Publications by authors named "Vincenzo Mazzaferro"

235 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

Long Term Survival Analysis in a Cohort of 125 Patients with Hepatocellular Carcinoma Treated with Transarterial Chemoembolization Using Small Drug Eluting Beads.

Cardiovasc Intervent Radiol 2021 Nov 24. Epub 2021 Nov 24.

Interventional Vascular and Hepatobiliary Unit, Department of Radiodiagnostics and Radiotherapy, IRCCS Fondazione Istituto Nazionale Tumori di Milano, Milan, Italy.

Purpose: Different types of drug-eluting beads have been proposed for hepatocellular carcinoma (HCC) treatment, but long-term results are not well known. We report safety, efficacy and long-term overall survival of HCC patients not amenable of curative therapies treated with transcatheter arterial chemoembolization (TACE) using drug-eluting beads sized 70-150 micron.

Materials And Methods: This single-center retrospective study included 125 patients with Barcelona Clinic Liver Cancer stage A (80), B (45) and compensated cirrhosis. TACE was executed injecting drug-elutings microparticles loaded with 75 mg of Doxorubicine and was repeated in patients with partial response or stable disease after one month. Adverse events, response according to modified Response Evaluation Criteria in Solid Tumors and overall survival were assessed.

Results: Chemoembolization with 70-150 micron beads revealed an objective response rate of 88% according to mRECIST criteria and complete response was 60%. After a median follow-up of 53.3 months, overall survival was 36.6 months. Data were censored at the date of liver transplantation in 35 patients. 33 on 125 patients (26,4%) experienced at least one adverse event. We recorded a total of 102 adverse events and 18 were of a high grade (G3-G4). 30 day mortality was 0%.

Conclusion: Chemoembolization with very small particles (70-150 µm) is an effective and safe treatment in unresectable HCC both as a primary therapy or as bridge to transplantation.
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http://dx.doi.org/10.1007/s00270-021-02991-2DOI 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

Immunotherapies for hepatocellular carcinoma.

Nat Rev Clin Oncol 2021 Nov 11. Epub 2021 Nov 11.

Ronald Reagan University of California, Los Angeles (UCLA) Medical Center, Los Angeles, CA, USA.

Liver cancer, more specifically hepatocellular carcinoma (HCC), is the second leading cause of cancer-related death and its incidence is increasing globally. Around 50% of patients with HCC receive systemic therapies, traditionally sorafenib or lenvatinib in the first line and regorafenib, cabozantinib or ramucirumab in the second line. In the past 5 years, immune-checkpoint inhibitors have revolutionized the management of HCC. The combination of atezolizumab and bevacizumab has been shown to improve overall survival relative to sorafenib, resulting in FDA approval of this regimen. More recently, durvalumab plus tremelimumab yielded superior overall survival versus sorafenib and atezolizumab plus cabozantinib yielded superior progression-free survival. In addition, pembrolizumab monotherapy and the combination of nivolumab plus ipilimumab have received FDA Accelerated Approval in the second-line setting based on early efficacy data. Despite these major advances, the molecular underpinnings governing immune responses and evasion remain unclear. The immune microenvironment has crucial roles in the development and progression of HCC and distinct aetiology-dependent immune features have been defined. Inflamed and non-inflamed classes of HCC and genomic signatures have been associated with response to immune-checkpoint inhibitors, yet no validated biomarker is available to guide clinical decision-making. This Review provides information on the immune microenvironments underlying the response or resistance of HCC to immunotherapies. In addition, current evidence from phase III trials on the efficacy, immune-related adverse events and aetiology-dependent mechanisms of response are described. Finally, we discuss emerging trials assessing immunotherapies across all stages of HCC that might change the management of this disease in the near future.
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http://dx.doi.org/10.1038/s41571-021-00573-2DOI Listing
November 2021

Gastrinoma and Zollinger Ellison syndrome: A roadmap for the management between new and old therapies.

World J Gastroenterol 2021 Sep;27(35):5890-5907

Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy.

Zollinger-Ellison syndrome (ZES) associated with pancreatic or duodenal gastrinoma is characterized by gastric acid hypersecretion, which typically leads to gastroesophageal reflux disease, recurrent peptic ulcers, and chronic diarrhea. As symptoms of ZES are nonspecific and overlap with other gastrointestinal disorders, the diagnosis is often delayed with an average time between the onset of symptoms and final diagnosis longer than 5 years. The critical step for the diagnosis of ZES is represented by the initial clinical suspicion. Hypergastrinemia is the hallmark of ZES; however, hypergastrinemia might recognize several causes, which should be ruled out in order to make a final diagnosis. Gastrin levels > 1000 pg/mL and a gastric pH below 2 are considered to be diagnostic for gastrinoma; some specific tests, including esophageal pH-recording and secretin test, might be useful in selected cases, although they are not widely available. Endoscopic ultrasound is very useful for the diagnosis and the local staging of the primary tumor in patients with ZES, particularly in the setting of multiple endocrine neoplasia type 1. Some controversies about the management of these tumors also exist. For the localized stage, the combination of proton pump inhibitory therapy, which usually resolves symptoms, and surgery, whenever feasible, with curative intent represents the hallmark of gastrinoma treatment. The high expression of somatostatin receptors in gastrinomas makes them highly responsive to somatostatin analogs, supporting their use as anti-proliferative agents in patients not amenable to surgical cure. Other medical options for advanced disease are super-imposable to other neuroendocrine neoplasms, and studies specifically focused on gastrinomas only are scant and often limited to case reports or small retrospective series. The multidisciplinary approach remains the cornerstone for the proper management of this composite disease. Herein, we reviewed available literature about gastrinoma-associated ZES with a specific focus on differential diagnosis, providing potential diagnostic and therapeutic algorithms.
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http://dx.doi.org/10.3748/wjg.v27.i35.5890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475006PMC
September 2021

Is minimally invasive liver surgery a reasonable option in recurrent HCC? A snapshot from the I Go MILS registry.

Updates Surg 2021 Oct 3. Epub 2021 Oct 3.

Division of General Surgery and Liver Transplantation, S. Camillo Hospital, Rome, Italy.

Laparoscopic liver resection (LLR) for Hepatocellular carcinoma (HCC) is a safe procedure. Repeat surgery is more often required, and the role of minimally invasive liver surgery (MILS) is not yet clearly defined. The present study analyzes data compiled by the Italian Group of Minimally Invasive Liver Surgery (IGoMILS) on LLR. To compare repeated LLR with the first LLR for HCC is the primary endpoint. The secondary endpoint was to evaluate the outcome of repeat LLR in the case of primary open versus primary MILS surgery. The data cohort is divided into two groups. Group 1: first liver resection and Group 2: Repeat LLR. To compare the two groups a 3:1 Propensity Score Matching is performed to analyze open versus MILS primary resection. Fifty-two centers were involved in the present study, and 1054 patients were enrolled. 80 patients underwent to a repeat LLR. The type of resection was different, with more major resections in the group 1 before matching the two groups. After propensity score matching 3:1, each group consisted of 222 and 74 patients. No difference between the two groups was observed. In the subgroup analysis, in 44 patients the first resection was performed by an open approach. The other 36 patients were resected with a MILS approach. We found no difference between these two subgroups of patients. The present study in repeat MILS for HCC using the IGoMILS Registry has observed the feasibility and safety of the MILS procedure.
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http://dx.doi.org/10.1007/s13304-021-01161-wDOI Listing
October 2021

Trans-arterial chemoembolization as a loco-regional inducer of immunogenic cell death in hepatocellular carcinoma: implications for immunotherapy.

J Immunother Cancer 2021 09;9(9)

Department of Oncology, University of Milan, Milano, Italy.

Background: Modulation of adaptive immunity may underscore the efficacy of trans-arterial chemoembolization (TACE). We evaluated the influence of TACE on T-cell function by phenotypic lymphocyte characterization in samples of patients undergoing surgery with (T+) or without (T-) prior-TACE treatment.

Methods: We profiled intratumoral (IT), peritumoral (PT) and non-tumoral (NT) background tissue to evaluate regulatory CD4+/FOXP3+ (T-reg) and immune-exhausted CD8+/PD-1+ T-cells across T+ (n=58) and T- (n=61). We performed targeted transcriptomics and T-cell receptor sequencing in a restricted subset of samples (n=24) evaluated in relationship with the expression of actionable drivers of anti-cancer immunity including PD-L1, indoleamine 2,3 dehydrogenase (IDO-1), cytotoxic T-lymphocyte associated protein 4 (CTLA-4), Lag-3, Tim-3 and CD163.

Results: We analyzed 119 patients resected (n=25, 21%) or transplanted (n=94, 79%) for Child-Pugh A (n=65, 55%) and Barcelona Clinic Liver Cancer stage A (n=92, 77%) hepatocellular carcinoma. T+ samples displayed lower IT CD4+/FOXP3+ (p=0.006), CD8+ (p=0.002) and CD8+/PD-1+ and NT CD8+/PD-1+ (p<0.001) compared with T-. Lower IT (p=0.005) and NT CD4+/FOXP3+ (p=0.03) predicted for improved recurrence-free survival. In a subset of samples (n=24), transcriptomic analysis revealed upregulation of a pro-inflammatory response in T+. T+ samples were enriched for IRF2 expression (p=0.01), an interferon-regulated transcription factor implicated in cancer immune-evasion. T-cell clonality and expression of PD-L1, IDO-1, CTLA-4, Lag-3, Tim-3 and CD163 was similar in T+ versus T-.

Conclusions: TACE is associated with lower IT density of immune-exhausted effector cytotoxic and T-regs, with significant upregulation of pro-inflammatory pathways. This highlights the pleiotropic effects of TACE in modulating the tumor microenvironment and strengthens the rationale for developing immunotherapy alongside TACE.
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http://dx.doi.org/10.1136/jitc-2021-003311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487214PMC
September 2021

The role of lymphadenectomy in the surgical treatment of intrahepatic cholangiocarcinoma: A review.

Eur J Surg Oncol 2021 Aug 10. Epub 2021 Aug 10.

Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy; HPB Surgery, Hepatology and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan, Italy.

Cholangiocarcinoma is the second most common primary tumor of the liver. The incidence and mortality of its intrahepatic form has been increasing over the past 2 decades. Currently, the only available curative treatment for intrahepatic cholangiocarcinoma is surgical resection. There is still no prospective evidence to support neoadjuvant systemic treatments in resectable disease, while adjuvant chemotherapy with Capecitabine is currently the only recommended systemic treatment after liver resection based on the results of randomised trial. Despite the implementation of perioperative treatments and improvements in resective surgery, intrahepatic cholangiocarcinoma remains a disease characterized by high incidence of recurrence and poor long-term survival. Lymph node metastases can be found in 45-65% of patients and are one of the most impacting prognostic factors after surgical resection. Preoperative imaging is not always sufficient in assessing lymph node status, thus hepatic pedicle lymphadenectomy can be important to ensure precise staging in surgical patients. An increasing trend in performing lymph node dissection during liver resection for intrahepatic cholangiocarcinoma has been observed in the last 20 years, although its actual efficacy compared to the potential complications remains debated. The current evidence on the prognostic role of the lymph node status, its preoperative predictability, the basis for a correct hepatic pedicle lymphadenectomy and its prognostic role in the surgical treatment of intrahepatic cholangiocarcinoma are presented.
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http://dx.doi.org/10.1016/j.ejso.2021.08.009DOI Listing
August 2021

Regorafenib Efficacy After Sorafenib in Patients With Recurrent Hepatocellular Carcinoma After Liver Transplantation: A Retrospective Study.

Liver Transpl 2021 Dec 16;27(12):1767-1778. Epub 2021 Sep 16.

Gastroenterology, Hepatology and Transplant Unit, Department of Specialty and Transplant Medicine, Azienda Socio Sanitaria Territoriale (ASST) Papa Giovanni XXIII, Bergamo, Italy.

Safety of regorafenib in hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) has been recently demonstrated. We aimed to assess the survival benefit of regorafenib compared with best supportive care (BSC) in LT patients after sorafenib discontinuation. This observational multicenter retrospective study included LT patients with HCC recurrence who discontinued first-line sorafenib. Group 1 comprised regorafenib-treated patients, whereas the control group was selected among patients treated with BSC due to unavailability of second-line options at the time of sorafenib discontinuation and who were sorafenib-tolerant progressors (group 2). Primary endpoint was overall survival (OS) of group 1 compared with group 2. Secondary endpoints were safety and OS of sequential treatment with sorafenib + regorafenib/BSC. Among 132 LT patients who discontinued sorafenib included in the study, 81 were sorafenib tolerant: 36 received regorafenib (group 1) and 45 (group 2) received BSC. Overall, 24 (67%) patients died in group 1 and 40 (89%) in group 2: the median OS was significantly longer in group 1 than in group 2 (13.1 versus 5.5 months; P < 0.01). Regorafenib treatment was an independent predictor of reduced mortality (hazard ratio, 0.37; 95% confidence interval [CI], 0.16-0.89; P = 0.02). Median treatment duration with regorafenib was 7.0 (95% CI, 5.5-8.5) months; regorafenib dose was reduced in 22 (61%) patients for adverse events and discontinued for tumor progression in 93% (n = 28). The median OS calculated from sorafenib start was 28.8 months (95% CI, 17.6-40.1) in group 1 versus 15.3 months (95% CI, 8.8-21.7) in group 2 (P < 0.01). Regorafenib is an effective second-line treatment after sorafenib in patients with HCC recurrence after LT.
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http://dx.doi.org/10.1002/lt.26264DOI Listing
December 2021

In Vitro Evaluation of Rigosertib Antitumoral and Radiosensitizing Effects against Human Cholangiocarcinoma Cells.

Int J Mol Sci 2021 Jul 30;22(15). Epub 2021 Jul 30.

Experimental Neurology Unit, School of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, 20900 Monza, Italy.

Cholangiocarcinoma is the first most common cancer of the biliary tract. To date, surgical resection is the only potentially curative option, but it is possible only for a limited percentage of patients, and in any case survival rate is quite low. Moreover, cholangiocarcinoma is often chemotherapy-resistant, and the only drug with a significant benefit for patient's survival is Gemcitabine. It is necessary to find new drugs or combination therapies to treat nonresectable cholangiocarcinoma and improve the overall survival rate of patients. In this work, we evaluate in vitro the antitumoral effects of Rigosertib, a multi-kinase inhibitor in clinical development, against cholangiocarcinoma EGI-1 cell lines. Rigosertib impairs EGI-1 cell viability in a dose- and time-dependent manner, reversibility is dose-dependent, and significant morphological and nuclear alterations occur. Moreover, Rigosertib induces the arrest of the cell cycle in the G2/M phase, increases autophagy, and inhibits proteasome, cell migration, and invasion. Lastly, Rigosertib shows to be a stronger radiosensitizer than Gemcitabine and 5-Fluorouracil. In conclusion, Rigosertib could be a potential therapeutic option, alone or in combination with radiations, for nonresectable patients with cholangiocarcinoma.
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http://dx.doi.org/10.3390/ijms22158230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8348961PMC
July 2021

Prognostic features of gastro-entero-pancreatic neuroendocrine neoplasms in primary and metastatic sites: Grade, mesenteric tumour deposits and emerging novelties.

J Neuroendocrinol 2021 08 16;33(8):e13000. Epub 2021 Jul 16.

1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Updates in classification of gastro-entero-pancreatic neuroendocrine neoplasms better reflect the biological characteristics of these tumours. In the present study, we analysed the characteristics of neuroendocrine tumours that could aid in a more precise stratification of risk groups. In addition, we have highlighted the importance of grade (re)assessment based on investigation of secondary tumour lesions. Two hundred and sixty-four cases of neuroendocrine tumours of gastro-entero-pancreatic origin from three centres were included in the study. Tumour morphology, mitotic count and Ki67 labelling index were evaluated in specimens of primary tumours, lymph node metastases and distant metastases. These variables were correlated with overall survival (OS) and relapse-free survival (RFS). Tumour stage, number of affected lymph nodes, presence of tumour deposits and synchronous/metachronous metastases were tested as possible prognostic features. Mitotic count, Ki-67 labelling index, primary tumour site, tumour stage, presence of tumour deposits and two or more affected lymph nodes were significant predictors of OS and RFS. At the same time, mitotic count and Ki-67 labelling index can be addressed as continuous variables determining prognosis. We observed a very high correlation between the measures of proliferative activity in primary and secondary tumour foci. The presence of isolated tumour deposits was identified as an important determinant of both RFS and OS for pancreatic (hazard ratio [HR] = 7.61, 95% confidence interval [CI] = 3.96-14.6, P < 0.0001 for RFS; HR = 3.28, 95% CI = 1.56-6.87, P = 0.0017 for OS) and ileal/jejunal neuroendocrine tumours (HR = 1.98, 95% CI = 1.25-3.13, P = 0.0036 for RFS and HR 2.59, 95% CI = 1.27-5.26, P = 0.009 for OS). The present study identifies the presence of mesenterial tumour deposits as an important prognostic factor for gastro-entero-pancreatic neuroendocrine tumours, provides evidence that proliferative parameters need to be treated as continuous variables and further supports the importance of grade determination in all available tumour foci.
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http://dx.doi.org/10.1111/jne.13000DOI Listing
August 2021

TremelImumab and Durvalumab Combination for the Non-OperatIve Management (NOM) of Microsatellite InstabiliTY (MSI)-High Resectable Gastric or Gastroesophageal Junction Cancer: The Multicentre, Single-Arm, Multi-Cohort, Phase II INFINITY Study.

Cancers (Basel) 2021 Jun 7;13(11). Epub 2021 Jun 7.

Gastrointestinal Surgery and Liver Transplantation Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.

In resectable gastric or gastroesophageal junction cancer (GC/GEJC), the powerful positive prognostic effect and the potential predictive value for a lack of benefit from the combination of adjuvant/peri-operative chemotherapy for the MSI-high status was demonstrated. Given the high sensitivity of MSI-high tumors for immunotherapy, exploratory trials showed that combination immunotherapy induces a high rate of complete pathological response (pCR), potentially achieving cancer cure without surgery. INFINITY is an ongoing phase II, multicentre, single-arm, multi-cohort trial investigating the activity and safety of tremelimumab and durvalumab as neoadjuvant (Cohort 1) or potentially definitive (Cohort 2) treatment for MSI-high/dMMR/EBV-negative, resectable GC/GEJC. About 310 patients will be pre-screened, to enroll a total of 31 patients, 18 and 13 in Cohort 1 and 2, at 25 Italian Centres. The primary endpoint of Cohort 1 is rate of pCR (ypT0N0) and negative ctDNA after neoadjuvant immunotherapy, of Cohort 2 is 2-year complete response rate, defined as absence of macroscopic or microscopic residual disease (locally/regionally/distantly) at radiological examinations, tissue and liquid biopsy, during non-operative management without salvage gastrectomy. The ongoing INFINITY proof-of-concept study may provide evidence on immunotherapy and the potential omission of surgery in localized/locally advanced GC/GEJC patients selected for dMMR/MSI-high status eligible for radical resection.
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http://dx.doi.org/10.3390/cancers13112839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201030PMC
June 2021

Inter-center agreement of mRECIST in transplanted patients for hepatocellular carcinoma.

Eur Radiol 2021 Dec 12;31(12):8903-8912. Epub 2021 Jun 12.

Department of Medical and Surgical Sciences - DIMEC, Alma Mater Studiorum - University of Bologna, Bologna, Italy.

Objectives: To evaluate the inter-observer reliability of modified Response Evaluation Criteria In Solid Tumours (mRECIST) of patients with hepatocellular carcinoma (HCC) undergoing neo-adjuvant treatments before liver transplant (LT). The agreement of tumor number, size, transplant criteria, and the radiological-pathological concordance were also assessed.

Methods: A total of 180 radiological studies before/after neo-adjuvant therapies performed on 90 patients prior to LT were reviewed from three expert centers. Kappa-statistic and intraclass correlation (ICC) were evaluated on mRECIST and on tumoral features. Complete radiological response (CR) was compared with complete pathological response (CPR).

Results: Before neo-adjuvant therapies, the agreement on tumor number, size, and transplant criteria ranged from moderate (defined as ICC of 0.41-0.60) to almost perfect (ICC of 0.81-0.99), being higher with magnetic resonance imaging (MRI) than CT (0.657-0.899 and 0.422-0.776, respectively). After neo-adjuvant therapies, the agreement decreased, as ICCs ranged between 0.518 and 0.663 with MRI and between 0.508 and 0.677 with CT. Concordant mRECIST pairs were 201 of 270 reviews (76.3%) with a kappa of 0.648 indicating substantial agreement. When the three observers completely agreed on CR, the positive predictive value for CPR was 51.6%. The negative predictive value was 94.2% with a kappa of 0.512 indicating fair agreement between radiology and pathology.

Conclusions: mRECIST agreement was substantial among the three observers involved. The agreement on tumor number, size, and transplant criteria ranged from moderate to almost perfect, with the highest ICCs obtained with MRI before neo-adjuvant therapies. Finally, the predictive value of mRECIST in the diagnosis of CPR was only fair.

Key Points: • The review of 180 radiological exams of patients with hepatocellular carcinoma before and after neo-adjuvant therapies showed that the concordance among three different raters on mRECIST diagnosis was substantial. • The inter-observer reliability on fulfilment of transplant criteria slightly decreased when evaluated through CT and after loco-regional therapies. • The radiological diagnosis of complete response after neo-adjuvant therapies was predictive of complete pathological response in only 51.6% of cases.
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http://dx.doi.org/10.1007/s00330-021-08088-1DOI Listing
December 2021

The Italian Consensus on minimally invasive simultaneous resections for synchronous liver metastasis and primary colorectal cancer: A Delphi methodology.

Updates Surg 2021 Aug 5;73(4):1247-1265. Epub 2021 Jun 5.

Department of Surgery, Regional Hospital of Treviso, Treviso, Italy.

At the time of diagnosis synchronous colorectal cancer, liver metastases (SCRLM) account for 15-25% of patients. If primary tumour and synchronous liver metastases are resectable, good results may be achieved performing surgical treatment incorporated into the chemotherapy regimen. So far, the possibility of simultaneous minimally invasive (MI) surgery for SCRLM has not been extensively investigated. The Italian surgical community has captured the need and undertaken the effort to establish a National Consensus on this topic. Four main areas of interest have been analysed: patients' selection, procedures, techniques, and implementations. To establish consensus, an adapted Delphi method was used through as many reiterative rounds were needed. Systematic literature reviews were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses instructions. The Consensus took place between February 2019 and July 2020. Twenty-six Italian centres participated. Eighteen clinically relevant items were identified. After a total of three Delphi rounds, 30-tree recommendations reached expert consensus establishing the herein presented guidelines. The Italian Consensus on MI surgery for SCRLM indicates possible pathways to optimise the treatment for these patients as consensus papers express a trend that is likely to become shortly a standard procedure for clinical pictures still on debate. As matter of fact, no RCT or relevant case series on simultaneous treatment of SCRLM are available in the literature to suggest guidelines. It remains to be investigated whether the MI technique for the simultaneous treatment of SCRLM maintain the already documented benefit of the two separate surgeries.
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http://dx.doi.org/10.1007/s13304-021-01100-9DOI Listing
August 2021

Postrecurrence Survival After Liver Transplantation for Liver Metastases From Neuroendocrine Tumors.

Transplantation 2021 Dec;105(12):2579-2586

HPB Surgery, Hepatology and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan, Italy.

Background: Liver metastases from neuroendocrine tumors (NETs) are an accepted indication for liver transplantation (LT). Despite strict patient selection, post-LT recurrence is observed in 30%-50% of cases. Postrecurrence survival is poorly investigated as well as factors influencing postrecurrence outcomes.

Methods: Consecutive patients treated at a single institution for post-LT recurrence of NET between January 1, 2004, and December 31, 2018, were included. Baseline patients' characteristics, data on the primary tumor, pretransplant therapies, posttransplant recurrence and treatments, and long-term outcomes were prospectively collected and retrospectively analyzed.

Results: Thirty-two patients presented with post-LT NET recurrence occurring 82.9 mo (interquartile range, 29.4-119.1 mo) from LT, and the most common sites were abdominal lymph nodes (59.4%), peritoneum (6.3%), and lungs (6.3%). Fourteen patients (43.8%) underwent surgery with radical intent. Five- and 10-y survival after recurrence were 76.3% and 45.5%, respectively. Only time from LT to recurrence had a significant impact on postrecurrence survival, being 5-y overall survival 89.5% versus 0% for patients recurring >24 mo after LT versus ≤24 mo, respectively (P = 0.001). Moreover, for patients with Ki-67 monoclonal antibody staining >2% at recurrence, 5 y overall survival was 87.5% versus 0% for those undergoing surgery versus locoregional or systemic treatments (P = 0.011).

Conclusions: The presented results, although based on a retrospective and relatively small series, show that excellent long-term survival is observed after post-LT NET recurrence, particularly in those patients recurring long after LT (>24 mo). An aggressive surgical treatment might result in a new chance of cure for a selected subgroup of patients.
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http://dx.doi.org/10.1097/TP.0000000000003802DOI Listing
December 2021

Improved management of grade B biliary leaks after complex liver resections using gadoxetic acid disodium-enhanced magnetic resonance cholangiography.

Surgery 2021 08 18;170(2):499-506. Epub 2021 Mar 18.

HPB Surgery, Hepatology and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy. Electronic address:

Background: Bile leaks occurring after complex liver resection and lasting >1 week (grade B) usually are managed by means of invasive cholangiography either endoscopic or percutaneous, with a substantial risk of procedure-related complications. The aim of this study was to investigate the ability of gadoxetic acid disodium-enhanced magnetic resonance cholangiography to detect postoperative biliary leaks and avoid invasive cholangiography in case of peripheral location of the fistula.

Methods: Patients with grade B biliary leak after complex liver resection from January 2018 to March 2020 underwent magnetic resonance cholangiography to guide the management of the leak (study group). The primary endpoint was the ability of magnetic resonance cholangiography to reduce the need for invasive cholangiography with respect to similar posthepatectomy leaks collected in the previous 2 years and approached with upfront invasive cholangiography (controls). A series of in-hospital outcomes also were compared.

Results: Out of 533 liver resections, 11 study patients versus 11 control patients with grade B leaks were compared. Magnetic resonance cholangiography achieved 100% accuracy in detection and location of the leak. Five out of 6 peripheral leaks healed without invasive cholangiography. Overall, 50% reduction in the use of invasive cholangiography was observed in the study versus control patients. Median healing time and hospital stay were 38 and 40 days in patients undergoing invasive cholangiography versus 10 and 11 days in patients treated conservatively (P = .007 and 0.012, respectively). Infection rate and other complications rate were 82% vs 20% (P = .01) and 35% vs 40% (P = .5), respectively.

Conclusion: Magnetic resonance cholangiography is a safe, precise, noninvasive tool to detect posthepatectomy bile leaks that can help clinicians in decision-making on conservative versus invasive treatment of fistulas.
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http://dx.doi.org/10.1016/j.surg.2021.02.018DOI Listing
August 2021

Liver resection for perihilar cholangiocarcinoma: Impact of biliary drainage failure on postoperative outcome. Results of an Italian multicenter study.

Surgery 2021 08 20;170(2):383-389. Epub 2021 Feb 20.

Department of General Surgery, Istituto Ospedaliero Fondazione Poliambulanza, Brescia, Italy.

Background: Preoperative biliary drainage may be essential to reduce the risk of postoperative liver failure after hepatectomy for perihilar cholangiocarcinoma. However, infectious complications related to preoperative biliary drainage may increase the risk of postoperative mortality. The strategy and optimal drainage method continues to be controversial.

Methods: This is a retrospective multicenter study including patients who underwent hepatectomy for perihilar cholangiocarcinoma between 2000 and 2016 at 14 Italian referral hepatobiliary centers. The primary end point was to evaluate independent predictors for postoperative outcome in patients undergoing liver resection for perihilar cholangiocarcinoma after preoperative biliary drainage.

Results: Of the 639 enrolled patients, 441 (69.0%) underwent preoperative biliary drainage. Postoperative mortality was 8.9% (12.5% after right-side hepatectomy versus 5.7% after left-side hepatectomy; P = .003). Of the patients, 40.5% underwent preoperative biliary drainage at the first admitting hospital, before evaluation at referral centers. Use of percutaneous preoperative biliary drainage was significantly more frequent at referral centers than at community hospitals where endoscopic preoperative biliary drainage was the most frequent type. The overall failure rate after preoperative biliary drainage was 43.3%, significantly higher at community hospitals than that at referral centers (52.7% v 36.9%; P = .002). Failure of the first preoperative biliary drainage was one of the strongest predictors for postoperative complications after right-side and left-side hepatectomies and for mortality after right-side hepatectomy. Type of preoperative biliary drainage (percutaneous versus endoscopic) was not associated with significantly different risk of mortality.

Conclusion: Failure of preoperative biliary drainage was significantly more frequent at community hospitals and it was an independent predictor for postoperative outcome. Centers' experience in preoperative biliary drainage management is crucial to reduce the risk of failure that is closely associated with postoperative morbidity and mortality.
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http://dx.doi.org/10.1016/j.surg.2021.01.021DOI Listing
August 2021

Transplantation of autologous extracellular vesicles for cancer-specific targeting.

Theranostics 2021 1;11(5):2034-2047. Epub 2021 Jan 1.

Department of Health Sciences, University of Milan, Milan, Italy.

Nano- and microsized extracellular vesicles (EVs) are naturally occurring cargo-bearing packages of regulatory macromolecules, and recent studies are increasingly showing that EVs are responsible for physiological intercellular communication. Nanoparticles encapsulating anti-tumor theranostics represent an attractive "exosome-interfering" strategy for cancer therapy. : Herein, by labeling plasma-derived EVs with indocyanine green (ICG) and following their biodistribution by and imaging, we demonstrate the existence of nanoparticles with a highly selective cancer tropism in the blood of colorectal cancer (CRC) patients but not in that of healthy volunteers. : In CRC patient-derived xenograft (PDX) mouse models, we show that transplanted EVs recognize tumors from the cognate nanoparticle-generating individual, suggesting the theranostic potential of autologous EVs encapsulating tumor-interfering molecules. In large canine breeds bearing spontaneous malignant skin and breast tumors, the same autologous EV transplantation protocol shows comparable safety and efficacy profiles. : Our data show the existence of an untapped resource of intercellular communication present in the blood of cancer patients, which represents an efficient and highly biocompatible way to deliver molecules directly to the tumor with great precision. The novel EV-interfering approach proposed by our study may become a new research direction in the complex interplay of modern personalized cancer therapy.
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http://dx.doi.org/10.7150/thno.51344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797692PMC
August 2021

No benefit after neoadjuvant chemoradiation in stage IV rectal cancer: A propensity score-matched analysis on a real-world population.

Dig Liver Dis 2021 Aug 22;53(8):1041-1047. Epub 2021 Jan 22.

Colorectal Surgery Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: Stage IV rectal cancer occurs in 25% of patients and locoregional control of primary tumor is usually poorly considered, since priority is the treatment of metastatic disease.

Aims: This study evaluates impact of neoadjuvant chemoradiation followed by surgery (nCHRTS) vs. upfront surgery on locoregional control and overall survival in stage IV rectal cancer.

Methods: All patients diagnosed with stage IV rectal carcinoma between 2009 and 2019, undergone elective surgery at the National Cancer Institute of Milan (Italy), were included. Propensity score-based matching was performed between the two study groups. Loco-regional recurrence-free survival (LRRFS) and overall survival (OS) were analysed using Kaplan-Meyer method.

Results: A total of 139 patients were analyzed. After propensity score matching, 88 patients were included in the final analysis. The 3-yr LRRFS rates were 80.3% for nCHRTS vs. 90.4% for upfront surgery patients (p = 0.35). The 3-yr OS rates were respectively 81.8% vs. 58% (p = 0.36). KRAS mutation (HR 2.506, p = 0.038) and extra-liver metastases (HR 4.308, p = 0.003) were both predictive of worse OS in univariate analysis.

Conclusion: The present study failed to demonstrate a significant impact of nCHRTS on LRRFS or OS in stage IV rectal cancer.
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http://dx.doi.org/10.1016/j.dld.2021.01.013DOI Listing
August 2021

Resection of Retro-Hepatic Vena Cava (RHVC) En-bloc with Caudate Lobe without Vascular Exclusion for a Low Grade Leiomyosarcoma of Inferior Vena Cava.

Ann Surg Oncol 2021 Oct 22;28(11):6848-6849. Epub 2021 Jan 22.

HPB Surgery and Liver Transplant Unit, IRCCS National Cancer Institute, University of Milan, Via Venezian 1, 20133, Milan, Italy.

Background: Leiomyosarcomas (LMS) of the inferior vena cava (IVC) originate in the retrohepatic (RHVC) portion in 15% of cases.1 Due to complex anatomy and need to preserve venous outflow from the infra-diaphragmatic viscera, the operation may require total vascular exclusion, veno-venous bypass and hypothermic liver resections.2,3 In this video, virtual planning of the operation allowed a parenchyma-sparing radical resection in a patient with limited liver reserve.

Methods: A 12-cm LMS of RHVC invading the entire segment 1 (i.e., Spiegel's lobe, paracaval portion, and caudate process) was diagnosed in a man with metabolic steato-hepatitis (BMI: 34). He had no response to previous chemotherapy. Major hepatectomy was excluded considering the high risk of postoperative liver failure. 3D-reconstruction of regional anatomy allowed planning of a parenchymal-sparing, en bloc resection of tumor, RHVC, and caudate lobe while avoiding hilar and suprahepatic venous clamping.

Results: The operation strategy relied on the en bloc separation of caudate lobe, RHVC, and tumor from the hepatic veins confluence and the posterior segments after complete mobilization of the liver. Vessel loop-assisted hanging maneuver, encircling tumor, and RHVC with superimposed 3D-reconstructions guided the parenchymal transection, while preserving the middle hepatic vein outflow. RHVC was replaced with prosthetic material.

Conclusions: Complex resection of primary tumor of the IVC en bloc with caudate lobe and RHVC can be attempted in chronic liver diseases at-risk of postoperative failure. Preservations of transhepatic flow and liver function depends on tumor size and preservation of noninvaded hepatic-veins confluence. Preoperative virtual 3D reconstruction is crucial in surgical planning.
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http://dx.doi.org/10.1245/s10434-020-09428-zDOI Listing
October 2021

Liver transplantation as last-resort treatment for patients with bile duct injuries following cholecystectomy: a multicenter analysis.

Ann Gastroenterol 2021 2;34(1):111-118. Epub 2020 Oct 2.

2 Department of Propaedeutic Surgery, Laiko General Hospital, National and Kapodistrian University of Athens, Athens, Greece (Peter Tsaparas, Nikolaos Machairas, Ioannis D. Kostakis, Georgios C. Sotiropoulos).

Background: Liver transplantation (LT) has been used as a last resort in patients with end-stage liver disease due to bile duct injuries (BDI) following cholecystectomy. Our study aimed to identify and evaluate factors that cause or contribute to an extended liver disease that requires LT as ultimate solution, after BDI during cholecystectomy.

Methods: Data from 8 high-volume LT centers relating to patients who underwent LT after suffering BDI during cholecystectomy were prospectively collected and retrospectively analyzed.

Results: Thirty-four patients (16 men, 18 women) with a median age of 45 (range 22-69) years were included in this study. Thirty of them (88.2%) underwent LT because of liver failure, most commonly as a result of secondary biliary cirrhosis. The median time interval between BDI and LT was 63 (range 0-336) months. There were 23 cases (67.6%) of postoperative morbidity, 6 cases (17.6%) of post-transplant 30-day mortality, and 10 deaths (29.4%) in total after LT. There was a higher probability that patients with concomitant vascular injury (hazard ratio 10.69, P=0.039) would be referred sooner for LT. Overall survival following LT at 1, 3, 5 and 10 years was 82.4%, 76.5%, 73.5% and 70.6%, respectively.

Conclusion: LT for selected patients with otherwise unmanageable BDI following cholecystectomy yields acceptable long-term outcomes.
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http://dx.doi.org/10.20524/aog.2020.0541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774661PMC
October 2020

Cancer-derived EVs show tropism for tissues at early stage of neoplastic transformation.

Nanotheranostics 2021 1;5(1):1-7. Epub 2021 Jan 1.

Department of Health Sciences, Center of Excellence on Neurodegenerative Diseases, University of Milan, Italy.

From the past decade, extracellular vesicles (EVs) have attracted considerable attention as tools for the selective delivery of anti-neoplastic drugs to cancer tissues. Compared to other nanoparticles, EVs display interesting unique features including immune compatibility, low toxicity and the ability to encapsulate a large variety of small- and macro-molecules. However, in virtually all studies, investigations on EVs have been focused on fully transformed cancers: the possibility to apply EV technology also to early-stage tumors has never been explored. Herein, we studied the ability of cancer-derived EVs to recognize and deliver their cargo also to incipient cancers. To this purpose, EV biodistribution was studied in MMTV-NeuT genetically modified mice during early mammary transformation, in fully developed breast tumors and in the normal gland of wild type syngeneic mice. EVs were loaded with indocyanine green (ICG), a near-infrared (NIR) dye together with oncolytic viruses and i.v. injected in mice. The nanoparticle biodistribution was assayed by and optical imaging (detecting the ICG) and semiquantitative real-time PCR (measuring the adenoviral genome) in different tissues. Our results demonstrate the ability of cancer-derived EVs to recognize early-stage neoplastic tissues opening the possibility to selectively deliver theranostics also for tumor prevention. Taken together our study demonstrates the ability of EVs to recognize and deliver diagnostic and therapeutic agents not only to fully transformed tissues but also to early stage tumors. These findings pave the way for the synthesis of "universal" EVs-based formulation for targeted cancer therapy.
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http://dx.doi.org/10.7150/ntno.47226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738946PMC
June 2021

ASO Author Reflections: Amid Anatomic Restrictions, Three-Dimensional Surgical Planning Eases En Bloc Resection of the Retro-Hepatic Vena Cava and the Caudate Lobe of the Liver.

Ann Surg Oncol 2021 10 2;28(11):6850-6851. Epub 2021 Jan 2.

GI-HPB and Liver Transplant Unit, IRCCS Istituto Nazionale Tumori, University of Milan, Milan, Italy.

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http://dx.doi.org/10.1245/s10434-020-09439-wDOI Listing
October 2021

DNA Methylation Profiling of Human Hepatocarcinogenesis.

Hepatology 2021 Jul 15;74(1):183-199. Epub 2021 Jun 15.

Division of Liver Diseases, Liver Cancer Program, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.

Background And Aims: Mutations in TERT (telomerase reverse transcriptase) promoter are established gatekeepers in early hepatocarcinogenesis, but little is known about other molecular alterations driving this process. Epigenetic deregulation is a critical event in early malignancies. Thus, we aimed to (1) analyze DNA methylation changes during the transition from preneoplastic lesions to early HCC (eHCC) and identify candidate epigenetic gatekeepers, and to (2) assess the prognostic potential of methylation changes in cirrhotic tissue.

Approach And Results: Methylome profiling was performed using Illumina HumanMethylation450 (485,000 cytosine-phosphateguanine, 96% of known cytosine-phosphateguanine islands), with data available for a total of 390 samples: 16 healthy liver, 139 cirrhotic tissue, 8 dysplastic nodules, and 227 HCC samples, including 40 eHCC below 2cm. A phylo-epigenetic tree derived from the Euclidean distances between differentially DNA-methylated sites (n = 421,997) revealed a gradient of methylation changes spanning healthy liver, cirrhotic tissue, dysplastic nodules, and HCC with closest proximity of dysplasia to HCC. Focusing on promoter regions, we identified epigenetic gatekeeper candidates with an increasing proportion of hypermethylated samples (beta value > 0.5) from cirrhotic tissue (<1%), to dysplastic nodules (≥25%), to eHCC (≥50%), and confirmed inverse correlation between DNA methylation and gene expression for TSPYL5 (testis-specific Y-encoded-like protein 5), KCNA3 (potassium voltage-gated channel, shaker-related subfamily, member 3), LDHB (lactate dehydrogenase B), and SPINT2 (serine peptidase inhibitor, Kunitz type 2) (all P < 0.001). Unsupervised clustering of genome-wide methylation profiles of cirrhotic tissue identified two clusters, M1 and M2, with 42% and 58% of patients, respectively, which correlates with survival (P < 0.05), independent of etiology.

Conclusions: Genome-wide DNA-methylation profiles accurately discriminate the different histological stages of human hepatocarcinogenesis. We report on epigenetic gatekeepers in the transition between dysplastic nodules and eHCC. DNA-methylation changes in cirrhotic tissue correlate with clinical outcomes.
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http://dx.doi.org/10.1002/hep.31659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144238PMC
July 2021

Development and Validation of a Comprehensive Model to Estimate Early Allograft Failure Among Patients Requiring Early Liver Retransplant.

JAMA Surg 2020 12 16;155(12):e204095. Epub 2020 Dec 16.

S. Orsola-Malpighi University Hospital, Bologna, Italy.

Importance: Expansion of donor acceptance criteria for liver transplant increased the risk for early allograft failure (EAF), and although EAF prediction is pivotal to optimize transplant outcomes, there is no consensus on specific EAF indicators or timing to evaluate EAF. Recently, the Liver Graft Assessment Following Transplantation (L-GrAFT) algorithm, based on aspartate transaminase, bilirubin, platelet, and international normalized ratio kinetics, was developed from a single-center database gathered from 2002 to 2015.

Objective: To develop and validate a simplified comprehensive model estimating at day 10 after liver transplant the EAF risk at day 90 (the Early Allograft Failure Simplified Estimation [EASE] score) and, secondarily, to identify early those patients with unsustainable EAF risk who are suitable for retransplant.

Design, Setting, And Participants: This multicenter cohort study was designed to develop a score capturing a continuum from normal graft function to nonfunction after transplant. Both parenchymal and vascular factors, which provide an indication to list for retransplant, were included among the EAF determinants. The L-GrAFT kinetic approach was adopted and modified with fewer data entries and novel variables. The population included 1609 patients in Italy for the derivation set and 538 patients in the UK for the validation set; all were patients who underwent transplant in 2016 and 2017.

Main Outcomes And Measures: Early allograft failure was defined as graft failure (codified by retransplant or death) for any reason within 90 days after transplant.

Results: At day 90 after transplant, the incidence of EAF was 110 of 1609 patients (6.8%) in the derivation set and 41 of 538 patients (7.6%) in the external validation set. Median (interquartile range) ages were 57 (51-62) years in the derivation data set and 56 (49-62) years in the validation data set. The EASE score was developed through 17 entries derived from 8 variables, including the Model for End-stage Liver Disease score, blood transfusion, early thrombosis of hepatic vessels, and kinetic parameters of transaminases, platelet count, and bilirubin. Donor parameters (age, donation after cardiac death, and machine perfusion) were not associated with EAF risk. Results were adjusted for transplant center volume. In receiver operating characteristic curve analyses, the EASE score outperformed L-GrAFT, Model for Early Allograft Function, Early Allograft Dysfunction, Eurotransplant Donor Risk Index, donor age × Model for End-stage Liver Disease, and Donor Risk Index scores, estimating day 90 EAF in 87% (95% CI, 83%-91%) of cases in both the derivation data set and the internal validation data set. Patients could be stratified in 5 classes, with those in the highest class exhibiting unsustainable EAF risk.

Conclusions And Relevance: This study found that the developed EASE score reliably estimated EAF risk. Knowledge of contributing factors may help clinicians to mitigate risk factors and guide them through the challenging clinical decision to allocate patients to early liver retransplant. The EASE score may be used in translational research across transplant centers.
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http://dx.doi.org/10.1001/jamasurg.2020.4095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593884PMC
December 2020

Transplant Oncology in Primary and Metastatic Liver Tumors: Principles, Evidence, and Opportunities.

Ann Surg 2021 03;273(3):483-493

HPB Surgery and Liver Transplantation, Department of Oncology, University of Milan, Milan, Italy and Istituto Nazionale Tumori, Fondazione IRCCS, Milan, Italy.

Transplant oncology defines any application of transplant medicine and surgery aimed at improving cancer patients' survival and/or quality of life. In practice, liver transplantation for selected hepato-biliary cancers is the only solid organ transplant with demonstrated efficacy in curing cancer. Four are the proposed future contributions of transplant oncology in hepato-biliary cancer (4-e). (1) evolutionary approach to cancer care that includes liver transplantation; (2) elucidation of self and non-self recognition systems, by linking tumor and transplant immunology; (3) exploration of innovative endpoints both in clinical and experimental settings taking advantage from the access to the entire liver explant; (4) extension of surgical limitation in the multidisciplinary approach to hepato-biliary oncology. The aim of this review is to define the principles of transplant oncology that may be applied to hepato-biliary cancer treatment and research, attempting to balance current evidences with future opportunities.
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http://dx.doi.org/10.1097/SLA.0000000000004071DOI Listing
March 2021

Mortality after Transplantation for Hepatocellular Carcinoma: A Study from the European Liver Transplant Registry.

Liver Cancer 2020 08 12;9(4):455-467. Epub 2020 May 12.

National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark.

Background And Aims: Prognosis after liver transplantation differs between hepatocellular carcinoma (HCC) arising in cirrhotic and non-cirrhotic livers and aetiology is poorly understood. The aim was to investigate differences in mortality after liver transplantation between these patients.

Methods: We included patients from the European Liver Transplant Registry transplanted due to HCC from 1990 to November 2016 and compared cirrhotic and non-cirrhotic patients using propensity score (PS) calibration of Cox regression estimates to adjust for unmeasured confounding.

Results: We included 22,787 patients, of whom 96.5% had cirrhosis. In the unadjusted analysis, non-cirrhotic patients had an increased risk of overall mortality with a hazard ratio (HR) of 1.37 (95% confidence interval [CI] 1.23-1.52). However, the HR approached unity with increasing adjustment and was 1.11 (95% CI 0.99-1.25) when adjusted for unmeasured confounding. Unadjusted, non-cirrhotic patients had an increased risk of HCC-specific mortality (HR 2.62, 95% CI 2.21-3.12). After adjustment for unmeasured confounding, the risk remained significantly increased (HR 1.62, 95% CI 1.31-2.00).

Conclusions: Using PS calibration, we showed that HCC in non-cirrhotic liver has similar overall mortality, but higher HCC-specific mortality. This may be a result of a more aggressive cancer form in the non-cirrhotic liver as higher mortality could not be explained by tumour characteristics or other prognostic variables.
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http://dx.doi.org/10.1159/000507397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506266PMC
August 2020

Minimally Invasive Stage 1 to Protect Against the Risk of Liver Failure: Results from the Hepatocellular Carcinoma Series of the Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy Italian Registry.

J Laparoendosc Adv Surg Tech A 2020 Oct 9;30(10):1082-1089. Epub 2020 Sep 9.

Department of General Surgery, Azienda Ospedaliero-Universitaria di Bologna, Maggiore Hospital, Bologna, Italy.

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has been described to treat hepatocellular carcinoma (HCC) but burdened, in its pioneering phase, by high morbidity and mortality. With the advent of minimally invasive (MI) techniques in liver surgery, surgical complications, including posthepatectomy liver failure (PHLF), have been dramatically reduced. The primary endpoint of this study was to compare the short-term outcomes of MI- versus open-ALPPS for HCC, with specific focus on PHLF. Data of patients submitted to ALPPS for HCC between 2012 and 2020 were identified from the ALPPS Italian Registry. Patients receiving an MI Stage 1 (MI-ALPPS) constituted the study group, whereas the patients who received an open Stage 1 (open-ALPPS) constituted the control group. Sixty-six patients were enrolled from 12 Italian centers. Stage 1 of ALPPS was performed in 14 patients using an MI approach (21.2%). MI-ALPPS patients were discharged after Stage 1 at a significantly higher rate compared with open-ALPPS (78.6% versus 9.6%,  < .001). After Stage 2, major morbidity after MI-ALPPS was 8.3% compared with 28.6% reported after open-ALPPS. Mortality was nil after MI-ALPPS. Length of hospital stay was significantly shorter in MI-ALPPS (12 days versus 22 days,  < .001). Univariate logistic regression analysis (Firth method) found that both MI-ALPPS (odds ratio [OR] = 0.05,  = .040) and partial parenchymal transection (OR = 0.04,  = .027) were protective against PHLF. This national multicenter study showed that a less invasive approach to ALPPS first stage was associated with a lower overall risk of PHLF.
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http://dx.doi.org/10.1089/lap.2020.0563DOI Listing
October 2020

mTOR Inhibition Is Most Beneficial After Liver Transplantation for Hepatocellular Carcinoma in Patients With Active Tumors.

Ann Surg 2020 11;272(5):855-862

CHRU de Montpellier, APEMAD, Hôpital Saint-Eloi, Service d'Hepato-Gastroentérologie et Transplantation Hepatique, Cedex 5, France.

Objective: The aim of this study was to evaluate the survival benefit of sirolimus in patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC) (exploratory analysis of the SiLVER-trial).

Summary And Background Data: Patients receiving LT) for HCC are at a high risk for tumor recurrence. Calcineurin inhibitors have shown evidence to promote cancer growth, whereas mammalian target of rapamycin (mTOR) inhibitors like sirolimus have anticancer effects. In the SiLVER-trial (Clinicaltrials.gov: NCT00355862), the effect of sirolimus on the recurrence of HCC after LT was investigated in a prospective randomized trial. Although the primary endpoint of improved disease-free survival (DFS) with sirolimus was not met, outcomes were improved for patients in the sirolimus-treatment arm in the first 3 to 5 years. To learn more about the key variables, a multivariate analysis was performed on the SiLVER-trial data.

Patients And Methods: Data from 508 patients of the intention-to-treat analysis were included in exploratory univariate and multivariate models for overall survival (OS), DFS and a competing risk analysis for HCC recurrence.

Results: Sirolimus use for ≥3 months after LT for HCC independently reduced the hazard for death in the multivariate analysis [hazard ratio (HR): 0.7 (95% confidence interval, CI: 0.52-0.96, P = 0.02). Most strikingly, patients with an alpha-fetoprotein (AFP) ≥10 ng/mL and having used sirolimus for ≥3 months, benefited most with regard to OS, DFS, and HCC-recurrence (HR: 0.49-0.59, P = 0.0079-0.0245).

Conclusions: mTOR-inhibitor treatment with sirolimus for ≥3 months improves outcomes in LT for HCC, especially in patients with AFP-evidence of higher tumor activity, advocating particularly for mTOR inhibitor use in this subgroup of patients.

Clinical Trial Registration: EudraCT: 2005-005362-36 CLINICALTRIALS.GOV:: NCT00355862.
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http://dx.doi.org/10.1097/SLA.0000000000004280DOI Listing
November 2020
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