Predictors for Survival in an International Cohort of Patients Undergoing Distal Pancreatectomy for Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Surgical factors, including resection of Gerota's fascia, R0-resection, and lymph node yield, may be associated with survival after distal pancreatectomy (DP) for pancreatic ductal adenocarcinoma (PDAC), but evidence from large multicenter studies is lacking. This study aimed to identify predictors for overall survival after DP for PDAC, especially those related to surgical technique. PATIENTS AND METHODS: Data from an international retrospective cohort including patients from 11 European countries and the USA who underwent DP for PDAC (2007-2015) were analyzed. Cox proportional hazard analyses were performed and included Gerota's fascia resection, R0 resection, lymph node ratio, extended resection, and a minimally invasive approach. RESULTS: Overall, 1200 patients from 34 centers with median follow-up of 15 months [interquartile range (IQR) 5-31 months] and median survival period of 30 months [95% confidence interval (CI), 27-33 months] were included. Gerota's fascia resection [hazard ratio (HR) 0.74; p = 0.019], R0 resection (HR 0.70; p = 0.006), and decreased lymph node ratio (HR 0.28; p < 0.001) were associated with improved overall survival, whereas extended resection (HR 1.75; p < 0.001) was associated with worse overall survival. A minimally invasive approach did not improve survival as compared with an open approach (HR 1.14; p = 0.350). Adjuvant chemotherapy (HR 0.67; p = 0.003) was also associated with improved overall survival. CONCLUSIONS: This international cohort identified Gerota's fascia resection, R0 resection, and decreased lymph node ratio as factors associated with improved overall survival during DP for PDAC. Surgeons should strive for R0 resection and adequate lymphadenectomy and could also consider Gerota's fascia resection in their routine surgical approach.

Risk of conversion to open surgery during robotic and laparoscopic pancreatoduodenectomy and effect on outcomes: international propensity score-matched comparison study.

BACKGROUND: Minimally invasive pancreatoduodenectomy (MIPD) is increasingly being performed because of perceived patient benefits. Whether conversion of MIPD to open pancreatoduodenectomy worsens outcome, and which risk factors are associated with conversion, is unclear. METHODS: This was a post hoc analysis of a European multicentre retrospective cohort study of patients undergoing MIPD (2012-2017) in ten medium-volume (10-19 MIPDs annually) and four high-volume (at least 20 MIPDs annually) centres. Propensity score matching (1 : 1) was used to compare outcomes of converted and non-converted MIPD procedures. Multivariable logistic regression analysis was performed to identify risk factors for conversion, with results presented as odds ratios (ORs) with 95 per cent confidence intervals (c.i). RESULTS: Overall, 65 of 709 MIPDs were converted (9.2 per cent) and the overall 30-day mortality rate was 3.8 per cent. Risk factors for conversion were tumour size larger than 40 mm (OR 2.7, 95 per cent c.i.1.0 to 6.8; P = 0.041), pancreatobiliary tumours (OR 2.2, 1.0 to 4.8; P = 0.039), age at least 75 years (OR 2.0, 1.0 to 4.1; P = 0.043), and laparoscopic pancreatoduodenectomy (OR 5.2, 2.5 to 10.7; P < 0.001). Medium-volume centres had a higher risk of conversion than high-volume centres (15.2 versus 4.1 per cent, P < 0.001; OR 4.1, 2.3 to 7.4, P < 0.001). After propensity score matching (56 converted MIPDs and 56 completed MIPDs) including risk factors, rates of complications with a Clavien-Dindo grade of III or higher (32 versus 34 per cent; P = 0.841) and 30-day mortality (12 versus 6 per cent; P = 0.274) did not differ between converted and non-converted MIPDs. CONCLUSION: Risk factors for conversion during MIPD include age, large tumour size, tumour location, laparoscopic approach, and surgery in medium-volume centres. Although conversion during MIPD itself was not associated with worse outcomes, the outcome in these patients was poor in general which should be taken into account during patient selection for MIPD.

Robotic versus laparoscopic distal pancreatectomy: multicentre analysis.

BACKGROUND: The role of minimally invasive distal pancreatectomy is still unclear, and whether robotic distal pancreatectomy (RDP) offers benefits over laparoscopic distal pancreatectomy (LDP) is unknown because large multicentre studies are lacking. This study compared perioperative outcomes between RDP and LDP. METHODS: A multicentre international propensity score-matched study included patients who underwent RDP or LDP for any indication in 21 European centres from six countries that performed at least 15 distal pancreatectomies annually (January 2011 to June 2019). Propensity score matching was based on preoperative characteristics in a 1 : 1 ratio. The primary outcome was the major morbidity rate (Clavien-Dindo grade IIIa or above). RESULTS: A total of 1551 patients (407 RDP and 1144 LDP) were included in the study. Some 402 patients who had RDP were matched with 402 who underwent LDP. After matching, there was no difference between RDP and LDP groups in rates of major morbidity (14.2 versus 16.5 per cent respectively; P = 0.378), postoperative pancreatic fistula grade B/C (24.6 versus 26.5 per cent; P = 0.543) or 90-day mortality (0.5 versus 1.3 per cent; P = 0.268). RDP was associated with a longer duration of surgery than LDP (median 285 (i.q.r. 225-350) versus 240 (195-300) min respectively; P < 0.001), lower conversion rate (6.7 versus 15.2 per cent; P < 0.001), higher spleen preservation rate (81.4 versus 62.9 per cent; P = 0.001), longer hospital stay (median 8.5 (i.q.r. 7-12) versus 7 (6-10) days; P < 0.001) and lower readmission rate (11.0 versus 18.2 per cent; P = 0.004). CONCLUSION: The major morbidity rate was comparable between RDP and LDP. RDP was associated with improved rates of conversion, spleen preservation and readmission, to the detriment of longer duration of surgery and hospital stay.

Laparoscopic versus open extended radical left pancreatectomy for pancreatic ductal adenocarcinoma: an international propensity-score matched study.

BACKGROUND: A radical left pancreatectomy in patients with pancreatic ductal adenocarcinoma (PDAC) may require extended, multivisceral resections. The role of a laparoscopic approach in extended radical left pancreatectomy (ERLP) is unclear since comparative studies are lacking. The aim of this study was to compare outcomes after laparoscopic vs open ERLP in patients with PDAC. METHODS: An international multicenter propensity-score matched study including patients who underwent either laparoscopic or open ERLP (L-ERLP; O-ERLP) for PDAC was performed (2007-2015). The ISGPS definition for extended resection was used. Primary outcomes were overall survival, margin negative rate (R0), and lymph node retrieval. RESULTS: Between 2007 and 2015, 320 patients underwent ERLP in 34 centers from 12 countries (65 L-ERLP vs. 255 O-ERLP). After propensity-score matching, 44 L-ERLP could be matched to 44 O-ERLP. In the matched cohort, the conversion rate in L-ERLP group was 35%. The L-ERLP R0 resection rate (matched cohort) was comparable to O-ERLP (67% vs 48%; P = 0.063) but the lymph node yield was lower for L-ERLP than O-ERLP (median 11 vs 19, P = 0.023). L-ERLP was associated with less delayed gastric emptying (0% vs 16%, P = 0.006) and shorter hospital stay (median 9 vs 13 days, P = 0.005), as compared to O-ERLP. Outcomes were comparable for additional organ resections, vascular resections (besides splenic vessels), Clavien-Dindo grade ≥ III complications, or 90-day mortality (2% vs 2%, P = 0.973). The median overall survival was comparable between both groups (19 vs 20 months, P = 0.571). Conversion did not worsen outcomes in L-ERLP. CONCLUSION: The laparoscopic approach may be used safely in selected patients requiring ERLP for PDAC, since morbidity, mortality, and overall survival seem comparable, as compared to O-ERLP. L-ERLP is associated with a high conversion rate and reduced lymph node yield but also with less delayed gastric emptying and a shorter hospital stay, as compared to O-ERLP.

Gemcitabine-based adjuvant chemotherapy in subtypes of ampullary adenocarcinoma: international propensity score-matched cohort study.

BACKGROUND: Whether patients who undergo resection of ampullary adenocarcinoma have a survival benefit from adjuvant chemotherapy is currently unknown. The aim of this study was to compare survival between patients with and without adjuvant chemotherapy after resection of ampullary adenocarcinoma in a propensity score-matched analysis. METHODS: An international multicentre cohort study was conducted, including patients who underwent pancreatoduodenectomy for ampullary adenocarcinoma between 2006 and 2017, in 13 centres in six countries. Propensity scores were used to match patients who received adjuvant chemotherapy with those who did not, in the entire cohort and in two subgroups (pancreatobiliary/mixed and intestinal subtypes). Survival was assessed using the Kaplan-Meier method and Cox regression analyses. RESULTS: Overall, 1163 patients underwent pancreatoduodenectomy for ampullary adenocarcinoma. After excluding 187 patients, median survival in the remaining 976 patients was 67 (95 per cent c.i. 56 to 78) months. A total of 520 patients (53·3 per cent) received adjuvant chemotherapy. In a propensity score-matched cohort (194 patients in each group), survival was better among patients who received adjuvant chemotherapy than in those who did not (median survival not reached versus 60 months respectively; P = 0·051). A survival benefit was seen in patients with the pancreatobiliary/mixed subtype; median survival was not reached in patients receiving adjuvant chemotherapy and 32 months in the group without chemotherapy (P = 0·020). Patients with the intestinal subtype did not show any survival benefit from adjuvant chemotherapy. CONCLUSION: Patients with resected ampullary adenocarcinoma may benefit from gemcitabine-based adjuvant chemotherapy, but this effect may be reserved for those with the pancreatobiliary and/or mixed subtype.

ANTECEDENTES: Actualmente se desconoce si la quimioterapia adyuvante ofrece un beneficio en la supervivencia de los pacientes que se someten a resección de un adenocarcinoma ampular. El objetivo de este estudio fue comparar la supervivencia mediante la concordancia estimada por emparejamiento por puntaje de propensión, entre pacientes con y sin quimioterapia adyuvante después de la resección de un adenocarcinoma ampular. MÉTODOS: Se realizó un estudio internacional de cohortes multicéntrico, que incluyó a los pacientes que se sometieron a una duodenopancreatectomía por adenocarcinoma ampular (2006-2017) en 13 centros de seis países. Los puntajes de propensión se usaron para emparejar a los pacientes que recibieron quimioterapia adyuvante con los que no; tanto en la cohorte completa como en dos subgrupos (subtipo pancreaticobiliar / mixto e intestinal). La supervivencia se evaluó utilizando el método de Kaplan-Meier y las regresiones de Cox. RESULTADOS: En total, 1.163 pacientes fueron sometidos a una duodenopancreatectomía por adenocarcinoma ampular. Después de excluir a 179 pacientes, la mediana de supervivencia de los 976 pacientes restantes fue de 67 meses (i.c. del 95%, 56-78), de los cuales un total de 520 pacientes (53%) recibieron quimioterapia adyuvante. En una cohorte de emparejamiento por puntaje de propensión (194 versus 194 pacientes), la mediana de supervivencia fue mejor en los pacientes tratados con quimioterapia adyuvante en comparación con aquellos sin quimioterapia adyuvante (no se alcanzó la mediana de supervivencia versus 60 meses, respectivamente; P = 0,051). En el subtipo pancreaticobiliar/mixto se observó un beneficio en la supervivencia; no se alcanzó la mediana de supervivencia en pacientes que recibieron quimioterapia adyuvante versus 32 meses en el grupo sin quimioterapia, P = 0,020. El subtipo intestinal no mostró beneficio en la supervivencia de la quimioterapia adyuvante. CONCLUSIÓN: Los pacientes con adenocarcinoma ampular resecado pueden beneficiarse de la quimioterapia adyuvante basada en gemcitabina, pero este efecto podría reservarse para aquellos pacientes con subtipo de tumor pancreaticobiliar y/o mixto.

Germline BRCA2 K3326X and CHEK2 I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma.

Rare truncating BRCA2 K3326X (rs11571833) and pathogenic CHEK2 I157T (rs17879961) variants have previously been implicated in familial pancreatic ductal adenocarcinoma (PDAC), but not in sporadic cases. The effect of both mutations in important DNA repair genes on sporadic PDAC risk may shed light on the genetic architecture of this disease. Both mutations were genotyped in germline DNA from 2,935 sporadic PDAC cases and 5,626 control subjects within the PANcreatic Disease ReseArch (PANDoRA) consortium. Risk estimates were evaluated using multivariate unconditional logistic regression with adjustment for possible confounders such as sex, age and country of origin. Statistical analyses were two-sided with p values <0.05 considered significant. K3326X and I157T were associated with increased risk of developing sporadic PDAC (odds ratio (ORdom ) = 1.78, 95% confidence interval (CI) = 1.26-2.52, p = 1.19 × 10-3 and ORdom = 1.74, 95% CI = 1.15-2.63, p = 8.57 × 10-3 , respectively). Neither mutation was significantly associated with risk of developing early-onset PDAC. This retrospective study demonstrates novel risk estimates of K3326X and I157T in sporadic PDAC which suggest that upon validation and in combination with other established genetic and non-genetic risk factors, these mutations may be used to improve pancreatic cancer risk assessment in European populations. Identification of carriers of these risk alleles as high-risk groups may also facilitate screening or prevention strategies for such individuals, regardless of family history.

Expert consensus on a train-the-trainer curriculum for robotic colorectal surgery.

AIM: Robotic techniques are being increasingly used in colorectal surgery. There is, however, a lack of training opportunities and structured training programmes. Robotic surgery has specific problems and challenges for trainers and trainees. Ergonomics, specific skills and user-machine interfaces are different from those in traditional laparoscopic surgery. The aim of this study was to establish expert consensus on the requirements for a robotic train-the-trainer curriculum amongst robotic surgeons and trainers. METHOD: This is a modified Delphi-type study involving 14 experts in robotic surgery teaching. A reiterating 19-item questionnaire was sent out to the same group and agreement levels analysed. A consensus of 0.8 or higher was considered to be high-level agreement. RESULTS: Response rates were 93-100% and most items reached high levels of agreement within three rounds. Specific requirements for a robotic faculty development curriculum included maximizing dual-console teaching, theatre team training, nontechnical skills training, patient safety, user-machine interface training and telementoring. CONCLUSION: A clear need for the development of a train-the-trainer curriculum has been identified. Further research is needed to assess feasibility, effectiveness and clinical impact of a robotic train-the-trainer curriculum.

Prognostic factors for pancreatic neuroendocrine neoplasms (pNET) and the risk of small non-functioning pNET.

BACKGROUND: Non-functioning (NF) pancreatic neuroendocrine tumors (pNET) often have an indolent outcome. A consensus to submit patients with large (>2 cm) NF-pNET to surgery already exists; but a conservative approach for small (≤2 cm) NF neoplasms has been proposed. AIM: To identify prognostic factors for survival and progression free survival (PFS) of NF-pNET, evaluating whether surgery may be avoided for small NF-pNET. SUBJECTS AND METHODS: Retrospective study of 77 consecutive patients with pNET submitted to surgery, of which 60 were NF. Pathological tissues were revised according to the 2000 and 2010 WHO classifications. Risk factors for survival and PFS were evaluated using the Kaplan-Meier method and the Cox regression model. RESULTS: The 8-year cause-specific survival of NF-pNET was 79.3%. At univariate analysis, high grading, high staging, large tumors, angioinvasion and peri-pancreatic infiltration were significantly associated with a shorter survival; at multivariate analysis only peri-pancreatic infiltration was significantly associated with a shorter NF-pNET survival. Most small NF-pNET were grade 1 (74%), compared to large NF-pNET (27%). Distant metastases were present in 29.7% (n = 11) and 17.4% (n = 4) of patients with large or small NF-pNET, respectively; among the 19 small NF-pNET without metastasis, five had a local malignancy (lymph node metastasis or local infiltration); thus, 39% of the 23 NF-pNET, turned out to have a malignant potential. CONCLUSIONS: Among NF-pNET, large neoplasms were associated with worse outcomes; however, small NF-pNET do not seem to have an invariable benign behavior. Whether surgery should be avoided in all patients with small NF-pNET is questionable.

Synergistic interaction of novel lactate dehydrogenase inhibitors with gemcitabine against pancreatic cancer cells in hypoxia.

BACKGROUND: Hypoxia is a driving force in pancreatic-ductal-adenocarcinoma (PDAC) growth, metastasis and chemoresistance. The muscle-isoform of lactate dehydrogenase (LDH-A) constitutes a major checkpoint for the switch to anaerobic glycolysis, ensuring supply of energy and anabolites in hypoxic-environments. Therefore, we investigated the molecular mechanisms underlying the pharmacological interaction of novel LDH-A inhibitors in combination with gemcitabine in PDAC cells. METHODS: Lactate dehydrogenase A levels were studied by quantitative RT-PCR, western blot, immunofluorescence and activity assays in 14 PDAC cells, including primary-cell-cultures and spheroids, in normoxic and hypoxic conditions. Cell proliferation, migration and key determinants of drug activity were evaluated by sulforhodamine-B-assay, wound-healing assay, PCR and LC-MS/MS. RESULTS: Lactate dehydrogenase A was significantly increased under hypoxic conditions (1% O2), where the novel LDH-A inhibitors proved to be particularly effective (e.g., with IC50 values of 0.9 vs 16.3 µM for NHI-1 in LPC006 in hypoxia vs normoxia, respectively). These compounds induced apoptosis, affected invasiveness and spheroid-growth, reducing expression of metalloproteinases and cancer-stem-like-cells markers (CD133+). Their synergistic interaction with gemcitabine, with combination index values <0.4 in hypoxia, might also be attributed to modulation of gemcitabine metabolism, overcoming the reduced synthesis of phosphorylated metabolites. CONCLUSION: Lactate dehydrogenase A is a viable target in PDAC, and novel LDH-A inhibitors display synergistic cytotoxic activity with gemcitabine, offering an innovative tool in hypoxic tumours.

Intraoperative intraductal ultrasonography of the main pancreatic duct during pancreatoduodenectomy: technical description of a pilot series.

The intraoperative risk stratification during pancreatoduodenectomy is gaining increasing significance. The main pancreatic duct wall is of particular importance as it represents the element of anchor of the anastomotic stiches. This study aims to describe the safety, feasibility, and reproducibility of a novel intraductal ultrasonography of the main pancreatic (MPD)-Wirsung duct (IWU) during pancreatoduodenectomy (PD).A prospective series of 58 patients underwent PD with anastomosis between the MPD and the jejunum. Just before the reconstructive phase, the remaining pancreatic stump underwent complete IWU with definition of Wirsung thickness (WT) at the anastomotic site, using a radial ultrasound probe of 1.7 mm in diameter.No IWU-related complications were reported. The median WT of the MPD was 1.1 mm (SD 0.2). The rates of postoperative pancreatic fistula (POPF), major morbidity, and mortality were 17, 5, and 0%, respectively.The use of IWU during PD demonstrated safety and feasibility. IWU represents a new tool aimed at determining structural characteristics of the MPD that could impact on the surgical strategy of the pancreatic anastomosis. Further validation and comparative analysis with the current standard of care are warranted within a prospective controlled framework.

The good, the bad and the ugly: a tale of miR-101, miR-21 and miR-155 in pancreatic intraductal papillary mucinous neoplasms.

BACKGROUND: This multicenter study evaluated three candidate microRNAs (miRNAs) (miR-21, miR-155 and miR-101) as potential biomarkers in intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. PATIENTS AND METHODS: miRNA expression was quantified by quantitative RT-PCR in 86 laser-microdissected specimens, including 65 invasive IPMNs, 16 non-invasive IPMNs and 5 normal pancreatic ductal tissues. Univariate and multivariate analyses compared miRNAs and clinical parameters with overall (OS) and disease-free survival (DFS). RESULTS: miR-21 and miR-155 were up-regulated in invasive IPMNs compared with non-invasive IPMNs, as well as in non-invasive IPMNs compared with normal tissues. Conversely, miR-101 levels were significantly higher in non-invasive IPMNs and normal tissues compared with invasive IPMNs. High levels of miR-21 were associated with worse OS [hazard ratio (HR) = 2.47, 95% confidence interval (CI) = 1.37-5.65, P = 0.0047]. Patients with high-miR-21 expression also had a shorter median DFS (10.9 versus 29.9 months, P = 0.01). Multivariate analysis confirmed miR-21 as independently prognostic for mortality and disease progression (death risk: HR = 3.3, 95% CI = 1.5-7.0, P = 0.02; progression risk: HR = 2.3, 95% CI = 1.2-4.8, P = 0.02), as well as positive lymph-node status (death risk: HR = 2.6, 95% CI = 1.1-6.3, P = 0.03; progression risk: HR = 2.2, 95% CI = 1.0-4.8, P = 0.04). CONCLUSIONS: miR-21, miR-155 and miR-101 showed significant differences in invasive versus non-invasive IPMNs. miR-21 emerged as an independent prognostic biomarker in invasive IPMNs and should be validated in prospective studies.

Prevalence and risk factors of extrapancreatic malignancies in a large cohort of patients with intraductal papillary mucinous neoplasm (IPMN) of the pancreas.

BACKGROUND: The objectives of this study are to estimate prevalence and incidence of extrapancreatic malignancies (EPMs) among intraductal papillary mucinous neoplasms (IPMNs) of the pancreas, and to identify risk factors for their occurrence. PATIENTS AND METHODS: We conducted multicentric cohort study in Italy from January 2010 to January 2011 including 390 IPMN cases. EPMs were grouped as previous, synchronous (both prevalent) and metachronous (incident). We calculated the observed/expected (O/E) ratio of prevalent EPMs, and compared the distribution of demographic, medical history and lifestyle habits. RESULTS: Ninety-seven EPMs were diagnosed in 92 patients (23.6%), among them 78 (80.4%) were previous, 14 (14.4%) were synchronous and 5 (5.2%) were metachronous. O/E ratios for prevalent EPMs were significantly increased for colorectal carcinoma (2.26; CI 95% 1.17-3.96), renal cell carcinoma (6.00; CI 95% 2.74-11.39) and thyroid carcinoma (5.56; CI 95% 1.80-12.96). Increased age, heavy cigarette smoking, alcohol consumption and first-degree family history of gastric cancer are significant risk factors for EPMs, while first-degree family history of colorectal carcinoma was borderline. CONCLUSION: We report an increased prevalence of EPMs in Italian patients with IPMN, especially for colorectal carcinoma, renal cell and thyroid cancers. A systematic surveillance of IPMN cases for such cancer types would be advised.

Feasibility of robotic pancreaticoduodenectomy.

BACKGROUND: Laparoscopic pancreaticoduodenectomy is feasible, but requires adaptations to established surgical techniques. The improved dexterity offered by robotic assistance provides the opportunity to see whether laparoscopic pancreaticoduodenectomy can be performed safely when faithfully reproducing the open operation. METHODS: Patients were selected for robotic pancreaticoduodenectomy when generally suitable for laparoscopy. Obese patients were excluded, and those with pancreatic cancer were highly selected. A prospectively designed database was used for data collection and analysis. RESULTS: Of 238 patients undergoing pancreaticoduodenectomy, 34 (14·3 per cent) were operated on robotically. No procedure was converted to conventional laparoscopy or open surgery, despite three patients requiring segmental resection of the superior mesenteric/portal vein and reconstruction. The mean duration of operation was 597 (range 420-960) min. The mean number of lymph nodes retrieved and analysed from patients with neoplasia was 32 (range 15-76). Four patients required blood transfusions and five developed postoperative complications exceeding Clavien-Dindo grade II. There were four grade B pancreatic fistulas. One patient died on postoperative day 40. Excess mean operative cost compared with open resection was €6193. CONCLUSION: Selected patients can safely undergo robotic pancreaticoduodenectomy. The main downsides are high costs and prolonged operating times compared with open resection.

ß-Cell inflammation in human type 2 diabetes and the role of autophagy.

ß-Cell failure is crucial for the onset and progression of human type 2 diabetes, and a few studies have suggested that inflammation may play a role. Immune cell infiltration has been reported in subpopulations of islets in some cases of human type 2 diabetes, and altered gene expression of a few cytokines and chemokines has been observed in isolated islets and laser captured ß-cells from diabetic subjects. Recent observations on the links between inflammation, apoptosis and autophagy are putting the focus on the possibility that modulating the autophagic processes could protect the ß-cells from cytotoxicity induced by inflammatory mediators.

Ectopic expression of FSH receptor isoforms in neoplastic but not in endothelial cells from pancreatic neuroendocrine tumors.

FSH receptor (FSHR) expression is restricted to gonads, where it drives FSH-dependent cell differentiation; in addition, FSHR plays an important role in the regulation of ovarian angiogenesis. Recently, FHSR expression has been shown in blood vessels of various tumors. However, pancreatic neuroendocrine tumors (p-NET), which have high-degree blood supply, were not included in that study. The aim of this study was to evaluate FSHR expression in p-NET. FSHR expression was evaluated in tumor samples from 30 patients with p-NET by immunohistochemistry and Western blot; fluorescence microscopy was used to localize FSHR in specific cells from tissue samples. von Willebrand factor (vWF) and chromograninA (chrA) was used as blood vessel and NET cells marker, respectively, to co-localize FSHR. FSHR expression was detected in all p-NET by immunohistochemistry. Western blot confirmed FSHR expression on p- NET although different FSHR isoforms, ranging from 240 kD to 55 kD were found in the samples studied. Surprisingly, FSHR co-localized with chrA but not with vWF, suggesting that neoplastic cells of neuroendocrine origin rather than blood vessels expressed FSHR. No relationship was found between degree of FSHR expression and histology of p-NET. FSHR may be aberrantly expressed in neoplastic cells from p-NET and not in tumor blood vessels; however, its biological significance as well as its clinical relevance remains to be elucidated.

Endovascular treatment of multiple anomalous splenic artery aneurysms in a Jehovah witness.

PURPOSE: The present report describes a full endovascular treatment of a multiple anomalous (Splenic artery aneurysms) SAA with combination of coils embolization and proximal occlusion of the splenic artery with the Amplatzer vascular plug. CASE REPORT: A 53-year-old Jehovah witness woman presented with multiple aneurysms arising from an anomalous splenic artery. An endovascular treatment was performed by implantation of multiple coils and an Amplatzer Vascular Plug. A CT scan 2 months after the procedure showed complete thrombosis of the aneurysms. DISCUSSION: Aneurysms involving an anomalous or aberrant splenic artery are rarely reported in the literature. Their surgical treatment involves potential difficulties as a consequence of anatomical position and vascular anomalies. A fully endovascular technique can be much more attractive compared to any surgical management, providing an effective and minimally invasive option.

A local glucagon-like peptide 1 (GLP-1) system in human pancreatic islets.

AIMS/HYPOTHESIS: Glucagon-like peptide 1 (GLP-1) is a major incretin, mainly produced by the intestinal L cells, with beneficial actions on pancreatic beta cells. However, while in vivo only very small amounts of GLP-1 reach the pancreas in bioactive form, some observations indicate that GLP-1 may also be produced in the islets. We performed comprehensive morphological, functional and molecular studies to evaluate the presence and various features of a local GLP-1 system in human pancreatic islet cells, including those from type 2 diabetic patients. METHODS: The presence of insulin, glucagon, GLP-1, proconvertase (PC) 1/3 and PC2 was determined in human pancreas by immunohistochemistry with confocal microscopy. Islets were isolated from non-diabetic and type 2 diabetic donors. GLP-1 protein abundance was evaluated by immunoblotting and matrix-assisted laser desorption-ionisation-time of flight (MALDI-TOF) mass spectrometry. Single alpha and beta cell suspensions were obtained by enzymatic dissociation and FACS sorting. Glucagon and GLP-1 release were measured in response to nutrients. RESULTS: Confocal microscopy showed the presence of GLP-1-like and PC1/3 immunoreactivity in subsets of alpha cells, whereas GLP-1 was not observed in beta cells. The presence of GLP-1 in isolated islets was confirmed by immunoblotting, followed by mass spectrometry. Isolated islets and alpha (but not beta) cell fractions released GLP-1, which was regulated by glucose and arginine. PC1/3 (also known as PCSK1) gene expression was shown in alpha cells. GLP-1 release was significantly higher from type 2 diabetic than from non-diabetic isolated islets. CONCLUSIONS/INTERPRETATION: We have shown the presence of a functionally competent GLP-1 system in human pancreatic islets, which resides in alpha cells and might be modulated by type 2 diabetes.