Publications by authors named "Stefano Partelli"

178 Publications

EZH2 Inhibition as New Epigenetic Treatment Option for Pancreatic Neuroendocrine Neoplasms (PanNENs).

Cancers (Basel) 2021 Oct 7;13(19). Epub 2021 Oct 7.

Institute of Pathology, University of Bern, 3008 Bern, Switzerland.

Pancreatic neuroendocrine neoplasms are epigenetically driven tumors, but therapies against underlying epigenetic drivers are currently not available in the clinical practice. We aimed to investigate EZH2 (Enhancer of Zest homolog) expression in PanNEN and the impact of EZH2 inhibition in three different PanNEN preclinical models. EZH2 expression in PanNEN patient samples ( = 172) was assessed by immunohistochemistry and correlated with clinico-pathological data. Viability of PanNEN cell lines treated with EZH2 inhibitor (GSK126) was determined in vitro. Lentiviral transduction of shRNA targeting EZH2 was performed in QGP1 cells, and cell proliferation was measured. Rip1TAG2 mice underwent GSK126 treatment for three weeks starting from week 10 of age. Primary cells isolated from PanNEN patients ( = 6) were cultivated in 3D as islet-like tumoroids and monitored for 10 consecutive days upon GSK126 treatment. Viability was measured continuously for the whole duration of the treatment. We found that high EZH2 expression correlated with higher tumor grade ( < 0.001), presence of distant metastases ( < 0.001), and shorter disease-free survival ( < 0.001) in PanNEN patients. Inhibition of EZH2 in vitro in PanNEN cell lines and in patient-derived islet-like tumoroids reduced cell viability and impaired cell proliferation, while inhibition of EZH2 in vivo in Rip1TAG2 mice reduced tumor burden. Our results show that EZH2 is highly expressed in high-grade PanNENs, and during disease progression it may contribute to aberrations in the epigenetic cellular landscape. Targeting EZH2 may represent a valuable epigenetic treatment option for patients with PanNEN.
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http://dx.doi.org/10.3390/cancers13195014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508156PMC
October 2021

ASO Visual Abstract: Long-Term Survivors After Upfront Resection for Pancreatic Ductal Adenocarcinoma: An Actual 5-Year Analysis of Disease-Specific and Post-Recurrence Survival.

Ann Surg Oncol 2021 Aug 30. Epub 2021 Aug 30.

Division of Pancreatic Surgery, Department of Surgery, Pancreas Translational and Clinical Research Center, Università Vita- Salute, IRCCS San Raffaele Scientific Institute, Milan, Italy.

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http://dx.doi.org/10.1245/s10434-021-10573-2DOI Listing
August 2021

Indications to total pancreatectomy for positive neck margin after partial pancreatectomy: a review of a slippery ground.

Updates Surg 2021 Aug 31;73(4):1219-1229. Epub 2021 Jul 31.

School of Medicine, Vita Salute San Raffaele University, Milan, Italy.

The extension of a partial pancreatectomy up to total pancreatectomy because of positive neck margin examined at intraoperative frozen section (IFS) analysis is an accepted procedure in modern pancreatic surgery with good accuracy. The goal of this practice is to improve the rate of radical (R0) resection in malignant tumors, mainly pancreatic ductal adenocarcinoma (PDAC), and to completely resect pre-invasive neoplasms such as intraductal papillary mucinous neoplasms (IPMNs). In the setting of IPMNs there is a consensus for pancreatic re-resection when high-grade dysplasia and invasive cancer are present at the neck margin. The presence of denudation is another indication for further resection in IPMNs. The role of IFS analysis in the management of pancreatic cancer is more debated. The presence of a positive intraoperative transection margin can be considered the surrogate of a biologically aggressive disease associated with a poorer prognosis. There are conflicting data regarding possible advantages of pancreatic re-resection up to total pancreatectomy, and the lack of randomized trials comparing different strategies does not offer a definitive answer. The goal of this review is to provide an up-to-date overview of the role IFS analysis of pancreatic margin and of pancreatic re-resection up to total pancreatectomy considering different pancreatic tumors.
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http://dx.doi.org/10.1007/s13304-021-01141-0DOI Listing
August 2021

Preoperative risk stratification of postoperative pancreatic fistula: A risk-tree predictive model for pancreatoduodenectomy.

Surgery 2021 Jul 24. Epub 2021 Jul 24.

Department of General and Pancreatic Surgery, Verona University Hospital, Italy.

Background: Existing postoperative pancreatic fistula risk scores rely on intraoperative parameters, which limits their value in the preoperative setting. A preoperative predictive model to stratify the risk of developing postoperative pancreatic fistula before pancreatoduodenectomy was built and externally validated.

Methods: A regression risk-tree model for preoperative postoperative pancreatic fistula risk stratification was developed in the Verona University Hospital training cohort using preoperative variables and then tested prospectively in a validation cohort of patients who underwent pancreatoduodenectomy at San Raffaele Hospital of Milan.

Results: In the study period 566 (training cohort) and 456 (validation cohort) patients underwent pancreatoduodenectomy. In the multivariable analysis body mass index, radiographic main pancreatic duct diameter and American Society of Anesthesiologists score ≥3 were independently associated with postoperative pancreatic fistula. The regression tree analysis allocated patients into 3 preoperative risk groups with an 8%, 21%, and 32% risk of postoperative pancreatic fistula (all P < .01) based on main pancreatic duct diameter (≥ or <5 mm) and body mass index (≥ or <25). The 3 groups were labeled low, intermediate, and high risk and consisted of 206 (37%), 188 (33%), and 172 (30%) patients, respectively. The risk-tree was applied to validation cohort, successfully reproducing 3 risk groups with significantly different postoperative pancreatic fistula risks (all P < .01).

Conclusion: In candidates for pancreatoduodenectomy, the risk of postoperative pancreatic fistula can be quickly and accurately determined in the preoperative setting based on the body mass index and main pancreatic duct diameter at radiology. Preoperative risk stratification could potentially guide clinical decision-making, improve patient counseling and allow the establishment of personalized preoperative protocols.
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http://dx.doi.org/10.1016/j.surg.2021.06.046DOI Listing
July 2021

Long-Term Survivors after Upfront Resection for Pancreatic Ductal Adenocarcinoma: An Actual 5-Year Analysis of Disease-Specific and Post-Recurrence Survival.

Ann Surg Oncol 2021 Jul 13. Epub 2021 Jul 13.

Division of Pancreatic Surgery, Department of Surgery, Pancreas Translational and Clinical Research Center, Università Vita-Salute, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Background: Data on long-term actual survival in patients with surgically resected pancreatic ductal adenocarcinoma (PDAC) are limited. The aim of this study was to evaluate the actual 5-year disease-specific survival (DSS) and post-recurrence survival (PRS) in patients who underwent pancreatectomy for PDAC.

Methods: Data from patients who underwent upfront surgical resection for PDAC between 2009 and 2014 were analyzed. Exclusion criteria included PDAC arising in the background of an intraductal papillary mucinous neoplasm and patients undergoing neoadjuvant therapy. All alive patients had a minimum follow-up of 60 months. Independent predictors of PRS, DSS, and survival > 5 years were searched.

Results: Of the 176 patients included in this study, 48 (27%) were alive at 5 years, but only 20 (11%) had no recurrence. Median PRS was 12 months. In the 154 patients after disease recurrence, independent predictors of shorter PRS were total pancreatectomy, G3 tumors, early recurrence (< 12 months from surgery), and no treatment at recurrence. Median DSS was 36 months. Independent predictors of DSS were CA19-9 at diagnosis > 200 U/mL, total pancreatectomy, N + status, G3 tumors and perineural invasion. Only the absence of perineural invasion was a favorable independent predictor of survival > 5 years.

Conclusion: More than one-quarter of patients who underwent upfront surgery for PDAC were alive after 5 years, although only 11% of the initial cohort were cancer-free. Long-term survival can also be achieved in tumors with more favorable biology in an upfront setting followed by adjuvant chemotherapy.
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http://dx.doi.org/10.1245/s10434-021-10401-7DOI Listing
July 2021

European Cancer Organisation Essential Requirements for Quality Cancer Care (ERQCC): Pancreatic Cancer.

Cancer Treat Rev 2021 Sep 20;99:102208. Epub 2021 Apr 20.

European Cancer Organisation (ECCO); Iridium Kankernetwerk and University of Antwerp, Wilrijk-Antwerp, Belgium.

European Cancer Organisation Essential Requirements for Quality Cancer Care (ERQCC) are written by experts representing all disciplines involved in cancer care in Europe. They give patients, health professionals, managers and policymakers a guide to essential care throughout the patient journey. Pancreatic cancer is an increasing cause of cancer mortality and has wide variation in treatment and care in Europe. It is a major healthcare burden and has complex diagnosis and treatment challenges. Care must be carried out only in pancreatic cancer units or centres that have a core multidisciplinary team (MDT) and an extended team of health professionals detailed here. Such units are far from universal in European countries. To meet European aspirations for comprehensive cancer control, healthcare organisations must consider the requirements in this paper, paying particular attention to multidisciplinarity and patient-centred pathways from diagnosis, to treatment, to survivorship.
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http://dx.doi.org/10.1016/j.ctrv.2021.102208DOI Listing
September 2021

Does chronic consumption of angiotensin-converting enzyme inhibitors affect survival after surgical resection of pancreatic ductal adenocarcinoma?

Dig Liver Dis 2021 Aug 16;53(8):1065-1067. Epub 2021 May 16.

Pancreato-Biliary Endoscopy and Endosonography Division. Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute IRCCS, Via Olgettina 60, Milan, Italy.

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http://dx.doi.org/10.1016/j.dld.2021.04.027DOI Listing
August 2021

Early Identification of Residual Disease After Neuroendocrine Tumor Resection Using a Liquid Biopsy Multigenomic mRNA Signature (NETest).

Ann Surg Oncol 2021 Nov 18;28(12):7506-7517. Epub 2021 May 18.

Wren Laboratories, Branford, CT, USA.

Introduction: Surgery is the only cure for neuroendocrine tumors (NETs), with R0 resection being critical for successful tumor removal. Early detection of residual disease is key for optimal management, but both imaging and current biomarkers are ineffective post-surgery. NETest, a multigene blood biomarker, identifies NETs with >90% accuracy. We hypothesized that surgery would decrease NETest levels and that elevated scores post-surgery would predict recurrence.

Methods: This was a multicenter evaluation of surgically treated primary NETs (n = 153). Blood sampling was performed at day 0 and postoperative day (POD) 30. Follow-up included computed tomography/magnetic resonance imaging (CT/MRI), and messenger RNA (mRNA) quantification was performed by polymerase chain reaction (PCR; NETest score: 0-100; normal ≤20). Statistical analyses were performed using the Mann-Whitney U-test, Chi-square test, Kaplan-Meier survival, and area under the receiver operating characteristic curve (AUROC), as appropriate. Data are presented as mean ± standard deviation.

Results: The NET cohort (n = 153) included 57 patients with pancreatic cancer, 62 patients with small bowel cancer, 27 patients with lung cancer, 4 patients with duodenal cancer, and 3 patients with gastric cancer, while the surgical cohort comprised patients with R0 (n = 102) and R1 and R2 (n = 51) resection. The mean follow-up time was 14 months (range 3-68). The NETest was positive in 153/153 (100%) samples preoperatively (mean levels of 68 ± 28). In the R0 cohort, POD30 levels decreased from 62 ± 28 to 22 ± 20 (p < 0.0001), but remained elevated in 30% (31/102) of patients: 28% lung, 29% pancreas, 27% small bowel, and 33% gastric. By 18 months, 25/31 (81%) patients with a POD30 NETest >20 had image-identifiable recurrence. An NETest score of >20 predicted recurrence with 100% sensitivity and correlated with residual disease (Chi-square 17.1, p < 0.0001). AUROC analysis identified an AUC of 0.97 (p < 0.0001) for recurrence-prediction. In the R1 (n = 29) and R2 (n = 22) cohorts, the score decreased (R1: 74 ± 28 to 45 ± 24, p = 0.0012; R2: 72 ± 24 to 60 ± 28, p = non-significant). At POD30, 100% of NETest scores were elevated despite surgery (p < 0.0001).

Conclusion: The preoperative NETest accurately identified all NETs (100%). All resections decreased NETest levels and a POD30 NETest score >20 predicted radiologically recurrent disease with 94% accuracy and 100% sensitivity. R0 resection appears to be ineffective in approximately 30% of patients. NET mRNA blood levels provide early objective genomic identification of residual disease and may facilitate management.
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http://dx.doi.org/10.1245/s10434-021-10021-1DOI Listing
November 2021

Impact of care pathway adherence on recovery following distal pancreatectomy within an enhanced recovery program.

HPB (Oxford) 2021 Apr 27. Epub 2021 Apr 27.

Division of Pancreatic Surgery, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy. Electronic address:

Background: In bowel surgery, adherence to enhanced recovery program (ERP) has been associated with improved recovery. The objective of this study was to evaluate the impact of adherence to ERP elements on outcomes, and identify factors associated with successful recovery following distal pancreatectomy (DP).

Methods: Data for 376 patients who underwent DP managed within an ERP including 16 perioperative elements were reviewed. Primary endpoint was successful recovery, a composite outcome defined as length of hospital stay≤7 days, no severe complications nor readmissions.

Results: Patients had a mean (SD) overall adherence of 76 (14)%. Overall, 166 (44%) patients had a successful recovery. There was a positive association between overall adherence and successful recovery (OR 1.19, 95%CI 1.08-1.31 for every additional element, p = 0.001), while an inverse relationship was found with comprehensive complication index (8% reduction, 95%CI -15 to -2%, p = 0.011). Adherence to postoperative phase interventions had the greatest impact on recovery (OR 1.29, 95%CI 1.13-1.47 for every additional postoperative element; p < 0.001). At multivariable regression, early termination of IV fluids was the only ERP element associated with successful recovery (OR 2.80, 95%CI 1.73-4.54; p < 0.001).

Conclusion: Increased adherence to ERP elements was associated with successful early recovery and reduction of postoperative complication severity.
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http://dx.doi.org/10.1016/j.hpb.2021.04.016DOI Listing
April 2021

Recurrence after surgical resection of pancreatic cancer: the importance of postoperative complications beyond tumor biology.

HPB (Oxford) 2021 Apr 20. Epub 2021 Apr 20.

Division of Pancreatic Surgery, Pancreas Translational & Clinical Research Center, Università Vita-Salute, IRCCS San Raffaele Scientific Institute, Milan, Italy. Electronic address:

Background: Current treatment of potentially resectable pancreatic ductal adenocarcinoma (PDAC) includes pancreatic resection followed by adjuvant therapy. Aim of this study is to identify factors that are related with overall and early recurrence after pancreatectomy for PDAC.

Methods: Retrospective analysis of patients with histologically confirmed PDAC who underwent pancreatectomy between September 2009 and December 2014. Early relapse was defined as recurrence within 12 months after surgery. Univariate/multivariate analysis was performed to identify prognostic factors for recurrence.

Results: 261 patients were included (54% males, mean age 67 years). Neoadjuvant and adjuvant treatments were performed in 55 (21%) and 243 (93%) patients. Overall morbidity was 56% with a rate of grade 3-4 Clavien-Dindo complications of 25%. Median disease-free survival was 18 months. Multivariate analysis identified nodal metastases (OR: 3.6) and perineural invasion (OR: 2.14) as independent predictors of disease recurrence in the entire cohort. 76 patients (29%) had an early recurrence. Poorly differentiated tumors (OR: 3.019) and grade 3-4 Clavien-Dindo complications (OR: 3.05) were independent risk factors for early recurrence.

Conclusion: Although overall recurrence is associated with tumor-related factors, severe postoperative complications represent an independent predictor of early recurrence. Patients at increased risk of severe postoperative complications may benefit from neoadjuvant therapy.
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http://dx.doi.org/10.1016/j.hpb.2021.04.004DOI Listing
April 2021

The role of acinar content at pancreatic resection margin in the development of postoperative pancreatic fistula and acute pancreatitis after pancreaticoduodenectomy.

Surgery 2021 Oct 28;170(4):1215-1222. Epub 2021 Apr 28.

Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy. Electronic address:

Background: A fatty infiltration of the pancreas has been traditionally regarded as the main histological risk factor for postoperative pancreatic fistula, whereas the role of the secreting acinar compartment has been poorly investigated. The aim of this study was to evaluate the role of acinar content at the pancreatic resection margin in the development of clinically relevant postoperative pancreatic fistula and clinically relevant postoperative acute pancreatitis after pancreaticoduodenectomy.

Methods: Data from 388 consecutive patients who underwent pancreaticoduodenectomy (2018-2019) were analyzed. Pancreatic section margins were histologically assessed for acinar, fibrosis, and fat content. Acinar content was categorized using median and third quartile as cut-offs. Univariate and multivariable analysis of possible predictors of clinically relevant postoperative pancreatic fistula and clinically relevant postoperative acute pancreatitis were performed.

Results: Acinar content was <60% in 166 patients (42.8%), ≥60% and ≤80% in 156 patients (40.2%), and >80% in 66 patients (17.0%). The rate of clinically relevant postoperative pancreatic fistula and clinically relevant postoperative acute pancreatitis was significantly higher in patients with acinar content >80% (39.4% and 33.3%, respectively) as well as in those with acinar content ≥60% and ≤80% (36.5% and 35.3%, respectively), compared with patients with acinar content <60% (10.2% and 5.4%, respectively) (P < .001). Acinar content was identified as an independent predictor of clinically relevant postoperative pancreatic fistula (≥60% and ≤80%, odds ratio 2.51, P = .008; >80%, odds ratio 2.93, P = .010) and clinically relevant postoperative acute pancreatitis (≥60% and ≤80%, odds ratio 9.42, P < .001; >80%, odds ratio 10.16, P < .001).

Conclusion: An acinar content at the pancreatic resection margin ≥60% is associated to an increased risk of clinically relevant postoperative pancreatic fistula and clinically relevant postoperative acute pancreatitis. Fat content was associated neither with clinically relevant postoperative pancreatic fistula nor with clinically relevant postoperative acute pancreatitis.
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http://dx.doi.org/10.1016/j.surg.2021.03.047DOI Listing
October 2021

The effect of high intraoperative blood loss on pancreatic fistula development after pancreatoduodenectomy: An international, multi-institutional propensity score matched analysis.

Surgery 2021 Oct 28;170(4):1195-1204. Epub 2021 Apr 28.

Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. Electronic address:

Background: The association between intraoperative estimated blood loss and outcomes after pancreatoduodenectomy has, thus far, been rarely explored.

Methods: In total, 7,706 pancreatoduodenectomies performed at 18 international institutions composing the Pancreas Fistula Study Group were examined (2003-2020). High estimated blood loss (>700 mL) was defined as twice the median. Propensity score matching (1:1 exact-match) was employed to adjust for variables associated with high estimated blood loss and clinically relevant pancreatic fistula occurrence. The study was powered to detect a 33% clinically relevant pancreatic fistula increase in the high estimated blood loss group, with α = 0.05 and β = 0.2.

Results: The propensity score model included 966 patients with high estimated blood loss and 966 patients with lower estimated blood loss; all covariate imbalantces were solved. Patients with high estimated blood loss patients experienced higher clinically relevant pancreatic fistula rates (19.4 vs 12.6%, odds ratio 1.66; P < .001), as well as higher severe complication rates (27.8 vs 15.6%), transfusions (50.1 vs 14.3%), reoperations (9.2 vs 4.0%), intensive care unit transfers (9.9 vs 4.8%) and 90-day mortality (4.7 vs 2.0%, all P < .001). High estimated blood loss was an independent predictor for clinically relevant pancreatic fistula (odds ratio 1.78, 95% confidence interval 1.37-2.32), as were prophylactic Octreotide administration (odds ratio 1.95, 95% confidence interval 1.46-2.61) and soft pancreatic texture (odds ratio 5.32, 95% confidence interval 3.74-5.57; all P < .001). Moreover, a second model including 1,126 pancreatoduodenectomies was derived including vascular resections as additional confounder (14.0% vascular resections performed in each group). On multivariable regression, high estimated blood loss was confirmed an independent predictor for clinically relevant pancreatic fistula reduction (odds ratio 1.80, 95% confidence interval 1.32-2.44; P < .001), whereas vascular resection was not (odds ratio 0.64, 95% confidence interval 0.34-1.88; P = .156).

Conclusion: This study better establishes the relationship between estimated blood loss and outcomes after pancreatoduodenectomy. Despite inherent contributions to blood loss, its minimization is an actionable opportunity for clinically relevant pancreatic fistula reduction and performance optimization in pancreatoduodenectomy. Accordingly, practical insights are offered to achieve this goal.
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http://dx.doi.org/10.1016/j.surg.2021.03.044DOI Listing
October 2021

Evaluation of cost-effectiveness among open, laparoscopic and robotic distal pancreatectomy: A systematic review and meta-analysis.

Am J Surg 2021 Sep 7;222(3):513-520. Epub 2021 Apr 7.

Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy. Electronic address:

Background: The cost-effectiveness of minimally invasive distal pancreatectomy (MIDP) is still a matter of debate. This study compares the cost-effectiveness of open (ODP), laparoscopic (LDP) and robotic distal pancreatectomy (RDP).

Methods: Pubmed, Web of Science and Cochrane Library databases were searched. Studies comparing cost-effectiveness of ODP and MIDP were included.

Results: A total of 1052 titles were screened and 16 articles were included in the study, 2431 patients in total. LDP resulted the most cost-efficient procedure, with a mean total cost of 14,682 ± 5665 € and the lowest readmission rates. ODP had lower surgical procedure costs, 3867 ± 768 €. RDP was the safest approach regarding hospital stay costs (5239 ± 1741 €), length of hospital stay, morbidity, clinically relevant pancreatic fistula and reoperations.

Conclusion: In this meta-analysis MIDP resulted as the most cost-effective approach. LDP seems to be protective against high costs, but RDP seems to be safer.
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http://dx.doi.org/10.1016/j.amjsurg.2021.03.066DOI Listing
September 2021

A tug-of-war in intraductal papillary mucinous neoplasms management: Comparison between 2017 International and 2018 European guidelines.

Dig Liver Dis 2021 Aug 10;53(8):998-1003. Epub 2021 Apr 10.

Division of Surgery, CLINTEC, Karolinska Institutet, Stockholm, Sweden; Division of Surgical Oncology, Department of Surgery - University of Colorado, Anschutz Medical Campus, Denver, United States.

Background: 2017 International and 2018 European guidelines are the most recent guidelines for intraductal papillary mucinous neoplasms management.

Aim: to evaluate the diagnostic accuracy of these guidelines in identifying malignant IPMN.

Methods: data from resected patients with IPMN were collected in two referral centers. Features of risk associated to cancerous degeneration described in International and European guidelines were retrospectively applied. Sensitivity, specificity, positive and negative predictive value in detecting malignant disease were calculated.

Results: the study includes 627 resected patients. European guidelines suggest resection in any patient with at least one feature of moderate-risk. International guidelines suggest that patients with moderate-risk features undergo endoscopic ultrasound before surgery. European guidelines had a higher sensitivity (99.2% vs. 83%) but a lower positive predictive value (59.5% vs. 65.8%) and Specificity (2% vs. 37.5%). European guidelines detected almost all malignancies, but 40% of resected patients had low-grade dysplasia. 297 patients underwent endoscopic ultrasound before surgery. 31/116 (26.7%) tumors radiologically classified as "worrisome features" were reclassified as "high-risk stigmata" by endoscopic ultrasound and 24/31 were malignant IPMN.

Conclusions: European and International guidelines have a relatively low diagnostic accuracy, being European guidelines more aggressive. Endoscopic ultrasound can improve guidelines accuracy in patients with moderate-risk features.
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http://dx.doi.org/10.1016/j.dld.2021.03.009DOI Listing
August 2021

Before sentinel bleeding: early prediction of postpancreatectomy hemorrhage (PPH) with a CT-based scoring system.

Eur Radiol 2021 Sep 4;31(9):6879-6888. Epub 2021 Mar 4.

Radiology Unit, San Raffaele Scientific Institute, via Olgettina 60, 20132, Milan, Italy.

Objectives: Clinically significant pancreatic fistula (POPF) has been established as a well-known risk factor for late and severe postpancreatectomy hemorrhage after pancreaticoduodenectomy (PD) (postpancreatectomy pancreatic fistula-associated hemorrhage [PPFH]). Our aim was to assess whether contrast-enhanced CT scan after PD is an effective tool for early prediction of PPFH.

Methods: From a prospectively acquired database, all consecutive patients who underwent PD between January 2013 and May 2019 were identified; within this database, all patients who were evaluated, for clinical suspicion of POPF, with at least one contrast-enhanced CT scan examination, were enrolled in this retrospective study. The selected CT findings included perianastomotic fluid collections and air bubbles; pancreaticojejunostomy (PJ) was analyzed in terms of dehiscence and defect.

Results: One hundred seventy-eight out of 953 PD patients (18.7%) suffered from clinically significant POPF; after exclusions, 166 patients were enrolled. Among this subset, 33 patients (19.9%) had at least one PPFH episode. In multivariable analysis, PPFH was associated with postoperative CT evidence of fluid collections (p = 0.046), air bubbles (p = 0.046), and posterior PJ defect (p < 0.001). Based on these findings, a practical 4-point prediction score was developed (AUC: 0.904, Se: 76%, Sp: 93.8%): patients with a score ≥ 3 demonstrated a significantly higher risk of PPFH development (OR = 45.6, 95% CI: 13.0-159.3).

Conclusions: Postoperative CT scan permits early stratification of PPFH risk, thus providing an actual aid for patients' management.

Key Points: • Postpancreatectomy hemorrhage (PPH) is a dramatic, clinically unpredictable occurrence. • After pancreaticoduodenectomy (PD), early identification of posterior pancreaticojejunostomy defect, perianastomotic air bubbles, and retroperitoneal fluid collections enables effective PPH risk stratification by means of a practical CT-based 4-point scoring system. • CT scan after PD allows a paradigm shift in the management PPH, from a conventional "wait and see" approach, to a more proactive one that relies on early anticipation and timely prevention.
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http://dx.doi.org/10.1007/s00330-021-07788-yDOI Listing
September 2021

Dual Tracer 68Ga-DOTATOC and 18F-FDG PET Improve Preoperative Evaluation of Aggressiveness in Resectable Pancreatic Neuroendocrine Neoplasms.

Diagnostics (Basel) 2021 Jan 28;11(2). Epub 2021 Jan 28.

Vita-Salute San Raffaele University, Via Olgettina 58, 20132 Milan, Italy.

Purpose: To define an imaging risk profile in a population of patients affected by Pancreatic neuroendocrine neoplasms (PanNENs) candidates to surgery, by assessing the predictive role of 68Ga-DOTATOC and 18F-FDG PET/CT and PET/MR derived parameters in risk stratification, particularly regarding histological features of aggressive behaviour.

Patients And Methods: Retrospective study including 83 patients (53 males, 30 females; median age: 60 years, interquartile range 52-66.5), who underwent to 68Ga-DOTATOC (PET/CT: = 77; PET/MR: = 6) and, 68/83 patients, also to 18F-FDG PET (PET/CT: = 65; PET/MR: = 3) before surgery for PanNEN between 2011 and 2019, with available histological and follow-up data. The PET scans were interpreted with both qualitative (positive vs. negative) and semiquantitative measurements as follows: maximum and mean standardized uptake value (SUVmax and SUVmean) for both 18F-FDG and 68Ga-DOTATOC scans, metabolic tumour volume (MTV) and tumour lesion glycolysis (TLG) for 18F-FDG scans and somatostatin receptor density (SRD) and total lesion somatostatin receptor density (TLSRD) for 68Ga-DOTATOC PET. Receiver Operating Characteristics (ROC) curve analysis was used to investigate the performance of several PET parameters in predicting tumour stage or characteristic. For each PET parameter, the optimal cut-off was derived. Logistic regression analysis was used to assess if the PET parameters, categorized with the optimal cut-off values, were able to predict significantly the corresponding tumour stage or characteristic.

Results: Overall, 29 (35%) patients had G1, 49 (59%) a G2 and five (6%) had a G3 PanNEN. The median Ki-67 index was 4% (interquartile range: 1-8%). SRD and TLSRD significantly discriminated between pT3 or pT4 PanNEN versus pT1 or pT2, as well as 18F-FDG MTV and TLG. 68Ga-DOTATOC SUVmax was able to significantly predict the presence of distant metastases with a threshold of 51.27 (sensitivity and specificity of 85.7 and 68.1%, respectively). 18F-FDG MTV and TLG were predictors of angioinvasion. The cut-off threshold for MTV was 7.98 (sensitivity and specificity of 69.7 and 82.4%, respectively) ( = 0.0004) whereas the cut-off for TLG was 32.4 (sensitivity and specificity of 69.7% and 82.4%, respectively) ( = 0.0004).

Conclusion: Dual tracer 68Ga-DOTATOC and 18F-FDG PET scans provide relevant information regarding tumour behaviour and aggressiveness, implementing the diagnostic preoperative work-up.
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http://dx.doi.org/10.3390/diagnostics11020192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912034PMC
January 2021

CT-derived radiomic features to discriminate histologic characteristics of pancreatic neuroendocrine tumors.

Radiol Med 2021 Jun 1;126(6):745-760. Epub 2021 Feb 1.

Department of Radiology, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy.

Purpose: To assess the ability of radiomic features (RF) extracted from contrast-enhanced CT images (ceCT) and non-contrast-enhanced (non-ceCT) in discriminating histopathologic characteristics of pancreatic neuroendocrine tumors (panNET).

Methods: panNET contours were delineated on pre-surgical ceCT and non-ceCT. First- second- and higher-order RF (adjusted to eliminate redundancy) were extracted and correlated with histological panNET grade (G1 vs G2/G3), metastasis, lymph node invasion, microscopic vascular infiltration. Mann-Whitney with Bonferroni corrected p values assessed differences. Discriminative power of significant RF was calculated for each of the end-points. The performance of conventional-imaged-based-parameters was also compared to RF.

Results: Thirty-nine patients were included (mean age 55-years-old; 24 male). Mean diameters of the lesions were 24 × 27 mm. Sixty-nine RF were considered. Sphericity could discriminate high grade tumors (AUC = 0.79, p = 0.002). Tumor volume (AUC = 0.79, p = 0.003) and several non-ceCT and ceCT RF were able to identify microscopic vascular infiltration: voxel-alignment, neighborhood intensity-difference and intensity-size-zone families (AUC ≥ 0.75, p < 0.001); voxel-alignment, intensity-size-zone and co-occurrence families (AUC ≥ 0.78, p ≤ 0.002), respectively). Non-ceCT neighborhood-intensity-difference (AUC = 0.75, p = 0.009) and ceCT intensity-size-zone (AUC = 0.73, p = 0.014) identified lymph nodal invasion; several non-ceCT and ceCT voxel-alignment family features were discriminative for metastasis (p < 0.01, AUC = 0.80-0.85). Conventional CT 'necrosis' could discriminate for microscopic vascular invasion (AUC = 0.76, p = 0.004) and 'arterial vascular invasion' for microscopic metastasis (AUC = 0.86, p = 0.001). No conventional-imaged-based-parameter was significantly associated with grade and lymph node invasion.

Conclusions: Radiomic features can discriminate histopathology of panNET, suggesting a role of radiomics as a non-invasive tool for tumor characterization.

Trial Registration Number: NCT03967951, 30/05/2019.
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http://dx.doi.org/10.1007/s11547-021-01333-zDOI Listing
June 2021

Improved survival after pancreatic re-resection of positive neck margin in pancreatic cancer patients. A systematic review and network meta-analysis.

Eur J Surg Oncol 2021 Jun 13;47(6):1258-1266. Epub 2021 Jan 13.

Vita Salute San Raffaele University Milan, Italy; Division of Pancreatic Surgery, IRCCS San Raffaele Scientific Institute, Milan, Italy.

The oncological benefit of achieving a negative pancreatic neck margin through re-resection after a positive frozen section (FS) is debated. Aim of this network meta-analysis is to evaluate the survival benefit of re-resection after intraoperative FS neck margin examination following pancreatectomy for ductal adenocarcinoma. A systematic search of studies comparing different strategies for the management of positive FS was performed. Patients were classified in three groups based on FS and permanent section (PS): Group A (FS-, PS-R0), Group B (FS+, PS-R0), Group C (FS±, PS-R1). A frequent random-effects network-meta-analysis was made reporting the surface under the cumulative ranking (SUCRA). Primary endpoint was overall survival (OS). Secondary endpoints were pathological outcomes. Seven retrospectives studies with 4205 patients were included and 99.1% of the pancreatic resections were pancreatoduodenectomies. Group A had the highest probability of better OS (SUCRA = 90%), compared to Group B (SUCRA = 48.7%) and Group C, which was the worst prognostic scenario (SUCRA = 11.3%). Group B had still a probability of longer OS compared to Group C (SUCRA = 48.7% vs 11.3%). Pathological features were more favourable in Group A, with the highest SUCRA for T1-T2 tumors (92.6%), N0 status (89.4%), absence of perineural invasion (92.3%). Heterogeneity was low (τ-value <0.1) for OS, and moderate (τ-values: 0.1-0.6) for pT, pN, and perineural invasion. In conclusion, negative neck margin after primary resection (FS negative) or re-resection of a positive FS was associated with improved survival compared with PS-R1. However, any intraoperative positive FS can be considered as a prognostic factor associated with a more aggressive disease.
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http://dx.doi.org/10.1016/j.ejso.2021.01.001DOI Listing
June 2021

Management of Asymptomatic Sporadic Nonfunctioning Pancreatic Neuroendocrine Neoplasms (ASPEN) ≤2 cm: Study Protocol for a Prospective Observational Study.

Front Med (Lausanne) 2020 23;7:598438. Epub 2020 Dec 23.

National NET Centre and ENETS Centre of Excellence, St Vincent's University Hospital, Dublin, Ireland.

The optimal treatment for small, asymptomatic, nonfunctioning pancreatic neuroendocrine neoplasms (NF-PanNEN) is still controversial. European Neuroendocrine Tumor Society (ENETS) guidelines recommend a watchful strategy for asymptomatic NF-PanNEN <2 cm of diameter. Several retrospective series demonstrated that a non-operative management is safe and feasible, but no prospective studies are available. Aim of the ASPEN study is to evaluate the optimal management of asymptomatic NF-PanNEN ≤2 cm comparing active surveillance and surgery. ASPEN is a prospective international observational multicentric cohort study supported by ENETS. The study is registered in ClinicalTrials.gov with the identification code NCT03084770. Based on the incidence of NF-PanNEN the number of expected patients to be enrolled in the ASPEN study is 1,000 during the study period (2017-2022). Primary endpoint is disease/progression-free survival, defined as the time from study enrolment to the first evidence of progression (active surveillance group) or recurrence of disease (surgery group) or death from disease. Inclusion criteria are: age >18 years, the presence of asymptomatic sporadic NF-PanNEN ≤2 cm proven by a positive fine-needle aspiration (FNA) or by the presence of a measurable nodule on high-quality imaging techniques that is positive at Gallium DOTATOC-PET scan. The ASPEN study is designed to investigate if an active surveillance of asymptomatic NF-PanNEN ≤2 cm is safe as compared to surgical approach.
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http://dx.doi.org/10.3389/fmed.2020.598438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785972PMC
December 2020

R Status is a Relevant Prognostic Factor for Recurrence and Survival After Pancreatic Head Resection for Ductal Adenocarcinoma.

Ann Surg Oncol 2021 Aug 3;28(8):4602-4612. Epub 2021 Jan 3.

Division of Pancreatic Surgery, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milano, Italy.

Background: The prognostic role of resection margins in pancreatic ductal adenocarcinoma (PDAC) is debated. This study aimed to investigate the impact that global and individual resection margin status after pancreatic head resection for PDAC has on disease-free survival (DFS) and disease-specific survival (DSS).

Methods: Surgical specimens of pancreaticoduodenectomy/total pancreatectomy performed for PDAC were examined with a standardized protocol. Surgical margin status (biliary, pancreatic neck, duodenal, anterior and posterior pancreatic, superior mesenteric vein groove and superior mesenteric artery margins) was classified as the presence of malignant cells (1) directly at the inked surface (R1 direct), (2) within less than 1 mm (R1 ≤ 1 mm), or (3) with a distance greater than 1 mm (R0). Patients with a positive neck margin at the final histology were excluded from the study.

Results: Of the 362 patients included in the study, 179 patients (49.4 %) had an R0 resection, 123 patients (34 %) had an R1 ≤ 1 mm resection, and 60 patients (16.6 %) had an R1 direct resection. The independent predictors of DFS were R1 direct resection (hazard ratio [HR], 1.49), R1 ≤ 1 mm resection (HR, 1.38), involvement of one margin (HR, 1.36), and involvement of two margins or more (HR, 1.55). When surgical margins were analyzed separately, only R1 ≤ 1 mm superior mesenteric vein margin (HR, 1.58) and R1 direct posterior margin (HR, 1.69) were independently associated with DFS.

Conclusions: Positive R status is an independent predictor of DFS (R1 direct and R1 ≤ 1 mm definitions) and of DSS (R1 direct). The presence of multiple positive margins is a risk factor for cancer recurrence and poor survival. Different surgical margins could have different prognostic roles.
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http://dx.doi.org/10.1245/s10434-020-09467-6DOI Listing
August 2021

Surgeon experience contributes to improved outcomes in pancreatoduodenectomies at high risk for fistula development.

Surgery 2021 04 30;169(4):708-720. Epub 2020 Dec 30.

Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. Electronic address:

Background: Pancreatoduodenectomies at high risk for clinically relevant pancreatic fistula are uncommon, yet intimidating, situations. In such scenarios, the impact of individual surgeon experience on outcomes is poorly understood.

Methods: The fistula risk score was applied to identify high-risk patients (fistula risk score 7-10) from 7,706 pancreatoduodenectomies performed at 18 international institutions (2003-2020). For each case, surgeon pancreatoduodenectomy career volume and years of practice were linked to intraoperative fistula mitigation strategy adoption and outcomes. Consequently, best operative approaches for clinically relevant pancreatic fistula prevention and best performer profiles were identified through multivariable analysis models.

Results: Eight hundred and thirty high-risk pancreatoduodenectomies, performed by 64 surgeons, displayed an overall clinically relevant pancreatic fistula rate of 33.7%. Clinically relevant pancreatic fistula rates decreased with escalating surgeon career pancreatoduodenectomy (-49.7%) and career length (-41.2%; both P < .001), as did transfusion and reoperation rates, postoperative morbidity index, and duration of stay. Great experience (≥400 pancreatoduodenectomies performed or ≥21-year-long career) was a significant predictor of clinically relevant pancreatic fistula prevention (odds ratio 0.52, 95% confidence interval 0.35-0.76) and was more often associated with pancreatojejunostomy reconstruction and prophylactic octreotide omission, which were both independently associated with clinically relevant pancreatic fistula reduction. A risk-adjusted performance analysis also correlated with experience. Moreover, minimizing blood loss (≤400 mL) significantly contributed to clinically relevant pancreatic fistula prevention (odds ratio 0.40, 95% confidence interval 0.22-0.74).

Conclusion: Surgeon experience is a key contributor to achieve better outcomes after high-risk pancreatoduodenectomy. Surgeons can improve their performance in these challenging situations by employing pancreatojejunostomy reconstruction, omitting prophylactic octreotide, and minimizing blood loss.
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http://dx.doi.org/10.1016/j.surg.2020.11.022DOI Listing
April 2021

Main Duct Thresholds for Malignancy Are Different in Intraductal Papillary Mucinous Neoplasms of the Pancreatic Head and Body-Tail.

Clin Gastroenterol Hepatol 2020 Dec 29. Epub 2020 Dec 29.

Division of Pancreatic Surgery, Pancreas Translational & Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan; Vita-Salute San Raffaele University, Milan. Electronic address:

Background & Aims: The risk of malignancy is uncertain for intraductal papillary mucinous neoplasms (IPMNs) with main pancreatic duct (MPD) of 5-9 mm. No study has correlated MPD size and malignancy considering the anatomic site of the gland (head versus body-tail). Our aim was to analyze the significance of MPD in pancreatic head/body-tail as a predictor of malignancy in main-duct/mixed IPMNs.

Methods: Retrospective analysis of resected patients between 2009-2018 was performed. Malignancy was defined as high-grade dysplasia and invasive carcinoma. MPD diameter was measured with magnetic resonance imaging. Receiver operating characteristic curve (ROC) analysis was utilized to identify optimal MPD cut-off for malignancy. Independent predictors of malignancy were searched.

Results: Malignancy was detected in 74% of 312 identified patients. 213 patients (68.3%) had IPMNs of the pancreatic head and 99 (31.7%) of the body-tail. ROC analysis identified 9 and 7 mm as the optimal MPD cut-offs for malignancy in IPMNs of head and body-tail of the pancreas, respectively. Multivariate analysis confirmed that MPD ≥9 mm (pancreatic head) and ≥7 mm (body-tail) were independent predictors of malignancy along with macroscopic solid components, positive cytology and elevated CA 19-9. The risk of malignancy was low for IPMNs with MPD ≤8 mm (pancreatic head) or ≤6 mm (pancreatic body-tail) unless high-risk stigmata or multiple worrisome features were present.

Conclusions: Different thresholds of MPD dilation are associated with malignancy in IPMNs of the head and body-tail of the pancreas. The risk of malignancy for IPMNs with MPD ≤8 mm (pancreatic head) or ≤6 mm (pancreatic body-tail) lacking high-risk stigmata or multiple worrisome features is low.
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http://dx.doi.org/10.1016/j.cgh.2020.12.028DOI Listing
December 2020

Portal vein resection during pancreaticoduodenectomy for pancreatic neuroendocrine tumors. An international multicenter comparative study.

Surgery 2021 05 7;169(5):1093-1101. Epub 2021 Jan 7.

Department of Surgery, Seoul National University College of Medicine, South Korea.

Background: The role of portal vein resection for pancreatic cancer is well established but not for pancreatic neuroendocrine neoplasms. Evidence from studies providing information on long-term outcome after venous resection in pancreatic neuroendocrine neoplasms patients is lacking.

Methods: This is a multicenter retrospective cohort study comparing pancreaticoduodenectomy with vein resection with standard pancreaticoduodenectomy in patients with pancreatic neuroendocrine neoplasms. The primary endpoint was to evaluate the long-term survival in both groups. Progression-free survival and overall survival were calculated using the method of Kaplan and Meier, but a propensity score-matched cohort analysis was subsequently performed to remove selection bias and improve homogeneity. The secondary outcome was Clavien-Dindo ≥3.

Results: Sixty-one (11%) patients underwent pancreaticoduodenectomy with vein resection and 480 patients pancreaticoduodenectomy. Five (1%) perioperative deaths were recorded in the pancreaticoduodenectomy group, and postoperative clinically relevant morbidity rates were similar in the 2 groups (pancreaticoduodenectomy with vein resection 48% vs pancreaticoduodenectomy 33%). In the initial survival analysis, pancreaticoduodenectomy with vein resection was associated with worse 3-year progression-free survival (48% pancreaticoduodenectomy with vein resection vs 83% pancreaticoduodenectomy; P < .01) and 5-year overall survival (67% pancreaticoduodenectomy with vein resection vs 91% pancreaticoduodenectomy). After propensity score matching, no significant difference was found in both 3-year progression-free survival (49% pancreaticoduodenectomy with vein resection vs 59% pancreaticoduodenectomy; P = .14) and 5-year overall survival (71% pancreaticoduodenectomy with vein resection vs 69% pancreaticoduodenectomy; P = .98).

Conclusion: This study demonstrates no significant difference in perioperative risk with a similar overall survival between pancreaticoduodenectomy and pancreaticoduodenectomy with vein resection. Tumor involvement of the superior mesenteric/portal vein axis should not preclude surgical resection in patients with locally advanced pancreatic neuroendocrine neoplasms.
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http://dx.doi.org/10.1016/j.surg.2020.11.015DOI Listing
May 2021

Bratislava Statement: consensus recommendations for improving pancreatic cancer care.

ESMO Open 2020 11;5(6):e001051

Catalonian Cancer Strategy, Department of Health, Barcelona, Spain; Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Catalunya, Spain.

Pancreatic cancer is one of the most lethal tumours, and it is the fourth cause of cancer death in Europe. Despite its important public health impact, no effective treatments exist, nor are there high-visibility research efforts to improve care. This alarming situation is emblematic of a larger group of cancer diseases, known as neglected cancers. To address the impact of these diseases, the European Commission-supported Innovative Partnership for Action Against Cancer launched a multi-stakeholder initiative to determine key steps that healthcare systems can rapidly implement to improve their response. A working group comprising 20 representatives from European medical societies, patient associations, cancer plan organisations and other relevant European healthcare stakeholders was organised. A consensus process based on the results of different studies, discussion of research outcomes, and development and endorsement of draft statements resulted in 22 consensus recommendations (the Bratislava Statement). The statement argues that substantial improvements can be achieved in patient outcomes by centralising pancreatic cancer care around state-of-the-art reference centres, staffed by expert multidisciplinary teams capable of providing high-quality care. This organisational model requires a specific care framework encompassing primary, palliative and survivorship care, and a policy environment prioritising the use of quality criteria and performance assessments as well as research investments dedicated to prevention, risk prediction, early detection and diagnosis. In order to address the challenges posed by neglected cancers in general and pancreatic cancer in particular, a specific control strategy tailored to this reality is required.
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http://dx.doi.org/10.1136/esmoopen-2020-001051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668355PMC
November 2020

The impact of minimally invasive surgery on hospital readmissions, emergency department visits and functional recovery after distal pancreatectomy.

Surg Endosc 2021 10 6;35(10):5740-5751. Epub 2020 Oct 6.

Division of Pancreatic Surgery, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy.

Background: A recent RCT showed similar postoperative outcomes and a reduced time to functional recovery in patients undergoing minimally invasive distal pancreatectomy (DP) compared to open approach. However, it reported very-high post-discharge readmission rates, calling for further investigation. The aim of our study was to evaluate the extent to which minimally invasive surgery impacts on postoperative readmissions following DP.

Methods: Clinical data for patients undergoing DP between 2011 and 2018 were reviewed. Primary outcome was hospital readmission at 90 days after surgery. Secondary outcomes included post-discharge emergency department (ED) visits and time to functional recovery. Regression analyses were performed to evaluate the impact of the laparoscopic approach and other perioperative factors.

Results: Overall, 376 consecutive patients underwent DP during the study period. Laparoscopy was successfully performed in 219 (58%) patients. Overall, 62 patients (16.5%) returned to the ED after discharge, 41 (18.7%) of laparoscopically operated patients, and 21 (13.4%) of those undergoing open surgery (p = 0.162). Forty-six (12.2%) of them required readmission, 31 (14.2%) after laparoscopic, and 15 (9.6%) after open procedures (p = 0.179). At multivariate regression, a low preoperative physical status (OR 2.3, 95% CI 1.2-4.7; p = 0.017), occurrence of pancreatic fistula (OR 6.8, 95% CI 2.9-15.9; p < 0.001), and post-pancreatectomy hemorrhage (OR 3.9, 95% CI 1.2-13.1; p = 0.025) were significantly associated with 90-day readmission, while laparoscopy had no impact. Median time to reach functional recovery was 5 (IQR 4-6) days. At multivariate analysis, laparoscopy reduced time to functional recovery by 13% (95% CI - 19 to - 6%; p < 0.001), time to adequate oral intake by 19% (95% CI - 27 to - 10%; p < 0.001), and time to adequate pain control by 12% (95% CI - 18 to - 5%; p < 0.001).

Conclusion: Hospital readmissions and ED visits following DP were not influenced by the surgical approach. A low preoperative physical status, occurrence of postoperative pancreatic fistula and hemorrhage were significantly associated with post-discharge readmission within 90 days. Laparoscopy reduced time to functional recovery.
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http://dx.doi.org/10.1007/s00464-020-08051-zDOI Listing
October 2021

Evidence of a common cell origin in a case of pancreatic mixed intraductal papillary mucinous neoplasm-neuroendocrine tumor.

Virchows Arch 2021 Jun 1;478(6):1215-1219. Epub 2020 Oct 1.

Pathology Unit, Pancreas Translational and Clinical Research Center, ENETS Center of Excellence, IRCCS San Raffaele Scientific Institute, via Olgettina 60, 20132, Milan, Italy.

Recently, the term mixed neuroendocrine non-neuroendocrine neoplasms (MiNEN) has been proposed as an umbrella definition covering different possible combinations of mixed neuroendocrine-exocrine neoplasms. Among these, the adenoma plus neuroendocrine tumor (NET) combination is among the rarest and not formally recognized by the 2019 WHO Classification. In this setting, the debate between either collision tumors or true mixed neoplasms is still unsolved. In this report, a pancreatic intraductal papillary mucinous neoplasm (IPMN) plus a NET is described, and the molecular investigations showed the presence in both populations of the same KRAS, GNAS, and CDKN2A mutations and the amplification of the CCND1 gene. These data prove clonality and support a common origin of both components, therefore confirming the true mixed nature. For this reason, mixed neuroendocrine-exocrine neoplasms, in which the exocrine component is represented by a glandular precursor lesion (adenoma/IPMN) only, should be included into the MiNEN family.
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http://dx.doi.org/10.1007/s00428-020-02942-1DOI Listing
June 2021

Chemopreventive Agents After Pancreatic Resection for Ductal Adenocarcinoma: Legend or Scientific Evidence?

Ann Surg Oncol 2021 Apr 12;28(4):2312-2322. Epub 2020 Sep 12.

Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute IRCCS, Vita-Salute San Raffaele University, Milan, Italy.

Background: Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth leading cause of cancer-related death in the USA. A wealth of evidence has demonstrated the chemopreventive activity of aspirin, statins, and metformin against PDAC. The aim of this study is to investigate the effect of aspirin, statins, and metformin on disease-free survival (DFS) and disease-specific survival (DSS) in a large population of PDAC patients undergoing pancreatic resection.

Patients And Methods: All patients who underwent pancreatic resections between January 2015 and September 2018 were retrospectively reviewed. The potentially "chemopreventive agents" considered for the analysis were aspirin, statins, and metformin. Drug use was defined in case of regular assumption at least 6 months before diagnosis and regularly after surgery along the follow-up period.

Results: A total of 430 patients were enrolled in this study, with median DFS and DSS of 21 months (IQR 13-30) months and 34 (IQR 26-52) months, respectively. On multivariable analysis, use of aspirin was associated with better DFS (HR: 0.62; p = 0.038). Metformin was associated with better DFS, without reaching statistical significance (p = 0.083). Use of statins did not influence DFS in the studied population. Aspirin, metformin, and statins were not associated with better DSS on multivariable analysis. Factors influencing DSS were pT3/pT4, N1, N2, no adjuvant treatment, G3, and ASA score > 3.

Conclusions: The results suggest that chronic use of aspirin is associated with increased DFS but not with better DSS after surgical resection in patients with PDAC.
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http://dx.doi.org/10.1245/s10434-020-09097-yDOI Listing
April 2021

Vascular resection during pancreatectomy for pancreatic head cancer: A technical issue or a prognostic sign?

Surgery 2021 02 8;169(2):403-410. Epub 2020 Sep 8.

Division of Pancreatic Surgery, Pancreas Translational & Clinical Research Center, Università Vita-Salute, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Background: There is an increased interest in venous vascular resection associated with pancreatic resection for pancreatic ductal adenocarcinoma as an upfront procedure or after neoadjuvant treatment. The aim of this study was to evaluate the impact of venous vascular resection for pancreatic ductal adenocarcinoma on postoperative and long-term outcomes.

Methods: The study is a retrospective analysis of patients who underwent pancreatectomy for pancreatic head pancreatic ductal adenocarcinoma with and without venous vascular resection between January 2010 and April 2018. The impact of venous vascular resection on postoperative and pathologic data was analyzed. Univariate and multivariate analyses of predictors of disease-free and disease-specific survival were analyzed for the entire cohort. A propensity-score matched cohort analysis was subsequently performed to remove selection bias and improve homogeneity.

Results: Four hundred and eighty-one patients were included, and 126 (26%) underwent a venous vascular resection. Patients undergoing venous vascular resection had higher morbidity (64% vs 54%; P = .026) with no differences in 90-day postoperative mortality (3.1 vs 2.8%; P = .5). Venous vascular resections were also significantly associated with R1 resections (52% vs 37%; P = .002) and perineural invasion (87% vs 77%; P = .017). Five-year disease-free survival in patients with and without venous vascular resection were 7% and 20% (P = .018), respectively. Independent predictors of worse disease-free survival included venous vascular resection, positive lymph node status, and perineural invasion. Independent predictors of worse disease-specific survival were perineural invasion and positive nodal status, while adjuvant treatment was a protective factor. Five-year disease-specific survival in patients with and without venous vascular resection were 19% and 35% (P = .42).

Conclusion: Pancreatectomy with venous vascular resection can be accomplished safely. Venous vascular resections are associated with poor prognostic factors and with a worse clinical outcome, being a significant predictor of cancer recurrence.
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http://dx.doi.org/10.1016/j.surg.2020.08.002DOI Listing
February 2021

Update on gastroenteropancreatic neuroendocrine tumors.

Dig Liver Dis 2021 02 8;53(2):171-182. Epub 2020 Sep 8.

Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, OSR ENETS Center of Excellence, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy. Electronic address:

The incidence gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) has dramatically risen over the last three decades, probably due to the increased detection of asymptomatic lesions. The diagnostic work-up for patients with suspected GEP-NENs is based on conventional imaging, endoscopy, pathology, and functional imaging, including Gallium-DOTATATE PET and F-FDG PET. The choice of the best treatment strategy should be based on the evaluation of tumor-related features and patient's characteristics. A conservative management, consisting of active surveillance or endoscopic resection, has been advocated for patients with small, incidentally discovered, nonfunctioning tumors without features of aggressiveness. On the other hand, surgery with lymphadenectomy, also with a minimally invasive approach, represents the gold standard for the curative treatment of localized disease. Moreover, surgical resection plays an important role also in the context of a multimodal treatment strategy for patients with advanced GEP-NENs. Finally, a wide range of medical therapies, comprising somatostatin analogues, peptide receptor radionuclide therapy, target therapies and several chemotherapy regimens, can be offered to patients with advanced GEP-NENs not amenable of surgical resection, according to the biological and molecular features of their disease.
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http://dx.doi.org/10.1016/j.dld.2020.08.031DOI Listing
February 2021

Gastro-entero-pancreatic neuroendocrine neoplasia: The rules for non-operative management.

Surg Oncol 2020 Dec 20;35:141-148. Epub 2020 Aug 20.

Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Center, ENETS Center of Excellence, IRCCS San Raffaele Scientific Institute - Vita-Salute San Raffaele University, Milan, Italy.

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) with favorable pathological and clinical features may be considered as indolent lesions, and therefore be amenable to conservative management. According to the primary tumor site, different non-aggressive approaches, based on endoscopic resection or simple active surveillance, can be proposed to selected patients fulfilling specific criteria. Tumor size, Ki67 proliferative index and depth of invasion are markers that can be used in order to identify these subjects. Patients with type I gastric NENs <1 cm as well as those with non-ampullary duodenal NENs <1 cm with no associated syndrome can be safely managed by endoscopic resection. On the other hand, an active surveillance approach is preferred over surgery for patients with asymptomatic, non-functioning pancreatic NENs ≤2 cm without dilation of the main pancreatic duct or bile duct. As far as NENs of the appendix are concerned, appendectomy should be considered as curative when a R0 resection has been achieved in the presence of a tumor ≤1.5 cm, graded as G1 and without lymphovascular invasion. Finally, G1 rectal NENs ≤1 cm without invasion of the muscular layer can be safely treated by endoscopic resection. Therefore, surgeons should be aware of the existence of indolent GEP-NENs, in order to avoid unnecessary operations with associated postoperative complications.
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http://dx.doi.org/10.1016/j.suronc.2020.08.015DOI Listing
December 2020
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