistent with a curative resection. DISCUSSION: TP-CAR with common hepatic artery resection and proper hepatic artery reconstruction in patients with locally advanced pancreatic body cancer after appropriate neoadjuvant therapy can be performed safely and be potentially curative in centers with an established track record in advanced pancreatic surgery involving major peripancreatic vessels. CONCLUSION: TP-CAR with proper hepatic artery reconstruction is a rare but potentially curative operation for selected patients with otherwise unresectable pancreatic adenocarcinoma.

Portal-mesenteric vein resection for pancreatic cancer: Results in par with the defined benchmark outcomes.

Background: Patients with pancreatic cancer (PC), which may involve major peripancreatic vessels, have been generally excluded from surgery, as resection was deemed futile. The purpose of this study was to analyze the results of portomesenteric vein resection in borderline resectable or locally advanced PC. This study comprises the largest series of such patients in Greece. Materials and Methods: Investigator-initiated, retrospective, noncomparative study of patients with borderline resectable or locally advanced adenocarcinoma undergoing pancreatectomy en-block with portal and/or superior mesenteric vein resection in a tertiary referral center in Greece between January 2014 and October 2021. Follow-up was complete up to December 2021. Operative and outcome measures were determined. Results: Forty patients were included. Neoadjuvant therapy was administered to only 58% and was associated with smaller tumor size (median: 2.9 cm vs. 4.2 cm, p = 0.004), but not with increased survival. Though venous wall infiltration was present in 55%, it was not associated with tumor size, or Eastern Cooperative Oncology Group (ECOG) status. Resection was extensive: a median of 27 LNs were retrieved, R0 resection rate (≥1 mm) was 87%, and median length of resected vein segments was 3 cm, requiring interposition grafts in 40% (polytetrafluoroethylene). Median ICU stay was 0 days and length of hospitalization 9 days. Postoperative mortality was 2.5%. Median follow-up was 46 months and median overall survival (OS) was 24 months. Two-, 3- and 5-year OS rates were 49%, 33%, and 22% respectively. All outcomes exceeded benchmark cutoffs. Lower ECOG status was positively correlated with longer survival (ECOG-0: 32 months, ECOG-1: 24 months, ECOG-2: 12 months, p = 0.02). Conclusion: This series of portomesenteric resection in borderline resectable or locally advanced PC demonstrated a median survival of 2 years, extending to 32 months in patients with good performance status, which meet or exceed current outcome benchmarks.

Body mass index does not affect postoperative morbidity and oncologic outcomes of total mesorectal excision for rectal adenocarcinoma.

INTRODUCTION: Obesity adds to the technical difficulty of colorectal surgery and is a risk factor for postoperative complications. We hypothesized that obese patients have increased morbidity and poor oncologic outcomes after proctectomy for rectal adenocarcinoma. METHODS: Adult patients undergoing total mesorectal excision (TME) for rectal adenocarcinoma at a tertiary referral center were retrospectively identified from a prospectively maintained database. Operative characteristics, postoperative complication rates, and oncologic outcomes were compared in patients with BMI > or = 30 kg/m(2) and BMI < 30 kg/m(2). RESULTS: Between 1997 and 2009, 254 patients underwent proctectomy for rectal adenocarcinoma, of whom 27% were obese. There were no significant differences in demographics, comorbidities or preoperative oncologic characteristics between obese and nonobese groups. Patients with BMI > or = 30 kg/m(2) had longer operative times (p = 0.04) and higher intraoperative blood loss (p < 0.001) but comparable postoperative complication rates (p = 0.80), number of lymph nodes retrieved (p = 0.57), margin-negative resections (p = 0.44), and disease-free survival (p = 0.11). Obese patients had longer overall survival (p = 0.05). Tumor stage was the only variable associated with disease-free (p < 0.001) and overall survival (p < 0.001). CONCLUSION: Despite increased technical difficulty of resection, obesity does not increase the risk of postoperative morbidity or adversely affect oncologic outcomes after total mesorectal excision of rectal adenocarcinoma.

Optic neuropathy following radiotherapy for Cushing's disease: case report and literature review.

Radiation-induced optic neuropathy is a rare adverse effect of radiotherapy applied for the treatment of pituitary adenomas. We report a patient with a recurrent adrenocorticotrophin secreting pituitary adenoma who received external beam irradiation after failing surgical and medical therapy. Sixteen months after radiotherapy, the patient was presented with declining visual acuity, and radiation-induced optic neuropathy was diagnosed. Despite treatment with glucocorticoids and hyperbaric oxygen, her vision did not improve. The pathophysiology, prevention and treatment of radiation-induced optic neuropathy, including the efficacy of hyperbaric oxygen therapy are reviewed.

Distal pancreatectomy with celiac axis resection (DP-CAR): Optimal perioperative outcome in a patient with locally advanced pancreas adenocarcinoma.

INTRODUCTION: Distal pancreatectomy with en bloc celiac axis resection (DP-CAR) is an operation technically demanding, uncommonly performed, even in high-volume pancreatic centers, which may offer a curative resection in patients with locally advanced cancer of the body of the pancreas, otherwise considered unresectable. PRESENTATION OF CASE: We present, in clinical and technical detail, a patient with DP-CAR with a very good intraoperative and postoperative course, no complications, short hospital stay, and histology consistent with a curative resection. DISCUSSION: Because of the scarcity of DP-CAR, even high-volume individual centers have been able to gather relatively limited experience, and only in a time frame of more than a decade each. CONCLUSION: DP-CAR can be curative for a minority of patients with pancreatic adenocarcinoma and is performed only in centers with a long, dedicated interest in advanced pancreatic surgery with a well-known track record in resection of borderline and locally advanced pancreatic cancer involving major peripancreatic veins.

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. Student's t-test and Fisher's 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.

Revisiting adrenal mass size as an indication for adrenalectomy.

BACKGROUND: Diagnostic tests that can accurately differentiate between benign and malignant adrenal lesions are lacking. Mass size is currently utilized as an indication for adrenalectomy in patients with adrenal masses. However, the accuracy of this criterion and the ideal size threshold are unclear. The aim of the present study was to determine the frequency of using mass size as the only indication for adrenalectomy and the ideal size threshold for distinguishing malignant primary adrenal tumors from lesions that do not require surgical resection. PATIENTS AND METHODS: The adrenalectomy database of the University of Wisconsin was retrospectively reviewed. Patients undergoing adrenalectomy for adrenal mass lesions were identified. Student's t-test and Fisher's exact test were used to compare continuous and noncontinuous variables respectively, with P< or =0.05 representing significance. RESULTS: Of 198 adrenalectomies performed between 1989 and 2007, 106 met inclusion criteria. There were no differences in age or gender distribution between patients with malignant and benign lesions. After complete clinical, imaging, and biochemical evaluation, mass size was the only indication for 16 adrenalectomies (15.1%). Adrenal mass size in these patients ranged from 3.3 to 14 cm (mean 5.9+/-0.6 cm). Only three of these lesions (18.8%) proved malignant. In total, eight malignant tumors were identified in this series (7.5%, size range 4-14 cm, mean 8.0+/-1.3 cm). Benign and non-neoplastic lesions accounted for the remaining masses (92.5%, size range 0.7-9.3 cm, mean 3.6+/-0.2 cm) and were significantly smaller than malignant lesions (P<0.001). CONCLUSION: Adrenal mass size is the only indication for adrenalectomy in a substantial number of patients. A size cut-off of 4 cm would have led to resection of all primary malignant adrenal tumors in this series and reduced the number of adrenalectomies for benign disease.

Portal-Mesenteric Vein Resection in Borderline Pancreatic Cancer; 33 Month-Survival in Patients with Good Performance Status.

Background: Patients with pancreatic cancer (PC), which is not upfront resectable, but borderline, involving major peripancreatic vessels, have not been generally considered for surgery, considering that resection in such a setting may be futile. Materials and Methods: Retrospective analysis of prospectively collected data on patients with borderline pancreatic adenocarcinoma undergoing pancreatectomy en-block with portal and/or superior mesenteric vein resection in a tertiary referral center in Greece between January 2012 and February 2017. Follow-up was complete up to January 2018. Results: Twenty-four patients were included. Neoadjuvant therapy (NAT) was administered to only 38%, but more commonly in the second half of the group (58% vs. 17%, p = 0.035). It was associated with smaller tumor size (median: 2.5 vs. 4.2 cm, p < 0.001), fewer positive lymph nodes (LNs) in the resected specimen (median: 2 vs. 5, p = 0.04), and higher likelihood of adjuvant therapy (78% vs. 40%, p = 0.01), but not with survival. Resection was extensive: a median of 26 LNs were retrieved, R0 resection rate (≥1 mm) was 79%, and median length of vein segments was 4 cm, requiring interposition grafts in 58% (mostly polytetrafluoroethylene). Median intensive care unit stay was 0 days and length of hospital stay was 9 days. Post-operative mortality was 12.5%. Median overall survival was 24 months. Eastern Cooperative Oncology Group (ECOG) status was significantly associated with survival (p < 0.001) with ECOG-0: 33 months, ECOG-1: 12 months, and ECOG-2: 6 months. Conclusion: This first Greek national series of portomesenteric vein resection in borderline PC demonstrates that it results to 2 years of median survival, extending to 33 months in patients with good performance status, especially if NAT is uniformly administered.

Transcription factor PDX-1 in human colorectal adenocarcinoma: a potential tumor marker?

AIM: To examine the expression of pancreatic duodenal homeobox-1 (PDX-1) transcription factor in human colorectal cancer. METHODS: RT-PCR, Western blotting, and immuno-histochemistry were performed to determine the expression pattern of transcription factor PDX-1 in primary colorectal tumor, hepatic metastasis, and benign colon tissue from a single patient. RESULTS: The highest PDX-1 transcription levels were detected in the metastasis material. Lower levels of PDX-1 were found to be present in the primary tumor, while normal colon tissue failed to express detectable levels of PDX-1. Western blot data revealed a PDX-1 expression pattern identical to that of mRNA expression. Immunohistochemistry confirmed high metastasis PDX-1 expression, lower levels in the primary tumor, and the presence of only traces of PDX-1 in normal colon tissue. CONCLUSION: These data argue for further evaluation of PDX-1 as a biomarker for colorectal cancer.

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.

A clinical prediction rule for perioperative mortality and major morbidity after laparoscopic giant paraesophageal hernia repair.

OBJECTIVE: In the current era, giant paraesophageal hernia repair by experienced minimally invasive surgeons has excellent perioperative outcomes when performed electively. However, nonelective repair is associated with significantly greater morbidity and mortality, even when performed laparoscopically. We hypothesized that clinical prediction tools using pretreatment variables could be developed that would predict patient-specific risk of postoperative morbidity and mortality. METHODS: We assessed 980 patients who underwent giant paraesophageal hernia repair (1997-2010; 80% elective and 97% laparoscopic). We assessed the association between clinical predictor covariates, including demographics, comorbidity, and urgency of operation, and risk for in-hospital or 30-day mortality and major morbidity. By using forward stepwise logistic regression, clinical prediction models for mortality and major morbidity were developed. RESULTS: Urgency of operation was a significant predictor of mortality (elective 1.1% [9/778] vs nonelective 8% [16/199]; P < .001) and major morbidity (elective 18% [143/781] vs nonelective 41% [81/199]; P < .001). The most common adverse outcomes were pulmonary complications (n = 199; 20%). A 4-covariate prediction model consisting of age 80 years or more, urgency of operation, and 2 Charlson comorbidity index variables (congestive heart failure and pulmonary disease) provided discriminatory accuracy for postoperative mortality of 88%. A 5-covariate model (sex, age by decade, urgency of operation, congestive heart failure, and pulmonary disease) for major postoperative morbidity was 68% predictive. CONCLUSIONS: Predictive models using pretreatment patient characteristics can accurately predict mortality and major morbidity after giant paraesophageal hernia repair. After prospective validation, these models could provide patient-specific risk prediction, tailored for individual patient characteristics, and contribute to decision-making regarding surgical intervention.

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.

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.

Routine evaluation of the distal colon remnant before Hartmann's reversal is not necessary in asymptomatic patients.

BACKGROUND: Reversal of Hartmann's is a common surgical procedure. Routine preoperative evaluation of the distal colonic/rectal remnant (DCRR) with contrast and/or endoscopic studies is frequently performed despite lack of evidence to support this practice. We hypothesize that asymptomatic patients can safely undergo Hartmann's reversal without preoperative DCRR evaluation. METHODS: Adult patients undergoing reversal of Hartmann's at a single institution were retrospectively identified. Operative characteristics and outcomes in patients with and without preoperative DCRR evaluation were compared. RESULTS: Between 1993 and 2008, 203 patients underwent reversal of Hartmann's at a tertiary referral center. Sixty-eight patients (33%) did not undergo preoperative DCRR evaluation and had comparable demographic characteristics, comorbidities, DCRR length, and perioperative outcomes to 135 patients who underwent preoperative contrast and/or endoscopic studies. After evaluation, 125 (93%) patients had normal findings, seven (5%) patients had abnormal studies that did not impact their management, and three (2%) patients underwent additional procedures. CONCLUSION: Hartmann's reversal without previous DCRR evaluation is acceptable in selected asymptomatic patients, without increased risk of complications.

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.

PDX-1 expression is associated with islet proliferation in vitro and in vivo.

BACKGROUND: Transcription factor pancreatic duodenal homeobox-1 (PDX-1) is critical for beta-cell differentiation and insulin gene expression. In this study, we investigated the role of PDX-1 in ductal-to-islet cell transdifferentiation, islet cell apoptosis, and proliferation in addition to other regulators associated with these processes in two developing beta-cell models. MATERIALS AND METHODS: CAPAN-1 cells were cultured with the GLP-1 analogue Exendin-4 (Ex-4) to induce transdifferentiation to an insulin-producing phenotype. Expression patterns of PDX-1, somatostatin receptors (SSTR) 1, 2, and 5, p27, and p38 were analyzed. To model pancreatic regeneration in vivo, subtotal pancreatectomies were performed in rats and remnant pancreata were compared to sham laparotomy controls to determine islet size, morphology, apoptosis, and PDX-1 expression. RESULTS: In Ex-4-treated cells, PDX-1 expression increased 67% above basal levels within 24 h and was followed by a 10-fold decline in expression by the end of the study. Expression of cell-cycle inhibitor p27 was down-regulated by 81% at 24 h, while levels of the pro-apoptotic modulator p38 significantly increased 4-fold. When compared to controls, SSTR1 expression declined, while SSTR2 and SSTR5 expression were significantly up-regulated in treated cells. Immunofluorescence of pancreatic remnants following subtotal pancreatectomy revealed increased PDX-1 staining at 24 h followed by a significant decline at 72 h post-pancreatectomy. CONCLUSION: GLP-1 analogue Ex-4 resulted in up-regulation of PDX-1 in CAPAN-1 cells and PDX-1 was up-regulated in proliferating islets following subtotal pancreatectomy in rats. The increase was seen in the first 24 h. These findings suggest a possible relationship between PDX-1 and the state of islet proliferation, islet-to-ductal transdifferentiation, apoptosis, and the expression of SSTRs.

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.

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.