Claudio Bassi

The Evolution of Surgical Strategies for Pancreatic Neuroendocrine Tumors (Pan-NENs)

Objective: The objective of the present analysis is 2-fold: first, to define the evolution of time trends on the surgical approach to pancreatic neuroendocrine neoplasms (Pan-NENs); second, to perform a complete analysis of the predictors of oncologic outcome. Background: Reflecting their rarity and heterogeneity, Pan-NENs represent a clinical dilemma. In particular, there is a scarcity of data regarding their long-term follow-up after surgical resection. Methods: From the Institutional Pan-NEN database, 587 resected cases from 1990 to 2015 were extracted. The time span was arbitrarily divided into 3 discrete clusters enabling a balanced comparison between patient groups. Analyses for predictors of recurrence and survival were performed, together with conditional survival analyses. Results: Among the 587 resected Pan-NENs, 75% were nonfunctioning tumors, and 5% were syndrome-associated tumors. The mean age was 54 years (±14 years), and 51% of the patients were female. The median tumor size was 20 mm (range 4 to 140), 62% were G1, 32% were G2, and 4% were G3 tumors. Time trends analysis revealed that the number of resected Pan-NENs constantly increased, while the size (from 25 to 20 mm) and G1 proportion (from 65% to 49%) decreased during the study period. After a mean follow-up of 75 months, recurrence analysis revealed that nonfunctioning tumors, tumor grade, N1 status, and vascular invasion were all independent predictors of recurrence. Regardless of size, G1 nonfunctioning tumors with no nodal involvement and vascular invasion had a negligible risk of recurrence at 5 years. Conclusions: Pan-NENs have been increasingly diagnosed and resected during the last 3 decades, revealing reliable predictors of outcome. Functioning and nodal status, tumor grade, and vascular invasion accurately predict survival and recurrence with resulting implications for patient follow-up.

Postoperative Management in Patients Undergoing Major Pancreatic Resections

Perioperative care following pancreatectomy in “high-volume” center is based on the application of standardized protocols. The clinical practice includes multimodal strategies that aim to limit postoperative complications, to improve recovery, and to reduce the length of hospital stay after surgery. This chapter discusses the perioperative care of patients undergoing pancreatic resections focusing on major topics such as fluid management, antimicrobial prophylaxis, feeding, drain management, administration of prophylactic somatostatin or its analogues, and radiological findings following surgery.

Perfusion Changes in Liver Metastases (LM) from Pancreatic Neuroendocrine Tumors (PanNETs) during Everolimus (E) Treatment: Update of Perfusion CT (P-CT) Study

Multidisciplinary Team (MDT) in Neuroendocrine Tumor (NET) Management : Results from the First Global NET Patient (pt) Survey - A Collaboration between the International Neuroendocrine Cancer Alliance (INCA) and Novartis PharmaceuticalsRadioembolization with 90Y-Labelled Resin Microspheres in Patients with Liver Metastases from Neuroendocrine TumorsIncremental Benefit of Preoperative Endoscopic Ultrasound for the Detection of Pancreatic Neuroendocrine Tumors : A Meta-AnalysisSmall intestinal neuroendocrine tumors (SI-NETs) originate from serotonin-producing enterochromaffin (EC) cells in the intestinal mucosa. Somatostatin analogs (SSAs) are mainly used to control hormonal secretion and tumor growth. However, the molecular mechanisms leading to the control of SI-NETs are unknown. Although microRNAs (miRNAs) are post transcriptional regulators deeply studied in many cancers, are not well-defined in SI-NETs. We adopted a two-pronged strategy to investigate SSAs and miRNAs: first, to provide novel insights into how SSAs control NET cells, and second, to identify an exclusive SI-NET miRNA expression, and investigate the biological functions of miRNA targets.To accomplish the first aim, we treated CNDT2.5 cells with octreotide for 16 months. Affymetrix microarray was performed to study gene variation of CNDT2.5 cells in the presence or absence of octreotide. The study revealed that octreotide induces six genes, ANXA1, ARHGAP18, EMP1, GDF15, TGFBR2 and TNFSF15.To accomplish the second aim, SI-NET tissue specimens were used to run genome-wide Affymetrix miRNA arrays. The expression of five miRNAs (miR-96, -182, -183, -196a and -200a) was significantly upregulated in laser capture microdissected (LCM) tumor cells versus LCM normal EC cells, whereas the expression of four miRNAs (miR-31, -129-5p, -133a and -215) was significantly downregulated in LCM tumor cells. We also detected nine tissue miRNAs in serum samples, showing that the expression of five miRNAs is significantly increased in SSA treated patients versus untreated patients. Conversely, SSAs do not change miRNA expression of four low expressed miRNAs. Silencing miR-196a expression was used to investigate functional activities in NET cells. This experimental approach showed that four miR-196a target genes, HOXA9, HOXB7, LRP4 and RSPO2, are significantly upregulated in silenced miR-196a NET cells.In conclusion, ANXA1, ARHGAP18, EMP1, GDF15, TGFBR2 and TNFSF15 genes might regulate cell growth and differentiation in NET cells, and play a role in an innovative octreotide signaling pathway. The global SI-NET miRNA profiling revealed that nine selected miRNAs might be involved in tumorigenesis, and play a potential role as novel markers for follow-up. Indeed, silencing miR-196a demonstrated that HOXA9, HOXB7, LRP4 and RSPO2 genes are upregulated at both transcriptional and translational levels.

After pancreatoduodenectomy, pancreo-gastroanastomosis produces a greater impairment of residual function than pancreo-jejunostomy – Results of an 8 year follow-up

Background: Recently the most relevant therapeutic progress in metastatic pancreatic cancer has come from the combination of several cytotoxics, such as the FOLFIRINOX, and the cisplatin-epirubicin-5-fluorouracil-gemcitabine, cisplatin-docetaxel-capecitabine-gemcitabine (PDXG), and cisplatin-epirubicin-capecitabine-gemcitabine (PEXG) regimens [Reni et al., Cancer Chemother Pharmacol 2012]. However the improved survival versus gemcitabine-alone did come at the cost of a significant increase in hematologic/extra-hematologic toxicities. Pharmacogenetic studies to identify patients who could benefit most from such therapies are urgently needed. Aim/methods: The Xeroderma-Pigmentosum-factor-D (XPD) polymorphism at codon-751 (XPD-Lys751Gln) emerged as the most significant independent predictor for deathand progression-risk in our previous pharmacogenetic study on 11 functional polymorphisms in 122 advanced pancreatic cancer patients treated with PDXG/PEFG[Giovannetti et al, Pharmacogenomics 2011]. Therefore, we further evaluated the correlation of XPD-Lys751Gln with clinical outcome in 246 patients treated with the same regimens. Results: Genotyping was successfully carried out in the vast majority of samples. Genotype frequencies followed Hardy–Weinberg equilibrium, and no correlations were detected with age, gender, performance-status, CA19.9 or stage. At univariate analysis, XPD-Lys751Glnwas associated with differential progression-free and overall-survival, and the Cox model used for the multivariate analysis confirmed its prognostic significance. In particular, XPD-Gln751Gln was significantly associated with risk of death (hazard ratio, HR1⁄41.7, 95%CI, 1.1–2.6, P1⁄40.011) and risk of progression (HR1⁄41.7, 95%CI, 1.1-2.5, P1⁄40.013). Conclusions: The increasing evidence of XPD-Lys751Gln impact on the outcome of gemcitabine/cisplatin-polychemotherapy leads to plan prospective studies. Ultimately, the validation of the role of this polymorphism will offer a new tool for optimization of currently available treatments in pancreatic cancer.

Cancer of the Exocrine Pancreas: Surgery and Multimodal Treatment

The optimal management of pancreatic ductal carcinoma remains poorly defined. Radical resection is possible in about 20–30% of patients, with an overall 5-year survival rate of only 20% [1]. In recent years, perioperative morbidity and mortality have significantly decreased, and different clinical trials have suggested an important role for adjuvant therapy [2].

Pancreatic Decompression in Chronic Pancreatitis

Chronic pancreatitis is a disease characterised by a dynamic course giving rise to fibrotic involution of the pancreatic parenchyma with a consequent progressive loss of both exocrine and endocrine function.