Francesca Gavazzi

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.

Preoperative Pancreatic Resection (PREPARE) score: a prospective multicenter-based morbidity risk score.

Objectives:Development of a simple preoperative risk score to predict morbidity related to pancreatic surgery. Background:Pancreatic surgery is standardized with little technical diversity among institutions and unchanging morbidity and mortality rates in recent years. Preoperative identification of high-risk patients is potentially one of the rare avenues for improving the clinical course of patients undergoing pancreatic surgery. Methods:Using a prospectively collected multicenter database of patients undergoing pancreatic surgery (n = 703), surgical complications were classified according to the Clavien-Dindo classification. A new scoring system for preoperative identification of high-risk patients that included only objective preoperatively assessable variables was developed using a multivariate regression model. Subsequently, this scoring system was prospectively validated from 2011 to 2013 (n = 429) in a multicenter setting. Results:Eight independent preoperatively assessable variables were identified and included in the scoring system: systolic blood pressure, heart rate, hemoglobin level, albumin level, ASA (American Society of Anesthesiologists) score, surgical procedure, elective surgery or not, and disease of pancreatic origin or not. On the basis of 3 subgroups (low risk, intermediate risk, high risk), the proposed scoring system reached an accuracy of 75% for correctly predicting occurrence or nonoccurrence of major surgical complications in 80% of all analyzed patients within the validation cohort (c-statistic index = 0.709, P < 0.001, 95% confidence interval = 0.657–0.760). Conclusions:We present an easily applied scoring system with convincing accuracy for identifying low-risk and high-risk patients. In contrast to other systems, the score is exclusively based on objective preoperatively assessable characteristics and can be rapidly and easily calculated.

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.

A Partnership Model Between High- and Low-Volume Hospitals to Improve Results in Hepatobiliary Pancreatic Surgery

Objective:To optimize the results of low-volume (LV) centers for hepatopancreaticobiliary (HPB) surgery. Background:High-volume (HV) centers for HPB surgery have lower mortality than LV. Strategies for collaboration between HV and LV centers are not well investigated. Methods:Postoperative outcomes of patients undergoing curative HPB resection were evaluated at an LV hospital before (2006–2008) and during the collaboration (2009–2012) and at 2 hospitals with HV for either liver or pancreatic resection (2009–2012). Itinerant tutor surgeons from the HV centers were involved in the pre-, intra- and postoperative course of HPB patients at the LV hospital. Results:HPB cases at the LV center increased from 18 to 40 patients per year from 2006 to 2012, whereas 6-month postoperative mortality decreased from 17.8% (2006–2008) to 6% (2009–2012), P < 0.05 (liver: 10.3% vs 4.7% and pancreas: 29.4% vs 7.9%). During the collaborative study period, outcomes for hepatectomy were similar for LV and HV (85 vs 507 cases): postoperative Clavien-Dindo scores 4 and 5 were 2% and 0.2% for HV versus 2.4% and 1.2% for LV, respectively. Outcomes for pancreatic procedures (LV 63 vs HV 269 cases) showed better postoperative Clavien-Dindo scores 4 and 5 in the HV (0.7% score 4 and 1.5% score 5 for HV vs 3.2% and 6.3%, respectively, for LV) but the difference disappeared in the last 2 years (2011–2012) and matching the cases. Conclusions:Our partnership model helped improve postoperative outcomes at the LV center. Results at the LV hospital were comparable with the HV centers, although 2 years of partnership were required to achieve this in pancreatic surgery.

Ultrasonic dissection versus conventional dissection techniques in pancreatic surgery: a randomized multicentre study

Objective:This prospective randomized multicenter trial was performed to assess the potential benefits of ultrasonic energy dissection compared with conventional dissection techniques in pancreatic surgery. Background:Surgical procedures for tumors of the pancreatic head involve time-consuming manual dissection. The primary hypothesis was that use of ultrasonic tissue and vessel dissection would lead to substantial saving in operative time during pancreatic resection. Methods:Patients eligible for pancreaticoduodenectomy (PD) or pylorus-preserving PD (PPPD) were randomized to group A (dissection with ultrasonic device) or group B (conventional dissection) from March 2009 to May 2011. The primary endpoint was overall duration of operation time. Secondary endpoints were time to end of resection phase, intraoperative blood loss, number of transfused units of blood, and postoperative morbidity. Results:Analysis of primary and secondary endpoints included 101 patients, who received either PD or PPPD. Demographical characteristics and clinical parameters were similar in both groups. The use of an ultrasonic dissection device did not significantly reduce overall operation time (median 316 minutes in group A and 319 minutes in group B, P = 0.95) and did not significantly increase the costs of surgery. Analysis of secondary endpoints revealed no difference in postoperative course. Conclusions:Tissue dissection and vessel closure using an ultrasonic device is equivalent to dissection with conventional techniques in pancreatic surgery.

Autologous Islet Transplantation in Patients Requiring Pancreatectomy: A Broader Spectrum of Indications Beyond Chronic Pancreatitis

Islet autotransplantation (IAT) is usually performed in patients undergoing pancreatic surgery for chronic pancreatitis. In the present series, IAT was offered also to patients undergoing pancreatic surgery for both nonmalignant and malignant diseases, having either completion pancreatectomy as treatment for severe pancreatic fistulas (n = 21) or extensive distal pancreatectomy for neoplasms of the pancreatic neck (n = 19) or pancreatoduodenectomy because of the high risk of pancreatic fistula (n = 32). Fifty‐eight of 72 patients who were eligible to this broader spectrum of indication actually received IAT. There was no evidence of a higher‐than‐expected rate of major complications for pancreatectomy. Forty‐five patients receiving IAT were still alive at the time of the last scheduled follow‐up (1375 ± 365 days). Eighteen (95%) of 19 and 11 (28%) of 39 patients reached insulin independence after partial or total pancreatectomy, respectively. The metabolic results were dependent on the transplanted islet mass. Thirty‐one of 58 patients had malignant diseases of the pancreas or periampullary region, and only three patients developed ex novo liver metastases after IAT (median follow‐up 914 ± 382 days). Our data demonstrate the feasibility, efficacy, and safety of IAT for a broader spectrum of clinical indications beyond chronic pancreatitis.

Morphohistological Features of Pancreatic Stump Are the Main Determinant of Pancreatic Fistula after Pancreatoduodenectomy

Introduction. Pancreatic surgery is challenging and associated with high morbidity, mainly represented by postoperative pancreatic fistula (POPF) and its further consequences. Identification of risk factors for POPF is essential for proper postoperative management. Aim of the Study. Evaluation of the role of morphological and histological features of pancreatic stump, other than main pancreatic duct diameter and glandular texture, in POPF occurrence after pancreaticoduodenectomy. Patients and Methods. Between March 2011 and April 2013, we performed 145 consecutive pancreaticoduodenectomies. We intraoperatively recorded morphological features of pancreatic stump and collected data about postoperative morbidity. Our dedicated pathologist designed a score to quantify fibrosis and inflammation of pancreatic tissue. Results. Overall morbidity was 59,3%. Mortality was 4,1%. POPF rate was 28,3%, while clinically significant POPF were 15,8%. Male sex (P = 0.009), BMI ≥ 25 (P = 0.002), prolonged surgery (P = 0.001), soft pancreatic texture (P < 0.001), small pancreatic duct (P < 0.001), pancreatic duct decentralization on stump anteroposterior axis, especially if close to the posterior margin (P = 0.031), large stump area (P = 0.001), and extended stump mobilization (P = 0.001) were related to higher POPF rate. Our fibrosis-and-inflammation score is strongly associated with POPF (P = 0.001). Discussion and Conclusions. Pancreatic stump features evaluation, including histology, can help the surgeon in fitting postoperative management to patient individual risk after pancreaticoduodenectomy.

Minimally Invasive versus Open Distal Pancreatectomy for Ductal Adenocarcinoma (DIPLOMA): A Pan-European Propensity Score Matched Study

Objective: The aim of this study was to compare oncological outcomes after minimally invasive distal pancreatectomy (MIDP) with open distal pancreatectomy (ODP) in patients with pancreatic ductal adenocarcinoma (PDAC). Background: Cohort studies have suggested superior short-term outcomes of MIDP vs. ODP. Recent international surveys, however, revealed that surgeons have concerns about the oncological outcomes of MIDP for PDAC. Methods: This is a pan-European propensity score matched study including patients who underwent MIDP (laparoscopic or robot-assisted) or ODP for PDAC between January 1, 2007 and July 1, 2015. MIDP patients were matched to ODP patients in a 1:1 ratio. Main outcomes were radical (R0) resection, lymph node retrieval, and survival. Results: In total, 1212 patients were included from 34 centers in 11 countries. Of 356 (29%) MIDP patients, 340 could be matched. After matching, the MIDP conversion rate was 19% (n = 62). Median blood loss [200 mL (60–400) vs 300 mL (150–500), P = 0.001] and hospital stay [8 (6–12) vs 9 (7–14) days, P < 0.001] were lower after MIDP. Clavien-Dindo grade ≥3 complications (18% vs 21%, P = 0.431) and 90-day mortality (2% vs 3%, P > 0.99) were comparable for MIDP and ODP, respectively. R0 resection rate was higher (67% vs 58%, P = 0.019), whereas Gerotas fascia resection (31% vs 60%, P < 0.001) and lymph node retrieval [14 (8–22) vs 22 (14–31), P < 0.001] were lower after MIDP. Median overall survival was 28 [95% confidence interval (CI), 22–34] versus 31 (95% CI, 26–36) months (P = 0.929). Conclusions: Comparable survival was seen after MIDP and ODP for PDAC, but the opposing differences in R0 resection rate, resection of Gerotas fascia, and lymph node retrieval strengthen the need for a randomized trial to confirm the oncological safety of MIDP.

Role of C-Reactive Protein Assessment as Early Predictor of Surgical Site Infections Development after Pancreaticoduodenectomy

Background: Surgical site infections (SSIs) are extremely common in pancreatic surgery and explain its considerable morbidity and mortality, even in tertiary centers. Early detection of these complications, with the help of laboratory assays, improve clinical outcome. The aim of the present study is to evaluate C-reactive protein (CRP) diagnostic accuracy as early predictor of SSIs after pancreaticoduodenectomy (PD). Methodology: We considered 251 consecutive PD. We prospectively recorded preoperative clinical and anthropometric data, intraoperative details and the postoperative outcome. In the first pool of consecutive patients (n = 150), we analyzed CRP levels from postoperative day 1 to 7 and investigated the prediction of SSIs. We then validated the diagnostic accuracy on the following 101 consecutive cases. Results: At multivariate analysis, high BMI and preoperative biliary stenting appeared to be independently associated with SSIs and organ-space SSI development. The CRP cutoff of 17.27 mg/dl on postoperative day 3 (78% sensitivity, 79% specificity) and of 14.72 mg/dl on postoperative day 4 (87% sensitivity, 82% specificity) was in a position to predict the course of 78.2 and 80.2% of patients, respectively. Conclusions: CRP on postoperative days 3 and 4 seems able to predict postoperative course, selecting patients deserving intensification of diagnostic assessment; patients not satisfying these conditions could be reasonably directed toward early discharge.

Indications for Surgery and Surgical Procedures for Chronic Pancreatitis

In the management of chronic pancreatitis, pain has remained the main indication for surgical treatment over the years, but for a long time the high morbidity and mortality associated with pancreatic operations limited the use of this procedure for benign disease.