Currently Debated Topics on Surgical Treatment of Pancreatic Ductal Adenocarcinoma: A Narrative Review on Surgical Treatment of Borderline Resectable, Locally Advanced, and Synchronous or Metachronous Oligometastatic Tumor.

BACKGROUND: Previously considered inoperable patients (borderline resectable, locally advanced, synchronous oligometastatic or metachronous pancreatic adenocarcinoma (PDAC)) are starting to become resectable thanks to advances in chemo/radiotherapy and the reduction in operative mortality. METHODS: This narrative review presents a chosen literature selection, giving a picture of the current state of treatment of these patients. RESULTS: Neoadjuvant therapy (NAT) is generally recognized as the treatment of choice before surgery. However, despite the increased efficacy, the best pathological response is still limited to 10.9-27.9% of patients. There are still limited data on the selection of possible NAT responders and how to diagnose non-responders early. Multidetector computed tomography has high sensitivity and low specificity in evaluating resectability after NAT, limiting the resection rate of resectable patients. Ca 19-9 and Positron emission tomography are giving promising results. The prediction of early recurrence after a radical resection of synchronous or metachronous metastatic PDAC, thus identifying patients with poor prognosis and saving them from a resection of little benefit, is still ongoing, although some promising data are available. CONCLUSION: In conclusion, high-level evidence demonstrating the benefit of the surgical treatment of such patients is still lacking and should not be performed outside of high-volume centers with interdisciplinary teams of surgeons and oncologists.

Surgical Treatment of Pancreatic Cancer: Currently Debated Topics on Vascular Resection.

Vascular resections involving the superior mesenteric and portal veins (SMV-PV), celiac axis (CA), superior mesenteric artery (SMA) and hepatic artery (HA) have multiplied in recent years, raising the resection rate for pancreatic cancer (PDAC) and the related morbidity and mortality rates. While resection is generally accepted for resectable SMV-PV, the usefulness of associated arterial resection in borderline resectable (BRPC) and locally-advanced PDAC (LAPC) is much debated. Careful selection of splenic vein reconstruction is very important to prevent left-sided portal hypertension (LSPH). During distal pancreatectomy (DP), CA and common HA resection is largely accepted, while there is debate on the value of SMA and proper HA resection and reconstruction. Their resection is useless according to several reviews and meta-analyses, and some international societies, although some high-volume centers have reported good results. Short- and long-term reconstructed vessel patency varies with the type of reconstruction, the material used, and the surgeon's experience. Laparoscopic and robotic pancreaticoduodenectomy and DP are generally accepted if done by surgeons performing at least 10 such procedures annually. The usefulness of associated vascular resection remains highly controversial. Surgeons need to complete numerous minimally-invasive procedures to overcome the learning curve, and prevent an increase in complications and surgical mortality. Higher resectability rates and satisfactory long-term results have been reported after neoadjuvant therapy (NAT) for BRPC and LAPC requiring vascular resection. It is essential to select the most appropriate NAT for a given patient and to assess PDAC resectability preoperatively.

Surgical treatment of pancreatic cancer: Currently debated topics on morbidity, mortality, and lymphadenectomy.

This review will examine several aspects of pancreatic surgery. Over the past twenty years, the need for a standardized postoperative complication report after resective pancreatic surgery has led to the definition both of a postoperative complication severity score, a postoperative pancreatic fistula (POPF) severity grading, a fistula risk score (FRS) and a postoperative morbidity index to establish the burden of complications. Unfortunately, three problems have hindered the success of standardization: first, the failure to define a minimum postoperative follow-up period that needs to be reported; second, the lack of a clear definition of POPF-related morbidity and mortality; third, the often-incomplete reporting of postoperative complications. The debate on the extent of lymphadenectomy to associate to pancreaticoduodenectomy started in the late 1980s when, based on retrospective studies, Japanese surgeons reported better survival after extended" than after "standard" lymphadenectomy. Subsequently, eight prospective randomized controlled trials showed that "extended" lymphadenectomy offers no advantage over "standard" lymphadenectomy. Several consensus conference and reviews tried to define the optimal extent of lymphadenectomy to be associated to pancreaticoduodenectomy and distal pancreatectomy (DP). At least nineteen lymph nodes (LN) are required for optimal tumor staging, but eleven LN are considered the minimum to prevent under staging. There is no general agreement about aborting PD in LN16-positive patients; some authors perform PD in fit patients. Based on retrospective studies, a significant increase of R0 resections, a decrease of recurrence rate, a decrease of local recurrence rate and an increase of median or overall disease-free survival were reported after mesopancreas excision.

Systematic review and meta-analysis of surgical drain management after the diagnosis of postoperative pancreatic fistula after pancreaticoduodenectomy: draining-tract-targeted works better than standard management.

PURPOSE: Drains' role after pancreaticoduodenectomy (PD) is debated by proponents of no drain, draining selected cases, and early drain removal. The aim of the study was to assess the effect of "standard" and "draining-tract-targeted" management of abdominal drains still in situ after diagnosing a postoperative pancreatic fistula (POPF). METHODS: PubMed and Scopus were searched for "pancreaticoduodenectomy or pancreatoduodenectomy or duodenopancreatectomy," "Whipple," "proximal pancreatectomy," "pylorus-preserving pancreatectomy," and "postoperative pancreatic fistula or POPF.". Main outcomes included clinically relevant (CR) POPF, grade-C POPF, overall mortality, POPF-related mortality, and CR-POPF-related mortality. Secondary outcomes were incidence of radiological and/or endoscopic interventions, reoperations, and completion pancreatectomies. RESULTS: Overall, 12,089 studies were retrieved by the search of the English literature (01/01/1990-31/12/2018). Three hundred and twenty-six studies (90,321 patients) reporting ≥ 100 PDs and ≥ 10 PD/year were finally included into the study. Average incidences were obtained by averaging the incidence rates reported in the single articles. Pooled incidences were calculated by combining the number of events and the total number of patients considered in the various studies. These were then meta-analyzed using DerSimonian and Laird's (1986) method. Pearson's chi-squared test was used to compare pooled incidences between groups. Post hoc testing was used to see which groups differed. The meta-analyzed incidences were compared using a fixed effect for moderators. "Draining-tract-targeted" management showed a significant advantage over "standard" management in four clinically relevant outcomes out of eight according to pool analysis and in one of them according to meta-analysis. CONCLUSION: Clinically, "draining-targeted" management of POPF should be preferred to "standard" management.

PDAC-derived exosomes enrich the microenvironment in MDSCs in a SMAD4-dependent manner through a new calcium related axis.

Tumor genetics and escape from immune surveillance concur in the poor prognosis of PDAC. In this study an experimental model was set up to verify whether SMAD4, deleted in about 55% PDAC and associated with poor prognosis, is involved in determining immunosuppression through Exosomes (Exo). Potential mechanisms and mediators underlying SMAD4-dependent immunosuppression were evaluated by studying intracellular calcium (Fluo-4), Exo-miRNAs (microarray) and Exo-proteins (SILAC). Two PDAC cell lines expressing (BxPC3-SMAD4+) or not-expressing (BxPC3) SMAD4 were used to prepare Exo-enriched conditioned media, employed in experiments with blood donors PBMCs. Exo expanded myeloid derived suppressor cells (gMDSC and mMDSC, flow cytometry) and altered intracellular calcium fluxes in an SMAD4 dependent manner. BxPC3-SMAD4+, but mainly BxPC3 Exo, increased calcium fluxes of PBMCs (p = 0.007) and this increased intracellular calcium trafficking characterized mMDSCs. The analysis of de-regulated Exo-miRNAs and transfection experiments revealed hsa-miR-494-3p and has-miR-1260a as potential mediators of SMAD4-associated de-regulated calcium fluxes. Eleven main biological processes were identified by the analysis of SMAD4-associated de-regulated Exo-proteins, including translation, cell adhesion, cell signaling and glycolysis. A reverse Warburg effect was observed by treating PBMCs with PDAC-derived Exo: BxPC3 Exo induced a higher glucose consumption and lactate production than BxPC3-SMAD4+ Exo. CONCLUSION: PDAC-derived Exo from cells with, but mainly from those without SMAD4 expression, create an immunosuppressive myeloid cell background by increasing calcium fluxes and glycolysis through the transfer of SMAD4-related differentially expressed miRNAs and proteins.

Pancreatoduodenectomy (PD) and postoperative pancreatic fistula (POPF): A systematic review and analysis of the POPF-related mortality rate in 60,739 patients retrieved from the English literature published between 1990 and 2015.

BACKGROUND: Pancreatoduodenectomy (PD) is one of the most technically demanding operations challenging surgeons, and a postoperative pancreatic fistula (POPF) can complicate an otherwise uneventful postoperative (PO) course. This review examined the methods and procedures used to prevent postoperative pancreatic fistula (POPF) after pancreatoduodenectomy (PD). METHODS: A comprehensive systematic search of the literature was performed using PubMed (Medline), Embase, Web of science, and the Cochrane databases for studies published between January 1, 1990 and December 31, 2015. English language articles involving at least 100 patients undergoing PDs carried out in centers performing at least 10 PDs/y were screened for data regarding the Grade of any POPFs according to the definition of the International Study Group on Pancreatic Fistula (ISGPF) and the overall rate of PO mortality related to POPF. RESULTS: We reviewed 7119 references through the major databases, and an additional 841 studies were identified by cross-checking the bibliographies of the full-text articles retrieved. After excluding 7379 out of 7960 studies, because they did not meet the eligibility criteria, the full texts of 581 articles were examined; 96 studies were excluded at this point, because they concerned partially or totally duplicate data that had already been reported. The remaining 485 articles were screened carefully for POPF-related mortality and POPF Grades as defined by the ISGPF. Of the 485 articles, 208 reported the POPF-related PO mortality rate and 162 the Grades (A, B, and C) of POPFs in 60,739 and 54,232 patients, respectively. The POPF-related mortality rates after pancreatojejunostomy and pancreatogastrostomy were similar but were less (0.5% vs. 1%; P = .014) when an externally draining, trans-anastomotic stent was placed intraoperatively. The incidence of the different Grades of POPF Grade was quite variable, but Grade C POPFs were associated with a PO mortality rate of 25.7% (range 0-100%). CONCLUSIONS: The POPF-related mortality rate has remained at approximately 1% over the past 25 years. Only externally draining, trans-anastomotic stents decreased the POPF-related mortality rate. However, adequately designed venting drains were never tested in randomized controlled trials (RCTs).

SLC22A3 polymorphisms do not modify pancreatic cancer risk, but may influence overall patient survival.

Expression of the solute carrier (SLC) transporter SLC22A3 gene is associated with overall survival of pancreatic cancer patients. This study tested whether genetic variability in SLC22A3 associates with pancreatic cancer risk and prognosis. Twenty four single nucleotide polymorphisms (SNPs) tagging the SLC22A3 gene sequence and regulatory elements were selected for analysis. Of these, 22 were successfully evaluated in the discovery phase while six significant or suggestive variants entered the validation phase, comprising a total study number of 1,518 cases and 3,908 controls. In the discovery phase, rs2504938, rs9364554, and rs2457571 SNPs were significantly associated with pancreatic cancer risk. Moreover, rs7758229 associated with the presence of distant metastases, while rs512077 and rs2504956 correlated with overall survival of patients. Although replicated, the association for rs9364554 did not pass multiple testing corrections in the validation phase. Contrary to the discovery stage, rs2504938 associated with survival in the validation cohort, which was more pronounced in stage IV patients. In conclusion, common variation in the SLC22A3 gene is unlikely to significantly contribute to pancreatic cancer risk. The rs2504938 SNP in SLC22A3 significantly associates with an unfavorable prognosis of pancreatic cancer patients. Further investigation of this SNP effect on the molecular and clinical phenotype is warranted.

SMAD4 loss enables EGF, TGFß1 and S100A8/A9 induced activation of critical pathways to invasion in human pancreatic adenocarcinoma cells.

Epidermal Growth Factor (EGF) receptor overexpression, KRAS, TP53, CDKN2A and SMAD4 mutations characterize pancreatic ductal adenocarcinoma. This mutational landscape might influence cancer cells response to EGF, Transforming Growth Factor ß1 (TGFß1) and stromal inflammatory calcium binding proteins S100A8/A9. We investigated whether chronic exposure to EGF modifies in a SMAD4-dependent manner pancreatic cancer cell signalling, proliferation and invasion in response to EGF, TGFß1 and S100A8/A9. BxPC3, homozigously deleted (HD) for SMAD4, and BxPC3-SMAD4+ cells were or not stimulated with EGF (100 ng/mL) for three days. EGF pre-treated and non pretreated cells were stimulated with a single dose of EGF (100 ng/mL), TGFß1 (0,02 ng/mL), S100A8/A9 (10 nM). Signalling pathways (Reverse Phase Protein Array and western blot), cell migration (Matrigel) and cell proliferation (XTT) were evaluated. SMAD4 HD constitutively activated ERK and Wnt/ß-catenin, while inhibiting PI3K/AKT pathways. These effects were antagonized by chronic EGF, which increased p-BAD (anti-apoptotic) in response to combined TGFß1 and S100A8/A9 stimulation. SMAD4 HD underlied the inhibition of NF-κB and PI3K/AKT in response to TGFß1 and S100A8/A9, which also induced cell migration. Chronic EGF exposure enhanced cell migration of both BxPC3 and BxPC3-SMAD4+, rendering the cells less sensitive to the other inflammatory stimuli. In conclusion, SMAD4 HD is associated with the constitutive activation of the ERK and Wnt/ß-catenin signalling pathways, and favors the EGF-induced activation of multiple signalling pathways critical to cancer proliferation and invasion. TGFß1 and S100A8/A9 mainly inhibit NF-κB and PI3K/AKT pathways and, when combined, sinergize with EGF in enhancing anti-apoptotic p-BAD in a SMAD4-dependent manner.

Blood expression of matrix metalloproteinases 8 and 9 and of their inducers S100A8 and S100A9 supports diagnosis and prognosis of PDAC-associated diabetes mellitus.

BACKGROUND: Based on the knowledge that matrix metalloproteinases (MMPs) and S100A8/A9 synergistically work in causing PDAC-associated type 2 diabetes mellitus (T2DM), we verified whether tissue and blood MMP8, MMP9, S100A8 and S100A9 expression might help in distinguishing PDAC among diabetics. METHODS: Relative quantification of MMP8, MMP9, S100A8 and S100A9 mRNA was performed in tissues obtained from 8 PDAC, 4 chronic pancreatitis (ChrPa), 4 non-PDAC tumors and in PBMCs obtained from 30 controls, 43 T2DM, 41 ChrPa, 91 PDAC and 33 pancreatic-biliary tract tumors. RESULTS: T2DM was observed in PDAC (66%), in pancreatic-biliary tract tumors (64%) and in ChrPa (70%). In diabetics, with or without PDAC, MMP9 tissue expression was increased (p<0.05). Both MMPs increased in PDAC and MMP9 increased also in pancreatic-biliary tract tumors PBMCs. In diabetics, MMP9 was independently associated with PDAC (p=0.025), but failed to enhance CA 19-9 discriminant efficacy. A highly reduced S100A9 expression, found in 7 PDAC, was significantly correlated with a reduced overall survival (p=0.015). CONCLUSIONS: An increased expression of tissue and blood MMP9 reflects the presence of PDAC-associated diabetes mellitus. This finding fits with the hypothesized role of MMPs as part of the complex network linking cancer to diabetes.

Mesenteric-Portal Vein Resection during Pancreatectomy for Pancreatic Cancer.

The aim of the present study was to determine the outcome of patients undergoing pancreatic resection with (VR+) or without (VR-) mesenteric-portal vein resection for pancreatic carcinoma. Between January 1998 and December 2012, 241 patients with pancreatic cancer underwent pancreatic resection: in 64 patients, surgery included venous resection for macroscopic invasion of mesenteric-portal vein axis. Morbidity and mortality did not differ between the two groups (VR+: 29% and 3%; VR-: 30% and 4.0%, resp.). Radical resection was achieved in 55/64 (78%) in the VR+ group and in 126/177 (71%) in the VR- group. Vascular invasion was histologically proven in 44 (69%) of the VR+ group. Survival curves were not statistically different between the two groups. Mean and median survival time were 26 and 15 months, respectively, in VR- versus 20 and 14 months, respectively, in VR+ group (p = 0.52). In the VR+ group, only histologically proven vascular invasion significantly impacted survival (p = 0.02), while, in the VR- group, R0 resection (p = 0.001) and tumor's grading (p = 0.01) significantly influenced long-term survival. Vascular resection during pancreatectomy can be performed safely, with acceptable morbidity and mortality. Long-term survival was the same, with or without venous resection. Survival was worse for patients with histologically confirmed vascular infiltration.

Extent of lymphadenectomy to associate with pancreaticoduodenectomy in patients with pancreatic head cancer for better tumor staging.

OBJECTIVES: To define the extent of lymphadenectomy to associate with surgery for pancreatic head cancer. BACKGROUND: Pancreaticoduodenectomy with extended lymphadenectomy fails to prolong patient survival. METHODS: Prospective randomized and nonrandomized controlled trials (RCTs and NRCTs), meta-analyses, retrospective reviews, consensus conferences and pre- and intraoperative diagnoses of lymph node (LN) metastases were retrieved. Standard and extended lymphadenectomies were reviewed, including their effects on postoperative complications, mortality rate and long-term survival. The minimum total number of LN examined (TNLE) for adequate tumor staging, and the incidence of metastasis to each LN station were also considered. A pros and cons analysis was performed on the removal of each LN station. RESULTS: Eleven retrospective studies (2514 patients), five prospective NRCTs (545 patients), and five prospective RCTs (586 patients) described different lymphadenectomies, which obtained similar long-term results. Five meta-analyses showed they did not influence long-term survival. However, N status is an important component of tumor staging. The recommended minimum TNLE is 15. The percent incidence of metastasis to each LN station was calculated considering at least 385 and up to 3725 patients. Preoperative imaging and intraoperative exploration frequently fail to identify metastatic nodes. A pros and cons analysis suggests that lymph node status is better established removing the following LN stations: 6, 8a-p, 12a-b-c, 13a-b, 14a-b-c-d, 16b1, 17a-b. Metastasis to 16b1 LNs significantly worsens prognosis. Their removal and frozen section examination, before proceeding with resection, may contraindicate resection. CONCLUSION: A standard lymphadenectomy demands an adequate TNLE and removal of the LN stations metastasizing more frequently, without increasing the surgical risk.

TERT gene harbors multiple variants associated with pancreatic cancer susceptibility.

A small number of common susceptibility loci have been identified for pancreatic cancer, one of which is marked by rs401681 in the TERT-CLPTM1L gene region on chromosome 5p15.33. Because this region is characterized by low linkage disequilibrium, we sought to identify whether additional single nucleotide polymorphisms (SNPs) could be related to pancreatic cancer risk, independently of rs401681. We performed an in-depth analysis of genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) genes, in 5,550 subjects with pancreatic cancer and 7,585 controls from the PANcreatic Disease ReseArch (PANDoRA) and the PanScan consortia. We identified a significant association between a variant in TERT and pancreatic cancer risk (rs2853677, odds ratio = 0.85; 95% confidence interval = 0.80-0.90, p = 8.3 × 10(-8)). Additional analysis adjusting rs2853677 for rs401681 indicated that the two SNPs are independently associated with pancreatic cancer risk, as suggested by the low linkage disequilibrium between them (r(2) = 0.07, D' = 0.28). Three additional SNPs in TERT reached statistical significance after correction for multiple testing: rs2736100 (p = 3.0 × 10(-5) ), rs4583925 (p = 4.0 × 10(-5) ) and rs2735948 (p = 5.0 × 10(-5) ). In conclusion, we confirmed that the TERT locus is associated with pancreatic cancer risk, possibly through several independent variants.