Publications by authors named "Roberto Salvia"

262 Publications

An Overview of Artificial Intelligence Applications in Liver and Pancreatic Imaging.

Cancers (Basel) 2021 Apr 30;13(9). Epub 2021 Apr 30.

Department of Radiology, G.B. Rossi University Hospital, University of Verona, 37129 Verona, Italy.

Artificial intelligence (AI) is one of the most promising fields of research in medical imaging so far. By means of specific algorithms, it can be used to help radiologists in their routine workflow. There are several papers that describe AI approaches to solve different problems in liver and pancreatic imaging. These problems may be summarized in four different categories: segmentation, quantification, characterization and image quality improvement. Segmentation is usually the first step of successive elaborations. If done manually, it is a time-consuming process. Therefore, the semi-automatic and automatic creation of a liver or a pancreatic mask may save time for other evaluations, such as quantification of various parameters, from organs volume to their textural features. The alterations of normal liver and pancreas structure may give a clue to the presence of a diffuse or focal pathology. AI can be trained to recognize these alterations and propose a diagnosis, which may then be confirmed or not by radiologists. Finally, AI may be applied in medical image reconstruction in order to increase image quality, decrease dose administration (referring to computed tomography) and reduce scan times. In this article, we report the state of the art of AI applications in these four main categories.
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http://dx.doi.org/10.3390/cancers13092162DOI Listing
April 2021

Early and Sustained Elevation in Serum Pancreatic Amylase Activity: A Novel Predictor of Morbidity after Pancreatic Surgery.

Ann Surg 2021 Apr 30. Epub 2021 Apr 30.

General and Pancreatic Surgery - The Pancreas Institute, University of Verona Hospital Trust, P. Le L.A. Scuro 10, 37134 Verona, Italy.

Objective: To characterize early postoperative serum pancreatic amylase (spAMY) trends after pancreatic resections.

Summary Background Data: A postoperative spAMY elevation is a common finding but uncertainties remain about its meaning and prognostic implications.

Methods: Analysis of patients who consecutively underwent pancreatectomy from 2016 to 2019. spAMY activity was assessed from postoperative day (POD) 0 to 3. Different patterns of spAMY have been identified based on the spAMY standard range (10-52 U/l).

Results: Three patterns were identified: (#1) spAMY values always< the lower limit of normal/within the reference range /a single increase in spAMY >upper limit of normal at any POD; (#2) Sustained increase in spAMY activity on POD 0 + 1; (#3) Sustained increase in spAMY activity including POD 1 + 2. Shifting through spAMY patterns was associated with increase morbidity (21% in #1 to 68% in #3 at POD 7; log rank < 0.001). Almost all severe complications (at least Clavien-Dindo ≥3) occurred in patients with pattern #3 (15% vs. 3% vs. 5% in #1 and #2 at POD 7, p = 0.006), without difference considering >3-times or >the spAMY normal limit (p = 0.85). POPF (9% in #1 vs. 48% in #3, p< 0.001) progressively increased across patterns. Pre-operative diabetes (OR 0.19), neoadjuvant therapy (OR 0.22), pancreatic texture (OR 8.8), duct size (OR 0.78), and final histology (OR 2.2) were independent predictors of pattern #3.

Conclusions: A sustained increase in spAMY activity including POD 1 + 2 (#3) represents an early postoperative predictor of overall and severe early morbidity. An early and dynamic evaluation of spAMY could crucially impact the subsequent clinical course with relevant prognostic implications.
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http://dx.doi.org/10.1097/SLA.0000000000004921DOI Listing
April 2021

High-risk Pancreatic Anastomosis vs. Total Pancreatectomy after Pancreatoduodenectomy: Postoperative Outcomes and Quality of Life Analysis.

Ann Surg 2021 Mar 4. Epub 2021 Mar 4.

*The Department of General and Pancreatic Surgery †Pathology ‡Anesthesia and Intensive Care of Verona University Hospital, Italy.

Objective: To evaluate total pancreatectomy (TP) as an alternative to pancreatoduodenectomy (PD) in patients at high-risk for postoperative pancreatic fistula (POPF).

Background: Outcomes of high-risk PD (HR-PD) and TP have never been compared.

Methods: All patients who underwent PD or TP between July 2017 and December 2019 were identified. HR-PD was defined according to the alternative Fistula Risk Score. Postoperative outcomes (primary endpoint), pancreatic insufficiency and quality of life after 12 months of follow-up (QoL) were compared between HR-PD or planned PD intraoperatively converted to TP (C-TP).

Results: A total of 566 patients underwent PD and 136 underwent TP during the study period. One hundred one (18%) PD patients underwent HR-PD, while 86 (63%) TP patients underwent C-TP. Postoperatively, the patients in the C-TP group exhibited lower rates of post-pancreatectomy hemorrhage (15% vs 28%), delayed gastric emptying (16% vs 34%), sepsis (10% vs 31%), and Clavien-Dindo ≥3 morbidity (19% vs 31%) and had shorter median lengths of hospital stay (10 vs 21 days) (all p<0.05). The rate of POPF in the HR-PD group was 39%. Mortality was comparable between the two groups (3% vs 4%). Although general, cancer- and pancreas-specific QoL were comparable between the HR-PD and C-TP groups, endocrine and exocrine insufficiency occurred in all the C-TP patients, compared to only 13% and 63% of the HR-PD patients respectively, and C-TP patients had worse diabetes-specific QoL.

Conclusions: C-TP may be considered rather than HR-PD only in few selected cases and after adequate counselling.
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http://dx.doi.org/10.1097/SLA.0000000000004840DOI Listing
March 2021

A Pretreatment Prognostic Score to Stratify Survival in Pancreatic Cancer.

Ann Surg 2021 Mar 4. Epub 2021 Mar 4.

*Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany †Department of General and Pancreatic Surgery, The Pancreas Institute, University of Verona Hospital Trust, Verona, Italy.

Objective: To develop and validate a pretreatment prognostic score in pancreatic cancer (PDAC).

Background: Pretreatment prognostication in PDAC is important for treatment decisions but remains challenging. Available prognostic tools are derived from selected cohorts of patients who underwent resection, excluding up to 20% of patients with exploration only, and do not adequately reflect the pretreatment scenario.

Methods: Patients undergoing surgery for PDAC in Heidelberg from 07/2006 to 06/2014 were identified from a prospective database. Pretreatment parameters were extracted from the database and the laboratory information system. Parameters independently associated with overall survival by uni- and multivariable analyses were used to build a prognostic score. A contemporary cohort from Verona was used for external validation.

Results: In 1197 patients, multiple pretreatment parameters were associated with overall survival by univariable analyses. ASA-classification, CA19-9, CEA, CRP, albumin, and platelet count were independently associated with survival and were used to create the Heidelberg Prognostic Pancreatic Cancer (HELPP)-score. The HELPP-score was closely associated with overall survival (median survival between 31.3 and 4.8 months; 5-year survival rates between 35% and 0%) and was able to stratify survival in subgroups with or without resection as well as in CA19-9 non-secretors. In the resected subgroup the HELPP-score stratified survival independently of pathological prognostic factors. The HELPP-score was externally validated and was superior to CA19-9 in both the development and validation cohorts.

Conclusion: The HELPP-score is a readily available prognostic tool based on pretreatment routine parameters to stratify survival in PDAC independently of resection status and pathological tumor stage.
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http://dx.doi.org/10.1097/SLA.0000000000004845DOI Listing
March 2021

Pancreatic Enucleation Patients Share the Same Quality of Life as the General Population at Long-Term Follow-Up: A Propensity-Score Matched Analysis.

Ann Surg 2021 Apr 14. Epub 2021 Apr 14.

Department of General and Pancreatic Surgery, Verona Hospital Trust, University of Verona, P.le A. Scuro 10, 37134, Verona, Italy.

Objective: To assess short- and long-term outcomes including quality of life (QoL) following PE.

Background: Pancreatic enucleation (PE) is deemed to preserve both the endocrine and the exocrine function while ensuring radicality. However, to assess whether this reflects an actual benefit perceived by patients, QoL has to be considered.

Methods: Data from all consecutive patients undergoing PE from January 2010 to December 2019 were retrospectively analysed. Surgical outcomes were graded according to the Clavien-Dindo classification, and EORTC-C30 and the EORTC-Pan26 were administered as a cross-sectional assessment of QoL. A control group consisting of healthy individuals from the general population was obtained and matched using the propensity score matching method.

Results: Eighty-one patients underwent PE using the open (59.3%), laparoscopic (27.2%) or robot-assisted (13.5%) approach. Sixty-five (80.2%) patients exhibited functioning/non-functioning pancreatic neuroendocrine tumours (PanNET) at final pathology.Surgical morbidity and complications of a Clavien-Dindo grade ≥ 3 were 48.1% and 16.0%, respectively. In-hospital mortality was 0%. Postoperative pancreatic fistula, post-pancreatectomy haemorrhage, and delayed gastric emptying rates were 21.0%, 9.9%, and 4.9%, respectively.Patients returned the questionnaires after a median of 74.2 months from the index surgery. Postoperative new onset of diabetes mellitus (NODM) was observed in five subjects (7.1%), with age being an independent predictor. Seven patients (10.0%) developed postoperative exocrine insufficiency. At the analysis of QoL, all function and symptom scales were comparable between the two groups, except for two of the EORTC-Pan 26 symptom scales, ("worries for the future" and "body image", p < 0.05).

Conclusion: Despite being associated with significant postoperative morbidity, PE provides excellent long-term outcomes. The risk of NODM is low and related to patient age, with QoL being comparable to the general population. Such information should drive surgeons to pursue PE whenever properly indicated.
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http://dx.doi.org/10.1097/SLA.0000000000004911DOI Listing
April 2021

Non-functional pancreatic neuroendocrine tumours: ATRX/DAXX and alternative lengthening of telomeres (ALT) are prognostically independent from ARX/PDX1 expression and tumour size.

Gut 2021 Apr 13. Epub 2021 Apr 13.

Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

Objective: Recent studies have found aristaless-related homeobox gene (ARX)/pancreatic and duodenal homeobox 1 (PDX1), alpha-thalassemia/mental retardation X-linked (ATRX)/death domain-associated protein (DAXX) and alternative lengthening of telomeres (ALT) to be promising prognostic biomarkers for non-functional pancreatic neuroendocrine tumours (NF-PanNETs). However, they have not been comprehensively evaluated, especially among small NF-PanNETs (≤2.0 cm). Moreover, their status in neuroendocrine tumours (NETs) from other sites remains unknown.

Design: An international cohort of 1322 NETs was evaluated by immunolabelling for ARX/PDX1 and ATRX/DAXX, and telomere-specific fluorescence in situ hybridisation for ALT. This cohort included 561 primary NF-PanNETs, 107 NF-PanNET metastases and 654 primary, non-pancreatic non-functional NETs and NET metastases. The results were correlated with numerous clinicopathological features including relapse-free survival (RFS).

Results: ATRX/DAXX loss and ALT were associated with several adverse prognostic findings and distant metastasis/recurrence (p<0.001). The 5-year RFS rates for patients with ATRX/DAXX-negative and ALT-positive NF-PanNETs were 40% and 42% as compared with 85% and 86% for wild-type NF-PanNETs (p<0.001 and p<0.001). Shorter 5-year RFS rates for ≤2.0 cm NF-PanNETs patients were also seen with ATRX/DAXX loss (65% vs 92%, p=0.003) and ALT (60% vs 93%, p<0.001). By multivariate analysis, ATRX/DAXX and ALT status were independent prognostic factors for RFS. Conversely, classifying NF-PanNETs by ARX/PDX1 expression did not independently correlate with RFS. Except for 4% of pulmonary carcinoids, ATRX/DAXX loss and ALT were only identified in primary (25% and 29%) and NF-PanNET metastases (62% and 71%).

Conclusions: ATRX/DAXX and ALT should be considered in the prognostic evaluation of NF-PanNETs including ≤2.0 cm tumours, and are highly specific for pancreatic origin among NET metastases of unknown primary.
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http://dx.doi.org/10.1136/gutjnl-2020-322595DOI Listing
April 2021

Development, validation, and comparison of a nomogram based on radiologic findings for predicting malignancy in intraductal papillary mucinous neoplasms of the pancreas: An international multicenter study.

J Hepatobiliary Pancreat Sci 2021 Apr 2. Epub 2021 Apr 2.

Department of Surgery, Sungkyunkwan University School of Medicine, Seoul, South Korea.

Background: Although we previously proposed a nomogram to predict malignancy in intraductal papillary mucinous neoplasms (IPMN) and validated it in an external cohort, its application is challenging without data on tumor markers. Moreover, existing nomograms have not been compared. This study aimed to develop a nomogram based on radiologic findings and to compare its performance with previously proposed American and Korean/Japanese nomograms.

Methods: We recruited 3708 patients who underwent surgical resection at 31 tertiary institutions in eight countries, and patients with main pancreatic duct >10 mm were excluded. To construct the nomogram, 2606 patients were randomly allocated 1:1 into training and internal validation sets, and area under the receiver operating characteristics curve (AUC) was calculated using 10-fold cross validation by exhaustive search. This nomogram was then validated and compared to the American and Korean/Japanese nomograms using 1102 patients.

Results: Among the 2606 patients, 90 had main-duct type, 900 had branch-duct type, and 1616 had mixed-type IPMN. Pathologic results revealed 1628 low-grade dysplasia, 476 high-grade dysplasia, and 502 invasive carcinoma. Location, cyst size, duct dilatation, and mural nodule were selected to construct the nomogram. AUC of this nomogram was higher than the American nomogram (0.691 vs 0.664, P = .014) and comparable with the Korean/Japanese nomogram (0.659 vs 0.653, P = .255).

Conclusions: A novel nomogram based on radiologic findings of IPMN is competitive for predicting risk of malignancy. This nomogram would be clinically helpful in circumstances where tumor markers are not available. The nomogram is freely available at http://statgen.snu.ac.kr/software/nomogramIPMN.
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http://dx.doi.org/10.1002/jhbp.962DOI Listing
April 2021

Solid Pseudopapillary Neoplasm of the Pancreas and Abdominal Desmoid Tumor in a Patient Carrying Two Different Germline Mutations: New Horizons from Tumor Molecular Profiling.

Genes (Basel) 2021 Mar 26;12(4). Epub 2021 Mar 26.

Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy.

This case report describes the history of a 41 year-old woman with a solid pseudopapillary neoplasm (SPN) of the pancreas and a metachronous abdominal desmoid tumor (DT) that occurred two years after the SPN surgical resection. At next-generation sequencing of 174 cancer-related genes, both neoplasms harbored a somatic mutation which was different in each tumor. Moreover, two pathogenic mutations were found in both tumors, confirmed as germline by the sequencing of normal tissue. The mutations were c.631G>A, resulting in the amino-acid change p.V211I, and c.7008-2A>T, causing a splice acceptor site loss. However, as the two neoplasms showed neither loss of heterozygosity nor somatic mutation in the second allele, they cannot be considered as -dependent tumors. Nevertheless, this study highlights the important opportunities opened by extensive tumor molecular profiling. In this particular case, it permitted the detection of -germline mutations, essential for addressing the necessary -related genetic counseling, surveillance, and screening for the patient and her family.
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http://dx.doi.org/10.3390/genes12040481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065547PMC
March 2021

Intracoronary monocyte expression pattern and HDL subfractions after non-ST elevation myocardial infarction.

Biochim Biophys Acta Mol Basis Dis 2021 Jun 2;1867(6):166116. Epub 2021 Mar 2.

Department of Interdisciplinary Medicine, "Aldo Moro" University of Bari, Bari, Italy; INBB, National Institute for Biostructures and Biosystems, 00136 Rome, Italy. Electronic address:

Aims: Coronary artery disease (CAD) is described as a range of clinical conditions including myocardial infarction (MI) and unstable angina. Lipid and apolipoprotein profiles together with the study of cholesterol deposit and efflux serve to identify novel pre and post infarct scenarios for the treatment of these patients. In (non-ST elevation myocardial infarction) NSTEMI patients, we analysed both systemic and intracoronary serum ability to accept cholesterol as well as cholesterol efflux capacity (CEC) of monocytes in terms of expression of genes involved in the reverse cholesterol transport (RCT).

Methods And Results: While HDL-C quantity was similar between systemic and coronary arterial blood, in 21 NSTEMI patients we observed a significant reduction of the preβ-HDL fraction and the levels of Apolipoproteins AI, AII, B and E in coronary versus systemic serum. These data are complemented with the observed reduction of CEC. On the contrary, compared to systemic arterial monocytes, in coronary microenvironment of NSTEMI patients after myocardial infarction, the monocytes exhibited a higher mRNA expression of nuclear receptor LXRα and its targets ABCA1 and APOE, which drive cholesterol efflux capacity.

Conclusion: In this cross-sectional study we observe that in the immediate post infarction period, there is a spontaneous bona fide ligand-induced activation of the LXR driven cholesterol efflux capacity of intracoronary monocytes to overcome the reduced serum ability to accept cholesterol and to inhibit the post-infarction pro-inflammatory local microenvironment.
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http://dx.doi.org/10.1016/j.bbadis.2021.166116DOI Listing
June 2021

Pancreatoduodenectomy at the Verona Pancreas Institute: the Evolution of Indications, Surgical Techniques and Outcomes: A Retrospective Analysis of 3000 Consecutive Cases.

Ann Surg 2021 Jan 15. Epub 2021 Jan 15.

*Department of General and Pancreatic Surgery, The Verona Pancreas Institute, University of Verona, Italy †Department of Surgery, Pederzoli Hospital, Peschiera del Garda, Italy ‡Pancreatic Surgery, IRCS San Raffaele Hospital, University "Vita e Salute", Milano, Italy.

Objective: The aim of the present study was to critically reappraise the experience at our high-volume institution to obtain new insights for future directions.

Summary Background Data: The indications, surgical techniques, and perioperative management of pancreatoduodenectomy (PD) have profoundly evolved over the last 20 years.

Methods: All consecutive PDs performed during the last 20 years at the Verona Pancreas Institute were divided into four 5-year timeframes and retrospectively analyzed in terms of indications, intraoperative features and surgical outcomes. Significant milestones were provided to understand practice changes using a before-after analysis method.

Results: The study population consisted of 3000 patients. The median age, ASA ≥ 3 and number of nonbenchmark cases significantly increased over time (p < 0.005). Pancreatic cancer was the leading indication, representing 60% of patients/year in the last timeframe, 40% of whom received neoadjuvant treatment. Conversely, after the development of International Guidelines, the proportion of resected cystic neoplasms progressively and thoroughly decreased. Given the increased complexity of surgery for pancreatic cancer, the evolution of technologies, surgical techniques and postoperative management allowed the maintenance of favorable surgical outcomes over time, with a stable 20.0% of patients with a Clavien-Dindo grade ≥ 3, an 11.7% failure to rescue and a 2.3% in-hospital mortality rate. The incidence of postoperative pancreatic fistula, hemorrhage and delayed gastric emptying was 22.4%, 13.4% and 12.4%, respectively.

Conclusions: Pancreatoduodenectomy significantly evolved in Verona over the past two decades. Surgeries of greater complexity are currently performed on increasingly frailer patients, mostly for pancreatic cancer and often after neoadjuvant chemotherapy. However, the progression of all fields of pancreatic surgery, including the expanding use of postoperative pancreatic fistula (POPF) mitigation strategies, has allowed satisfactory outcomes to be maintained.
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http://dx.doi.org/10.1097/SLA.0000000000004753DOI Listing
January 2021

Guidelines on Pancreatic Cystic Neoplasms: Major Inconsistencies With Available Evidence and Clinical Practice- Results From an International survey.

Gastroenterology 2021 Feb 17. Epub 2021 Feb 17.

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

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http://dx.doi.org/10.1053/j.gastro.2021.02.026DOI Listing
February 2021

A phase II trial proposal of total neoadjuvant treatment with primary chemotherapy, stereotactic body radiation therapy, and intraoperative radiation therapy in borderline resectable pancreatic adenocarcinoma.

BMC Cancer 2021 Feb 16;21(1):165. Epub 2021 Feb 16.

Unit of General and Pancreatic Surgery, University of Verona Hospital Trust, Policlinico Rossi, Piazzale L.A. Scuro 10, 37134, Verona, Italy.

Background: The current management guidelines recommend that patients with borderline resectable pancreatic adenocarcinoma (BRPC) should initially receive neoadjuvant chemotherapy. The addition of advanced radiation therapy modalities, including stereotactic body radiation therapy (SBRT) and intraoperative radiation therapy (IORT), could result in a more effective neoadjuvant strategy, with higher rates of margin-free resections and improved survival outcomes.

Methods/design: In this single-center, single-arm, intention-to-treat, phase II trial newly diagnosed BRPC will receive a "total neoadjuvant" therapy with FOLFIRINOX (5-fluorouracil, irinotecan and oxaliplatin) and hypofractionated SBRT (5 fractions, total dose of 30 Gy with simultaneous integrated boost of 50 Gy on tumor-vessel interface). Following surgical exploration or resection, IORT will be also delivered (10 Gy). The primary endpoint is 3-year survival. Secondary endpoints include completion of neoadjuvant treatment, resection rate, acute and late toxicities, and progression-free survival. In the subset of patients undergoing resection, per-protocol analysis of disease-free and disease-specific survival will be performed. The estimated sample size is 100 patients over a 36-month period. The trial is currently recruiting.

Trial Registration: NCT04090463 at clinicaltrials.gov.
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http://dx.doi.org/10.1186/s12885-021-07877-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885611PMC
February 2021

Long-term Outcomes After Surgical Resection of Pancreatic Metastases from Renal Clear-Cell Carcinoma.

Ann Surg Oncol 2021 Feb 11. Epub 2021 Feb 11.

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

Background: Pancreatic metastases (PM) from renal cell carcinoma (RCC) are uncommon. We herein describe the long-term outcomes associated with pancreatectomy at two academic institutions, with a specific focus on 10-year survival.

Methods: This investigation was limited to patients undergoing pancreatectomy for PM between 2000 and 2008 at the University of Verona and Memorial Sloan Kettering Cancer Center, allowing a potential for 10 years of surveillance. The probabilities of further RCC recurrence and RCC-related death were estimated using a competing risk analysis (method of Fine and Gray) to account for patients who died of other causes during follow-up.

Results: The study population consisted of 69 patients, mostly with isolated metachronous PM (77%). The median interval from nephrectomy to pancreatic metastasectomy was 109 months, whereas the median post-pancreatectomy follow-up was 141 months. The 10-year cumulative incidence of new RCC recurrence was 62.7%. In the adjusted analysis, the relative risk of repeated recurrence was significantly higher in PM synchronous to the primary RCC (sHR = 1.27) and in patients receiving extended pancreatectomy (sHR = 3.05). The 10-year cumulative incidence of disease-specific death was 25.5%. The only variable with an influence on disease-specific death was the recurrence-free interval following metastasectomy (sHR = 0.98). In patients with repeated recurrence, the 10-year cumulative incidence of RCC-related death was 35.4%.

Conclusion: In a selected group of patients followed for a median of 141 months and mostly with isolated metachronous PM, resection was associated with a high possibility of long-term disease control in surgically fit patients with metastases confined to the pancreas.
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http://dx.doi.org/10.1245/s10434-021-09649-wDOI Listing
February 2021

ASO Author Reflections: Long-Term Outcomes After Surgical Resection of Pancreatic Metastases from Renal Clear-Cell Carcinoma.

Ann Surg Oncol 2021 Feb 9. Epub 2021 Feb 9.

Unit of Pancreatic Surgery, Pederzoli Hospital, Peschiera del Garda, Italy.

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http://dx.doi.org/10.1245/s10434-021-09653-0DOI Listing
February 2021

DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association.

Commun Biol 2021 Feb 3;4(1):155. Epub 2021 Feb 3.

University of Sydney, Sydney, New South Wales, 2006, Australia.

Here we report the DNA methylation profile of 84 sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX, DAXX and MEN1 wild-type genotypes. The T2 subgroup contained tumors with mutations in ATRX, DAXX and MEN1 and recurrent patterns of chromosomal losses in half of the genome with no association between regions with recurrent loss and methylation levels. T2 tumors were larger and had lower methylation in the MGMT gene body, which showed positive correlation with gene expression. The T3 subgroup harboured mutations in MEN1 with recurrent loss of chromosome 11, was enriched for grade G1 tumors and showed histological parameters associated with better prognosis. Our results suggest a role for methylation in both driving tumorigenesis and potentially stratifying prognosis in PanNETs.
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http://dx.doi.org/10.1038/s42003-020-01469-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859232PMC
February 2021

Dual-tracer (68Ga-DOTATOC and 18F-FDG-)-PET/CT scan and G1-G2 non-functioning pancreatic neuroendocrine tumors: A single-center retrospective evaluation of 124 non-metastatic resected cases.

Neuroendocrinology 2021 Jan 28. Epub 2021 Jan 28.

Introduction: The combined use of 68Gallium [68GA]-DOTA-peptides and 18Fluorine-fluoro-2-deoxyglucose [18F-FDG] PET/TC scans in the work-up of pancreatic neuroendocrine tumors (PanNETs) is controversial. This study aimed at assessing both tracers' capability to identify tumors and to assess its association with pathological predictors of recurrence.

Methods: Prospectively collected, preoperative, dual-tracer PET/CT scan data of G1-G2, non-metastatic, PanNETs that underwent surgery between January 2013 and October 2019 were retrospectively analyzed.

Results: The final cohort consisted of 124 cases. There was an approximately equal distribution of males and females(50.8%/49.2%), and G1 and G2 tumors(49.2%/50.8%). The disease was detected in 122(98.4%) and 64(51.6%) cases by 68Ga-DOTATOC and by 18F-FDG PET/CT scans, respectively, with a combined sensitivity of 99.2%. 18F-FDG-positive examinations found G2 tumors more often than G1 (59.4% versus 40.6%;p = 0.036), and 18F-FDG-positive PanNETs were larger than negative ones (median tumor size 32 mm, IQR 21 versus 26 mm, IQR 20;p = 0.019). The median Ki67 for 18F-FDG-positive and -negative examinations was 3(IQR 4) and 2(IQR 4), respectively, (p = 0.029). At least one pathologic predictor of recurrence was present in 74.6% of 18F-FDG-positive cases (versus 56.7%;p = 0.039), whereas this was not found when dichotomizing the PanNETs by their dimensions (≤/> 20 mm). None of the two tracers predicted nodal metastasis. ROC curve analysis showed that 18F-FDG uptake higher than 4.2 had a sensitivity of 49.2%, and specificity of 73.3% for differentiating G1 from G2 (AUC=0.624, p=0.009).

Conclusion: The complementary adoption of 68Ga-DOTATOC and 18F-FDG tracers may be valuable in the diagnostic work-up of PanNETs despite not being a game-changer for the management of PanNETs ≤ 20 mm.
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http://dx.doi.org/10.1159/000514809DOI Listing
January 2021

A phase II study of liposomal irinotecan with 5-fluorouracil, leucovorin and oxaliplatin in patients with resectable pancreatic cancer: the nITRO trial.

Ther Adv Med Oncol 2020 4;12:1758835920947969. Epub 2020 Sep 4.

Medical Oncology Unit, University and Hospital Trust of Verona, Verona, Italy.

Background: Up-front surgery followed by postoperative chemotherapy remains the standard paradigm for the treatment of patients with resectable pancreatic cancer. However, the risk for positive surgical margins, the poor recovery after surgery that often impairs postoperative treatment, and the common metastatic relapse limit the overall clinical outcomes achieved with this strategy. Polychemotherapeutic combinations are valid options for postoperative treatment in patients with good performance status. liposomal irinotecan (Nal-IRI) is a novel nanoliposome formulation of irinotecan that accumulates in tumor-associated macrophages improving the therapeutic index of irinotecan and has been approved for the treatment of patients with metastatic pancreatic cancer after progression under gemcitabine-based therapy. Thus, it remains of the outmost urgency to investigate introduction of the most novel agents, such as nal-IRI, in perioperative approaches aimed at increasing the long-term effectiveness of surgery.

Methods: The nITRO trial is a phase II, single-arm, open-label study to assess the safety and the activity of nal-IRI with fluorouracil/leucovorin (5-FU/LV) and oxaliplatin in the perioperative treatment of patients with resectable pancreatic cancer. The primary tumor must be resectable with no involvement of the major arteries and no involvement or <180° interface between tumor and vessel wall of the major veins. A total of 72 patients will be enrolled to receive a perioperative treatment of three cycles before and three cycles after surgical resection with nal-IRI 50 mg/m, oxaliplatin 60 mg/m, leucovorin 200 mg/m, and 5-fluorouracil 2400 mg/m2, days 1 and 15 of a 28-day cycle. The primary objective is to improve from 40% to 55% the proportion of patients achieving R0 resection after preoperative treatment.

Discussion: The nITRO trial will contribute to strengthen the clinical evidence supporting perioperative strategies in resectable pancreatic cancer patients. Moreover, this study represents a unique opportunity for translational analyses aimed to identify novel immune-related prognostic and predictive factors in this setting.

Trial Registration: Clinicaltrial.gov: NCT03528785. Trial registration data: 1 January 2018Protocol number: CRC 2017_01EudraCT Number: 2017-000345-46.
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http://dx.doi.org/10.1177/1758835920947969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745557PMC
September 2020

Dosimetric Feasibility Study of Dose Escalated Stereotactic Body Radiation Therapy (SBRT) in Locally Advanced Pancreatic Cancer (LAPC) Patients: It Is Time to Raise the Bar.

Front Oncol 2020 17;10:600940. Epub 2020 Dec 17.

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

Background And Objective: To assess the dosimetric feasibility of a stereotactic body radiotherapy (SBRT) dose escalated protocol, with a simultaneous integrated boost (SIB) and a simultaneous integrated protection (SIP) approach, in patients with locally advanced pancreatic cancer (LAPC).

Material And Methods: Twenty LAPC lesions, previously treated with SBRT at our Institution, were re-planned. The original prescribed and administered dose was 50/30/25 Gy in five fractions to PTV (tumor-vessel interface [TVI])/PTV (tumor volume)/PTV (overlap area between PTV and planning organs at risk volume [PRV]), respectively. At re-planning, the prescribed dose was escalated up to 60/40/33 Gy in five fractions to PTV/PTV/PTV, respectively. All plans were performed using an inspiration breath hold (IBH) technique and generated with volumetric modulated arc therapy (VMAT). Well-established and accepted OAR dose constraints were used (D < 33 Gy for luminal OARs and D < 38 Gy for corresponding PRV). The primary end-point was to achieve a median dose equal to the prescription dose for the PTV with D≥ 95% (95% of prescription dose is the minimum dose), and a coverage for PTV and PTV of D≥95%, with minor deviations in OAR dose constraints in < 10% of the plans.

Results: PTV median (± SD) dose/D/conformity index (CI) were 60.54 (± 0.85) Gy/58.96 (± 0.86) Gy/0.99 (± 0.01), respectively; whilst PTV median (± SD) dose/D were 44.51 (± 2.69) Gy/38.44 (± 0.82) Gy, and PTV median (± SD) dose/D were 35.18 (± 1.42) Gy/33.01 (± 0.84) Gy, respectively. With regard to OARs, median (± SD) maximum dose (D) to duodenum/stomach/bowel was 29.31 (± 5.72) Gy/25.29 (± 6.90) Gy/27.03 (± 5.67) Gy, respectively. A minor acceptable deviation was found for a single plan (bowel and duodenum D=34.8 Gy). V38 < 0.5 cc was achieved for all PRV luminal OARs.

Conclusions: In LAPC patients SBRT, with a SIB/SIP dose escalation approach up to 60/40/33 Gy in five fractions to PTV/PTV/PTV, respectively, is dosimetrically feasible with adequate PTVs coverage and respect for OAR dose constraints.
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http://dx.doi.org/10.3389/fonc.2020.600940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773844PMC
December 2020

Serous Cystic Neoplasms of the Pancreas Management in the Real-world: Still Operating on a Benign Entity.

Ann Surg 2020 Dec 23;Publish Ahead of Print. Epub 2020 Dec 23.

Department of Surgery, Verona University Hospital Trust, Verona, Italy.

Objective: Our aim is to provide a real-life picture of serous cystic neoplasms (SCNs) management once a presumptive diagnosis is made.

Summary Background Data: SCNs of the pancreas are invariably benign entities. While consensus about their management is lacking, surgical resection still plays a role.

Methods: Presumed SCNs evaluated from 1990 to 2018 were included. Indications for surgery, predictors of resection, rate and predictors of misdiagnosis in the surgical cohort and time trends of management strategies were the main outcomes.

Results: A total of 672 presumed SCNs were included. Presence of symptoms (37%) and large size (34.1%) were the most frequent indications for surgery. Symptoms (60.4 vs 19.0%, p < 0.001), size (45 vs 30 mm, p < 0.001), solid components (19.7 vs 6.2%, p < 0.001), thick walls (14.4 vs 5.6%, p = 0.001) and main pancreatic duct dilation (13.4 vs 5.6%, p = 0.004) were associated with upfront resection (n = 134, 19.9%). Upfront resection decreased over time and 15.4% of patients eventually crossed over to surgery. Increase in size (6,9 vs 1,3 mm/year), development of symptoms (25.3 vs 3.4%, p < 0.001), solid component (6.0 vs 1.4%, p = 0.010) or jaundice (3.6 vs 0.7%, p = 0.028) were associated with crossing over to surgery. Major morbidity and mortality occurred in 17.1% and 1.7% of patients, respectively. Misdiagnosis occurred mostly in case of macrocystic/unilocular lesions of the body-tail.

Conclusions: In the real-life scenario, SCNs still represent an indication for surgery particularly once large and symptomatic. During surveillance, resection occurs mostly in younger individuals for body/tail lesions. Evidence-based consensus on appropriate indications for surgery is urgently needed.
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http://dx.doi.org/10.1097/SLA.0000000000004716DOI Listing
December 2020

Magnetic resonance (MR) for mural nodule detection studying Intraductal papillary mucinous neoplasms (IPMN) of pancreas: Imaging-pathologic correlation.

Pancreatology 2021 Jan 3;21(1):180-187. Epub 2020 Dec 3.

Department of Surgery, G.B. Rossi Hospital, University of Verona, Piazzale L.A. Scuro 10, 37134, Verona, Italy.

Purpose: Magnetic Resonance (MR) is recommended to diagnose Intraductal Papillary Mucinous Neoplasms (IPMN) and in the follow-up of borderline lesions. The purpose of this work is to evaluate the diagnostic accuracy of dynamic MR with Diffusion Weighted Imaging (DWI) in the identification of mural nodules of pancreatic IPMN by using pathological analysis as gold standard.

Materials And Methods: Ninety-one preoperative MR with histopathological diagnosis of IPMN were reviewed by two radiologists. Presence, number and size of mural nodule, signal intensity of the nodule on T1-weighted imaging (T1-WI) after contrast medium administration and on DWI. Inter-observer agreement was evaluated.

Results: Significant correlation (p < 0.0001) were found for presence of nodules > 5 mm on MR and pathological specimen, size and number of mural nodules evaluated on pathological review and degree of dysplasia, size and number of mural nodules evaluated on MR and tumoral dysplasia, presence of nodule > 5 mm with enhancement after contrast medium administration and hyperintensity on DWI and degree of dysplasia. Interobserver agreement was moderate for the presence of mural nodule (K = 0.56), for the presence of high signal intensity on DWI (K = 0.57) and enhancement of mural nodule (K = 0.58). Apparent Diffusion Coefficient (ADC) map histogram analysis showed a correlation between Entropy of the entire cystic lesion and the degree of dysplasia (p < 0.034).

Conclusions: MR with dynamic and DWI sequences was an accurate method for the identification of ≥ 5 mm solid nodules of the IPMNs and correlate with the lesion malignancy. Entropy, calculated from the histogram analysis of the IPMN ADC map, correlated with the lesion dysplasia.
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http://dx.doi.org/10.1016/j.pan.2020.11.024DOI Listing
January 2021

Forecasting surgical costs: Towards informed financial consent and financial risk reduction.

Pancreatology 2021 Jan 23;21(1):253-262. Epub 2020 Dec 23.

Department of Surgery, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand; HBP / Upper GI Unit, Department of General Surgery, Auckland City Hospital, Auckland, New Zealand. Electronic address:

Background: Health care expenditure is increasing around the world and surgery is a major cause of financial hardship to patients and their families. Using pancreatoduodenectomy (PD), one of the most complex, morbid and costly operation as an example, this study aimed to identify the cost drivers of surgery, estimate relative contribution of these drivers, and derive and validate a cohort-specific cost forecasting tool.

Methods: Data on the costs of 1406 patients undergoing PD in three tertiary hospitals in India, Italy and the United States were analysed. Cost drivers were identified and cost models developed using a 4-stage process.

Results: There was a significant difference in overall cost of PD between the 3 cohorts. The cost drivers common to the 3 cohorts included duration of hospital stay and the outcome of death (Clavien-Dindo 5). Significant cohort-specific cost drivers included co-morbidities, operating theatre utilisation times and operative blood loss, development of pancreatectomy-specific complications (POPF, DGE, PPH), and need for interventional radiology to manage complications. Based on this, a cost forecasting tool was developed.

Conclusions: Drivers of costs for a surgical procedure (e.g. PD) are different between hospitals. Developing cost models/nomograms to predict the expected cost of surgery and perioperative care will not be applicable between hospitals. However, the approach could be used to develop context-specific data that will provide patients (at the time of the informed financial consent) and funding agencies with a more realistic cost estimate for a given operation. The developed cost forecasting tool warrants future validation.
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http://dx.doi.org/10.1016/j.pan.2020.12.014DOI Listing
January 2021

Laser Treatment of Pancreatic Cancer with Immunostimulating Interstitial Laser Thermotherapy Protocol: Safety and Feasibility Results From Two Phase 2a Studies.

J Surg Res 2021 03 2;259:1-7. Epub 2020 Dec 2.

Department of Surgery, Aix-Marseille University, Institut Paoli-Calmettes, CNRS, Inserm, CRCM, Marseille, France.

Purpose: Ablative techniques have emerged as new potential therapeutic options for patients with locally advanced pancreatic cancer (LAPC). We explored the safety and feasibility of using TRANBERG|Thermal Therapy System (Clinical Laserthermia Systems AB, Lund, Sweden) in feedback mode for immunostimulating Interstitial Laser Thermotherapy (imILT) protocol, the newest ablative technique introduced for the treatment of LAPC.

Methods: The safety and feasibility results after the use of imILT protocol treatment in 15 patients of a prospective series of postsystemic therapy LAPC in two high-volume European institutions, the General and Pancreatic Unit of the Pancreas Institute, of the University of Verona, Italy, and the Department of Surgical Oncology of the Institut Paoli-Calmettes of Marseille, France, were assessed.

Results: The mean age was 66 ± 5 years, with a mean tumor size of 34.6 (±8) mm. The median number of cycles of pre-imILT chemotherapy was 6 (6-12). The procedure was performed in 13 of 15 (86.6%) cases; indeed, in two cases, the procedure was not performed; in one, the procedure was considered technically demanding; in the other, liver metastases were found intraoperatively. In all treated cases, the procedure was completed. Three late pancreatic fistulas developed over four overall adverse events (26.6%) and were attributed to imILT. Mortality was nil. A learning curve is necessary to interpret and manage the laser parameters.

Conclusions: Safety, feasibility, and device handling outcomes of using TRANBERG|Thermal Therapy System with temperature probes in feedback mode and imILT protocol on LAPC were not satisfactory. The metastatic setting may be appropriate to evaluate the hypothetic abscopal effect.#NCT02702986 and #NCT02973217.
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http://dx.doi.org/10.1016/j.jss.2020.10.027DOI Listing
March 2021

Characterization of postoperative acute pancreatitis (POAP) after distal pancreatectomy.

Surgery 2021 04 23;169(4):724-731. Epub 2020 Oct 23.

Department of General and Pancreatic Surgery-The Pancreas Institute, University of Verona Hospital Trust, Verona, Italy. Electronic address:

Background: Postoperative acute pancreatitis has recently been reported as a specific complication after pancreatoduodenectomy. The aim of this study was to characterize postoperative acute pancreatitis after distal pancreatectomy.

Methods: We analyzed the outcomes retrospectively of 368 patients who underwent distal pancreatectomies during the period January 2016 to December 2019. Postoperative acute pancreatitis was defined as an increase of serum amylase activity greater than our laboratory normal upper limit on postoperative days 0 to 2. We assessed the incidence of postoperative acute pancreatitis after distal pancreatectomy and examined possible predictors of postoperative acute pancreatitis and relationships of postoperative acute pancreatitis with postoperative pancreatic fistula.

Results: The rates of postoperative acute pancreatitis and postoperative pancreatic fistula after distal pancreatectomy were 67.9% and 28.8%, respectively. Patients who developed postoperative acute pancreatitis experienced an increased rate of severe morbidity (18.4 vs 9.3%; P = .030). Neoadjuvant therapy (odds ratio 0.28, 0.09-0.85; P = .025), age ≥ 65 y (odds ratio 0.34, 0.13-0.85; P = .020), duct size (odds ratio 0.02, 0.002-0.47; P = .013), pancreatic thickness (odds ratio 3.4, 1.29-8.9; P = .013), resection at the body-tail level (odds ratio 4.3, 1.15-23.19; P = .041), and neuroendocrine histology (odds ratio 1.14, 1.06-3.90; P = .013) were independent predictors of postoperative acute pancreatitis. Furthermore, postoperative acute pancreatitis was an independent predictor of postoperative pancreatic fistula (odds ratio 5.8, 2.27-15.20; P < .001). Postoperative pancreatic fistula occurred in 37% of patients who developed postoperative acute pancreatitis. Patients developing postoperative acute pancreatitis alone demonstrated a statistically significantly increased rate of biochemical leakage and bacterial contamination in the peripancreatic drainage fluid.

Conclusion: Postoperative acute pancreatitis is a frequent event after distal pancreatectomy and, despite its close association with postoperative pancreatic fistula, evidently represents a separate phenomenon. A universally accepted definition of postoperative acute pancreatitis that applies to all types of pancreatic resections is needed, because it may identify patients at greater risk for additional morbidity immediately after pancreatic resections.
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http://dx.doi.org/10.1016/j.surg.2020.09.008DOI Listing
April 2021

Negative pressure wound therapy for prevention of surgical site infection in patients at high risk after clean-contaminated major pancreatic resections: A single-center, phase 3, randomized clinical trial.

Surgery 2020 Nov 27. Epub 2020 Nov 27.

Department of General and Pancreatic Surgery- The Pancreas Institute, University of Verona Hospital Trust, Verona, Italy.

Background: Surgical site infections are an important burden of pancreatic surgery, prolonging hospitalization and delaying adjuvant treatment. The aim of this study was to compare negative pressure wound therapy with standard sterile dressing in terms of the prevention of non-organ-space surgical site infection (superficial and deep surgical site infection) in the high-risk setting.

Methods: The trial was conducted at the University of Verona Hospital Trust, Verona, Italy, from July 25, 2018, through October 10, 2019, among adults undergoing surgery for periampullary neoplasms. Only patients at high-risk for surgical site infection based on body mass index, diabetes, steroids, neoadjuvant therapy, American Society of Anesthesiologists score, Charlson comorbidity index, duration of surgery, and blood loss were included and randomized.

Results: A total of 351 patients were screened, 100 met the inclusion criteria and were 1:1 allocated in the 2 arms. The difference in terms of non-organ-space surgical site infection comparing negative pressure wound therapy with standard sterile dressing was not significant (10.9 vs 12.2%, risk ratio [RR] 1.144, confidence interval [CI] 95% 0.324-4.040, P = 1.000). Hematomas (4.3 vs 2%, RR 1.565, CI 95% 0.312-7.848, P = .609) and organ-space infections (46.7 vs 43.8%, RR 1.059, CI 95% 0.711-1.576, P = .836) were similar. Negative pressure wound therapy prevented the development of seromas (0 vs 12.2%, RR 0.483, CI 95% 0.390-0.599, P = .027). The aesthetic result assessed on postoperative day 7 was better in the negative pressure wound therapy group (visual analogue scale, 8 vs 7, P = .029; Stony Brook Scar Evaluation Scale, 3.2 vs 2.5, P = .009), but it was no more evident on postoperative day 30 after a total number of 23 dropouts.

Conclusion: Compared with standard sterile dressing, negative pressure wound therapy is not associated with an improved rate of non-organ-space surgical site infection after surgery for periampullary neoplasms in patients at high risk for surgical site infection. Additional studies will help identify the population that could benefit most from this intervention.
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http://dx.doi.org/10.1016/j.surg.2020.10.029DOI Listing
November 2020

Prevalence of depression in a cohort of 400 patients with pancreatic neoplasm attending day hospital for major surgery: Role on depression of psychosocial functioning and clinical factors.

Psychooncology 2021 Apr 15;30(4):455-462. Epub 2020 Dec 15.

Department of Surgery, Dentistry, Pediatrics and Gynecology, University of Verona, Verona, Italy.

Objective: (1) To determine the prevalence and type of depressive symptoms at day-hospital clinical evaluation, before undergoing major surgery in patients diagnosed with pancreatic neoplasm. (2) To analyze the association between depression and sociodemographic, clinical, and psychosocial variables. (3) To understand how coping strategies, perceived social support, and self-efficacy might affect depressive symptoms in this cohort of patients.

Methods: Secondary data analysis collected during the baseline phase of a randomized controlled trial performed at the Pancreas Institute of the University Hospital of Verona, Italy, between June 2017 and June 2018.

Results: 18.5% of pancreatic patients had a PHQ-9 score ≥10 (cut-off). Depressed patients were basically more often female (p = 0.07), younger (p = 0.06), and married/with a partner (p = 0.02). Depression was associated to high trait anxiety (p < 0.01), the use of anxiolytics (p < 0.01), sleep-inducing drugs (p < 0.01), and painkillers (p < 0.01). Among psychosocial variables, depressed patients showed lower perceived self-efficacy (p < 0.01) and family and friends' social support (p < 0.01) and used significantly more often dysfunctional coping strategies (p < 0.01), compared to nondepressed. A logistic multivariate model using psychosocial variables as explanatory and depression as dependent was calculated and post hoc analyses were conducted to describe the contribution of each psychosocial variable on depression.

Conclusions: Our study advocates the need for screening for distress and depression in cancer surgery units and recommends to strengthen patients' adaptive coping, social support, and sense of effectiveness in facing the challenges related to the medical condition and treatment process.
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http://dx.doi.org/10.1002/pon.5607DOI Listing
April 2021

Pros and pitfalls of externalized trans-anastomotic stent as a mitigation strategy of POPF: a prospective risk-stratified observational series.

HPB (Oxford) 2020 Nov 19. Epub 2020 Nov 19.

Department of General and Pancreatic Surgery, The Pancreas Institute, University of Verona Hospital Trust, Italy. Electronic address:

Background: Several advantages and pitfalls have been related to externalized trans-anastomotic stents (ETS) after pancreaticoduodenectomy. The purpose of this study was to investigate the effect of an ETS effect in a risk-stratified setting.

Methods: Data from patients at either intermediate- or high-risk for postoperative pancreatic fistula (POPF) following pancreaticoduodenectomy were prospectively analyzed from January 2016 to December 2019. Outcomes included POPF rate, mean complication burden (ACB), and complications related to ETS malfunction.

Results: A total of 540 patients met the inclusion criteria. Following an intention-to-treat analysis, there was no difference in terms of POPF and the ACB in the intermediate (22 vs.29%, p = 0.148; 0.38 vs.0.24, p = 0.082) and high-risk categories (58 vs.37%, p = 0.103; 0.33 vs.0.33, p = 0.478) comparing PJ to PJ-ETS. Excluding patients experiencing ETS malfunction (n = 45, 22%), ETS was associated with a significantly reduced ACB in the intermediate-risk (0.38 vs.0.26, p = 0.009) and POPF rate in the high-risk category (58 vs.32%, p = 0.033). In patients with ETS malfunction an increased rate of severe morbidity (Clavien-Dindo ≥ III, 33 vs.19%, p = 0.044) was observed as compared to patients with functioning ETS.

Conclusion: ETS provides crucial advantages for prevention and mitigation of POPF depending on risk setting and its correct functioning. ETS malfunction is not uncommon and increases morbidity. Improving ETS design and fixing technique might lead to better outcomes.
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http://dx.doi.org/10.1016/j.hpb.2020.10.025DOI Listing
November 2020

Risk prediction for malignant intraductal papillary mucinous neoplasm of the pancreas: logistic regression versus machine learning.

Sci Rep 2020 11 18;10(1):20140. Epub 2020 Nov 18.

Pancreatic Surgery Unit, Division of Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute At Center for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden.

Most models for predicting malignant pancreatic intraductal papillary mucinous neoplasms were developed based on logistic regression (LR) analysis. Our study aimed to develop risk prediction models using machine learning (ML) and LR techniques and compare their performances. This was a multinational, multi-institutional, retrospective study. Clinical variables including age, sex, main duct diameter, cyst size, mural nodule, and tumour location were factors considered for model development (MD). After the division into a MD set and a test set (2:1), the best ML and LR models were developed by training with the MD set using a tenfold cross validation. The test area under the receiver operating curves (AUCs) of the two models were calculated using an independent test set. A total of 3,708 patients were included. The stacked ensemble algorithm in the ML model and variable combinations containing all variables in the LR model were the most chosen during 200 repetitions. After 200 repetitions, the mean AUCs of the ML and LR models were comparable (0.725 vs. 0.725). The performances of the ML and LR models were comparable. The LR model was more practical than ML counterpart, because of its convenience in clinical use and simple interpretability.
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http://dx.doi.org/10.1038/s41598-020-76974-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676251PMC
November 2020

Reassessment of the Optimal Number of Examined Lymph Nodes in Pancreatoduodenectomy for Pancreatic Ductal Adenocarcinoma.

Ann Surg 2020 Nov 9. Epub 2020 Nov 9.

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

Objective: To reappraise the optimal number of examined lymph nodes (ELN) in pancreatoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC).

Summary Background Data: The well-established threshold of 15 ELN in PD for PDAC is optimized for detecting one positive node (PLN) per the previous 7 edition of the AJCC staging manual. In the framework of the 8 edition, where at least four PLN are needed for an N2 diagnosis, this threshold may be inadequate for accurate staging.

Methods: Patients who underwent upfront PD at two academic institutions between 2000 and 2016 were analyzed. The optimal ELN threshold was defined as the cut-point associated with a 95% probability of identifying at least 4 PLN in N2 patients. The results were validated addressing the N-status distribution and stage migration.

Results: Overall, 1218 patients were included. The median number of ELN was 26 (IQR 17-37). ELN was independently associated with N2-status (OR 1.27, p < 0.001). The estimated optimal threshold of ELN was 28. This cut-point enabled improved detection of N2 patients and stage III disease (58% versus 37%, p = 0.001). The median survival was 28.6 months. There was an improved survival in N0/N1 patients when ELN exceeded 28, suggesting a stage migration effect (47 versus 29 months, adjusted HR 0.649, p < 0.001). In N2 patients, this threshold was not associated with survival on multivariable analysis.

Conclusion: Examining at least 28 LN in PD for PDAC ensures optimal staging through improved detection of N2/stage III disease. This may have relevant implications for benchmarking processes and quality implementation.
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http://dx.doi.org/10.1097/SLA.0000000000004552DOI Listing
November 2020

Clinical Outcomes after Total Pancreatectomy: A Prospective Multicenter Pan-European Snapshot Study.

Ann Surg 2020 Nov 9. Epub 2020 Nov 9.

Department of Abdominal Surgery, University Medical Centre Ljubljana, Ljubljana, Slovenia.

Objective: To assess outcomes among patients undergoing total pancreatectomy (TP) including predictors for complications and in-hospital mortality.

Background: Current studies on TP mostly originate from high-volume centers and span long time periods and therefore may not reflect daily practice.

Methods: This prospective pan-European snapshot study included patients who underwent elective (primary or completion) TP in 43 centers in 16 European countries (June 2018-June 2019). Subgroup analysis included cut-off values for annual volume of pancreatoduodenectomies (<60 vs. ≥60). Predictors for major complications and in-hospital mortality were assessed in multivariable logistic regression.

Results: In total, 277 patients underwent TP, mostly for malignant disease (73%). Major postoperative complications occurred in 70 patients (25%). Median hospital stay was 12 days (IQR 9-18) and 40 patients were readmitted (15%). In-hospital mortality was 5% and 90-day mortality 8%. In the subgroup analysis, in-hospital mortality was lower in patients operated in centers with ≥60 pancreatoduodenectomies compared < 60 (4% vs. 10%, p = 0.046). In multivariable analysis, annual volume < 60 pancreatoduodenectomies (OR 3.78, 95%CI 1.18-12.16, p = 0.026), age (OR 1.07, 95%CI 1.01-1.14, p = 0.046), and estimated blood loss ≥2L (OR 11.89, 95%CI 2.64-53.61, p = 0.001) were associated with in-hospital mortality. ASA ≥3 (OR 2.87, 95%CI 1.56-5.26, p = 0.001) and estimated blood loss ≥2L (OR 3.52, 95%CI 1.25-9.90, p = 0.017) were associated with major complications.

Conclusion: This pan-European prospective snapshot study found a 5% in-hospital after TP. The identified predictors for mortality, including low-volume centers, age, and increased blood loss, may be used to improve outcomes.
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http://dx.doi.org/10.1097/SLA.0000000000004551DOI Listing
November 2020

KRAS wild-type pancreatic ductal adenocarcinoma: molecular pathology and therapeutic opportunities.

J Exp Clin Cancer Res 2020 Oct 28;39(1):227. Epub 2020 Oct 28.

Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134, Verona, Italy.

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease, whose main molecular trait is the MAPK pathway activation due to KRAS mutation, which is present in 90% of cases.The genetic landscape of KRAS wild type PDAC can be divided into three categories. The first is represented by tumors with an activated MAPK pathway due to BRAF mutation that occur in up to 4% of cases. The second includes tumors with microsatellite instability (MSI) due to defective DNA mismatch repair (dMMR), which occurs in about 2% of cases, also featuring a high tumor mutational burden. The third category is represented by tumors with kinase fusion genes, which marks about 4% of cases. While therapeutic molecular targeting of KRAS is an unresolved challenge, KRAS-wild type PDACs have potential options for tailored treatments, including BRAF antagonists and MAPK inhibitors for the first group, immunotherapy with anti-PD-1/PD-L1 agents for the MSI/dMMR group, and kinase inhibitors for the third group.This calls for a complementation of the histological diagnosis of PDAC with a routine determination of KRAS followed by a comprehensive molecular profiling of KRAS-negative cases.
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http://dx.doi.org/10.1186/s13046-020-01732-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594413PMC
October 2020