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IDH1-mutated intrahepatic cholangiocarcinomas (IDH1m iCCAs) could be treated with anti-IDH1 drugs, although the high heterogeneity in this class of tumours could limit treatment efficacy.We selected 125 IDH1m iCCAs that were treated as resectable, locally advanced, or metastatic and were screened by the NGS-based FoundationOne gene panel. We conducted a mutation-based clustering of tumours and survival analysis.Three main clusters were identified. The most altered pathways in cluster 1 were cell cycle and apoptosis, RTK/RAS, PI3K, and chromatin modification. Of note, CDKN2A/2B were mutated in 41/44 patients of this cluster. In cluster 2, the most affected pathways were as follows: Chromatin modification, DNA damage control, PI3K, and RTK/RAS. In this cluster, the most frequently mutated genes were ARID1A and PBRM1. The most altered pathways in cluster 3 were as follows: Cell cycle and apoptosis, DNA damage control, TP53, and chromatin modification. Importantly, TP53 was mutated only in cluster 3 patients. In the cohort of patients treated with surgery, cluster 2 showed statistically significant better disease-free survival (DFS) and overall survival (OS) compared with patients in cluster 3 and cluster 1 (p = 0.0014 and p = 0.0003, respectively). In the advanced setting, cluster 2 experienced a statistically significant better PFS (p = 0.0012), a tendency toward a better OS from first-line treatment, and a better OS from first-line progression compared with patients in cluster 1 and cluster 3 (p = 0.0017). We proposed an easy-to-use algorithm able to stratify patients in the three clusters on the basis of the genomic profile.We highlighted three different mutation-based clusters with prognostic significance in a cohort of IDH1m iCCAs.

Background: This multicenter study investigated the predictive value of baseline AFP and on-treatment AFP response for survival in hepatocellular carcinoma (HCC) patients with regorafenib. Materials & methods: A total of 578 patients with HCC treated with regorafenib from 12 institutions in South Korea and Italy were included. Baseline AFP (cutoff, 400 ng/ml) and AFP response (20% reduction from baseline) were analyzed for overall survival (OS) and progression-free survival (PFS). Results: Baseline AFP below 400 ng/ml was a significant factor that was independently associated with longer OS and PFS. AFP response was also a significant factor independently associated with longer OS and PFS. Conclusion: Baseline AFP and AFP response may be used as prognostic factors for survival in HCC treated with regorafenib.

The results of the phase III ClarIDHy trial have led to US FDA approval of ivosidenib as a therapeutic option for patients with locally advanced or metastatic cholangiocarcinoma (CCA) harboring isocitrate dehydrogenase 1 (IDH1) mutations.In this study, we report the first real-world experience including eight patients with previously treated locally advanced or metastatic IDH1-mutated CCA treated with ivosidenib.Patients treated with ivosidenib as second and third line for advanced CCA were collected with the aim of evaluating the survival outcomes. A molecular study has been performed by next-generation sequencing assay.After a median follow up of 9.4 months, median progression-free survival (PFS) from the start of treatment with ivosidenib was 4.4 months (95% confidence interval [CI] 3.3-5.8), whereas median overall survival (OS) was not reached. The disease control rate was 62.5%, with two patients achieving a partial response (25%); 12.5% of patients experienced a treatment-related adverse event (AE), but no grade 3 or higher AEs were reported. The observed grade 2 AEs were prolonged QT interval and hypomagnesemia (25% of the sample). Molecular profiling was performed on six of eight patients, highlighting TP53, BAP1, CDKN2A and CDKN2B as the most common co-altered genes in these patients.Efficacy outcomes were consistent with those reported in the ClarIDHy trial. Real-world experiences on larger samples are needed in order to confirm our results.

Biliary tract cancers are rare malignancies with a poor prognosis and scarce therapeutic strategies. The significance of BRCAness in this setting is already unknown.Tissue specimens of BTC patients treated with platinum-based chemotherapy have been analyzed through the FOUNDATIONPne assay.72/150 (48%) BRCAness mutated and 78/150 (52.0%) wild type (WT) patients were included. The most commonly mutated genes in the BRCAness mutated group were: ARID1A (N = 32, 44%), CDKN2A (N = 23, 32%), KRAS/NRAS (N = 16, 22%), CDKN2B (N = 13, 18%), BRCA2 (N = 13, 18%), PBRM1 (N = 12, 17%), ATM (N = 11, 15%), FGFR2 (N = 10, 14%), TP53 (N = 8, 11%), IRS2 (N = 7, 10%), CREBBP (N = 7, 10%) (table 3, figure 1). At the univariate analysis BRCAness mutation was associated with longer median Progression Free Survival (mPFS) (HR 0.68; 95% CI 0.49-0.95; p = 0.0254); it was not associated with longer mOS but a trend toward a benefit in survival was found (HR 0.77; 95% CI 0.50-1.19; p = 0.2388). Patients with BRCAness mutation showed a higher percentage of disease control rate (77.8 vs 67.9; p = 0.04) compared to patients WT. Multivariate analysis confirmed BRCAness mutation (HR 0.66; 95% CI: 0.45-0.98; p = 0.0422) as independent favorable prognostic factors for PFS and a positive trend was found for OS (HR 0.84; 95% CI: 0.53-1.33; p = 0.3652).BRCAness BTC patients showed a better PFS compared BRCAnessWT patients after exposure to platinum-based chemotherapy. Moreover, the OS curves' trend showed in our analysis suggests that BRCAness mutated patients could benefit from a maintenance therapy with PARPi.

Valentina Burgio,1 Massimo Iavarone,2 Giovanni Giuseppe Di Costanzo,3 Fabio Marra,4 Sara Lonardi,5,6 Emiliano Tamburini,7 Fabio Piscaglia,8 Gianluca Masi,9,10 Ciro Celsa,11 Francesco Giuseppe Foschi,12 Marianna Silletta,13 Daniela Caterina Amoruso,14 Margherita Rimini,15 Mariangela Bruccoleri,2 Raffaella Tortora,3 Claudia Campani,4 Caterina Soldà ,6 Massimo Giuseppe Viola,16 Antonella Forgione,8 Fabio Conti,12 Francesca Salani,9,10 Silvia Catanese,9,10 Carmelo Marco Giacchetto,17 Claudia Fulgenzi,13 Carmine Coppola,14 Pietro Lampertico,18 Antonio Pellino,6,19 Gabriele Rancatore,17 Giuseppe Cabibbo,17 Francesca Ratti,20 Federica Pedica,21 Angelo Della Corte,22 Massimo Colombo,18 Francesco De Cobelli,23 Luca Aldrighetti,20 Stefano Cascinu,1,23 Andrea Casadei-Gardini1,23 1Department of Medical Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, 20132, Italy; 2Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, Milan, Italy; 3Department of Hepatology, Naples, 80131, Italy; 4Dipartimento di Medicina Sperimentale e Clinica, Università di Firenze, Firenze, Italy; 5Early Phase Clinical Trial Unit, Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy; 6Medical Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy; 7Department of Oncology and Palliative Care, Cardinale Hospital, Naples, Italy; 8Division of Internal Medicine, Hepatobiliary and Immunoallergic Disease, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; 9Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy; 10Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy; 11Department of Surgical, Oncological and Oral Sciences (Di.Chir.On.S.), University of Palermo, Palermo, 90127, Italy; 12Internal Medicine, Infermi Hospital, Faenza (AUSL ROMAGNA), Ravenna, Italy; 13Department of Oncology, Campus Bio Medico, Roma, Italy; 14Hepatology Unit, Internal Medicine, Area Stabiese Hospital, Naples, Italy; 15Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, 4121, Italy; 16Department of General Surgery and Emergency Surgery, Cardinale Hospital, Tricase, Italy; 17Section of Gastroenterology & Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, 90127, Italy; 18Liver Center, IRCCS San Raffaele Scientific Institute, Milan, 20132, Italy; 19Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy; 20Hepatobiliary Surgery Division, Liver Center, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, 20132, Italy; 21Department of Experimental Oncology, Pathology Unit, IRCCS San Raffaele Scientific Institute, Milan, 20132, Italy; 22Department of Radiology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, 20132, Italy; 23School of Medicine, Vita-Salute San Raffaele University, Milan, 20132, ItalyCorrespondence: Andrea Casadei-GardiniDepartment of Medical Oncology, IRCCS San Raffaele Hospital, Via Olgettina n. 60, Milan, ItalyEmail casadeigardini@gmail.comBackground: Lenvatinib has been approved in Italy since October 2019 as a first-line therapy for advanced hepatocellular carcinoma (HCC) and to date data on effectiveness and safety of lenvatinib are not available in our region. To fill this gap, we performed a multicentric analysis of the real-world treatment outcomes with the propensity score matching in a cohort of Italian patients with unresectable HCC who were treated with either sorafenib or lenvatinib.Aims and Methods: To evaluate the effectiveness of sorafenib and lenvatinib as primary treatment of advanced HCC in clinical practice we performed a multicentric analysis of the treatment outcomes of 288 such patients recruited in 11 centers in Italy. A propensity score was used to mitigate confounding due to referral biases in the assessment of mortality and progression-free survival.Results: Over a follow-up period of 11 months the Cox regression model showed 48% reduction of death risk for patients treated with lenvatinib (95% CI: 0.34– 0.81; p = 0.0034), compared with those treated with sorafenib. The median PFS was 9.0 and 4.9 months for lenvatinib and sorafenib arm, respectively. Patients treated with lenvatinib showed a higher percentage of response rate (29.4% vs 2.8%; p < 0.00001) compared with patients treated with sorafenib. Sorafenib was shown to be correlated with more HFSR, diarrhea and fatigue, while lenvatinib with more hypertension and fatigue.Conclusion: Our study highlighted for the first time the efficacy and safety of lenvatinib in an Italian cohort of patients.Keywords: hepatocarcinoma, sorafenib, lenvatinib

Purpose: The purpose of this study is to compare response rates of lenvatinib and atezolizumab plus bevacizumab, in first-line real-world setting. Methods: Overall cohort included Western and Eastern hepatocellular carcinoma (HCC) patient populations from 46 centres in 4 countries (Italy, Germany, Japan, and Republic of Korea). Results: 1312 patients were treated with lenvatinib, and 823 patients were treated with atezolizumab plus bevacizumab. Objective response rate (ORR) was 38.6% for patients receiving lenvatinib, and 27.3% for patients receiving atezolizumab plus bevacizumab (p < 0.01; odds ratio 0.60). For patients who achieved complete response (CR), overall survival (OS) was not reached in both arms, but the result from univariate Cox regression model showed 62% reduction of death risk for patients treated with atezolizumab plus bevacizumab (p = 0.05). In all multivariate analyses, treatment arm was not found to be an independent factor conditioning OS. Comparing ORR achieved in the two arms, there was a statistically significant difference in favor of lenvatinib compared to atezolizumab plus bevacizumab in all subgroups except for Eastern patients, Child-Pugh B patients, presence of portal vein thrombosis, α-feto-protein ≥ 400 ng/mL, presence of extrahepatic disease, albumin-bilirubin (ALBI) grade 2, and no previous locoregional procedures. Conclusion: Lenvatinib achieves higher ORR in all patient subgroups. Patients who achieve CR with atezolizumab plus bevacizumab can achieve OS so far never recorded in HCC patients. This study did not highlight any factors that could identify patient subgroups capable of obtaining CR.

Introduction: The prognostic nutritional index (PNI) is a multiparametric score introduced by Onodera based on the blood levels of lymphocytes and albumin in patients with gastrointestinal neoplasms. Regarding hepatocellular carcinoma (HCC), its prognostic role has been demonstrated in patients treated with sorafenib and lenvatinib. The aim of this real-world study is to investigate the association between clinical outcomes and PNI in patients being treated with atezolizumab plus bevacizumab. Methods: The overall cohort of this multicentric study included 871 consecutive HCC patients from 4 countries treated with atezolizumab plus bevacizumab in first-line therapy. The PNI was calculated as follows: 10 × serum albumin concentration (g/dL) + 0.005 × peripheral lymphocyte count (number/mm3). Results: For only 773 patients, data regarding lymphocyte counts and albumin levels were available, so only these patients were included in the final analysis. The cut-off point of the PNI was determined to be 41 by receiver operating characteristic (ROC) analysis. 268 patients (34.7%) were categorized as the PNI-low group, while the remaining 505 (65.3%) patients as the PNI-high group. At the univariate analysis, high PNI was associated with longer overall survival (OS) (22.5 vs. 10.1 months, HR 0.34, p < 0.01) and progression-free survival (PFS) (8.7 vs. 5.8 months, HR 0.63, p < 0.01) compared to patients with low PNI. At the multivariate analysis, high versus low PNI resulted as an independent prognostic factor for OS (HR 0.49 , p < 0.01) and PFS (HR 0.82, p = 0.01). There was no difference in objective response rate (ORR) between the two groups (high 26.1% vs. low 19.8%, p = 0.09), while disease control rate (DCR) was significantly higher in the PNI-high group (76.8% vs. 66.4%, p = 0.01). Conclusion: PNI is an independent prognostic factor for OS and PFS in HCC patients on first-line treatment with atezolizumab plus bevacizumab.

Biliary tract cancer’s (BTC) treatment main stone for advanced stages is constituted by chemotherapy. Surgical centralization and physicians’ confidence in the use of new technologies and molecular analysis turned out to be of interest and potentially influencing survival. After applying a random-effect model, the relationship between each clinical variable on the main outcome was investigated through multilevel mixed-effects logistic regression. The risk-standardized outcomes were calculated for each centre involved. In the unadjusted cohort the median survival was 8.6 months (95%C.I.: 7.8–9.3) with a 9-month survival rate of 48.3% (95%C.I.: 45.0–51.5). A substantial heterogeneity across hospitals was found (I2: 70.3%). In multilevel mixed effect logistic regression, male, being treated for gallbladder cancer, higher ECOG, increased NLR, CEA and Ca 19.9 and low value of haemoglobin showed to increase the odds for 9-month mortality. The model estimated that the residual variance observed in 9-month mortality was attributable for the 2.6% to the treating hospital. Through a multilevel mixed effect model, average risk-standardized mortality within 9 months was 50.1%. As noticeable, all hospital’s risk-standardized mortality falls within 95%C.I., thus all participating centres provided similar outcomes when adjusted for patient case-mix. Heterogenicity between hospital did not affect the outcome in term of overall survival.

Lenvatinib was the first drug approved in 2017 for first-line treatment of hepatocarcinoma (HCC) after 10 years of Sorafenib as exclusive standard of care. The therapeutic armamentarium has recently expanded following the approval of atezolizumab plus bevacizumab.Numerous studies have been conducted during the past 5 years on Lenvatinib use in real-world settings in an effort to determine prognostic and predictive factors of Lenvatinib efficacy. In order to choose the most effective therapeutic approach, it may be helpful to summarize these results in this review.A subgroup that appears to benefit most from Lenvatinib therapy are patients with non-viral cirrhosis. This aspect is of great importance today considering the increase in NASH prevalence. Also, a significant proportion of BCLC B patients appear to respond well to Lenvatinib therapy. The biological heterogeneity highlighted in HCC patients, along with the growing number of therapeutic options, makes the identification of stratification tools able to define which patients are more likely to respond to a treatment rather than another one of crucial interest. Further investigation deepening the biological pathways underlying HCC carcinogenesis are of particular interest in order to pave the way for precision medicine even for HCC patients.

Recent advances in systemic therapeutic options have led to improved survival in patients with advanced hepatocellular carcinoma. In order to optimize patient outcomes across different disease stages, attempts are being made at exploiting combinations of loco-regional treatments and systemic therapeutic regimens. The possibilities of a beneficial synergistic effect are strongly supported by biological evidence of changes in tumor microenvironment and systemic immunity. With the advent of newer interventional technologies and newer biological and immunological drugs, these possibilities keep on gaining interest and expectations, yet many questions remain unanswered as to how to best manipulate and combine the two therapeutic approaches.This review aims at providing a general overview of biological foundations, preliminary clinical applications, critical issues and future directions of this constantly growing field.

Atezolizumab plus bevacizumab and lenvatinib have not been compared in a randomised controlled trial. We conducted a retrospective multi-centre study to compare the clinical efficacy and safety of lenvatinib and atezolizumab with bevacizumab as a first-line treatment for patients with unresectable HCC in the real-world scenario.Clinical features of lenvatinib and atezolizumab plus bevacizumab patients were balanced through inverse probability of treatment weighting (IPTW) methodology, which weights patients' characteristics and measured outcomes of each patient in both treatment arms. Overall survival (OS) was the primary end-point.The analysis included 1341 patients who received lenvatinib, and 864 patients who received atezolizumab plus bevacizumab. After IPTW adjustment, atezolizumab plus bevacizumab did not show a survival advantage over lenvatinib HR 0.97 (p = 0.739). OS was prolonged by atezolizumab plus bevacizumab over lenvatinib in viral patients (HR: 0.76; p = 0.024). Conversely, OS was prolonged by lenvatinib in patients with non-alcoholic steatohepatitis/non-alcoholic fatty liver disease (HR: 1.88; p = 0.014). In the IPTW-adjusted population, atezolizumab plus bevacizumab provided better safety profile for most of the recorded adverse events.Our study did not identify any meaningful difference in OS between atezolizumab plus bevacizumab and lenvatinib. Although some hints are provided suggesting that patients with non-alcoholic steatohepatitis/non-alcoholic fatty liver disease might benefit more from lenvatinib therapy and patients with viral aetiology more from atezolizumab plus bevacizumab.

Introduction: Biliary Tract Cancer (BTC) is a heterogeneous group of malignant neoplasms with a complex molecular pathogenesis. The prognosis of metastatic disease is dramatically dismal and therapeutic options are scarce. Systemic chemotherapy is the gold standard for the metastatic disease. However, because of the disappointing results with conventional chemotherapy, investigators have turned to new biological therapeutic options targeting the main molecular pathways, neo-angiogenesis, involved in the disease pathogenesis.Areas covered: This paper examines the rationale of using antiangiogenic therapies in this setting, evaluates the therapeutic implications, and highlights ongoing studies and future perspectives. A Pubmed systematic review of preclinical and clinical data was performed which enabled the composition of this paper.Expert opinion: Amore in-depth understanding of the interplay between the neo-angiogenesis pathways, and the microenvironment will could propel the design new therapeutic strategies. Nowadays, the combination of antiangiogenic drugs and immune check-point inhibitors looks promising, but further, more comprehensive data are necessary to gain afuller picture. In an era of novel technologies and techniques, which includes radiomics, the challenge is to identify the biomarkers of response to antiangiogenic drugs which will permit the selection of patients that are more likely to respond to antiangiogenic therapies.

Background: Regorafenib has been shown to improve clinical outcomes compared to placebo, becoming a standard second-line therapy for sorafenib-progressed and -tolerated hepatocellular carcinoma (HCC) patients. Objective: We performed a multicentre, retrospective study in Italy and Korea to evaluate the effectiveness of the treatment sequence sorafenib–regorafenib compared with sorafenib and physician’s choice in a real-life setting. Patients and Methods: A propensity score model was developed to control the results for baseline variable imbalances between the arm treated with sorafenib and regorafenib (S–R) and the arm treated with sorafenib and physician’s choice (S–P). Survival analysis was conducted on the matched population. Results: After the application of propensity score matching, we analysed 99 patients in the arm treated with S–R and 99 patients in the arm treated with S–P. For the S–R group, the median overall survival was 22.2 months (95% CI 17.1–27.4), compared to 17.9 months (95% CI 15.1–50.0) for the S–P group. The results of the univariate analysis showed a 31% reduction of death risk for patients treated with S–R (p = 0.0382) compared to patients treated with S–P. Interaction tests highlighted the predictive role of alpha-fetoprotein (AFP), neutrophil-to-lymphocyte ratio (NLR), and extrahepatic spread. Conclusion: This study provides additional proof of the superiority of the S–R treatment over the S–P treatment approach in advanced HCC patients from a real-life setting.

579 Background: Atezolizumab plus bevacizumab and lenvatinib have not been compared in a randomized controlled trial. We conducted a retrospective multi-center study to compare the clinical efficacy and safety of lenvatinib and atezolizumab with bevacizumab as a first-line treatment for patients with unresectable HCC in the real-world scenario. Methods: Clinical features of lenvatinib and atezolizumab plus bevacizumab patients were balanced through inverse probability of treatment weighting (IPTW) methodology, which weights patients' characteristics and measured outcomes of each patient in both treatment arms. Overall survival was the primary endpoint. Results: The analysis included 1,341 patients who received lenvatinib, and 864 patients who received atezolizumab plus bevacizumab. After IPTW adjustment, atezolizumab plus bevacizumab did not show a survival advantage over lenvatinib HR 0.97 (p=0.739). OS was prolonged by atezolizumab plus bevacizumab over lenvatinib in viral patients (HR: 0.76; p=0.024). Conversely, OS was prolonged by lenvatinib in patients with NASH/NAFLD (HR: 1.88; p=0.014). In the IPTW-adjusted population, atezolizumab plus bevacizumab provided better safety profile for most of the recorded adverse events. Conclusions: Our study did not identify any meaningful difference in overall survival between atezolizumab plus bevacizumab and lenvatinib. Although some hints are provided suggesting that patients with NASH/NAFLD might benefit more from lenvatinib therapy and patients with viral etiology more from atezolizumab plus bevacizumab.

The aim of this review is to describe the relevance of minimally invasive liver resection (MILR) for the treatment of most common primary liver tumors. The uptake has been slow but steady, and thus MILR has become a well-established field of hepatobiliary surgery and is considered a landmark change of the past 30 years. There is evidence that the advantage of MILR regarding specific complications of liver surgery for HCC (reduced incidence of postoperative hepatic decompensation and ascites) can be a tool to potentially expand the indications to surgical treatment. Evidence for intrahepatic cholangiocarcinoma is early and exploratory; however, it is beginning to be documented that the fundamental principles of surgical oncology for this tumor can be respected while offering patients the advantages of minimal invasiveness.

Combined Hepatocellular-Cholangiocarcinoma is a heterogenous primary malignant epithelial tumor of the liver with variable morphological and immunophenotypical features. Although the biology of this tumor has been described in the literature, changes in classification and its heterogeneity imply difficulties in collecting reliable homogenous groups to compare. The article aims to review available data on morphology and immunohistochemistry for practicing pathologists integrated with original data from our referral Center.

Hepatocellular carcinoma (HCC) is a complex disease, which involves diverse molecular pathways and etiologies. In recent years, several new systemic treatments have improved survival in advanced stage disease, but numerous significant challenges remain. No significant improvements have been achieved in the intermediate stage disease; this may be attributed to the difficulties in stratification of patients and the broad spectrum of clinical situations in terms of tumor burden and liver function.This article considers the recent progress in first- and second-line therapy for advanced HCC. Investigational strategies conducted in intermediate stage HCC, which involve mainly combination therapy with locoregional approaches, and systemic drugs, antiangiogenics, immunotherapies (or both) are then examined. Later, the paper offers insights on the questions and challenges that lie ahead for treating HCC.Clinical and biomolecular markers for the stratification of patients are needed for therapeutic progress. Further molecular profiling data could enhance our knowledge of the molecular pathways underlying this tumor and facilitate the identification of targetable aberrations. This could offer opportunities for precision medicine approaches and improved survival.

Lurbinectedin is responsible for DNA recognition and binding, producing double-strand DNA (dsDNA) breaks thus resulting in apoptosis. Sensitivity to lurbinectedin is linked to the nucleotide excision repair (NER) system. Furthermore, irinotecan, a topoisomerase I inhibitor, provokes dsDNA breaks that could be reinforced abrogating the NER system using lurbinectedin. BRCA-mutated patients, already treated with platinum-derived drugs, who suffered DNA damage, cannot repair the breaks due to lurbinectedin interaction, whereas irinotecan provokes a dsDNA break that promotes synthetic lethality. This article describes an exceptional response to lurbinectedin alone followed by the association with irinotecan in a BRCA-mutated platinum-resistant ovarian cancer patient. A 44-year-old BRCA1-mutated ovarian cancer patient was treated in sixth line with lurbinectedin and irinotecan with a time to further progression (TTFP) equal to 8 months. In our case, the association with irinotecan overcame the resistance to lurbinectedin alone. In conclusion, lurbinectedin and irinotecan demonstrated a promising response in platinum-resistant patients. However, further studies should be conducted to validate our findings and future trials will be important to further define the clinical utility of lurbinectedin.

Isocitrate dehydrogenase (IDH)1/2 mutations are the most frequent druggable alterations in intrahepatic cholangiocarcinoma (iCCA), reported in ~20% of cases. Preclinical evidence indicates that these mutations are associated with homologous recombination deficiency (HRD), which could be exploited as a target for platinum chemotherapy (ChT) and PARP inhibitors. However, the role of IDH1/2 mutations as surrogate biomarkers for platinum efficacy is unknown. We conducted a multicenter, propensity score-matched analysis to investigate the impact of IDH1/2 mutations on progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) in patients with iCCA treated with platinum-based ChT. An exploratory comparison of complex HRD estimates between IDH1/2 mutated and wild-type tumors from TCGA was also performed. A total of 120 cases were matched in a 1:1 ratio (60 IDH1/2 mutant and 60 wild-type). No differences were observed for platinum-based PFS (7.7 vs 7.3 months, P = .970), DCR (66.1% vs 74.1%, P = .361) and ORR (27.8% vs 25.0%, P = .741). IDH1/2 mutations showed mutual exclusivity with genomic alterations in ATM, BRCA2, MST1R, NF1, FGFR2 and CDKN2A/B losses, respectively, with no clear survival and response differences. Among TCGA tumors, IDH1/2 mutated CCA did not show higher HRD compared to wild-type cases. IDH1/2 mutations are not associated with increased sensitivity to platinum-based ChT in iCCA patients. Deeper genomic sequencing is needed to elucidate the HRD phenotype in IDH1/2 mutant iCCA and exploit its therapeutic vulnerabilities.

Aim The identification of new prognostic factors able to stratify hepatocellular carcinoma patients candidate to first-line therapy is urgent. In the present work we validated the prognostic value of the lenvatinib prognostic index. Methods Data of Eastern and Western patients treated with lenvatinib as first-line for Barcelona Clinic Liver Cancer stage B or C hepatocellular carcinoma were recollected. The lenvatinib prognostic index was composed by three classes of risk according with our previous study. The "low risk" group includes patients with prognostic nutritional index (PNI) >43.3 and with previous transarterial chemoembolization. The "medium risk" group includes patients with PNI >43.3, but without previous transarterial chemoembolization and patients with PNI

Locally advanced and metastatic cutaneous squamous cell carcinoma (cSCC) of the skin is a rare entity and with a poor prognosis. Although less than 5% of patients with squamous carcinoma develop metastases or relapses locally after surgical removal, cSCC is difficult to treat. It tends to develop especially in elderly, frail or patients with important comorbidities and therefore not suitable for receiving aggressive treatments. Traditionally, platinum-based therapy has been considered a conventional option, but not feasible in elderly patients. The high number of advanced cSCC mutations constitutes the rationale for a systemic immunotherapy approach that can represent a turning point for these patients. Furthermore, it is necessary that more professional figures (dermatologist, oncologist, surgeon, radiotherapist, geriatrician) work in a multidisciplinary environment so that these patients can be better managed during their care path.

Background After the advent of new treatment options for advanced hepatocellular carcinoma (HCC), the identification of prognostic factors is crucial for the selection of the most appropriate therapy for each patient. Patients and methods With the aim to fill this gap, we applied recursive partitioning analysis (RPA) to a cohort of 404 patients treated with lenvatinib. Results The application of RPA resulted in a classification based on five variables that originated a new prognostic score, the lenvatinib prognostic index (LEP) index, identifying three groups: low risk [patients with prognostic nutritional index (PNI) >43.3 and previous trans-arterial chemoembolization (TACE)]; medium risk [patients with PNI >43.3 but without previous TACE and patients with PNI, Highlights • This study shows a new prognostic index (LEP index) for patients undergoing systemic therapy for hepatocellular carcinoma. • LEP index is an easy-to-use tool, based on clinical and laboratory features, that identifies three risk groups. • LEP index may be used to stratify hepatocellular carcinoma patients in order to select the most appropriate treatment.

Purpose: Neuroendocrine carcinomas (NECs) are a rare subgroup of neuroendocrine neoplasms that occasionally originate from gastro-entero-pancreatic (GEP) tract. Evidence of the effectiveness of chemotherapy is scarce. Platinum plus Etoposide regimens are currently the standard treatment in first-line, while little data are available on second-line treatments. The aim of this study is to evaluate the efficacy and safety of Irinotecan (IRI)-based chemotherapy in a series of extrapulmonary NECs. Methods: Patients with NEC diagnosis treated at University Hospitals of Modena, Florence, Pisa, and European Institute of Oncology of Milan with an IRI-based regimen (FOLFIRI or XELIRI) after progression to a first-line platinum-based therapy were enrolled. Objective responses were assessed according to RECIST criteria. Progression-free survival (PFS) and overall survival (OS) were calculated. Results: 34 patients, 16 males, and 18 females, median age of 59 years (range 32-77), with metastatic NEC were included. Twenty-seven pts had Ki-67 ≥ 55% and 4 pts Ki-67 of < 55% (for 3 pts data was not available). The median number of treatment cycles of the IRI-based regimen was 7.5 (range 1-16). Six partial responses (17.6%) and 9 stable diseases (26.5%) were observed, with a disease control rate of 44.1%. Median PFS and OS were 4.4 and 5.9 months, respectively. Neutropenia, anemia, and nausea were the only G3-G4 toxicities reported. Conclusion: Despite the relatively small sample size, IRI-based therapy demonstrated to be a valid option for patients with pre-treated extrapulmonary NEC.

INTRODUCTION: Prognostic classifications for patients treated with sorafenib for hepatocellular carcinoma (HCC) facilitate stratification in trials and inform clinical decision making. Recently, 3 different prognostic models (hepatoma arterial-embolization prognosis [HAP] score, sorafenib advanced HCC prognosis [SAP] score, and Prediction Of Survival in Advanced Sorafenib-treated HCC [PROSASH]-II) have been proposed specifically for patients treated with sorafenib. This study aimed to compare the prognostic performance of different scores. METHODS: We analyzed a large prospective database gathering data of 552 patients treated with sorafenib from 7 Italian centers. The performance of the HAP, SAP, and PROSASH–II models were compared with those of generic HCC prognostic models (including the Barcelona Clinic for Liver Cancer and Italian Liver Cancer staging systems, albumin–bilirubin grade, and Child-Pugh score) to verify whether they could provide additional information. RESULTS: The PROSASH-II model improved discrimination (C-index 0.62) compared with existing prognostic scores (C-index ≤0.59). Its stratification significantly discriminated patients, with a median overall survival of 21.5, 15.3, 9.3, and 6.0 months for risk group 1, 2, 3, and 4, respectively. The HAP and SAP score were also validated but with a poorer performance compared with the PROSASH-II. DISCUSSION: Although suboptimal, PROSASH-II is the most effective prognostic classification model among other available scores in a large Italian population of patients treated with sorafenib.

Aim: A link has been established between malnutrition, immunological status, and hepatocellular carcinoma (HCC). The prognostic nutritional index (PNI) has been recognized as a prognostic indicator in early-stage HCC and in patients treated with first-line therapy. However, to date, the role of the PNI in HCC patients treated with regorafenib has not been reported. Methods: We undertook a multicentric analysis on a cohort of 284 patients affected by advanced HCC treated with regorafenib. The PNI was calculated as follows: 10×serum albumin concentration (g/dl)+0.005×peripheral lymphocyte count (number/mm3). Univariate and multivariate analyses were used to investigate the association between PNI and survival outcomes. Results: A PNI cut-off value of 44.45 was calculated by a receiver operating characteristic analysis. The median overall survival was 12.8 and 7.8 months for patients with high (>44.45) and low (≤44.45) PNI, respectively (hazard ratio, 0.58; 95% confidence interval, 0.43–0.77; p=0.0002). In the univariate and multivariate analyses, low PNI value and increased serum bilirubin level emerged as independent prognostic factors for overall survival. No differences were found between high and low PNI in terms of progression-free survival (p=0.14). Conclusion: If validated, the PNI could represent an easy-to-use prognostic tool able to guide the clinical decision-making process in HCC patients treated with regorafenib.

4069 Background: Recently, several evidences have suggested that patients with a no-viral hepatocellular carcinoma (HCC) might be less responsive to immunotherapy and more response to Lenvatinib. Methods: The study population derived from prospectively collected retrospectively analyzed data of patients treated with atezolizumab plus bevacizumab (AB) or lenvatinib (L) or sorafenib (S) as first-line treatment for advanced HCC or intermediate HCC deemed not eligible for loco-regional therapies. The overall cohort included Western and Eastern patient populations from 36 centers located in 4 countries(Italy, Japan, Republic of Korea, and United Kingdom) undergoing treatment with L or AB or with S. The primary endpoint was OS of AB versus L; the secondary endpoints were OS of AB versus S. Results: 569 patients received L, 190 patients received AB and 210 received S. In the whole population OS was 17.8 months (95%CI:15.8-43.8) for patients receiving L, and 12.1 months(95%CI:11.1-16.8)for patients treated with AB (HR 0.71; 95% CI:0.50-1.06; p=0.1028); multivariate analysis for imbalance patients characteristic highlighted that L is an independent prognostic factor for OS (HR 0.65; 95% CI:0.44-0.95; p=0.0268), compared AB. In the population affected by NASH/NAFLD, 254 patients were treated with L and 82 patients were treated with AB. OS was 21.2 months (95% CI:18.4-30.6) for patients receiving L, and 12.2 months (95% CI:10.0-16.8) for patients treated with AB (HR 0.46; 95% CI:0.25-0.88; p = 0.0181); multivariate analysis for imbalance patients characteristic highlighted that L is an independent prognostic factor for OS (HR 0.46; 95% CI:0.26-0.84; p=0.031),compared AB. In the cohort of no viral and no NASH/NAFLD patients, no statistically significant differences were reported in terms of OS between patients treated with L versus AB. All these results were confirmed following propensity score matching analysis. By comparing patients receiving AB versus S, no significant differences were found in terms of OS in the whole population, in the NASH/NAFLD population and in no viral/no NASH/NAFLD population. Conclusions: The present analysis conducted on a large number of non-viral HCC patients showed for the first time a significant survival benefit from lenvatinib over atezolizumab plus bevacizumab, in particular in patients with NAFLD/NASH-related HCC.

Regorafenib has been shown to improve clinical outcomes compared to placebo, becoming a standard second-line therapy for sorafenib-progressed and -tolerated hepatocellular carcinoma (HCC) patients.We performed a multicentre, retrospective study in Italy and Korea to evaluate the effectiveness of the treatment sequence sorafenib-regorafenib compared with sorafenib and physician's choice in a real-life setting.A propensity score model was developed to control the results for baseline variable imbalances between the arm treated with sorafenib and regorafenib (S-R) and the arm treated with sorafenib and physician's choice (S-P). Survival analysis was conducted on the matched population.After the application of propensity score matching, we analysed 99 patients in the arm treated with S-R and 99 patients in the arm treated with S-P. For the S-R group, the median overall survival was 22.2 months (95% CI 17.1-27.4), compared to 17.9 months (95% CI 15.1-50.0) for the S-P group. The results of the univariate analysis showed a 31% reduction of death risk for patients treated with S-R (p = 0.0382) compared to patients treated with S-P. Interaction tests highlighted the predictive role of alpha-fetoprotein (AFP), neutrophil-to-lymphocyte ratio (NLR), and extrahepatic spread.This study provides additional proof of the superiority of the S-R treatment over the S-P treatment approach in advanced HCC patients from a real-life setting.

Pancreatic cancer represents a very challenging disease, with an increasing incidence and an extremely poor prognosis. Peculiar features of this tumor entity are represented by pancreatic exocrine insufficiency and an early and intense nutritional imbalance, leading to the highly prevalent and multifactorial syndrome known as cancer cachexia. Recently, also the concept of sarcopenic obesity has emerged, making the concept of pancreatic cancer malnutrition even more multifaceted and complex. Overall, these nutritional derangements play a pivotal role in contributing to the dismal course of this malignancy. However, their relevance is often underrated and their assessment is rarely applied in clinical daily practice with relevant negative impact for patients’ outcome in neoadjuvant, surgical, and metastatic settings. The proper detection and management of pancreatic cancer-related malnutrition syndromes are of primary importance and deserve a specific and multidisciplinary (clinical nutrition, oncology, etc.) approach to improve survival, but also the quality of life. In this context, the introduction of a “Nutritional Oncology Board” in routine daily practice, aimed at assessing an early systematic screening of patients and at implementing nutritional support from the time of disease diagnosis onward seems to be the right path to take.

Anal squamous cell carcinoma (SCC) is a rare tumor, and bio-humoral predictors of response to chemo-radiation (CT-RT) are lacking. We developed a prognostic score system based on laboratory inflammation parameters. We investigated the correlation between baseline clinical and laboratory variables and disease-free (DFS) and overall (OS) survival in anal SCC patients treated with CT-RT in five institutions. The bio-humoral parameters of significance were included in a new scoring system, which was tested with other significant variables in a Cox’s proportional hazard model. A total of 308 patients was included. We devised a prognostic model by combining baseline hemoglobin level, SII, and eosinophil count: the Hemo-Eosinophils Inflammation (HEI) Index. We stratified patients according to the HEI index into low- and high-risk groups. Median DFS for low-risk patients was not reached, and it was found to be 79.5 months for high-risk cases (Hazard Ratio 3.22, 95% CI: 2.04–5.10, p &lt, 0.0001). Following adjustment for clinical covariates found significant at univariate analysis, multivariate analysis confirmed the HEI index as an independent prognostic factor for DFS and OS. The HEI index was shown to be a prognostic parameter for DFS and OS in anal cancer patients treated with CT-RT. An external validation of the HEI index is mandatory for its use in clinical practice.

Background and Aims: In the last few years, there has been increasing interest in non-cancer medications and their potential anti-cancer activity. Data are not available in cholangiocarcinoma (CCA) patients. The aim of this study is to fill this gap by investigating the potential impact in terms of clinical outcome of the common non-cancer medications. Methods: All consecutive patients with CCAs were retrospectively identified from 7 Italian medical institutions. We investigated the role of intake of vitamin D, aspirin, metformin, statins, and diuretics. Results: A total of 537 patients with CCAs were identified; 197 patients undergoing surgery were evaluated for disease-free survival (DFS), and 509 patients with an advanced stage were evaluated for overall survival (OS). A longer DFS was found in patients with intake of vitamin D versus never users (HR 0.55, 95% CI 0.32–0.92, p = 0.02). In an advanced stage an association with OS was found in patients with intake of metformin versus never users (HR 0.70, 95% CI 0.52–0.93, p = 0.0162), and in patients who have started taking metformin after chemotherapy versus before chemotherapy and never users (HR 0.44, 95% CI 0.26–0.73, p = 0.0016). Conclusions: Our results highlighted that vitamin D intake improves DFS in patients undergoing surgery. Metformin intake after starting chemotherapy can improve the clinical outcome in advanced disease. These results could open up new therapeutic strategies in cholangiocarcinoma patients. We are planning to undertake a prospective study to validate these data.

Background: Recently, three published phase III trials highlighted the superiority of investigational drugs compared to placebo, thus leading to their approval in the second-line setting. We report here a MAIC of second-line MKI options for patients with HCC previously treated with sorafenib using individual real-world data of regorafenib and aggregate data of second-line cabozantinib from the CELESTIAL trial. Methods: Data from 278 patients who received regorafenib as second-line therapy after sorafenib failure for unresectable HCC were used as IPD. Data inclusion were adapted to those reported in the CELESTIAL trial in the subset of patients who received sorafenib as the only prior therapy. Survival medians and rates were obtained from Kaplan–Meier curves, and differences between regorafenib and cabozantinib groups were explored through Cox regression adjusted for weights originating from MAIC. Results: The median OS of the weighted regorafenib group was 11.1months (IQR: 5.6–16.4) and 11.3 (IQR: 6.7–22.4) for cabozantinib; HR 0.83 (95%CI 0.62–1.09). The median PFS of the weighted regorafenib group was 3.0months (IQR: 1.9–4.8) and 5.5 (IQR: 2.3–9.3) for cabozantinib; HR 0.50 (95%CI 0.41–0.62). In the subgroup who received prior sorafenib for < 3months, the median OS of the regorafenib group was 6.5months (IQR: 4.7–10.9) and 9.5months (IQR: 5.9–18.2) for cabozantinib; HR 0.68 (95%CI 0.39–1.16). In the subgroup receiving prior sorafenib for 3 to < 6months, the median OS of the regorafenib group was 8.0months (IQR: 4.2–15.2) and 11.5 (IQR: 6.5–23.9) for cabozantinib; HR 0.66 (95%CI 0.42–1.02). In the subgroup receiving prior sorafenib for ≥ 6months, the median OS of the regorafenib group was 13.4 (IQR: 8.1–46.5) and 12.3 (IQR: 6.6–22.9) for cabozantinib; HR 0.89 (95%CI 0.52–1.51). Conclusion: Our results confirmed no differences between regorafenib and cabozantinib in terms of OS. However, in earlier progressors on prior sorafenib a larger benefit might be expected from cabozantinib treatment.

Background: The results of the pivotal RESORCE trial led to the approval of the tyrosine kinase inhibitor regorafenib as second-line treatment in advanced hepatocellular carcinoma (HCC) after sorafenib failure. Data about prognostic factors in a second-line HCC setting are scarce. Objective: The aim of the present study was to investigate prognostic factors in a cohort of patients with advanced HCC treated with regorafenib after progressing on sorafenib. Methods: We retrieved the data of 259 patients affected by advanced HCC treated with regorafenib as second-line treatment from four different Italian institutions and one South Korean institution and performed a recursive partitioning analysis to build a score system. Results: At the first-step univariate analysis for overall survival (OS), alkaline phosphatase (ALP) was the most significant parameter and was chosen as the first node in our tree model. In the subpopulation of patients presenting with ALP ≤122 U/L (n=155) at baseline, the most statistically significant split was by progression-free survival (PFS) on previous sorafenib treatment, between patients with a PFS ≥ 6 months (n = 59) and patients with a PFS < 6 months (n = 96). In the subpopulation of patients with ALP ≤ 122 U/L and PFS to sorafenib ≥ 6 months, the final split was determined between patients with hepatitis B virus (HBV)-related liver disease (n = 22) and patients with no HBV-related liver disease (n = 37). In the subpopulation of patients presenting ALP >122 U/L (n = 104) at baseline, the most statistically significant split was by aspartate aminotransferase (AST) value, between patients with AST ≤ 56 U/L (n = 48) and patients with AST > 56 U/L (n = 56). We built the Regorafenib Prognostic Index (REP index) stratifying the population into “low-risk,” “medium-risk,” and “high-risk” groups. The difference in median OS between the three risk groups was statistically significant, being 20.8 months (95% confidence interval [CI] 10.0–46.3) in the “low-risk” group, 8.4 months (95% CI 7.2–1435.8) in the “medium-risk” group, and 5.5 months (95% CI 3.5–13.2) in the “high risk” group. The median PFS was 7.7 months (95% CI 3.7–19.3), 2.5 months (95% CI 2.1–28.8), and 2.4 months (95% CI 1.6–9.1) for the “low-risk,” “medium-risk,” and “high-risk” groups, respectively. Conclusion: The REP index is an independent prognostic factor for OS and PFS in patients with advanced HCC treated with regorafenib.

Background Hepatocellular carcinoma (HCC) treatment remains a big challenge in the field of oncology. The liver disease (viral or not viral) underlying HCC turned out to be crucial in determining the biologic behavior of the tumor, including its response to treatment. The aim of this analysis was to investigate the role of the etiology of the underlying liver disease in survival outcomes. Patients and methods We conducted a multicenter retrospective study on a large cohort of patients treated with lenvatinib as first-line therapy for advanced HCC from both Eastern and Western institutions. Univariate and multivariate analyses were performed. Results Among the 1232 lenvatinib-treated HCC patients, 453 (36.8%) were hepatitis C virus positive, 268 hepatitis B virus positive (21.8%), 236 nonalcoholic steatohepatitis (NASH) correlate (19.2%) and 275 had other etiologies (22.3%). The median progression-free survival (mPFS) was 6.2 months [95% confidence interval (CI) 5.9-6.7 months] and the median overall survival (mOS) was 15.8 months (95% CI 14.9-17.2 months). In the univariate analysis for OS NASH-HCC was associated with longer mOS [22.2 versus 15.1 months; hazard ratio (HR) 0.69; 95% CI 0.56-0.85; P = 0.0006]. In the univariate analysis for PFS NASH-HCC was associated with longer mPFS (7.5 versus 6.5 months; HR 0.84; 95% CI 0.71-0.99; P = 0.0436). The multivariate analysis confirmed NASH-HCC (HR 0.64; 95% CI 0.48-0.86; P = 0.0028) as an independent prognostic factor for OS, along with albumin–bilirubin (ALBI) grade, extrahepatic spread, neutrophil-to-lymphocyte ratio, portal vein thrombosis, Eastern Cooperative Oncology Group (ECOG) performance status and alpha-fetoprotein. An interaction test was performed between sorafenib and lenvatinib cohorts and the results highlighted the positive predictive role of NASH in favor of the lenvatinib arm (P = 0.0047). Conclusion NASH has been identified as an independent prognostic factor in a large cohort of patients with advanced HCC treated with lenvatinib, thereby suggesting the role of the etiology in the selection of patients for tyrosine kinase treatment. If validated, this result could provide new insights useful to improve the management of these patients., Highlights • Evidence supported the idea that etiology could sustain a crucial role in biological behavior. • NASH constitutes one of the more important risk factors for hepatocarcinoma, and its incidence is increasing very fast. • We performed an analysis in patients treated with lenvatinib as the first-line therapy. • NASH was found to be an independent prognostic factor.

Neuroendocrine carcinomas (NECs) are a rare subgroup of neuroendocrine neoplasms that occasionally originate from gastro-entero-pancreatic (GEP) tract. Evidence of the effectiveness of chemotherapy is scarce. Platinum plus Etoposide regimens are currently the standard treatment in first-line, while little data are available on second-line treatments. The aim of this study is to evaluate the efficacy and safety of irinotecan (IRI)-based chemotherapy in a series of extrapulmonary NECs. Patients with NEC diagnosis treated at University Hospitals of Modena, Florence, Pisa, and European Institute of Oncology of Milan with an IRI-based regimen (FOLFIRI or XELIRI) after progression to a first-line platinum-based therapy were enrolled. Objective responses were assessed according to RECIST criteria. Progression-free survival (PFS) and overall survival (OS) were calculated. Thirty-four patients, 16 males, and 18 females, median age of 59 years (range 32–77), with metastatic NEC were included. Twenty-seven patients had Ki-67 ≥ 55% and four patients Ki-67 of