Publications by authors named "Giovanni Butturini"

113 Publications

Role of next-generation genomic sequencing in targeted agents repositioning for pancreaticoduodenal cancer patients.

Pancreatology 2021 Apr 19. Epub 2021 Apr 19.

Pancreatic Surgical Unit, Pederzoli Hospital, Peschiera Del Garda, Verona, Italy.

Background: Pancreaticoduodenal cancer (PDC) is a group of malignant tumors arising in the ampullary region, which lack approved targeted therapies for their treatment.

Methods: This retrospective, observational study is based on Secondary Data Use (SDU) previously collected during a multicenter collaboration, which were subsequently entered into a predefined database and analyzed. FoundationOne CDx or Liquid, a next-generation DNA sequencing (NGS) service, was used to identify genomic alterations of patients who failed standard treatments. Detected alterations were described according to ESMO Scale of Clinical Actionability for molecular Targets (ESCAT).

Results: NGS analysis was performed in 68 patients affected by PDC. At least one alteration ranking tier I, II, III, or IV according to ESCAT classification was detected in 8, 1, 9, and 12 patients respectively (44.1%). Ten of them (33.3%) received a matched therapy. Patients with ESCAT tier I to IV were generally younger than the overall population (median = 54, range = 26-71 years), had an EGOG performance status score = 0 (83.3%), and an uncommon histological or clinical presentation. The most common mutations with clinical evidence of actionability (ESCAT tier I-III) involved genes of the RAF (10.3%), BRCA (5.9%) or FGFR pathways (5.9%). We present the activity of the RAF kinases inhibitor sorafenib in patients with RAF-mutated advanced PDC.

Conclusions: In advanced PDC, NGS is a feasible and valuable method for enabling precision oncology. This genomic profiling method might be considered after standard treatments failure, especially in young patients maintaining a good performance status, in order to detect potentially actionable mutations and offer molecularly targeted therapeutic approaches.
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http://dx.doi.org/10.1016/j.pan.2021.04.004DOI Listing
April 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

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

Ann Surg Oncol 2021 Jun 11;28(6):3100-3108. 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
June 2021

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

Ann Surg Oncol 2021 Jun 9;28(6):3109-3110. 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
June 2021

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

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

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

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

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

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

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

FOLFIRINOX after first-line gemcitabine-based chemotherapy in advanced pancreatic cancer: a retrospective comparison with FOLFOX and FOLFIRI schedules.

Ther Adv Med Oncol 2020 29;12:1758835920947970. Epub 2020 Sep 29.

Department of Clinical Medicine and Surgery, Oncology Division, University of Naples Federico II, Via Pansini 5, Naples, 80131, Italy.

Background: Pancreatic adenocarcinoma is the fourth leading cause of cancer-related death. In cases with metastasis, the combination of 5-fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) or gemcitabine-based chemotherapy regimens are considered the standard of care. However, the optimal sequence of these regimens is unclear.

Methods: This retrospective study initially evaluated 186 patients with locally advanced/metastatic pancreatic cancer at three Italian institutions between February 2013 and October 2019. All patients had progressed after receiving gemcitabine-based first-line chemotherapy and were subsequently offered second-line FOLFIRINOX, FOLFOX-6, or FOLFIRI treatment. This study evaluated progression-free survival (PFS), overall survival from the start of second-line treatment (OS2), overall survival from the start of first-line treatment (OS1), and safety outcomes.

Results: A total of 77 patients received ⩾4 cycles of second-line chemotherapy and were considered eligible: 15 patients received FOLFIRINOX, 32 patients received FOLFOX-6, and 30 patients received FOLFIRI. The FOLFIRINOX group had median PFS of 26.29 weeks and median OS2 of 47.86 weeks, while the FOLFIRI group had median PFS of 10.57 weeks and median OS2 of 25.00 weeks ( = 0.038). No significant differences were observed between the FOLFIRINOX and FOLFOX-6 groups in terms of PFS (26.29 weeks 23.07 weeks) or OS2 (47.86 weeks 42.00 weeks). The most common grade 3-4 toxicities were anemia, neutropenia, and thrombocytopenia, which occurred more frequently in the FOLFIRINOX and FOLFOX-6 groups.

Conclusion: Relative to the FOLFIRI regimen, the FOLFIRINOX regimen had a favorable toxicity profile and better survival outcomes. No significant differences were observed relative to the FOLFOX-6 regimen.
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http://dx.doi.org/10.1177/1758835920947970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533956PMC
September 2020

Evaluation of Adjuvant Chemotherapy in Patients With Resected Pancreatic Cancer After Neoadjuvant FOLFIRINOX Treatment.

JAMA Oncol 2020 Nov;6(11):1733-1740

Department of Surgery, Universitaet zu Luebeck, Luebeck, Germany.

Importance: The benefit of adjuvant chemotherapy after resection of pancreatic cancer following neoadjuvant combination treatment with folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) is unclear.

Objective: To assess the association of adjuvant chemotherapy with overall survival (OS) in patients after pancreatic cancer resection and neoadjuvant FOLFIRINOX treatment.

Design, Setting, And Participants: This international, multicenter, retrospective cohort study was conducted from January 1, 2012, to December 31, 2018. An existing cohort of patients undergoing resection of pancreatic cancer after FOLFIRINOX was updated and expanded for the purpose of this study. All consecutive patients who underwent pancreatic surgery after at least 2 cycles of neoadjuvant FOLFIRINOX chemotherapy for nonmetastatic pancreatic cancer were retrospectively identified from institutional databases. Patients with resectable pancreatic cancer, borderline resectable pancreatic cancer, and locally advanced pancreatic cancer were eligible for this study. Patients with in-hospital mortality or who died within 3 months after surgery were excluded.

Exposures: The association of adjuvant chemotherapy with OS was evaluated in different subgroups including interaction terms for clinicopathological parameters with adjuvant treatment in a multivariable Cox model. Overall survival was defined as the time starting from surgery plus 3 months (moment eligible for adjuvant therapy), unless mentioned otherwise.

Results: We included 520 patients (median [interquartile range] age, 61 [53-66] years; 279 [53.7%] men) from 31 centers in 19 countries. The median number of neoadjuvant cycles of FOLFIRINOX was 6 (interquartile range, 5-8). Overall, 343 patients (66.0%) received adjuvant chemotherapy, of whom 68 (19.8%) received FOLFIRINOX, 201 (58.6%) received gemcitabine-based chemotherapy, 14 (4.1%) received capecitabine, 45 (13.1%) received a combination or other agents, and 15 (4.4%) received an unknown type of adjuvant chemotherapy. Median OS was 38 months (95% CI, 36-46 months) after diagnosis and 31 months (95% CI, 29-37 months) after surgery. No survival difference was found for patients who received adjuvant chemotherapy vs those who did not (median OS, 29 vs 29 months, univariable hazard ratio [HR], 0.99; 95% CI, 0.77-1.28; P = .93). In multivariable analysis, only the interaction term for lymph node stage with adjuvant therapy was statistically significant: In patients with pathology-proven node-positive disease, adjuvant chemotherapy was associated with improved survival (median OS, 26 vs 13 months; multivariable HR, 0.41 [95% CI, 0.22-0.75]; P = .004). In patients with node-negative disease, adjuvant chemotherapy was not associated with improved survival (median OS, 38 vs 54 months; multivariable HR, 0.85; 95% CI, 0.35-2.10; P = .73).

Conclusions And Relevance: These results suggest that adjuvant chemotherapy after neoadjuvant FOLFIRINOX and resection of pancreatic cancer was associated with improved survival only in patients with pathology-proven node-positive disease. Future randomized studies should be conducted to confirm this finding.
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http://dx.doi.org/10.1001/jamaoncol.2020.3537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489392PMC
November 2020

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

Genomic characterization of malignant progression in neoplastic pancreatic cysts.

Nat Commun 2020 08 14;11(1):4085. Epub 2020 Aug 14.

Service de Pathologie, AP-HP, Hôpital Cochin, Université Paris Descartes, Paris, France.

Intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are non-invasive neoplasms that are often observed in association with invasive pancreatic cancers, but their origins and evolutionary relationships are poorly understood. In this study, we analyze 148 samples from IPMNs, MCNs, and small associated invasive carcinomas from 18 patients using whole exome or targeted sequencing. Using evolutionary analyses, we establish that both IPMNs and MCNs are direct precursors to pancreatic cancer. Mutations in SMAD4 and TGFBR2 are frequently restricted to invasive carcinoma, while RNF43 alterations are largely in non-invasive lesions. Genomic analyses suggest an average window of over three years between the development of high-grade dysplasia and pancreatic cancer. Taken together, these data establish non-invasive IPMNs and MCNs as origins of invasive pancreatic cancer, identifying potential drivers of invasion, highlighting the complex clonal dynamics prior to malignant transformation, and providing opportunities for early detection and intervention.
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http://dx.doi.org/10.1038/s41467-020-17917-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428044PMC
August 2020

The Italian National Registry for minimally invasive pancreatic surgery: an initiative of the Italian Group of Minimally Invasive Pancreas Surgery (IGoMIPS).

Updates Surg 2020 Jun 29;72(2):379-385. Epub 2020 May 29.

Università di Pisa, Pisa, Italy.

The value of minimally invasive pancreatic surgery (MIPS) is still uncertain, despite the growing number of publications, including reviews and meta-analyses, and the quick diffusion of these procedures worldwide. The Italian Group of Minimally Invasive Pancreas Surgery (IGoMIPS) was created under the auspices of three Scientific Societies: Associazione Italiana Studio Pancreas (AISP), Associazione Italiana Chirurgia Epato-Bilio-Pancreatica (AICEP, former IT-IHPBA), and Società Italiana di Chirurgia Endoscopica (SICE). The main aim of IGoMIPS is to develop and implement a national registry for MIPS. IGoMIPS was founded on February 22, 2019 in Pisa. The IGoMIPS registry became operational in September 2019, following approval by the Ethic Committees of founding Institutions, inscription into the Registry of Patient Registries (RoPR), and a wrap-up meeting held in Bologna during the Annual Congress of the Italian Surgical Society. During this meeting IGoMIPS members approved that the Italian Registry will provide data to the European Registry, while retaining the right to analyze and publish Italian data. An audience survey was also conducted to obtain information on perceived value and current implementation of MIPS in founding Institutions. MIPS is performed in 94.7% of IGoMIPS centers, including pancreaticoduodenectomy in 42.1%. Robotic assistance was employed in 52.6% of Institutions. The annual volume of MIPS was 6-10 cases in 38.9% of the centers, 11-20 cases in 16.7%, 21-30 cases in 22.2%, and > 30 cases in 22.2%. The registry was felt to be extremely important for both safety improvement and educational purposes by 94.5% of the centers.
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http://dx.doi.org/10.1007/s13304-020-00808-4DOI Listing
June 2020

Outcomes of Elective and Emergency Conversion in Minimally Invasive Distal Pancreatectomy for Pancreatic Ductal Adenocarcinoma: An International Multicenter Propensity Score-matched Study.

Ann Surg 2019 Dec 10. Epub 2019 Dec 10.

Department of Surgery, Southampton University Hospital NHS Foundation Trust, Southampton, United Kingdom.

Objective: The aim of this study was to investigate the impact of conversion during minimally invasive distal pancreatectomy (MIDP) for pancreatic ductal adenocarcinoma (PDAC) on outcome by a propensity-matched comparison with open distal pancreatectomy (ODP).

Background: MIDP is associated with faster recovery as compared with ODP. The high conversion rate (15%-25%) in patients with PDAC, however, is worrisome and may negatively influence outcome.

Methods: A post hoc analysis of a retrospective cohort including distal pancreatectomies for PDAC from 34 centers in 11 countries. Patients requiring conversion were matched, using propensity scores, to ODP procedures (1:2 ratio). Indications for conversion were classified as elective conversions (eg, vascular involvement) or emergency conversions (eg, bleeding).

Results: Among 1212 distal pancreatectomies for PDAC, 345 patients underwent MIDP, with 68 (19.7%) conversions, mostly elective (n = 46, 67.6%). Vascular resection (other than splenic vessels) was required in 19.1% of the converted procedures. After matching (61 MIDP-converted vs 122 ODP), conversion did not affect R-status, recurrence of cancer, nor overall survival. However, emergency conversion was associated with increased overall morbidity (61.9% vs 31.1%, P= 0.007) and a trend to worse oncological outcome compared with ODP. Elective conversion was associated with comparable overall morbidity.

Conclusions: Elective conversion in MIDP for PDAC was associated with comparable short-term and oncological outcomes in comparison with ODP. However, emergency conversions were associated with worse both short- and long-term outcomes, and should be prevented by careful patient selection, awareness of surgeons' learning curve, and consideration of early conversion when unexpected intraoperative findings are encountered.
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http://dx.doi.org/10.1097/SLA.0000000000003717DOI Listing
December 2019

Impact of Neoadjuvant Therapy in Resected Pancreatic Ductal Adenocarcinoma of the Pancreatic Body or Tail on Surgical and Oncological Outcome: A Propensity-Score Matched Multicenter Study.

Ann Surg Oncol 2020 Jun 17;27(6):1986-1996. Epub 2019 Dec 17.

Department of Surgery, Southampton University Hospital NHS Foundation Trust, Southampton, UK.

Background: Several studies have suggested a survival benefit of neoadjuvant therapy (NAT) for pancreatic ductal adenocarcinoma (PDAC) in the pancreatic head. Data concerning NAT for PDAC located in pancreatic body or tail are lacking.

Methods: Post hoc analysis of an international multicenter retrospective cohort of distal pancreatectomy for PDAC in 34 centers from 11 countries (2007-2015). Patients who underwent resection after NAT were matched (1:1 ratio), using propensity scores based on baseline characteristics, to patients who underwent upfront resection. Median overall survival was compared using the stratified log-rank test.

Results: Among 1236 patients, 136 (11.0%) received NAT, most frequently FOLFIRINOX (25.7%). In total, 94 patients receiving NAT were matched to 94 patients undergoing upfront resection. NAT was associated with less postoperative major morbidity (Clavien-Dindo ≥ 3a, 10.6% vs. 23.4%, P = 0.020) and pancreatic fistula grade B/C (9.6% vs. 21.3%, P = 0.026). NAT did not improve overall survival [27 (95% CI 14-39) versus 31 months (95% CI 19-42), P = 0.277], as compared with upfront resection. In a sensitivity analysis of 251 patients with radiographic tumor involvement of splenic vessels, NAT (n = 37, 14.7%) was associated with prolonged overall survival [36 (95% CI 18-53) versus 20 months (95% CI 15-24), P = 0.049], as compared with upfront resection.

Conclusion: In this international multicenter cohort study, NAT for resected PDAC in pancreatic body or tail was associated with less morbidity and pancreatic fistula but similar overall survival in comparison with upfront resection. Prospective studies should confirm a survival benefit of NAT in patients with PDAC and splenic vessel involvement.
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http://dx.doi.org/10.1245/s10434-019-08137-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210228PMC
June 2020

Nonconventional Doses of Somatostatin Analogs in Patients With Progressing Well-Differentiated Neuroendocrine Tumor.

J Clin Endocrinol Metab 2020 01;105(1)

NET Team Bologna ENETS Center of Excellence, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Bologna, Italy.

Purpose: To evaluate the antiproliferative activity and safety of nonconventional high doses of somatostatin analogs (HD-SSA) in patients with well-differentiated gastroenteropancreatic (GEP) neuroendocrine tumors (NET) with radiological disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria on a previous treatment.

Methods: A retrospective analysis of prospectively maintained databases from 13 Italian NET-dedicated centers was performed. Main inclusion criteria were: well-differentiated G1 or G2 GEP-NET, progressive disease on a previous treatment, and subsequent treatment with HD-SSA (either by increased administered dose [dose intensity] or shortened interval between administrations [dose density]). Main endpoints were progression-free survival (PFS) and safety.

Results: Of 198 patients, 140 matched inclusion criteria and were included in the analysis. Overall, median PFS was 31 months. Use of HD-SSA as second-line treatment was associated with reduced risk for progression or death compared with third- or further-line treatment (HR: 2.12; P = 0.004). There was no difference in PFS between HD-SSA by increased dose density (N = 133; 95%) or intensity (N = 7; 5%). Partial response according to RECIST criteria was observed in 12 patients (8.6%), and stable disease was achieved in 106 (75.7%) patients. Adverse events occurred in 21 patients (15.0%), 2 of whom had grade 3 biliary stone disease. No patients discontinued HD-SSA treatment due to adverse events.

Conclusions: HD-SSA is an active and safe treatment option in patients with progressive well-differentiated GEP-NET. The high rate of objective responses observed deserves prospective validation in ad hoc clinical trials.
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http://dx.doi.org/10.1210/clinem/dgz035DOI Listing
January 2020

Full Robotic Distal Pancreatectomy: Safety and Feasibility Analysis of a Multicenter Cohort of 236 Patients.

Surg Innov 2020 Feb 9;27(1):11-18. Epub 2019 Aug 9.

Università Cattolica del Sacro Cuore of Rome, Fondazione Policlinico "A Gemelli" IRCCS of Rome, Rome, Italy.

. Despite the widespread use of the robotic technology, only a few studies with small sample sizes report its application to pancreatic diseases treatment. Our aim is to present the results of a multicenter study on the safety and feasibility of robot-assisted distal pancreatectomy (RDP). . All RDPs for benign, borderline, and malignant diseases performed in 5 referral centers from 2008 to 2016 were included. Perioperative outcomes were evaluated. . Two hundred thirty-six patients were included. Spleen preservation was performed in 114 cases (48.3%). Operative time was 277.8 ± 93.6 minutes. Progressive improvement in operative time was observed over the study period. Conversion rate was 6.3%. Morbidity occurred in 102 cases (43.2%), mainly due to grade A fistulas. Reoperation was required in 10 patients. Postoperatively, 2 patients died of sepsis due to a grade C fistula. Hospital readmission was necessary in 11 cases. A R0 resection was always achieved, with a mean number of 16.2 ± 15 harvested lymph nodes. . To our knowledge, this is one of the largest RDP series. Safety and feasibility including the low conversion rate, the high spleen preservation rate, the adequate operative time, and the acceptable morbidity and mortality rates confirm the validity of this technique. Appropriate oncological outcomes have been also obtained.
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http://dx.doi.org/10.1177/1553350619868112DOI Listing
February 2020

Implantation of amniotic membrane over pancreatic anastomosis after pancreaticoduodenectomy: report of the first case.

J Surg Case Rep 2019 May 9;2019(5):rjz097. Epub 2019 May 9.

Pancreatic Surgical Unit, Pederzoli Hospital, Peschiera del Garda, Verona, Italy.

The amniotic membrane (AM) has an increasing role as a scaffold for tissue repair due to its unique biological properties. The implantation of AM on pancreatic anastomosis after pancreaticoduodenectomy might improve the anastomotic healing and strengthen its structure, however has never been used in pancreatic surgery. We present the first application of AM after a pancreaticoduodenectomy was performed for a malignant tumor of the pancreatic head. After completing the pancreatic anastomosis, the AM was placed around the pancreatic anastomosis and fixed to it with single stiches. The AM, due to its physical characteristics, could be easily manipulated and adapted to the pancreatic anastomosis. This interesting and unique case shows that covering a pancreatic anastomosis with the AM is safe and technically feasible. The AM has no adverse effects while it may eventually provide a beneficial impact over the anastomotic healing.
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http://dx.doi.org/10.1093/jscr/rjz097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6507795PMC
May 2019

Short-term and long-term outcomes after robot-assisted versus laparoscopic distal pancreatectomy for pancreatic neuroendocrine tumors (pNETs): a multicenter comparative study.

Langenbecks Arch Surg 2019 Jun 4;404(4):459-468. Epub 2019 May 4.

Fondazione Policlinico "A.Gemelli" IRCCS of Rome, CRMPG (Gemelli Pancreatic Advanced Research Center), Università Cattolica del Sacro Cuore of Rome, Largo Agostino Gemelli 8, 00166, Rome, Italy.

Purpose: Minimally invasive surgery has increasingly gained popularity as a treatment of choice for pancreatectomy with encouraging initial results in robotic distal pancreatectomy (RDP). However, few data are available on the comparison between RDP and laparoscopic distal pancreatectomy (LDP) for pancreatic neuroendocrine tumors (pNETs). Our aim, thus, is to compare perioperative and long-term outcomes as well as total costs of RDP and LDP for pNETs.

Methods: All RDPs and LDPs for pNETs performed in four referral centers from 2008 to 2016 were included. Perioperative outcomes, histopathological results, overall (OS) and disease-free survival (DFS), and total costs were evaluated.

Results: Ninety-six RDPs and 85 LDPs were included. Demographic and clinical characteristics were comparable between the two cohorts. Operative time was 36.5 min longer in the RDP group (p = 0.009) but comparable to LDP after removing the docking time (247.9 vs 233.7 min; p = 0.6). LDP related to a lower spleen preservation rate (44.7% vs 65.3%; p < 0.0001) and higher blood loss (239.7 ± 112 vs 162.5 ± 98 cc; p < 0.0001). Advantages in operative time for RDP were documented in case of the spleen preservation procedures (265 ± 41.52 vs 291 ± 23 min; p = 0.04). Conversion rate, postoperative morbidity, and pancreatic fistula rate were similar between the two groups, as well as histopathological data, OS, and DFS. Significant advantages were evidenced for LDP regarding mean total costs (9235 (± 1935) € vs 11,226 (± 2365) €; p < 0.0001).

Conclusions: Both RDP and LDP are safe and efficacious for pNETs treatment. However, RDP offers advantages with a higher spleen preservation rate and lower blood loss. Costs still remain the main limitation of the robotic approach.
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http://dx.doi.org/10.1007/s00423-019-01786-xDOI Listing
June 2019

Long term outcome after minimally invasive and open Warshaw and Kimura techniques for spleen-preserving distal pancreatectomy: International multicenter retrospective study.

Eur J Surg Oncol 2019 Sep 8;45(9):1668-1673. Epub 2019 Apr 8.

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

Background: The Warshaw (WT) and the Kimura (KT) techniques are both used for open or minimally invasive (MI) spleen preserving distal pancreatectomy (SPDP). Multicenter studies on long-term outcome of WT and KT are lacking.

Methods: Multicenter retrospective study with transversal follow-up moment, including patients who underwent SPDP from 2000 to 2017 at three high-volume centers in Italy and the Netherlands. Primary endpoint was the incidence of short and long term complications. Patients without regular follow-up were interviewed about symptoms and complications.

Results: In total, 164 patients were enrolled, 55 WT (33.5%) and 109 kT (66.5%), of which 95 (57.9%) MI. There was no 30-day mortality (0%).The only significant difference in short-term outcome was more delayed gastric emptying (DGE) after WT (9.1% vs 1.8%, p = 0.043). MI-SPDP was associated with less blood loss (median 150 vs 250 ml, respectively, p < 0.001), less DGE (0% vs 10%, p = 0.002), less abdominal abscesses (8.4% vs 18.4%, p = 0.03) and less splenic infarctions (3.2% vs. 13%, p = 0.042), than open SPDP. Long-term follow-up (median 41 months) was available for 111 patients (67.7%) of whom 18 (16.2%) had an SPDP-related long-term sequela, mostly perigastric varices (n = 11, 9%) but without differences between WT and KT. Less long-term sequelae were reported after MI as compared to open SPDP (12.5% vs 21.2%, p = 0.032).

Conclusions: In this international retrospective study, the WT and KT had comparable short- and long-term outcomes. If a KT does not seem feasible during SPDP, a WT is recommended, rather than performing a splenectomy. MI-SPDP was associated with less short- and long term complications as compared to an open SPDP.
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http://dx.doi.org/10.1016/j.ejso.2019.04.004DOI Listing
September 2019

Residual pancreatic function after pancreaticoduodenectomy is better preserved with pancreaticojejunostomy than pancreaticogastrostomy: A long-term analysis.

Pancreatology 2019 Jun 16;19(4):595-601. Epub 2019 Apr 16.

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

Background: Pancreatico-enteric anastomosis after pancreaticoduodenectomy can be performed using either a pancreaticojejunostomy (PJ) or pancreaticogastrostomy (PG). Differences in surgical outcomes are still a matter of debate, and less is known about long-term functional outcomes.

Methods: Twelve years after the conclusion of a comparative study evaluating the surgical outcomes of PJ and PG (Bassi et al., Ann Surg 2005), available patients underwent morphological and functional pancreatic assessment: pancreatic volume and duct diameter measured by MRI, impaired secretion after secretin, fecal fat, fecal elastase-1 (FE-1), serum vitamin D and endocrine function. Quality of life and symptom scores were evaluated with the EORTC QLQ-C30 questionnaire.

Results: Only 34 patients were available for assessment. No differences were found in terms of BMI variation, endocrine function, quality of life or symptoms. Exocrine function was more severely impaired after PG than after PJ (fecal fats 26.6 ± 4.1 vs 18.2 ± 3.6 g/day; FE-1 121.4 ± 6.7 vs 170.2 ± 25.5 μg/g, vitamin D 18.1 ± 1.8 vs. 23.2 ± 3.1 ng/mL). MRI assessment identified a lower pancreatic volume (26 ± 3.1 vs. 36 ± 4.1 cm) and a more dilated pancreatic duct (4.6 ± 0.92 vs. 2.4 ± 0.18 mm) in patients with PG compared to those with PJ.

Conclusion: Compared to PJ, PG is associated with a more severely impaired exocrine function long-term, but they result similar endocrine function and quality of life. In patients with a long life expectancy, this should be taken into account.
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http://dx.doi.org/10.1016/j.pan.2019.04.004DOI Listing
June 2019

Results of First-Round of Surveillance in Individuals at High-Risk of Pancreatic Cancer from the AISP (Italian Association for the Study of the Pancreas) Registry.

Am J Gastroenterol 2019 04;114(4):665-670

Pancreatic Surgery Unit, Humanitas Clinical and Research Center, Milano, Italy.

Introduction: Surveillance programs on high-risk individuals (HRIs) can detect pre-malignant lesions or early pancreatic cancer (PC). We report the results of the first screening round of the Italian multicenter program supported by the Italian Association for the study of the Pancreas (AISP).

Methods: The multicenter surveillance program included asymptomatic HRIs with familial (FPC) or genetic frailty (GS: BRCA1/2, p16/CDKN2A, STK11/LKB1or PRSS1, mutated genes) predisposition to PC. The surveillance program included at least an annual magnetic resonance cholangio pancreatography (MRCP). Endoscopic ultrasound (EUS) was proposed to patients who refused or could not be submitted to MRCP.

Results: One-hundreds eighty-seven HRIs underwent a first-round screening examination with MRCP (174; 93.1%) or EUS (13; 6.9%) from September 2015 to March 2018.The mean age was 51 years (range 21-80).One-hundreds sixty-five (88.2%) FPC and 22 (11.8%) GF HRIs were included. MRCP detected 28 (14.9%) presumed branch-duct intraductal papillary mucinous neoplasms (IPMN), 1 invasive carcinoma/IPMN and one low-grade mixed-type IPMN, respectively. EUS detected 4 PC (2.1%): 1 was resected, 1 was found locally advanced intraoperatively, and 2 were metastatic. Age > 50 (OR 3.3, 95%CI 1.4-8), smoking habit (OR 2.8, 95%CI 1.1-7.5), and having > 2 relatives with PC (OR 2.7, 95%CI 1.1-6.4) were independently associated with detection of pre-malignant and malignant lesions. The diagnostic yield for MRCP/EUS was 24% for cystic lesions. The overall rate of surgery was 2.6% with nil mortality.

Discussion: The rate of malignancies found in this cohort was high (2.6%). According to the International Cancer of the Pancreas Screening Consortium the screening goal achievement was high (1%).
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http://dx.doi.org/10.1038/s41395-018-0414-zDOI Listing
April 2019

Intravoxel incoherent motion diffusion-weighted MR imaging of solid pancreatic masses: reliability and usefulness for characterization.

Abdom Radiol (NY) 2019 01;44(1):131-139

Department of Radiology, Ospedale P. Pederzoli, Via Monte Baldo, 24, 37019, Peschiera del Garda, Italy.

Purpose: IVIM-DW imaging has shown potential usefulness in the study of pancreatic lesions. Controversial results are available regarding the reliability of the measurements of IVIM-derived parameters. The aim of this study was to evaluate the reliability and the diagnostic potential of IVIM-derived parameters in differentiation among focal solid pancreatic lesions and normal pancreas (NP).

Methods: Fifty-seven patients (34 carcinomas-PDACs, 18 neuroendocrine neoplasms-panNENs, and 5 autoimmune pancreatitis-AIP) and 50 subjects with NP underwent 1.5-T MR imaging including IVIM-DWI. Images were analyzed by two independent readers. Apparent diffusion coefficient (ADC), slow component of diffusion (D), incoherent microcirculation (Dp), and perfusion fraction (f) were calculated. Interobserver reliability was assessed with intraclass correlation coefficient (ICC). A Kruskal-Wallis H test with Steel-Dwass post hoc test was used for comparison. The diagnostic performance of each parameter was evaluated through receiver operating characteristic (ROC) curve analysis.

Results: Overall interobserver agreement was excellent (ICC = 0.860, 0.937, 0.968, and 0.983 for ADC, D, Dp, and f). D, Dp, and f significantly differed among PDACs and panNENs (p = 0.002, < 0.001, and < 0.001), albeit without significant difference at the pairwise comparison of ROC curves (p = 0.08-0.74). Perfusion fraction was higher in AIP compared with PDACs (p = 0.024; AUC = 0.735). Dp and f were higher in panNENs compared with AIP (p = 0.029 and 0.023), without differences at ROC analysis (p = 0.07).

Conclusions: IVIM-derived parameters have excellent reliability and could help in differentiation among solid pancreatic lesions and NP.
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http://dx.doi.org/10.1007/s00261-018-1684-zDOI Listing
January 2019

Polyester sutures for pancreaticojejunostomy protect against postoperative pancreatic fistula: a case-control, risk-adjusted analysis.

HPB (Oxford) 2018 10 28;20(10):977-983. Epub 2018 May 28.

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

Background: There is wide variability in the use of suture material for pancreatic anastomosis after pancreaticoduodenectomy (PD). This study evaluates the role of suture material on clinically relevant postoperative pancreatic fistula (CR-POPF) after pancreaticojejunostomy (PJ) in a risk-adjusted setting.

Methods: A retrospective study comparing (polyester) PE with polydioxanone (PDO) in 520 PDs. Patients were matched for risk for CR-POPF according to the fistula risk score (FRS) with the propensity score.

Results: The matched PE and PDO groups consisted of 232 patients. The incidence of CR-POPF was lower for PE group (11.6 vs. 22%, p<0.01), with a lower rate of grade B (10.3 vs. 15.5%, p<0.01) and C (1.3 vs. 6.5%, p<0.01). After stratifying by fistula risk zone, PE suture remained associated with a reduced incidence of CR-POPF (9.4 vs. 15.6% low-, p = 0.04; 15.6 vs. 28.1% intermediate-, p = 0.02; 16.7 vs. 83.3% high-risk zone, p<0.01, respectively). Multivariable analysis demonstrated that pancreatic texture, preoperative diagnosis, FRS and the use of PE sutures were independent predictors of CR-POPF.

Conclusions: In the setting of a case-control matched for risk analysis, the use of PE suture for PJ is associated with a significant reduction of CR-POPF.
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http://dx.doi.org/10.1016/j.hpb.2018.04.007DOI Listing
October 2018

Technique, safety, and feasibility of EUS-guided radiofrequency ablation in unresectable pancreatic cancer.

Surg Endosc 2018 09 15;32(9):4022-4028. Epub 2018 May 15.

Department of Hepato-Pancreato-Biliary Surgery, Pederzoli Hospital, via Monte Baldo 24, 37019, Peschiera del Garda, VR, Italy.

Background And Aims: Radiofrequency ablation (RFA) is a well-recognized local ablative technique applied in the treatment of different solid tumors. Intraoperative RFA has been used for non-metastatic unresectable pancreatic ductal adenocarcinoma (PDAC), showing increased overall survival in retrospective studies. A novel RFA probe has recently been developed, allowing RFA under endoscopic ultrasound (EUS) guidance. Aim of the present study was to assess the feasibility and safety of EUS-guided RFA for unresectable PDACs.

Methods: Patients with unresectable non-metastatic PDAC were included in the study following neoadjuvant chemotherapy. EUS-guided RFA was performed using a novel monopolar 18-gauge electrode with a sharp conical 1 cm tip for energy delivery. Pre- and post-procedural clinical and radiological data were prospectively collected.

Results: Ten consecutive patients with unresectable PDAC were enrolled. The procedure was successful in all cases and no major adverse events were observed. A delineated hypodense ablated area within the tumor was observed at the 30-day CT scan in all cases.

Conclusions: EUS-guided RFA is a feasible and safe minimally invasive procedure for patients with unresectable PDAC. Further studies are warranted to demonstrate the impact of EUS-guided RFA on disease progression and overall survival.
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http://dx.doi.org/10.1007/s00464-018-6217-xDOI Listing
September 2018

Pancreatic ductal adenocarcinoma can be detected by analysis of volatile organic compounds (VOCs) in alveolar air.

BMC Cancer 2018 May 4;18(1):529. Epub 2018 May 4.

Department of Diagnostics and Public Health - Occupational Medicine Unit, University of Verona, Policlinico Borgo Roma, Piazzale LA Scuro 10, 37134, Verona, Italy.

Background: In the last decade many studies showed that the exhaled breath of subjects suffering from several pathological conditions has a peculiar volatile organic compound (VOC) profile. The objective of the present work was to analyse the VOCs in alveolar air to build a diagnostic tool able to identify the presence of pancreatic ductal adenocarcinoma in patients with histologically confirmed disease.

Methods: The concentration of 92 compounds was measured in the end-tidal breath of 65 cases and 102 controls. VOCs were measured with an ion-molecule reaction mass spectrometry. To distinguish between subjects with pancreatic adenocarcinomas and controls, an iterated Least Absolute Shrinkage and Selection Operator multivariate Logistic Regression model was elaborated.

Results: The final predictive model, based on 10 VOCs, significantly and independently associated with the outcome had a sensitivity and specificity of 100 and 84% respectively, and an area under the ROC curve of 0.99. For further validation, the model was run on 50 other subjects: 24 cases and 26 controls; 23 patients with histological diagnosis of pancreatic adenocarcinomas and 25 controls were correctly identified by the model.

Conclusions: Pancreatic cancer is able to alter the concentration of some molecules in the blood and hence of VOCs in the alveolar air in equilibrium. The detection and statistical rendering of alveolar VOC composition can be useful for the clinical diagnostic approach of pancreatic neoplasms with excellent sensitivity and specificity.
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http://dx.doi.org/10.1186/s12885-018-4452-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935919PMC
May 2018

Can histogram analysis of MR images predict aggressiveness in pancreatic neuroendocrine tumors?

Eur Radiol 2018 Jun 19;28(6):2582-2591. Epub 2018 Jan 19.

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

Objectives: To evaluate MRI derived whole-tumour histogram analysis parameters in predicting pancreatic neuroendocrine neoplasm (panNEN) grade and aggressiveness.

Methods: Pre-operative MR of 42 consecutive patients with panNEN >1 cm were retrospectively analysed. T1-/T2-weighted images and ADC maps were analysed. Histogram-derived parameters were compared to histopathological features using the Mann-Whitney U test. Diagnostic accuracy was assessed by ROC-AUC analysis; sensitivity and specificity were assessed for each histogram parameter.

Results: ADC was significantly higher in G2-3 tumours with ROC-AUC 0.757; sensitivity and specificity were 83.3 % (95 % CI: 61.2-94.5) and 61.1 % (95 % CI: 36.1-81.7). ADC was higher in panNENs with vascular involvement, nodal and hepatic metastases (p= .008, .021 and .008; ROC-AUC= 0.820, 0.709 and 0.820); sensitivity and specificity were: 85.7/74.3 % (95 % CI: 42-99.2 /56.4-86.9), 36.8/96.5 % (95 % CI: 17.2-61.4 /76-99.8) and 100/62.8 % (95 % CI: 56.1-100/44.9-78.1). No significant differences between groups were found for other histogram-derived parameters (p >.05).

Conclusions: Whole-tumour histogram analysis of ADC maps may be helpful in predicting tumour grade, vascular involvement, nodal and liver metastases in panNENs. ADC and ADC are the most accurate parameters for identification of panNENs with malignant behaviour.

Key Points: • Whole-tumour ADC histogram analysis can predict aggressiveness in pancreatic neuroendocrine neoplasms. • ADC entropy and kurtosis are higher in aggressive tumours. • ADC histogram analysis can quantify tumour diffusion heterogeneity. • Non-invasive quantification of tumour heterogeneity can provide adjunctive information for prognostication.
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http://dx.doi.org/10.1007/s00330-017-5236-7DOI Listing
June 2018

The Evolution of Surgical Strategies for Pancreatic Neuroendocrine Tumors (Pan-NENs): Time-trend and Outcome Analysis From 587 Consecutive Resections at a High-volume Institution.

Ann Surg 2019 04;269(4):725-732

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

Objective: The objective of the present analysis is 2-fold: first, to define the evolution of time trends on the surgical approach to pancreatic neuroendocrine neoplasms (Pan-NENs); second, to perform a complete analysis of the predictors of oncologic outcome.

Background: Reflecting their rarity and heterogeneity, Pan-NENs represent a clinical dilemma. In particular, there is a scarcity of data regarding their long-term follow-up after surgical resection.

Methods: From the Institutional Pan-NEN database, 587 resected cases from 1990 to 2015 were extracted. The time span was arbitrarily divided into 3 discrete clusters enabling a balanced comparison between patient groups. Analyses for predictors of recurrence and survival were performed, together with conditional survival analyses.

Results: Among the 587 resected Pan-NENs, 75% were nonfunctioning tumors, and 5% were syndrome-associated tumors. The mean age was 54 years (±14 years), and 51% of the patients were female. The median tumor size was 20 mm (range 4 to 140), 62% were G1, 32% were G2, and 4% were G3 tumors. Time trends analysis revealed that the number of resected Pan-NENs constantly increased, while the size (from 25 to 20 mm) and G1 proportion (from 65% to 49%) decreased during the study period. After a mean follow-up of 75 months, recurrence analysis revealed that nonfunctioning tumors, tumor grade, N1 status, and vascular invasion were all independent predictors of recurrence. Regardless of size, G1 nonfunctioning tumors with no nodal involvement and vascular invasion had a negligible risk of recurrence at 5 years.

Conclusions: Pan-NENs have been increasingly diagnosed and resected during the last 3 decades, revealing reliable predictors of outcome. Functioning and nodal status, tumor grade, and vascular invasion accurately predict survival and recurrence with resulting implications for patient follow-up.
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http://dx.doi.org/10.1097/SLA.0000000000002594DOI Listing
April 2019

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

Ann Surg 2019 01;269(1):10-17

Department of Surgery, Pederzoli Hospital, Peschiera, Italy.

Objective: The aim of this study was to compare oncological outcomes after minimally invasive distal pancreatectomy (MIDP) with open distal pancreatectomy (ODP) in patients with pancreatic ductal adenocarcinoma (PDAC).

Background: Cohort studies have suggested superior short-term outcomes of MIDP vs. ODP. Recent international surveys, however, revealed that surgeons have concerns about the oncological outcomes of MIDP for PDAC.

Methods: This is a pan-European propensity score matched study including patients who underwent MIDP (laparoscopic or robot-assisted) or ODP for PDAC between January 1, 2007 and July 1, 2015. MIDP patients were matched to ODP patients in a 1:1 ratio. Main outcomes were radical (R0) resection, lymph node retrieval, and survival.

Results: In total, 1212 patients were included from 34 centers in 11 countries. Of 356 (29%) MIDP patients, 340 could be matched. After matching, the MIDP conversion rate was 19% (n = 62). Median blood loss [200 mL (60-400) vs 300 mL (150-500), P = 0.001] and hospital stay [8 (6-12) vs 9 (7-14) days, P < 0.001] were lower after MIDP. Clavien-Dindo grade ≥3 complications (18% vs 21%, P = 0.431) and 90-day mortality (2% vs 3%, P > 0.99) were comparable for MIDP and ODP, respectively. R0 resection rate was higher (67% vs 58%, P = 0.019), whereas Gerota's fascia resection (31% vs 60%, P < 0.001) and lymph node retrieval [14 (8-22) vs 22 (14-31), P < 0.001] were lower after MIDP. Median overall survival was 28 [95% confidence interval (CI), 22-34] versus 31 (95% CI, 26-36) months (P = 0.929).

Conclusions: Comparable survival was seen after MIDP and ODP for PDAC, but the opposing differences in R0 resection rate, resection of Gerota's fascia, and lymph node retrieval strengthen the need for a randomized trial to confirm the oncological safety of MIDP.
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http://dx.doi.org/10.1097/SLA.0000000000002561DOI Listing
January 2019