Publications by authors named "Salvatore Paiella"

103 Publications

Pancreaticoduodenectomy in octogenarians: The importance of "biological age" on clinical outcomes.

Surg Oncol 2021 Nov 24;40:101688. Epub 2021 Nov 24.

Gemelli Pancreatic Center, Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS, Largo Agostino Gemelli, 8, 00168, Rome, Italy; CRMPG (Advanced Pancreatic Research Center), Largo Agostino Gemelli, 8, 00168, Rome, Italy; Università Cattolica del Sacro Cuore di Roma, Largo Francesco Vito 1, 00168, Rome, Italy.

Introduction: With the prolongation of life expectancy, an increasing number of elderly patients are evaluated for pancreatic surgery. However, the influence of increasing age on outcomes after pancreaticoduodenectomy (PD) is still unclear, especially in octogenarians. Aim of this study is to evaluate the perioperative characteristics and outcomes of octogenarians undergoing PD.

Methods: Data for 812 patients undergoing PD between 2019 and 2020 in 10 referral centers in Italy were reviewed. Patients aged 80 years or older were matched based on nearest neighbor propensity scores in a 1:1 ratio to patients younger than 80 years. Propensity scores were calculated using 7 perioperative variables including gender, ASA score, neoadjuvant treatment (NAT), biliary stent positioning, type of surgical approach (open, laparoscopic, robot-assisted), associated vascular resections, type of lesion. Perioperative characteristics and short-term postoperative outcomes were compared before and after matching.

Results: Overall, 81 (10%) patients had 80 years or more. Before matching, octogenarians had a higher rate of ASA score≥ 3 (n = 35, 43.2% vs. n = 207, 28.3%; p = 0.005) and less frequently underwent NAT (n = 11, 13.6% vs. n = 213, 29.1%; p = 0.003). Matching was successfully performed for 70 octogenarians. After matching, no differences in preoperative and intraoperative characteristics were found. Postoperatively, ICU admission was more frequent in octogenarians (50% vs 30%; p = 0.01). Although in-hospital mortality was higher in octogenarians before matching (7.4% vs 2.9% in the younger cohort; p = 0.03), no difference was noted between the matched cohorts (p = 0.36). Postoperative morbidity was comparable between groups in the whole and selected populations. At the multivariate analysis, chronological age was not recognized as a prognostic factor for cumulative major complications, while ASA ≥3 was the only confirmed influencing feature (OR 2.98; 95%CI: 1.6-6.8; p = 0.009).

Conclusio: In high-volume centers, PD in octogenarians shows similar outcomes than younger patients. Age itself should not be considered an exclusion criterion for PD, but a focused preoperative assessment is essential for adequate patient selection.
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http://dx.doi.org/10.1016/j.suronc.2021.101688DOI Listing
November 2021

Quantitative assessment of the impact of COVID-19 pandemic on pancreatic surgery: an Italian multicenter analysis of 1423 cases from 10 tertiary referral centers.

Updates Surg 2021 Nov 24. Epub 2021 Nov 24.

Department of Surgery, Gemelli Pancreatic Center, Fondazione Policlinico Universitario "Agostino Gemelli", IRCCS, Largo Agostino Gemelli, 8, 00168, Rome, Italy.

Few evidences are present on the consequences of coronavirus disease 2019 (COVID-19) pandemic on pancreatic surgery. Aim of this study is to evaluate how COVID-19 influenced the diagnostic and therapeutic pathways of surgical pancreatic diseases. A comparative analysis of surgical volumes and clinical, surgical and perioperative outcomes in ten Italian referral centers was conducted between the first semester 2020 and 2019. One thousand four hundred and twenty-three consecutive patients were included in the analysis: 638 from 2020 and 785 from 2019. Surgical volume in 2020 decreased by 18.7% (p < 0.0001). Benign/precursors diseases (- 43.4%; p < 0.0001) and neuroendocrine tumors (- 33.6%; p = 0.008) were the less treated diseases. No difference was reported in terms of discussed cases at the multidisciplinary tumor board (p = 0.43), mean time between diagnosis and neoadjuvant treatment (p = 0.91), indication to surgery and surgical resection (p = 0.35). Laparoscopic and robot-assisted procedures dropped by 45.4% and 61.9%, respectively, during the lockdown weeks of 2020. No difference was documented for post-operative intensive care unit accesses (p = 0.23) and post-operative mortality (p = 0.06). The surgical volume decrease in 2020 will potentially lead, in the near future, to the diagnosis of a higher rate of advanced stage diseases. However, the reassessment of the Italian Health Service kept guarantying an adequate level of care in tertiary referral centers. Clinicaltrials.gov ID: NCT04380766.
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http://dx.doi.org/10.1007/s13304-021-01171-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8611384PMC
November 2021

Pancreatic surgery during COVID-19 pandemic: major activity disruption of a third-level referral center during 2020.

Updates Surg 2021 Oct 23. Epub 2021 Oct 23.

Department of General and Pancreatic Surgery-The Pancreas Institute, Verona University Hospital Trust, Piazzale Scuro 10, 37134, Verona, Italy.

Introduction: The COVID-19 pandemic has severely limited the access to cancer surgery, but it is not known to what extent referral centers for pancreatic diseases were affected by its outbreak. The aim of this study is to describe the effect of COVID-19 pandemic on a third-level referral center for pancreatic surgery in Italy.

Methods: The 2020 activity of The Pancreas Institute of the University of Verona was reviewed, comparing different phases of the COVID-19 pandemic outbreaks using the pre-COVID era as a control. Endpoints were the overall caseload of pancreatic resections, surgical waiting list, administration of preoperative therapy, major morbidity and mortality, residents' training; number of inpatients beds, outpatient visits/procedures/diagnostics.

Results: In 2020, there was an overall significant reduction of pancreatic resections performed (394 vs. 506 in 2019), particularly during the first (March-May) and second (October-December) COVID-19 outbreaks, with an all-time-low of 16 resections/months in April (compared to 43 average resection/month in 2019). The rates of major morbidity (Clavien-Dindo ≥ 3) and mortality were similar to 2019 (16 vs 12%, p = 0.11 and 3 vs 2%, p = 0.29, respectively). During the first and second outbreaks resident's training, inpatient beds, outpatient visits, diagnostics, and procedures were severely impaired, while the waiting list for up-front cancer resections and the use of preoperative chemotherapy concomitantly raised.

Conclusion: The COVID-19 pandemic has severely disrupted the activity of a third-level referral center for pancreatic surgery, affecting the access to cancer surgical procedures and raising concerns regarding the solidity of the current centralization model.
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http://dx.doi.org/10.1007/s13304-021-01197-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8541802PMC
October 2021

Timeline of development of pancreatic cancer and implications for successful early detection in high-risk individuals.

Gastroenterology 2021 Oct 19. Epub 2021 Oct 19.

Division of Gastroenterology, Johns Hopkins University School of Medicine, The Sol Goldman Pancreatic Cancer Research Center, Baltimore, Maryland, United States of America.

Background And Aims: To successfully implement imaging-based pancreatic cancer (PC) surveillance, it is key to understand the timeline and morphological features of neoplastic progression. We aimed to investigate the progression to neoplasia from serial prediagnostic pancreatic imaging tests in high-risk individuals, and identify factors associated with successful early detection.

Methods: We retrospectively examined the development of pancreatic abnormalities in high-risk individuals who were diagnosed with PC and/or underwent pancreatic surgery in 16 international surveillance programs.

Results: Of 2552 high-risk individuals under surveillance, 28 (1%) developed neoplastic progression to PC or high-grade dysplasia during follow-up (median 29 months after baseline, IQR 40). 46% (13/28) presented with a new lesion (median size 15 mm, range 7-57), a median of 11 months (IQR 8, range 3-17) after a prior examination, by which time 77% (10/13) had progressed beyond the pancreas. The other 54% (15/28) had neoplastic progression in a previously detected lesion (12 originally cystic, 2 indeterminate, 1 solid); 11 (73%) had PC progressed beyond the pancreas. The 12 patients with cysts had been followed for 21 months (IQR 15) and had a median growth of 5 mm/year (IQR 8). Successful early detection (as high-grade dysplasia or PC confined to the pancreas) was associated with resection of cystic lesions (versus solid or indeterminate lesions, OR 5.388, 95%CI 1.525-19.029) and small lesions (OR 0.890/mm, 95%CI 0.812-0.976).

Conclusion: Nearly half of high-risk individuals developing high-grade dysplasia or PC have no prior lesions detected by imaging, yet present at an advanced stage. Progression can occur before the next scheduled annual examination. More sensitive diagnostic tools or a different management strategy for rapidly-growing cysts are needed.
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http://dx.doi.org/10.1053/j.gastro.2021.10.014DOI Listing
October 2021

Neoadjuvant treatment: A window of opportunity for nutritional prehabilitation in patients with pancreatic ductal adenocarcinoma.

World J Gastrointest Surg 2021 Sep;13(9):885-903

Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Roma 00168, Italy.

Patients affected by pancreatic ductal adenocarcinoma (PDAC) frequently present with advanced disease at the time of diagnosis, limiting an upfront surgical approach. Neoadjuvant treatment (NAT) has become the standard of care to downstage non-metastatic locally advanced PDAC. However, this treatment increases the risk of a nutritional status decline, which in turn, may impact therapeutic tolerance, postoperative outcomes, or even prevent the possibility of surgery. Literature on prehabilitation programs on surgical PDAC patients show a reduction of postoperative complications, length of hospital stay, and readmission rate, while data on prehabilitation in NAT patients are scarce and randomized controlled trials are still missing. Particularly, appropriate nutritional management represents an important therapeutic strategy to promote tissue healing and to enhance patient recovery after surgical trauma. In this regard, NAT may represent a new interesting window of opportunity to implement a nutritional prehabilitation program, aiming to increase the PDAC patient's capacity to complete the planned therapy and potentially improve clinical and survival outcomes. Given these perspectives, this review attempts to provide an in-depth view of the nutritional derangements during NAT and nutritional prehabilitation program as well as their impact on PDAC patient outcomes.
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http://dx.doi.org/10.4240/wjgs.v13.i9.885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462076PMC
September 2021

A randomized controlled trial of stapled versus ultrasonic transection in distal pancreatectomy.

Surg Endosc 2021 Sep 13. Epub 2021 Sep 13.

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

Background: The pancreatic transection method during distal pancreatectomy is thought to influence postoperative fistula rates. Yet, the optimal technique for minimizing fistula occurrence is still unclear. The present randomized controlled trial compared stapled versus ultrasonic transection in elective distal pancreatectomy.

Methods: Patients undergoing distal pancreatectomy from July 2018 to July 2020 at two high-volume institutions were considered for inclusion. Exclusion criteria were contiguous organ resection and a parenchymal thickness > 17 mm on intraoperative ultrasound. Eligible patients were randomized in a 1:1 ratio to stapled transection (Endo GIA Reinforced Reload with Tri-Staple Technology®) or ultrasonic transection (Harmonic Focus® + or Harmonic Ace® + shears). The primary endpoint was postoperative pancreatic fistula. Secondary endpoints included overall complications, abdominal collections, and length of hospital stay.

Results: Overall, 72 patients were randomized in the stapled transection arm and 73 patients in the ultrasonic transection arm. Postoperative pancreatic fistula occurred in 23 patients (16%), with a comparable incidence between groups (12% in stapled transection versus 19% in ultrasonic dissection arm, p = 0.191). Overall complications did not differ substantially (35% in stapled transection versus 44% in ultrasonic transection arm, p = 0.170). There was an increased incidence of abdominal collections in the ultrasonic dissection group (32% versus 14%, p = 0.009), yet the need for percutaneous drain did not differ between randomization arms (p = 0.169). The median length of stay was 8 days in both groups (p = 0.880). Intraoperative blood transfusion was the only factor independently associated with postoperative pancreatic fistula on logistic regression analysis (OR 4.8, 95% CI 1.2-20.0, p = 0.032).

Conclusion: The present randomized controlled trial of stapled versus ultrasonic transection in elective distal pancreatectomy demonstrated no significant difference in postoperative pancreatic fistula rates and no substantial clinical impact on other secondary endpoints.
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http://dx.doi.org/10.1007/s00464-021-08724-3DOI Listing
September 2021

Evaluation of the reporting quality of clinical practice guidelines on pancreatic cancer using the RIGHT checklist.

Ann Transl Med 2021 Jul;9(13):1088

Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Background: The International Reporting Items for Practice Guidelines in Health Care (RIGHT) statement is a set of recommendations for the reporting in clinical practice guidelines (CPGs). We aimed to assess the reporting quality of CPGs for pancreatic cancer following the RIGHT checklist.

Methods: Guidelines for pancreatic cancer were identified by searching electronic databases, guideline databases, and medical society websites. The reporting quality was evaluated by calculating the adherence to the items of the RIGHT checklist and summarizing them over the seven domains and the entire checklist. We also present results stratified by selected characteristics.

Results: A total of 22 guidelines were found eligible. Mean overall adherence to the RIGHT items was 60.0%. All guidelines adhered to the RIGHT items 3, 7a, 13a, while no guidelines reported the items 14c or 18b, which are some of the topics dealing with rationale for recommendations and funding source, respectively. Of the seven domains of the RIGHT checklist, "" and "" had the lowest reporting rates (25.0% and 43.2%, respectively); the remaining five domains had reporting rates >50%. CPGs that reported funding support, were published in higher-impact journals, and that applied a grading system for the quality of evidence, tended to have higher reporting rates.

Conclusions: Our results show that reporting quality of pancreatic cancer CPGs still needs to be improved. The use of the RIGHT statement should be encouraged when developing new guidelines.
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http://dx.doi.org/10.21037/atm-21-2644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339847PMC
July 2021

Gα15 in early onset of pancreatic ductal adenocarcinoma.

Sci Rep 2021 07 21;11(1):14922. Epub 2021 Jul 21.

Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, c/o GB Rossi General Hospital, P.le L.A. Scuro, 37134, Verona, Italy.

The GNA15 gene is ectopically expressed in human pancreatic ductal adenocarcinoma cancer cells. The encoded Gα15 protein can promiscuously redirect GPCR signaling toward pathways with oncogenic potential. We sought to describe the distribution of GNA15 in adenocarcinoma from human pancreatic specimens and to analyze the mechanism driving abnormal expression and the consequences on signaling and clinical follow-up. We detected GNA15 expression in pre-neoplastic pancreatic lesions and throughout progression. The analysis of biological data sets, primary and xenografted human tumor samples, and clinical follow-up shows that elevated expression is associated with poor prognosis for GNA15, but not any other GNA gene. Demethylation of the 5' GNA15 promoter region was associated with ectopic expression of Gα15 in pancreatic neoplastic cells, but not in adjacent dysplastic or non-transformed tissue. Down-modulation of Gα15 by shRNA or CRISPR/Cas9 affected oncogenic signaling, and reduced adenocarcimoma cell motility and invasiveness. We conclude that de novo expression of wild-type GNA15 characterizes transformed pancreatic cells. The methylation pattern of GNA15 changes in preneoplastic lesions coincident with the release a transcriptional blockade that allows ectopic expression to persist throughout PDAC progression. Elevated GNA15 mRNA correlates with poor prognosis. In addition, ectopic Gα15 signaling provides an unprecedented mechanism in the early steps of pancreas carcinogenesis distinct from classical G protein oncogenic mutations described previously in GNAS and GNAQ/GNA11.
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http://dx.doi.org/10.1038/s41598-021-94150-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295279PMC
July 2021

Open radiofrequency ablation as upfront treatment for locally advanced pancreatic cancer: Requiem from a randomized controlled trial.

Pancreatology 2021 Oct 21;21(7):1342-1348. Epub 2021 Jun 21.

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

Background: Local ablation of pancreatic cancer has been suggested as an option to manage locally advanced pancreatic cancer (LAPC) although no robust evidence has been published to date to support its application. The aim of this study is to compare overall survival (OS) and progression-free survival (PFS) in patients receiving both radiofrequency ablation (RFA) and conventional chemoradiotherapy (CHRT) with patients receiving CHRT only.

Methods: This is a multicentre prospective randomized controlled trial (RCT). Patients with LAPC diagnosed by the Pancreas-Ablation-Team-Verona were randomly assigned to open RFA (Group A) or CHRT (Group B). Survival analyses were performed using the Kaplan-Meier method and compared using the log-rank test. Statistical significance was set at p < 0.05.

Results: One hundred LAPC patients were enrolled from January 2014 to August 2016. 33% of patients in Group A did not receive the designated procedure because of intraoperative findings of liver (18.7%) or peritoneal metastases (43.8%), or technical contraindications (37.5%). We did not observe any statistically significant survival benefit from RFA compared to CHRT, neither in terms of OS (medians of 14.2 months and 18.1 months, respectively, p = 0.639) nor PFS (medians of 8 months and 6 months respectively, p = 0.570). Mortality was nil and RFA-related morbidity was 15.6%. In 13% of subjects, conversion to surgery occurred (2 after RFA and 11 after CHRT).

Conclusions: This is the first RCT evaluating the impact of upfront RFA in the multimodal treatment of LAPC. Compared to CHRT, RFA alone did not provide any advantage in terms of OS or PFS. It could be considered as a therapeutic option for LAPC within a multimodal context and after neoadjuvant therapies.
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http://dx.doi.org/10.1016/j.pan.2021.06.005DOI Listing
October 2021

Homologous Recombination Deficiency in Pancreatic Cancer: A Systematic Review and Prevalence Meta-Analysis.

J Clin Oncol 2021 08 1;39(23):2617-2631. Epub 2021 Jul 1.

Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.

Purpose: To analyze the prevalence of homologous recombination deficiency (HRD) in patients with pancreatic ductal adenocarcinoma (PDAC).

Materials And Methods: We conducted a systematic review and meta-analysis of the prevalence of HRD in PDAC from PubMed, Scopus, and Cochrane Library databases, and online cancer genomic data sets. The main outcome was pooled prevalence of somatic and germline mutations in the better characterized HRD genes (, , , , , , , and the genes). The secondary outcomes were prevalence of germline mutations overall, and in sporadic and familial cases; prevalence of germline mutations in Ashkenazi Jewish (AJ); and prevalence of HRD based on other definitions (ie, alterations in other genes, genomic scars, and mutational signatures). Random-effects modeling with the Freeman-Tukey transformation was used for the analyses. PROSPERO registration number: (CRD42020190813).

Results: Sixty studies with 21,842 participants were included in the systematic review and 57 in the meta-analysis. Prevalence of germline and somatic mutations was : 0.9%, : 3.5%, : 0.2%, : 2.2%, : 0.3%, : 0.5%, : 0.0%, and : 0.1%. Prevalence of germline mutations was : 0.9% (2.4% in AJ), : 3.8% (8.2% in AJ), : 0.2%, : 2%, : 0.3%, and : 0.4%. No significant differences between sporadic and familial cases were identified. HRD prevalence ranged between 14.5%-16.5% through targeted next-generation sequencing and 24%-44% through whole-genome or whole-exome sequencing allowing complementary genomic analysis, including genomic scars and other signatures (surrogate markers of HRD).

Conclusion: Surrogate readouts of HRD identify a greater proportion of patients with HRD than analyses limited to gene-level approaches. There is a clear need to harmonize HRD definitions and to validate the optimal biomarker for treatment selection. Universal HRD screening including integrated somatic and germline analysis should be offered to all patients with PDAC.
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http://dx.doi.org/10.1200/JCO.20.03238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8331063PMC
August 2021

Assessment of difficulty in laparoscopic distal pancreatectomy: A modification of the Japanese difficulty scoring system - A single-center high-volume experience.

J Hepatobiliary Pancreat Sci 2021 Sep 7;28(9):770-777. Epub 2021 Aug 7.

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

Background: The Japanese difficulty scoring system (DSS) was developed to assess the difficulty of laparoscopic distal pancreatectomy (LDP). The study aimed to validate a modified DSS (mDSS) in a European high-volume center.

Methods: Patients' clinical data underwent LDP for benign and malignant pancreatic lesion between September 2013 and February 2020 were reviewed. Expert laparoscopic surgeons performed the procedures. The mDSS consisted of seven variables, such as type of operation, malignancy, neoadjuvant therapy, pancreatic resection line, tumor close to major vessels, tumor extension to peripancreatic tissue, and left-sided portal hypertension and/or splenomegaly. According to the difficulty level and previous score, the mDSS was subdivided into three classes: low, intermediate, and high. Surrogates of case complexity (operative time, intraoperative blood loss and blood transfusion requirements, conversion rate) were used to validate the new scoring system.

Results: The study population included 140 LDP. Ninety-five (68%), 35 (25%) and 10 (7%) patients belonged to low, intermediate, and high difficulty groups. The mDSS identified the complexity of the surgical case of the series for all the surrogates of complexity considered, namely conversion rate (P = .004), operative time (P = .033) and intraoperative blood loss (P = .009). No differences were recorded in the postoperative outcomes (P > .05).

Conclusion: The mDSS for LDP better stratified the pancreatic procedures according to their complexity. The new scoring system may allow an appropriate preoperative evaluation of surgical difficulty, facilitating LDP's training program. Future prospective studies are needed to validate the mDSS.
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http://dx.doi.org/10.1002/jhbp.1010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8518381PMC
September 2021

Risk Adapted Ablative Radiotherapy After Intensive Chemotherapy for Locally Advanced Pancreatic Cancer.

Front Oncol 2021 20;11:662205. Epub 2021 Apr 20.

Department of Radiation Oncology, University of Verona Hospital Trust, Verona, Italy.

Background And Objective: To assess the efficacy of a Risk-Adapted Ablative Radiotherapy (RAdAR) approach, after intensive induction chemotherapy, in patients with locally advanced pancreatic cancer (LAPC).

Material And Methods: Patients with LAPC who received RAdAR following induction chemotherapy from January 2017 to December 2019 were included in this observational study. The RAdAR approach consisted of an anatomy- and simultaneous integrated boost (SIB)-based dose prescription strategy. RAdAR was delivered with stereotactic ablative radiation therapy (SAbR), administering 30 Gy in 5 fractions to the tumor volume (PTV) and 50 Gy SIB (BED 100 Gy) to the vascular involvement, or with (hypo-)fractionated ablative radiotherapy (HART) prescribing 50.4 Gy in 28 fractions to the PTV, with a vascular SIB of 78.4 Gy (BED 100 Gy). Primary end points were freedom from local progression (FFLP), overall survival (OS), and progression-free survival (PFS).

Results: Sixty-four LAPC patients were included.Induction chemotherapy consisted of gemcitabine/nab-paclitaxel in 60.9% and FOLFIRINOX in 39.1% of cases. SAbR was used in 52 (81.2%) patients, and HART in 12 (18.8%). After RAdAR, surgery was performed in 17 (26.6%) patients. Median follow-up was 16.1 months. Overall local control (LC) rate was 78.1%, with no difference between resected and non-resected patients (2-year FFLP 75.3% vs 56.4%; p = 0.112). Median OS and PFS were 29.7 months and 8.7 months, respectively, for the entire cohort. Resected patients had a better median OS (not reached versus 26.1 months; p = 0.0001) and PFS (19 versus 5.6 months; p < 0.0001) compared to non-resected patients. In non-resected patients, no significant difference was found between SAbR and HART for median FFLP (28.1 versus 18.5 months; p = 0.614), OS (27.4 versus 25.3 months; p = 0.624), and PFS (5.7 versus 4.3 months; p = 0.486). One patient (1.6%) experienced acute grade 4 gastro-intestinal bleeding. No other acute or late grade ≥ 3 toxicities were observed.

Conclusions: The RAdAR approach, following intensive induction chemotherapy, is an effective radiation treatment strategy for selected LAPC patients, representing a promising therapeutic option in a multimodality treatment regimen.
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http://dx.doi.org/10.3389/fonc.2021.662205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093383PMC
April 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

Screening for pancreatic cancer-a compelling challenge.

Hepatobiliary Surg Nutr 2021 Apr;10(2):264-266

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

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http://dx.doi.org/10.21037/hbsn-20-861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050588PMC
April 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

Preoperative standardized phase angle at bioimpedance vector analysis predicts the outbreak of antimicrobial-resistant infections after major abdominal oncologic surgery: A prospective trial.

Nutrition 2021 06 31;86:111184. Epub 2021 Jan 31.

School of Medicine and Surgery, University of Milano-Bicocca and Department of Surgery, San Gerardo Hospital, Monza, Italy Monza, Italy; Department of General Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany.

Objectives: Infectious morbidity is the most common and costly among all surgery-related complications, and infections by multidrug-resistant microorganisms (MDR) are associated with poor outcomes. Derangements of body composition is a recognized risk factor for infections. The aim of this study was to investigate the potential association between specific traits of body composition and the risk of having MDR-related infections.

Methods: This was a prospective study with patients scheduled for major abdominal surgery for gastrointestinal cancer. Bioimpedance vector analysis (BIVA), a reliable tool for body composition assessment, was performed the day before the operation. Postoperative complications were collected focusing on resistance patterns and site of infection. Patterns of resistance were compared with BIVA parameters.

Results: Data from 182 patients suffering from pancreatic (n = 76, 41.7%), rectal (n = 38, 20.9%), gastric (n = 31, 17%), or hepatic (n = 37, 20.3%) malignancy were collected. Overall complications occurred in 108 patients (59%), and in 45 patients (28%) bacterial infections were proven at culture. Of these, 15 (8%) were multidrug-sensitive (MDS), 38 MDR, and 2 extended drug-resistant (XDR) infections. The standardized phase angle measured (SPA) at BIVA was significantly lower in the MDR/XDR infections (-0.02 ± 1.20) than for no infection/MDS (0.56 ± 1.53; P = 0.029). A multivariate analysis showed that SPA was the only independent variable for MDR/XDR infections with an odds ratio of 3.057 (95% confidence interval, 1.354-6903; P = 0.007). The predictive ability of SPA revealed an area under the receiver operating characteristic curve of 0.662, with an optimal threshold of -0.3.

Conclusions: In surgical cancer patients, preoperative value of SPA lower than -0.3 is associated with the outbreak of MDR bacterial infections.
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http://dx.doi.org/10.1016/j.nut.2021.111184DOI 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

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

[Ablative therapies of pancreatic neoplasms.]

Recenti Prog Med 2021 Jan;112(1):75-80

The interest for pancreatic neoplasm ablation under endoscopic ultrasound (EUS) guidance has increased during the last decade because of technology advancement and availability of dedicated devices for thermal ablation. The most commonly used technique is radiofrequency ablation (RFA). Currently, three needle-electrodes and one "through-the-needle" probe are available. Published studies mainly demonstrated the feasibility and safety of the procedure. However, the role of EUS-RFA for the treatment of pancreatic ductal adenocarcinoma is not yet well defined. Randomized studies are needed to assess any advantage in terms of survival and quality of life when RFA is included in a multimodal treatment strategy compared with chemo(radio)therapy alone. In the setting of pancreatic neuroendocrine tumors (pNETs), published studies are consistent in demonstrating the efficacy of EUS-RFA in relieving symptoms related to hormone secretion by functioning pNETs. Moreover, EUS-RFA could find a role even in selected patients with small non-functioning pNETs when treatment is indicated but surgical resection would like to be avoided. Finally, EUS-RFA can be applied also for the treatment of pancreatic cystic neoplasm. However, patients should be carefully selected taking into account the low incidence of progression of cystic neoplasms towards malignancy and factors related to the patient, such as age, symptoms, comorbidity, and life expectancy.
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http://dx.doi.org/10.1701/3525.35127DOI Listing
January 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

Comparison between EUS-guided fine-needle aspiration cytology and EUS-guided fine-needle biopsy histology for the evaluation of pancreatic neuroendocrine tumors.

Pancreatology 2021 Mar 24;21(2):443-450. Epub 2020 Dec 24.

Department of Diagnostics and Public Health, G.B. Rossi University Hospital, Verona, Italy.

Background/objectives: Studies comparing EUS-guided fine-needle aspiration (EUS-FNA) with EUS-guided fine-needle biopsy (EUS-FNB) for the evaluation of pancreatic neuroendocrine tumors (pNETs) are lacking. We aimed at comparing EUS-FNA with EUS-FNB in terms of Ki-67 proliferative index (PI) estimation capability, cellularity of the samples, and reliability of Ki-67 PI/tumor grading compared with surgical specimens.

Methods: Patients diagnosed with pNETs on EUS and/or surgical specimens were retrospectively identified. Specimens were re-evaluated to assess Ki-67 PI feasibility, sample cellularity by manual counting, and determination of Ki-67 PI value. Outcomes in the EUS-FNA and EUS-FNB groups were compared. Kendall rank test was used for Ki-67 PI correlation between EUS and surgical specimens. Subgroup analysis including small (≤20 mm), non-functioning pNETs was performed.

Results: Three-hundred samples from 292 lesions were evaluated: 69 EUS-FNA cytology and 231 EUS-FNB histology. Ki-67 PI feasibility was similar for EUS-FNA and EUS-FNB (91.3% vs. 95.7%, p = 0.15), while EUS-FNB performed significantly better in the subgroup of 179 small pNETs (88.2% vs. 96.1%, p = 0.04). Rate of poor cellulated (<500 cells) specimens was equal between EUS-FNA and EUS-FNB. A significant correlation for Ki-67 PI values between EUS and 92 correspondent surgical specimens was found in both groups, but it was stronger with EUS-FNB (tau = 0.626, p < 0.0001 vs. tau = 0.452, p = 0.031). Correct grading estimation was comparable between the two groups (p = 0.482).

Conclusion: Our study showed stronger correlation for Ki-67 values between EUS-FNB and surgical specimens, and that EUS-FNB outperformed EUS-FNA in the evaluation of small pNETs. EUS-FNB should become standard of care for grading assessment of suspected pNETs.
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http://dx.doi.org/10.1016/j.pan.2020.12.015DOI Listing
March 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

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

Antibiotic Prophylaxis with Piperacillin-Tazobactam Reduces Post-Operative Infectious Complication after Pancreatic Surgery: An Interventional, Non-Randomized Study.

Surg Infect (Larchmt) 2021 Jun 23;22(5):536-542. Epub 2020 Oct 23.

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

This study aimed to evaluate the effectiveness of piperacillin-tazobactam as antibiotic prophylaxis in patients affected by a peri-ampullary tumor submitted to pancreatic surgery. A prospective, non-randomized, non-blinded, interventional study was conducted from January 2015 to March 2018. Patients were screened pre-operatively for Enterobacteriaceae producing extended-spectrum beta-lactamases (ESBL-PE). During the baseline period (January 2015-October 2016), surgical prophylaxis was performed with ampicillin-sulbactam. In the intervention phase (November 2016-March 2018), patients received piperacillin-tazobactam. Statistical analysis was performed by univariable and multivariable analysis with logistic regression models. Overall, 383 patients were included in the baseline period and 296 in the intervention period. The surveillance strategy identified 47 ESBL-PE carriers (14%) in the baseline phase and 29 (10%) in the intervention phase. In the baseline period, the patients had a higher rate of hospital-acquired infection (43% versus 33%; p = 0.004), superficial surgical site infection (SSI) (11% versus 2%; p < 0.001), and pneumonia (16% versus 9%; p = 0.006). After the logistic regression, the baseline group had an odds ratio to develop superficial SSI and pneumonia of 7.7 (95% confidence interval [CI] 3-20) and 1.8 (95% CI 1-3.3), respectively. The ESBL colonization increased the mortality rate significantly (8% versus 3%; p = 0.017). Adopting antibiotic prophylaxis based on piperacillin-tazobactam is associated with a reduction in post-operative SSI, particularly superficial-SSIs. Further randomized studies would be warranted to evaluate this antibiotic combination more extensively in preventive strategies.
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http://dx.doi.org/10.1089/sur.2020.260DOI Listing
June 2021

Pancreatic surgery is a safe teaching model for tutoring residents in the setting of a high-volume academic hospital: a retrospective analysis of surgical and pathological outcomes.

HPB (Oxford) 2021 Apr 25;23(4):520-527. Epub 2020 Aug 25.

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

Background: Academic hospitals must train future surgeons, but whether residents could negatively affect the outcomes of major procedures is a matter of concern. The aim of this study is to assess if pancreatic surgery is a safe teaching model.

Methods: Outcomes of 1230 major pancreatic resections performed at a high-volume pancreatic teaching hospital between 2015 and 2018 were compared according to the first surgeon type, attending vs resident.

Results: Residents performed a selection of 132 (16%) pancreaticoduodenectomies (PD) and 46 (11%) distal pancreatectomies (DP). For PD, pancreatic fistula (25% vs 0, p < 0.001), biliary fistula (7.1% vs 3.5%, p = 0.04) and operative time (400 vs 390 min, p < 0.001) were lower for residents but post-pancreatectomy hemorrhage was higher (20.5% vs 13% p = 0.024). For DP, pancreatic fistula rate was lower for residents (31.7% vs 17.5% p = 0.046). There was no difference in terms of lymph nodes retrieval both for PDs and DPs, while the R1 resections were more frequent among PDs performed by attending surgeons (31.5% vs 15.7%, p = 0.023).

Conclusion: The active participation of residents does not negatively affect outcomes of major pancreatic resections in a high-volume center. By means of case selection and continuous tutoring, pancreatic surgery represents a safe and valid teaching model.
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http://dx.doi.org/10.1016/j.hpb.2020.08.007DOI Listing
April 2021

Italian registry of families at risk of pancreatic cancer: AISP Familial Pancreatic Cancer Study Group.

Dig Liver Dis 2020 10 17;52(10):1126-1130. Epub 2020 Aug 17.

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

Pancreatic cancer is one of the main causes of cancer-related death worldwide, with a survival rate around 9%. In Italy 13,500 new cases of pancreatic cancer occurred in 2019. It is estimated that at least 5% have a hereditary background. Surveillance is advisable for healthy individuals with specific genetic syndromes with or without family history of pancreatic cancer or members of families with multiple cases of pancreatic cancer, irrespective of genetic syndromes. In 2010 the Italian Association for the Study of the Pancreas (AISP) defined criteria to include individuals in such surveillance programs with the first-round results published in 2019. In order to include other categories at high-risk and increase the diagnostic yield of surveillance, these criteria have recently been modified. The present position paper presents the updated criteria of the Italian Registry of Families at Risk of Pancreatic Cancer (IRFARPC) with their diagnostic yield calculation. Also, AISP priority projects concerning: (a) increasing awareness of citizens and primary care physicians through a dedicated App; (b) increasing access to germline testing to personalize surveillance; (c) measuring psychological impact of surveillance; (d) investigating the role of risk-modifiers and (e) evaluating the cost-effectiveness and ability to save lives of the program are briefly presented.
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http://dx.doi.org/10.1016/j.dld.2020.07.027DOI Listing
October 2020

Seasonal variations in pancreatic surgery outcome A retrospective time-trend analysis of 2748 Whipple procedures.

Updates Surg 2020 Sep 20;72(3):693-700. Epub 2020 Aug 20.

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

Background: Observing cyclic patterns in surgical outcome is a common experience. We aimed to measure this phenomenon and to hypothesize possible causes using the experience of a high-volume pancreatic surgery department.

Methods: Outcomes of 2748 patients who underwent a Whipple procedure at a single high-volume center from January 2000 to December 2018 were retrospectively analyzed. Three different hypotheses were tested: the effect of climate changes, the "July effect" and the effect of vacations.

Results: Clavien-Dindo ≥ 3 morbidity was similar during warm vs. cold months (22.5% vs. 19.8%, p = 0.104) and at the beginning of activity of new trainees vs. the rest of the year (23.5 vs. 22.5%, p = 0.757). Patients operated when a high percentage of staff is on vacation showed an increased Clavien-Dindo ≥ 3 morbidity (22.3 vs. 18.5%, p = 0.022), but similar mortality (2.3 vs. 1.8%, p = 0.553). The surgical waiting list was also significantly longer during these periods (37 vs. 27 days, p = 0.037). Being operated in such a period of the year was an independent predictor of severe morbidity (OR 1.271, CI 95% 1.086-1.638, p = 0.031).

Conclusion: Being operated when more staff is on vacation significantly affects severe morbidity rate. Future healthcare system policies should prevent the relative shortage of resources during these periods.
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http://dx.doi.org/10.1007/s13304-020-00868-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481160PMC
September 2020
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