M Del Chiaro

Gliclazide protects human islet beta-cells from apoptosis induced by intermittent high glucose.

Decreased beta‐cell mass, mainly due to apoptosis, is crucial for the development and progression of type 2 diabetes. Chronic exposure to high glucose levels is a probable underlying mechanism, whereas the role of oral anti‐diabetic agents (sulphonylureas in particular) is still unsettled.

Prolonged fixed dose rate infusion of gemcitabine with autologous haemopoietic support in advanced pancreatic adenocarcinoma.

This study aimed to define the maximum-tolerated dose (MTD) of fixed dose rate (FDR) of gemcitabine (2′-2′-difluorodeoxycitidine) infusion with circulating haemopoietic progenitor support and to evaluate the activity of the treatment. Secondary end points were pharmacokinetic of gemcitabine and difluorodeoxyuridina (dFdU) measured at first course and the activity andexpression profile of cytidine deaminase (CdA) on circulating mononuclear cells. Patients with advanced pancreatic carcinoma received escalating dose of gemcitabine 10 mg m−2 min−1 every 2 weeks with circulating haemopoietic progenitor support. First dose level was 3000 mg m−2 and the doses were increased by 500 mg m−2 until MTD. In all, 23 patients were enrolled. Toxicities were mild or moderate; the only patient treated at 7000 mg m−2 died because of toxicity; therefore; the MTD was established at 6500 mg m−2. The overall response rate was 22.2%. The AUC of gemcitabine showed a dose-dependent increase, while the AUC of dFdU reached a plateau at 4500 mg m−2. A significant relationship was found between the AUC of dFdU and CdA expression and activity (P<0.05). Moreover, progression rate and survival were significantly related to CdA expression and activity levels. The activity of high-dose gemcitabine is not superior to that reported with less intensive FDR schedules. The predictive role of CdA expression and activity on outcome deserves further investigation.

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.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.

Total Duodenectomy with Enteric Duct Drainage: A Rescue Operation for Duodenal Complications Occurring after Pancreas Transplantation

Duodenal graft complications (DGC) occur frequently after pancreas transplantation but rarely cause graft loss. Graft pancreatectomy, however, may be required when DGC compromise recipients safety. We herein report on two patients with otherwise untreatable DGC in whom the entire pancreas was salvaged by means of total duodenectomy with enteric drainage of both pancreatic ducts. The first patient developed recurrent episodes of enteric bleeding, requiring hospitalization and blood transfusions, starting 21 months after transplantation. The disease causing hemorrhage could not be defined, despite extensive investigations, but the donor duodenum was eventually identified as the site of bleeding. The second patient was referred to us with a duodenal stump leak, 5 months after transplantation. Two previous surgeries had failed to seal the leak, despite opening a diverting stoma above the duodenal graft. Thirty‐nine and 16 months after total duodenectomy with dual duct drainage, respectively, both patients are insulin‐independent and free from abdominal complaints. Magnetic resonance pancreatography shows normal ducts both basal and after intravenous injection of secretin. The two cases presented herein show that when DGC jeopardize pancreas function or recipient safety, total duodenectomy with enteric duct drainage may become an option.

Correlation of basal EGFR expression with pancreatic cancer grading but not with clinical outcome after gemcitabine-based treatment

Philip et al. [1] recently published the results of a phase III study in 745 patients with locally advanced/metastatic pancreatic ductal adenocarcinoma (PDAC) treated either with gemcitabine and the anti-epidermal growth factor receptor (EGFR) cetuximab or with gemcitabine alone. This trial was based on evidence from earlier studies that suggested the combination had sufficient activity to warrant further testing but failed to meet its primary end point of improving overall survival (OS). However, the combination of gemcitabine with the epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) erlotinib translated into a significant improvement of OS [2]. Although increase in tumor control rates and association between rash and outcome seen in the gemcitabine + erlotinib study suggested that therapeutic benefit is confined to a subset of patients, in both trials analysis of EGFR expression failed to reveal a correlation with outcome. No correlation with OS was also observed in patients treated with single-agent gemcitabine [1]. However, previous studies showed a correlation of EGFR expression with grading and prognosis in PDAC patients who underwent only surgical treatment [3]. Therefore, we carried out an immunohistochemical analysis of EGFR in 100 Caucasian patients who underwent PDAC resection and were treated with gemcitabine in order to evaluate the correlation with (i) histological grading and (ii) outcome. Furthermore, we evaluated by uni-/multivariate analysis the role of stage (I–II/ III–IV), lymph node/neural infiltration (yes/no) and resection margin (R0/R1). EGFR staining was detectable at membrane and cytoplasmatic level (Figure 1A) in 84% and 82% of the patients, respectively. The values of EGFR expression, as evaluated by a total score from the analysis of both the number of positive cells and the staining intensity [4], ranged between 0 and 10 (median = 7) (Figure 1B and C). EGFR expression was significantly higher in grade 3 PDAC (P = 0.036, ‘Mann–Whitney test’). The histological differentiation resulted as a prognostic factor, with median OS of 24.8 [95% confidence interval (CI) 15.8–33.7] versus 11.1 months (95% CI 0.2–22.1) in patients with grade 1/2 and grade 3 tumors, respectively (P = 0.018, ‘log-rank test’) (Figure 1D). Similarly, patients with grade 1/2 and grade 3 PDAC had median Progression Free Survival (PFS) of 16.6 (95% CI 11.4–21.8) and 7.3 (95% CI 5.5–9.2) months, respectively (P = 0.007). Among other possible prognostic factors, only lymph node-positive status was correlated with significantly shorter OS and PFS (P = 0.016 and 0.006, respectively). In the Cox proportional hazards model, both grade 3 and lymph node-positive status resulted independent predictive parameters of death (Hazard Ratio (HR) = 2.0, 95% CI 1.1–3.8, P = 0.036 and HR = 3.1, 95% CI 1.1–8.6, P = 0.033, respectively) and progression risk (HR = 2.2, 95% CI 1.2–4.0, P = 0.012 and HR = 3.3, 95% CI 1.3–8.3, P = 0.012, respectively). In contrast, no correlation was observed between EGFR expression and both PFS and OS (Figure 1E), as well as with stage, lymph node/neural infiltration and resection margin. The lack of correlation between EGFR expression and outcome in these patients might be caused by several factors, including modulation of EGFR expression/phosphorylation or related pathways in the relapse/metastatic tumors, which might then differ from resected specimens. Previous studies showed that resistance to cetuximab–gemcitabine in PDAC xenografts was caused by persistent mitogenactivated protein kinase activation and impaired EGFR internalization, associated with constitutive ErBb3 signaling [5]. In conclusion, EGFR expression is correlated with PDAC grading, but it lacks predictive value with respect to outcome in gemcitabine-treated patients both in the palliative and in the adjuvant setting ([1], present study). Future trials should provide the platforms for additional necessary translational research to identify other biomarkers/targets that can improve gemcitabine activity in PDAC.

Role of color Doppler sonography in post-transplant surveillance of vascular complications involving pancreatic allografts

PURPOSE To evaluate the role of color Doppler ultrasonography in the postoperative surveillance of the vascular complications involving pancreas allografts. METHODS A retrospective analysis of a consecutive series of 223 pancreas transplantations was performed. All recipients received antithrombotic prophylaxis, which was tailored to the individuals estimated risk of thrombosis. All patients were monitored with daily color Doppler ultrasonography during the first post-transplant week and thereafter whenever clinically indicated. Vascular complications were defined as all thrombotic events requiring: increased anticoagulant therapy, angiography with fibrinolytic therapy, or repeat surgery. RESULTS The overall patient survival rates at one, three, and five years after transplantation were 94.7%, 93.3%, and 91%, respectively. The overall graft survival rates at the same time points were 87.4%, 79.6%, and 75.6%, respectively. In 28 of the 223 cases (12.5%) graft thromboses were diagnosed with Doppler ultrasound within the first 10 days after transplantation. In 3 cases, graft pancreatectomies were performed because of a complete loss of blood flow in the parenchyma. An attempt to rescue the graft was made in 18 patients. Fourteen of these grafts were saved and are still functioning (77.7%); and 4 rescue attempts failed and the grafts were subsequently explanted (32.3%). CONCLUSION Color Doppler ultrasound is a suitable tool for postoperative surveillance of pancreas transplant recipients. Its use can lead to early diagnosis and timely treatment of vascular complications.

Secretin-stimulated multi-detector CT versus mangafodipir trisodium-enhanced MR imaging plus MRCP in characterization of non-metastatic solid pancreatic lesions

BACKGROUND AND AIM Our study was aimed to compare multiphasic multi-detector computed tomography after secretin stimulation and mangafodipir trisodium-enhanced magnetic resonance imaging plus MR cholangiopancreatography in the characterization of solid pancreatic lesions. PATIENTS AND METHODS Forty patients with ultrasound diagnosis of solid pancreatic lesion prospectively underwent both multi-detector computed tomography and magnetic resonance imaging. Three minutes after intravenous administration of secretin, post-contrast computed tomography scans were performed 40, 80, and 180 s after contrast medium injection. MR protocol included axial/coronal, thin/thick-slab, single-shot T2 w sequences and axial/coronal T1 w breath-hold spoiled gradient-echo images before and 30-40 min after intravenous infusion of manganese dipyri-doxal diphosphate. Different observers blindly evaluated the ability of computed tomography and magnetic resonance imaging to characterize focal pancreatic lesions. Surgery, biopsy, and/or follow-up were considered as our diagnostic gold standard. RESULTS Thirty-five focal pancreatic lesions (adenocarcinoma, n=18; focal chronic pancreatitis, n=4; endocrine tumor, n=6; metastasis, n=1; cystic tumor, n=3; indeterminate cystic lesions, n=3) were present in 34 patients since the remaining 6 subjects showed no pathological finding. Both multi-detector computed tomography and magnetic resonance imaging showed a statistically significant correlation with the gold standard and between themselves in the characterization of 29 solid lesions of the pancreas (p<0.05). CONCLUSION Both imaging techniques well correlate to final diagnosis of non-metastatic solid pancreatic lesions and particularly of adenocarcinomas with a slight advantage for mangafodipir trisodium-enhanced magnetic resonance imaging plus MR cholangiopancreatography.

P.1.30: SECONDARY CANCERS IN PATIENTS WITH INTRADUCTAL PAPILLARY MUCINOUS NEOPLASM OF THE PANCREAS (IPMN): PRELIMINARY RESULTS OF A PROSPECTIVE MULTICENTRE ITALIAN STUDY

and moderate-severe steatosis (OR 2.1; 95%CI, 1.1-4.1; p=0.03). SVR rates were not related to HOMA in the overall population [63% (220/351) vs 60% (29/48), p=0.75], nor in subgroup analysis by virus genotype [genotype 1: 43% (61/143) for ≤ 2 HOMA vs 53% (9/17) for > 2 HOMA (p=0.45); genotype 2 and 3: 83% (143/173) vs 80% (20/25), p=0.78, respectively]. In SVR patients, baseline and follow up HOMA values were similar (1.12±0.82 vs 1.17±1.1, p=0.25). Conversely, nonresponders had increased HOMA values trough 18 months follow up (from 1.17±0.7 to 1.49±1.3, p=0.007); IR de-novo occurred more frequently in non-SVR than in SVR patients [24% (25/106) vs 8% (16/198), p=0.0003]. Conclusions: While the outcome of Peg-IFN/Rbv therapy is not influenced by IR, the latter is prevented once SVR is achieved.

PANCREAS TRANSPLANT ALONE IN TYPE 1 DIABETIC RECIPIENTS WITH OVERT DIABETIC NEPHROPATHY: RENAL FUNCTION OUTCOME: 2378

U. Boggi1, F. Vistoli1, C. Croce1, S. Signori1, C. Moretto1, M. Del Chiaro1, G. Amorese2, M. Barsotti3, P. Marchetti4 1Azienda Ospedaliero-universitaria Pisana, U.O. Chirurgia Generale e Trapianti, Pisa/ITALY, 2Azienda Ospedaliero-universitaria Pisana, U.O. Anestesia e Terapia Intensiva, Pisa/ITALY, 3Azienda Ospedalierouniversitaria Pisana, U.O. Nefrologia e Dialisi con Trapianti, Pisa/ITALY, 4Azienda Ospedaliero-universitaria Pisana, S.V.D. Endocrinologia e Metabolismo dei Trapianti d’Organo e Cellulari, Pisa/ ITALY

OUTCOME OF PANCREAS TRANSPLANTATION WITH 5 YEARS FOLLOW-UP OR MORE: 2312

F. Vistoli1, C. Croce1, S. Signori1, C. Moretto1, M. Del Chiaro1, G. Amorese2, M. Barsotti3, P. Marchetti4, U. Boggi1 1Azienda Ospedaliero-universitaria Pisana, U.O. Chirurgia Generale e Trapianti, Pisa/ITALY, 2Azienda Ospedaliero-universitaria Pisana, U.O. Anestesia e Terapia Intensiva, Pisa/ITALY, 3Azienda Ospedalierouniversitaria Pisana, U.O. Nefrologia e Dialisi con Trapianti, Pisa/ITALY, 4Azienda Ospedaliero-universitaria Pisana, S.V.D. Endocrinologia e Metabolismo dei Trapianti d’Organo e Cellulari, Pisa/ ITALY