Giovanni Capretti

Effect of hospital volume on outcome of pancreaticoduodenectomy in Italy

An inverse relationship between hospital volume and death following pancreatico duodenectomy (PD) has been reported from several countries. The aim of this study was to assess the volume–outcome effect of PD in Italy.

A prognostic score to predict major complications after pancreaticoduodenectomy.

Objective:To develop and validate a simple prognostic score to predict major postoperative complications after pancreaticoduodenectomy (PD). Background:PD still carries a high rate of severe postoperative complications. No specific score is currently available to stratify the patients risk of major morbidity. Methods:Between 2002 and 2010, preoperative, intraoperative, and outcome data from 700 consecutive patients undergoing PD in our institution were prospectively collected in an electronic database. Major complications were defined as levels III to V of Clavien-Dindo classification. On the basis of a multivariate regression model, the score was developed using a random two-thirds of the population (n = 469) and was validated on the remaining 231 patients. Results:Major complication rate was 16.7% (117/700). Significant predictors included in the scoring system were: pancreas texture, pancreatic duct diameter, operative blood loss, and ASA score. The mean risk of developing major postoperative complications was 7% in patients with score 0 to 3, 13% in patients with score 4 to 7, 23% in patients with score 8 to 11, and 36% in patients with score 12 to 15. In the validation population, the predicted risk of major complications was 15.2% versus a 16.9% observed risk (C-statistic index = 0.743). Conclusion:This new score may accurately predict a patients postoperative outcome. Early identification of high-risk patients could help the surgeon to adopt intraoperative and postoperative strategies tailored on individual basis.

Dual prognostic significance of tumour-associated macrophages in human pancreatic adenocarcinoma treated or untreated with chemotherapy

Objective Tumour-associated macrophages (TAMs) play key roles in tumour progression. Recent evidence suggests that TAMs critically modulate the efficacy of anticancer therapies, raising the prospect of their targeting in human cancer. Design In a large retrospective cohort study involving 110 patients with pancreatic ductal adenocarcinoma (PDAC), we assessed the density of CD68-TAM immune reactive area (%IRA) at the tumour–stroma interface and addressed their prognostic relevance in relation to postsurgical adjuvant chemotherapy (CTX). In vitro, we dissected the synergism of CTX and TAMs. Results In human PDAC, TAMs predominantly exhibited an immunoregulatory profile, characterised by expression of scavenger receptors (CD206, CD163) and production of interleukin 10 (IL-10). Surprisingly, while the density of TAMs associated to worse prognosis and distant metastasis, CTX restrained their protumour prognostic significance. High density of TAMs at the tumour–stroma interface positively dictated prognostic responsiveness to CTX independently of T-cell density. Accordingly, in vitro, gemcitabine-treated macrophages became tumoricidal, activating a cytotoxic gene expression programme, inhibiting their protumoural effect and switching to an antitumour phenotype. In patients with human PDAC, neoadjuvant CTX was associated to a decreased density of CD206+ and IL-10+ TAMs at the tumour–stroma interface. Conclusions Overall, our data highlight TAMs as critical determinants of prognostic responsiveness to CTX and provide clinical and in vitro evidence that CTX overall directly re-educates TAMs to restrain tumour progression. These results suggest that the quantification of TAMs could be exploited to select patients more likely to respond to CTX and provide the basis for novel strategies aimed at re-educating macrophages in the context of CTX.

Spatial distribution of B cells predicts prognosis in human pancreatic adenocarcinoma

ABSTRACT B-cell responses are emerging as critical regulators of cancer progression. In this study, we investigated the role of B lymphocytes in the microenvironment of human pancreatic ductal adenocarcinoma (PDAC), in a retrospective consecutive series of 104 PDAC patients and in PDAC preclinical models. Immunohistochemical analysis revealed that B cells occupy two histologically distinct compartments in human PDAC, either scatteringly infiltrating (CD20-TILs), or organized in tertiary lymphoid tissue (CD20-TLT). Only when retained within TLT, high density of B cells predicted longer survival (median survival 16.9 mo CD20-TLThi vs. 10.7 mo CD20-TLTlo; p = 0.0085). Presence of B cells within TLT associated to a germinal center (GC) immune signature, correlated with CD8-TIL infiltration, and empowered their favorable prognostic value. Immunotherapeutic vaccination of spontaneously developing PDAC (KrasG12D-Pdx1-Cre) mice with α-enolase (ENO1) induced formation of TLT with active GCs and correlated with increased recruitment of T lymphocytes, suggesting induction of TLT as a strategy to favor mobilization of immune cells in PDAC. In contrast, in an implanted tumor model devoid of TLT, depletion of B cells with an anti-CD20 antibody reinstated an antitumor immune response. Our results highlight B cells as an essential element of the microenvironment of PDAC and identify their spatial organization as a key regulator of their antitumor function. A mindfully evaluation of B cells in human PDAC could represent a powerful prognostic tool to identify patients with distinct clinical behaviors and responses to immunotherapeutic strategies.

Enhanced recovery after surgery: a survey among anaesthesiologists from 27 countries.

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Management and Outcomes of Pancreatic Resections Performed in High-Volume Referral and Low-Volume Community Hospitals Lead by Surgeons Who Shared the Same Mentor: The Importance of Training

Background: High hospital volume improves outcomes after pancreatic resection. The aim of this study was to assess if practice and outcomes differed between high- and low-volume centers across which chief surgeons shared a similar training and mentoring. Methods: Data on patients undergoing standard pancreatic resections (2010-2013) at 7 Italian hospitals were collected. Chiefs of pancreatic surgery at each hospital had received the same training, with the same mentor. Two centers were high-volume referral hospitals for pancreatic disease, while 5 were low-volume hospitals. Results: A total of 856 patients were included, with median annual volume of resections 82 at high-volume referral hospitals and 11 at low-volume hospitals. Patients at low-volume hospitals were older, had more comorbidities, and were more often referred from the emergency room. Intraoperative techniques and reconstruction methods were similar. Comparable rates of major postoperative complications (18 vs. 22%; p = 0.236) and pancreatic fistula (29 vs. 32%; p = 0.287) were achieved in both groups, with no significant increases in failure to rescue from grade B-C fistula (6.2 vs. 15.0%; p = 0.108) and mortality (2.4 vs. 4.1%; p = 0.233) in low-volume hospitals. Postoperative length of stay was shorter in high-volume referral hospitals (10 vs. 15 days; p < 0.001). Conclusion: Similar postoperative outcomes can be achieved across high- and low-volume centers where chief surgeons shared a similar training and mentoring. However, multidisciplinary postoperative provision more often associated with high-volume centers may also affect outcomes.

Survivals of distal cholangiocarcinoma and pancreatic adenocarcinoma after pancreaticoduodenectomy: post-operative complications really matter?

Introduction: Pancreaticoduodenectomy (PD) has been established as the standard surgical procedure for ampullary cancer. Alternatively, ampullectomy (PR) has also been performed for benign tumors and early cancers (T1). The aim of this study was to evaluate the prognostic indicators for recurrence and survival after curative resection for ampullary cancer and to investigate whether PR can substitute for PD in T1 ampullary cancer. Methods: Eighty-eight consecutive patients with ampullary cancer underwent initial curative resection (73 PD, 15 PR) between 1985 and 2016. Clinicopathologic factors for recurrence and survival were evaluated retrospectively. Results: In univariate analysis, preoperative biliary drainage, high level of CA19-9, non-exposed protruded type, moderate or poor differentiation, pT2-4, lymph node metastasis (pN1), microvascular invasion, lymphovascular invasion, and perineural invasion were significant factors for both recurrence and survival (p < 0.05). In multivariate analysis, high CA19-9 (p = 0.036), moderate or poor differentiation (p = 0.041), pT2-4 (p = 0.040), and pN1 (p = 0.008) were independent factors for recurrence, and high CA19-9 (p = 0.030) and pN1 (p = 0.006) for survival. High CA19-9 (p = 0.030) and pT2-4 (p = 0.048) predicted pN1. Of the 37 patients with pT1, four (10.8%) had pN1. Six (40.0%) of 15 patients (12 pT1, 3 pT2) undergoing PR had recurrence. Conclusions: High CA19-9 and pN1 were the most important predictor for poor prognosis after radical surgery for ampullary cancer, therefore, more effective systemic adjuvant therapy should be considered in such patients. We suggest that PD is the optimal surgical procedure even for T1 cancer. PR should be selected carefully due to the high rate of recurrence.

Salvage Islet Auto Transplantation after Relaparatomy

Background To assess feasibility, safety, and metabolic outcome of islet auto transplantation (IAT) in patients undergoing completion pancreatectomy because of sepsis or bleeding after pancreatic surgery. Methods From November 2008 to October 2016, approximately 22 patients were candidates to salvage IAT during emergency relaparotomy because of postpancreatectomy sepsis (n = 11) or bleeding (n = 11). Feasibility, efficacy, and safety of salvage IAT were compared with those documented in a cohort of 36 patients who were candidate to simultaneous IAT during nonemergency preemptive completion pancreatectomy through the pancreaticoduodenectomy. Results The percentage of candidates that received the infusion of islets was significantly lower in salvage IAT than simultaneous IAT (59.1% vs 88.9%, P = 0.008), mainly because of a higher rate of inadequate islet preparations. Even if microbial contamination of islet preparation was significantly higher in candidates to salvage IAT than in those to simultaneous IAT (78.9% vs 20%, P < 0.001), there was no evidence of a higher rate of complications related to the procedure. Median follow-up was 5.45 ± 0.52 years. Four (36%) of 11 patients reached insulin independence, 6 patients (56%) had partial graft function, and 1 patient (9%) had primary graft nonfunction. At the last follow-up visit, median fasting C-peptide was 0.43 (0.19-0.93) ng/mL; median insulin requirement was 0.38 (0.04-0.5) U/kg per day, and median HbA1c was 6.6% (5.9%-8.1%). Overall mortality, in-hospital mortality, metabolic outcome, graft survival, and insulin-free survival after salvage IAT were not different from those documented after simultaneous IAT. Conclusions Our data demonstrate the feasibility, efficacy, and safety of salvage IAT after relaparotomy.

Commentary to paper "Primary versus secondary delayed gastric emptying (DGE) grades B and C of the International Study Group of Pancreatic Surgery after pancreatoduodenectomy: a retrospective analysis on a group of 132 patients".

Delayed gastric emptying (DGE) is usually considered the most frequent complication of pancreatoduodenectomy (PD), after pancreatic fistula and its septic and hemorrhagic sequels. In the past, the incidence of DGE was reported as highly relevant, approaching 40–50 % [1]. The efforts, mainly by the International Study Group on Pancreatic Fistula (ISGPS), in careful recording and classifying complications after PD, lead to a better knowledge of rate and characteristics of this complication. In particular, the severity of DGE has been precisely defined, similarly to other complications, like pancreatic fistula: type A DGE, clinically not relevant, was clearly separated from grade B and C. After the introduction of this classification, nearly all papers adopted this terminology, making much more easy to compare different reports in terms of DGE occurrence: we now usually refer to grade B and C of DGE in evaluating postoperative course of PD. The pathogenesis of DGE has always represented an important topic of debate, and also in the present paper by Courvoisier et al. [2] it is widely discussed. Several reasons have been proposed, like disruption of the vagal nerve system, ischemic injury to the antro-pyloric mechanism, decreased plasma motilin stimulation due to resection of duodenum, transient torsion or angulation of the reconstructed alimentary tract. However, none of these mechanisms has been convincingly demonstrated to be the main reason for DGE occurrence after PD. Many efforts aimed to reduce the incidence of DGE have been attempted: pyloric dilatation, preservation of right gastric artery, preoperative use of erythromycin; none of these proved to be effective. Also the preservation of the pylorus was suggested to be related to the occurrence of DGE, and some authors speculated on the role of the length of the preserved portion of duodenum at this regard. However, also the decision to preserve the pylorus instead to perform an antrectomy, as in the classical Whipple procedure, seemed to not influence the occurrence of DGE, as underlined by a recent metanalysis [3]. More relevant from a clinical point of view is the observation that DGE is most often secondary to the presence of a pancreatic fistula and its related complications, and very seldom a primary event [1]. Also in the present paper by Courvoisier et al. [2], this observation is underlined and supported by convincing data. Only in less than one-third of cases DGE is a primary event and occurs as an isolated complication: clinical relevance of DGE after PD is then less important than it could appear from its rough rate of incidence, because in secondary DGE the clinical picture is overlooked by pancreatic fistula and its sequels. Moreover, if we consider that the incidence of DGE after PD has decreased during the years (grade B-C DGE is now currently reported in 10–15 % of cases), we understand that the role of this complication in the postoperative course of PD is less relevant than in the past. There are two main reasons for the decrease in DGE incidence: the widespread use of antecolic reconstruction of the gastro/duodenojejunostomy and the introduction of ERAS protocols. For what antecolic reconstruction is concerned, after evidence provided by a randomized study from Japan [4] of a sharp decrease in the rate of DGE when antecolic & Alessandro Zerbi alessandro.zerbi@humanitas.it

One-Hundred Laparoscopic Distal Pancreatectomies in a Single Institution

Context The laparoscopic approach for benign and malignant lesions of the left pancreas is increasingly applied. Methods Retrospective study on prospectively collected data. Perioperative data and operative outcome of consecutive laparoscopic distal pancreatectomies performed between March 2006 and March 2013 were analyzed (intent-to-treat analysis). Operative outcome of the subgroup of patients with conversion to open surgery was compared to patients with successful laparoscopy to assess the consequences of conversion. Results Among 341 distal pancreatectomies, 100 patients (29%) had a laparoscopic approach (with a progressively increasing rate from 6% in 2006 to 62% in 2012). Malignancy was not a contraindication. Mean age was 57.4 years (range: 24-83 years; 42 males and 58 females). Mean BMI was 25.3 kg/m 2 (range: 17-39 kg/m 2 ). Conversion rate was 19% (11 cases because of the difficulty to isolate the pancreas or lesion from the peripancreatic vessels, 6 cases due to intraoperative bleeding, 2 cases due to the site and/or dimension of the lesion). Mean operative time was 244 min (range: 110-490 min). Median blood loss was 250 mL (range: 30-1,800 mL), with 20 patients receiving blood transfusion. Mortality was nihil, morbidity was 68%, with 5% grade ≥3 according to Clavien-Dindo classification (2 cases percutaneous drainage, 3 cases relaparotomy). Pancreatic fistula occurred in 55 cases (of which 8 grade B, 1 grade C). Mean postoperative stay was 8.2 days (range: 4-23 days). Readmission occurred in 7 cases. Spleen preservation (performed with preservation of splenic vessels) was planned in 64% of cases and was successful in 48%; in 12 cases splenectomy was intraoperatively decided due to adhesions with splenic vessels, in 4 cases due to bleeding. The 19 patients with conversion to open surgery, when compared to patients without conversion, had a longer operative time (P=0.01), higher blood loss (P<0.001), higher transfusion amount (P<0.001), and longer postoperative stay (P=0.001); no difference was observed in morbidity rate (P=0.42). At final histology 25 cases were adenocarcinoma, 33 NET (9 insulinoma), 23 cystoadenoma (17 mucinous, 6 serous), 8 IPMN, 5 solid pseudopapillary tumors, 4 chronic pancreatitis and pseudocysts, 2 metastases from RCC. R0 resection was obtained in 97% of cases. Mean number of retrieved lymph nodes was 14.4. Conclusions Laparoscopic distal pancreatectomy can be performed in more than 60% of overall distal pancreatectomy, with a successful spleen preservation rate of 75% of cases. A worse operative outcome is to be expected in patients requiring conversion to open surgery.