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Objective The coronavirus disease 2019 (COVID‐19) outbreak has been declared a global pandemic of unprecedented proportions. Italy is a country which has been heavily affected. Cancer patients are at a higher risk owing to their intrinsic fragility related to their underlying disease and oncologic treatment. Against this backdrop, we conducted a survey to investigate how patients perceived their condition, clinical management and availability of information during the pandemic. Methods Between 15 April and 1 May 2020 a survey was submitted to cancer patients at oncology departments in the Marche region. Questions regarding the perception of personal safety, continuity of cancer care, information quality and psychological distress. Results Seven hundred patients participated in the survey; 59% were female and 40% were aged between 46 and 65. The majority of the participants perceived compliance with appropriate safety standards by cancer care providers and 80% were reassured about their concerns during the medical interview. 40% were worried of being at a higher risk of infection and 71% felt they were at a greater risk because of chemotherapy. 55% felt that postponing cancer treatment could reduce its efficacy, however 76% declared they did not feel abandoned at the time of treatment postponement. Patients between 46 and 65 years declared a significant reduction in sleep (p

Background and Aim: The aim of the present study is to evaluate a new index (PECS (PsECogSii)index) influenced by PS ECOG and systemic immune-inflammation index (SII) in unresectable locally advanced or metastatic BTC patients treated with first-line chemotherapy. Methods: This multicenter, international, study was conducted on a training cohort of 130 patients and in three European and Korean validation cohorts The PECS index was calculated as ECOG × SII index (neutrophil count × platelet count/lymphocyte count). Event-time distributions were estimated using the Kaplan–Meier method and survival curves were compared using the log-rank test. Results: In the training cohort, the median overall survival (mOS) was 13.2months, 8.7months, and 3.8months for patients with PECS-0, PECS-1, and PECS-2, respectively (PECS-0: HR=1; PECS-1: HR 1.41; PECS-2: HR 3.23) (p&nbsp

Background: Standard treatment of advanced biliary tract cancer (aBTC) is represented by first-line chemotherapy (CT1). However, some patients do not gain any benefit from CT1, contributing to the overall dismal prognosis of aBTC. The present study aimed to devise a prognostic model in aBTC patients receiving CT1. Methods: A large panel of clinical, laboratory, and pathology variables, available before the start of CT1, were retrospectively assessed in a multi-centric cohort to determine their prognostic value on univariate and multivariate regression analysis. The variables that showed a significant correlation with overall survival (OS) were computed in a three-tier prognostic score. External validation of the prognostication performance was carried out. Results: Clinical histories of 935 patients (median OS 10.3 months), with diagnosis dates ranging from 2001 to 2017, were retrieved from 14 institutions. According to multivariate analysis, Eastern Cooperative Oncology Group performance status, carbohydrate antigen 19.9, albumin levels, and neutrophil/lymphocyte ratio were strongly associated with OS (p

Background and Aim: The need to estimate prognosis of advanced BTC (aBTC) patients treated with first-line chemotherapy is compelling. The aim of the study is to evaluate the ECSIPOT (psECogSIiPnigOT) index, influenced by PECS (PsECogSii) index, prognostic nutritional index (PNI), and GOT. Methods: This international study was conducted on a training cohort of 126 patients and in three validation cohorts, both European and Korean. ECSIPOT index formula: (PECS:0 = 1 point; PECS:1 = 1.4 points; PECS:2 = 3.2 points) + (PNI > 36.7 = 1 point; PNI < 36.7 = 2 points) + (GOT < 100 = 1 point; GOT > 100 = 2 points). Event-time distributions were estimated using the Kaplan–Meier method, and survival curves were compared using the log-rank test. Results: In the training cohort, mOS was 12.9, 6.3, and 2.8months for patients with ECSIPOT-0, ECSIPOT-1, and ECSIPOT-2, respectively (ECSIPOT-0: HR 1; ECSIPOT-1: HR 2.11; ECSIPOT-2: HR 4.93; p < 0.0001). In the first validation cohort, mOS was 11.5, 7.3, and 3.3months for ECSIPOT-0, ECSIPOT-1, and ECSIPOT-2, respectively (ECSIPOT-0: HR 1; ECSIPOT-1: HR 1.74; ECSIPOT-2: HR 3.41; p < 0.0001). In the second validation cohort, mOS was 25.2, 12.5, and 3.0months for ECSIPOT-0, ECSIPOT-1, and ECSIPOT-2, respectively (ECSIPOT-0: HR = 1; ECSIPOT-1: HR 2.33; ECSIPOT-2: HR 8.46; p < 0.0001). In the third validation cohort, mOS was 11.8, 8.1, and 4.6months for ECSIPOT-0, ECSIPOT-1, and ECSIPOT-2, respectively (ECSIPOT-0: HR = 1; ECSIPOT-1: HR 1.47; ECSIPOT-2: HR 3.17; p < 0.0001). Multivariate analysis in all cohorts confirmed the ECSIPOT index as an independent prognostic factor for OS. Conclusion: The easy assessment and good risk-stratification performance make the ECSIPOT index a promising tool to comprehensively estimate the prognosis of aBTC patients.

Sorafenib represents the standard of care for advanced hepatocellular carcinoma (HCC), even though a large number of patients have reported limited efficacy. The aim of the present study was to evaluate the prognostic value of single-nucleotide polymorphisms on angiopoietin-2 (ANGPT2) and endothelial-derived nitric oxide synthase (NOS3) genes in 135 patients with advanced HCC receiving sorafenib. Eight ANGPT2 polymorphisms were analyzed by direct sequencing in relation to overall survival (OS) and progression-free survival (PFS). In univariate analysis, ANGPT2rs55633437 and NOS3 rs2070744 were associated with OS and PFS. In particular, patients with ANGPT2rs55633437 TT/GT genotypes had significantly lower median OS (4.66 vs. 15.5 months, hazard ratio (HR) 4.86, 95% CI 2.73&ndash, 8.67, p &lt, 0.001) and PFS (1.58 vs. 6.27 months, HR 4.79, 95% CI 2.73&ndash, 8.35, p &lt, 0.001) than those homozygous for the G allele. Moreover, patients with NOS3 rs2070744 TC/CC genotypes had significantly higher median OS (15.6 vs. 9.1 months, HR 0.65, 95% CI 0.44&ndash, 0.97, p = 0.036) and PFS (7.03 vs. 3.5 months, HR 0.43, 95% CI 0.30&ndash, 0.63, p &lt, 0.001) than patients homozygous for the T allele. Multivariate analysis confirmed these polymorphisms as independent prognostic factors. Our results suggest that ANGPT2rs55633437 and NOS3 rs2070744 polymorphisms could identify a subset of HCC patients more resistant to sorafenib.

Purpose: After 10 years of clinical practice and research studies, there are still no validated prognostic or predictive factors of response to sorafenib for hepatocellular carcinoma (HCC). On the basis of the results of our two retrospective studies, we designed the multicenter INNOVATE study with the aim to validate the role of nitric oxide synthase 3 (NOS3) and ANGPT2 polymorphisms in patients with HCC treated with sorafenib [NCT02786342]. Patients and Methods: This prospective multicenter study was conducted at 10 centers in Italy. All eligible patients received a continuous oral treatment with 400 mg of sorafenib twice daily. Genotyping analysis was performed for NOS3 (rs2070744) and ANGPT2 SNPs (rs55633437). The primary outcome was progression-free survival (PFS), whereas secondary outcomes included overall survival (OS) and disease-control rate. Results: A total of 165 patients were enrolled between March 2016 and June 2018. NOS3 rs2070744 CC/CT genotypes were significantly associated with a higher median PFS (5.9 months vs. 2.4 months; HR = 0.43; P = 0.0007) and OS (15.7 months vs. 8.6 months; HR = 0.38; P < 0.0001) compared with TT genotype. There was no statistically significant association between ANGPT2 rs55633437 TT/GT genotypes and PFS (2.4 months vs. 5.7 months; HR = 1.93; P = 0.0833) and OS (15.1 months vs. 13.0 months; HR = 2.68; P = 0.55) when compared with the other genotype. Following adjustment for clinical covariates, multivariate analysis confirmed NOS3 as an independent prognostic factor for PFS (HR = 0.50; P = 0.0128) and OS (HR = 0.29; P = 0.0041). Conclusions: The INNOVATE study met the primary endpoint, confirming that patients with advanced HCC with NOS3 rs2070744 CC/CT genotypes had a better prognosis with respect to TT genotype patients.

Introduction: The association between pancreatic ductal adenocarcinoma (PDAC) and type 2 diabetes mellitus (DM2) has long been evaluated and the role of antidiabetic medications such as metformin has also been investigated. The objective of this study was to examine the association between insulin use and overall survival (OS) in patients with advanced PDAC and DM2. Methods: We retrospectively collected data from 164 patients, including an exploratory cohort of 96 patients from Medical Oncology Unit, University Hospital and University of Cagliari, Italy, and a validation cohort of 68 patients from Medical Oncology of Modena University Hospital. Patients had metastatic disease and received a first-line gemcitabine-based chemotherapy and, subsequently, a second-line fluoropyrimidines-based chemotherapy. We performed univariate analysis to evaluate correlation between long-term diabetes and overall survival. Then we performed multivariate analysis, adjusting for sex, metastatic sites, Eastern Cooperative Oncology Group Performance Status, Ca19.9 levels, N/L ratio, and lactate dehydrogenase levels at diagnosis, to confirm the independence of the variable. Results: In the exploratory cohort, DM2 was significantly associated with higher median OS at univariate analysis (16 vs 10 months; p = 0.004). This result was confirmed by validation cohort (11 months vs 6 months; p = 0.01). In multivariate analysis, insulin-treated patients compared with non diabetic patients showed a significantly increased survival of 4.6 months ( p = 0.03). Conclusions: Patients with insulin-treated metastatic PDAC showed better OS than non diabetic patients, as demonstrated by both cohorts. The correlation between OS and insulin-treated DM2 should be investigated further through a prospective clinical trial.

Objective: Hypertension is a common adverse event with targeted agents in cancer patients and can lead to serious and sometimes lethal cardiovascular complications. The authors performed a meta-analysis of clinical trials aiming to evaluate the incidence and Relative Risk (RR) of developing all-grade and high-grade Hypertension Events (HE) in patients with solid tumors receiving targeted therapy.Methods: A review of citations from PubMed was performed and studies were selected based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The search was limited to randomized phase III trials published in English focused on the efficacy and safety of targeted agents in cancer patients, reporting data on HE. Incidence, RR and relative 95% CIs were analyzed using random or fixed-effects models. Overall incidences were calculated and further compared with the chi-squared test for proportions.Results: Ninety-three phase III trials were included, with a total of 68,077 patients. Prostate cancer was the most represented (18.9%), followed by breast cancer (17.3%) and colorectal cancer (16.4%). The incidence of all- and high-grade HE was 23.47% and 8.57%, respectively, with the highest incidence of serious HE reported by adjuvant Sunitib/Sorafenib (29.03%). The highest RR of high-grade HE was observed with Bevacizumab in patients with advanced cervical cancer. By drug category, the highest RR of high-grade HE was reported by VEGFR/EGFR TKIs.Conclusion: According to these data, monitoring this class of toxicities is of primary importance to avoid hypertension worsening and, thus, the risk of major cardiovascular events.

Introduction: Although sorafenib is the upfront standard of care for advanced hepatocellular carcinoma (HCC), molecular predictors of efficacy have not been identified yet. In the ALICE-1 study, rs2010963 of VEGF-A and VEGF-C proved to be independent predictive factors for progression-free survival (PFS) and overall survival (OS) in multivariate analysis. The ALICE-1 study results were confirmed in the ALICE-2 study, in which VEGF and VEGFR SNPs were analyzed. In the ePHAS study we analyzed the SNPs of eNOS. In univariate analysis, patients homozygous for an eNOS haplotype (HT1: T-4b at eNOS-786/eNOS VNTR) had significantly shorter median PFS and OS than those with other haplotypes. These data were confirmed in the validation set. Methods: This nonpharmacological, interventional, prospective multicenter study aims to determine whether eNOS, HIF-1, VEGF, Ang2 and VEGFR polymorphisms play a role in predicting the objective response rate, PFS, and OS of advanced HCC patients treated with sorafenib. The study will involve 160 advanced HCC patients with Child-Pugh class A disease. The primary aim is to validate the prognostic or predictive roles of eNOS, Ang2, HIF-1, VEGF and VEGFR polymorphisms in relation to the clinical outcome (PFS) of HCC patients treated with sorafenib. Conclusions: Overall, our data may suggest that polymorphism analysis of the VEGF, VEGFR-2, HIF and eNOS genes can identify HCC patients who are more likely to benefit from sorafenib.

The incidence of hepatocellular carcinoma deriving from metabolic dysfunctions has increased in the last years. Sirtuin- (SIRT-3), phospho-mammalian target of rapamycin (p-mTOR) and hypoxia-inducible factor- (HIF-1&alpha, ) are involved in metabolism and cancer. However, their role in hepatocellular carcinoma (HCC) metabolism, drug resistance and progression remains unclear. This study aimed to better clarify the biological and clinical function of these markers in HCC patients, in relation to the presence of metabolic alterations, metformin therapy and clinical outcome. A total of 70 HCC patients were enrolled: 48 and 22 of whom were in early stage and advanced stage, respectively. The expression levels of the three markers were assessed by immunohistochemistry and summarized using descriptive statistics. SIRT-3 expression was higher in diabetic than non-diabetic patients, and in metformin-treated than insulin-treated patients. Interestingly, p-mTOR was higher in patients with metabolic syndrome than those with different etiology, and, similar to SIRT-3, in metformin-treated than insulin-treated patients. Moreover, our results describe a slight, albeit not significant, benefit of high SIRT-3 and a significant benefit of high nuclear HIF-1&alpha, expression in early-stage patients, whereas high levels of p-mTOR correlated with worse prognosis in advanced-stage patients. Our study highlighted the involvement of SIRT-3 and p-mTOR in metabolic dysfunctions that occur in HCC patients, and suggested SIRT-3 and HIF-1&alpha, as predictors of prognosis in early-stage HCC patients, and p-mTOR as target for the treatment of advanced-stage HCC.

The surgical approach to renal cell carcinoma (RCC) primary tumor and distant metastases has been the focus of a series of studies in the last years. On this scenario, Lebacle et al . (1) evaluated the role of neoadjuvant axitinib in cT2 RCC. They conducted an open-label, non-randomized, multicenter phase II study (AXIPAN) with the main goal of creating the favorable conditions for Partial Nephrectomy (PN) in patients with cT2 clear cell (cc)RCC. From the literature it is well known that radical nephrectomy (RN) is recommended in cases of large (>7 cm) or highly complex tumors (2), while PN is feasible in some T2 tumors (3) and can preserve a better renal function compared to RN and improve the survival rate (4). However, PN is technically challenging and requires expert surgeons.

Background: Sorafenib has been established as the standard of care for patients with advanced hepatocellular carcinoma (HCC) since 2007 on the basis of two landmark trials (SHARP and Asia-Pacific). Ten years have passed since then and, despite much research in the field, still no validated real-life prognostic markers are available for HCC patients treated with this drug. Therefore, going through 10 years of research into sorafenib of several Italian Cancer Centers, we conducted a field-practice study aimed at identifying baseline clinical factors that could be significantly associated with overall survival (OS). Method: Univariate/multivariate analyses were conducted to retrospectively identify the impact of baseline characteristics on the OS of 398 advanced HCC patients treated with sorafenib. Results: Based on univariate analysis, α-fetoprotein (AFP), albumin, AST, bilirubin, Child-Pugh, ECOG, systemic immune-inflammation index (SII), albumin-bilirubin (ALBI) grade, and portal vein thrombosis were significantly associated with shorter OS. Following adjustment for clinical covariates positive in univariate analysis, the multivariate analysis including AFP, age, etiology, albumin, aspartate transaminase (AST), bilirubin, Child-Pugh, LDH, platelet-to-lymphocyte ratio, ECOG, ALBI grade, portal vein thrombosis, SII, and BCLC stage identified increase in LDH, age >70 years, no viral etiologies, ECOG >0, albumin 40 as prognostic factors for poorer OS based on the 5% significance level. Conclusion: Our study highlights that baseline hepatic function, patient-centered variables, and etiology have prognostic value. These findings might have implications in terms of therapeutic decision-making and patient counseling.

Upper tract urothelial carcinoma (UTUC) accounts for 5% of urothelial carcinomas (UCs), the estimated annual incidence being 1–2 cases per 100,000 inhabitants. Similarly to bladder UC, divergent differentiations and histologic variants confer an adverse risk factor in comparison with pure UTUC. Molecular and genomic characterization studies on UTUC have shown changes occurring at differing frequencies from bladder cancer, with unique molecular and clinical subtypes, potentially with different responses to treatment. Systemic chemotherapy is the standard approach for patients with inoperable locally advanced or metastatic UCs. Although initial response rates are high, the median survival with combination chemotherapy is about 15 months. In first-line chemotherapy several cisplatin-based regimens have been proposed. For patients with advanced UC who progress to first-line treatment, the only product licensed in Europe is vinflunine, a third-generation, semisynthetic, vinca alkaloid. Better response rates (15–60%), with higher toxicity rates and no overall survival (OS) benefit, are generally achieved in multidrug combinations, which often include taxanes and gemcitabine. The US FDA has recently approved five agents targeting the programmed death-1 and programmed death ligand-1 pathway as a second-line therapy in patients with locally advanced or metastatic UC with disease progression during or following platinum-containing chemotherapy. Potential therapeutic targets are present in 69% of tumours analyzed. Specific molecular alterations include those involved in the RTK/Ras/PI(3)K, cell-cycle regulation and chromatin-remodeling pathways, many of them have either targeted therapies approved or under investigation. Angiogenic agents, anti-epidermal growth factor receptor therapy, phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) pathway inhibitors and immunotherapeutic drugs are being successfully investigated.

Background and Aims: The aim of the present study is to evaluate a new index influenced by the balance between the immune system, α-fetoprotein (AFP), and lactate dehydrogenase (LDH) (RAPID index) as a prognostic factor in patients treated with sorafenib. Methods: This study was conducted on a training cohort of 159 hepatocellular carcinoma (HCC) patients and a validation cohort of 68 HCC patients treated with sorafenib. The RAPID index was calculated as neutrophil/lymphocyte count × LDH × AFP. Results: In the training cohort, the median overall survival (OS) was 23.2 months (95% CI 11–25) and 12.1 months (95% CI 9–15) for patients with a low (≤3,226) and high (>3,226) RAPID index, respectively (ref. p = 0.017). Following adjustment for clinical covariates, multivariate analysis confirmed the RAPID index ≤3,226 versus >3,226 (HR = 0.37, 95% CI 0.18–0.74, p = 0.0054) as an independent prognostic factor for OS. In the validation cohort, the median OS was 26.9 months (95% CI 17.6–26.9) and 7.0 months (95% CI 6.2–9.2) for patients with a low (≤ 3,226) and high (>3,226) RAPID index, respectively (ref. p < 0.0001). Performing the same multivariate analysis of the training cohort (AFP, Eastern Cooperative Oncology Group, aspartate aminotransferase, neutrophil, platelet, systemic inflammatory index and RAPID index), the RAPID index 3,226 (HR = 3.86, 95% CI 1.45–10.29, p = 0.007) was found to be an independent prognostic factor for predicting OS. Conclusion: The low cost, easy assessment, and reproducibility of a full blood count make the RAPID index a promising tool for assessing HCC prognosis in future clinical practice.

Preliminary studies suggest that capecitabine may be safe and effective in HCC patients. The aim of this study was to retrospectively evaluate the safety and efficacy of metronomic capecitabine as second-line treatment. This multicentric study retrospectively analyzed data of HCC patients unresponsive or intolerant to sorafenib treatment with metronomic capecitabine or best supportive care (BSC).Median progression free survival was 3.1 months in patients treated with capecitabine (95%CI: 2.7–3.5). Median overall survival was 12.0 months (95% CI: 10.7–15.8) in patients receiving capecitabine, while 9.0 months (95% CI: 6.5–13.9) in patients receiving BSC. The result of univariate unweighted Cox regression model shows a 46% reduction in death risk for patients on capecitabine (95%CI: 0.357–0.829; p =0.005) compared to patients receiving BSC alone. After weighting for potential confounders, death risk remained essentially unaltered (45%; 95%CI: 0.354–0.883; p = 0.013). Metronomic capecitabine seems a safe second-line treatment for HCC patients in terms of management of adverse events, showing a potential anti-tumour activity which needs further evaluation in phase III studies.

// Maristella Bianconi 1 , Luca Faloppi 1 , Cristian Loretelli 1 , Antonio Zizzi 2 , Riccardo Giampieri 1 , Alessandro Bittoni 1 , Kalliopi Andrikou 1 , Michela Del Prete 1 , Luciano Burattini 1 , Rodolfo Montironi 2 , Mario Scartozzi 3, * , Stefano Cascinu 1, * 1 Department of Oncology, AOU Ospedali Riuniti, Polytechnic University of The Marche Region, Ancona, Italy 2 Institute of Pathological Anatomy, AOU Ospedali Riuniti, Polytechnic University of The Marche Region, Ancona, Italy 3 Department of Medical Oncology, Universita degli Studi di Cagliari - Azienda Ospedaliero Universitaria, Cagliari, Italy * Co-last authors Correspondence to: Maristella Bianconi, email: stellabianconi@gmail.com Keywords: renal cell carcinoma, VEGF, angiogenesis, sunitinib, pazopanib Received: September 22, 2015 Accepted: March 28, 2016 Published: May 9, 2016 ABSTRACT Introduction: Recent data from the COMPARZ study seem to suggest a non-inferiority of pazopanib confronted with sunitinib in PFS and OS. We previously reported how VEGF and VEGFR polymorphisms might have a predictive role in patients treated with first-line sunitinib. Aim of our study was to investigate whether tumour angiogenesis genotyping could influence clinical outcome in RCC patients treated with either sunitinib or pazopanib, in order to help clinicians select the appropriate treatment for each patient. Results: 19 patients were treated with pazopanib while 78 received sunitinib. VEGF A rs833061 resulted significant in PFS in sunitinib vs pazopanib patients (CC+CT>TT in sunitinib, TT>CC+CT in pazopanib; p CC in sunitinib, CC>GG+CG in pazopanib; p CC in sunitinib, CC>AA+AC in pazopanib; p

Background: The coronavirus disease 2019 (COVID-19) outbreak has been declared a global pandemic, and Italy is one of the first and most heavily affected countries. Cancer patients are a population at higher risk from COVID-19 both for intrinsic fragility bound to their underlying disease and oncologic treatment delay. The aim of our survey was to investigate how cancer patients perceived their health condition, their clinical management, and information communication by their medical oncologists during the pandemic. Methods: Between 15th April and 1st May, 2020, a survey was submitted to cancer patients under treatment at hospitals of Marche Region that had been invested by the pandemic. It consisted of questions regarding the perception of personal safety, continuity of cancer care, and information quality provided by the Oncology Department and individual psychological distress. Results: A total of 661 patients participated in the survey; 60.2% were female and 40.4% were aged between 46 and 65. Almost all of the attendees (97.7%) stated that the Oncologic Department complied with the appropriate safety standards, and 78% were reassured about their concerns during the medical interview, but 41% were worried of being at higher risk of infection upon entry into the Oncology Department and 53.3% felt at greater risk of infection because of chemotherapy treatment in general. The majority of the participants (62.2%) felt that postponing cancer treatment could reduce its efficacy; however, 80% declared they did not feel abandoned at the time of treatment delay. 79.4% of the attendees felt more worried for their underlying disease in this emergency situation, but the mood worsened for only 34.2% of the participants. Conclusions: Our survey reveals that Oncology Departments have been considered worthy of the emergency in terms of safety standards and care management by cancer patients. However, the majority of attendees perceived the mutual negative influence between their underlying oncologic disease and risk of Sars-CoV-2 infection and manifested concerns about their health condition, highlighting the need for special measures to ensure safe continuity of care. Citation Format: Filippo Merloni, Nicoletta Ranallo, Lucia Bastianelli, Francesca Vitarelli, Luca Cantini, Zelmira Ballatore, Giulia Ricci, Ilaria Fiordoliva, Laura Tassone, Benedetta Ferretti, Paolo Alessandroni, Michela Del Prete, Silvia Chiorrini, Safi Mobin, Rita Ficarelli, Giovanni Benedetti, Luca Faloppi, Rosa Stoico, Rossana Berardi. COVID-19 pandemic: Patients’ perspective during cancer treatment [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr PO-052.

Background: The coronavirus disease 2019 (COVID-19) outbreak has been declared global pandemic and Italy is one of the first and heavily affected countries Cancer patients are a population at higher risk from COVID-19 both for intrinsic fragility bound to their underlying disease and oncologic treatment delay Aim of our survey was to investigate how cancer patients perceived their health condition, their clinical management and information communication by their medical oncologists during the pandemic Methods: Between 15th April and 1st May 2020 a survey was submitted to cancer patients under treatment at hospitals of Marche Region which had been invested by the pandemic It consisted of questions regarding the perception of personal safety, continuity of cancer care and information quality provided by the Oncology Department and individual psychological distress Results: A total of 661 patients participated in the survey;60 2% was female and 40 4% was aged between 46 and 65 Almost all of the attendees (97 7%) stated that the Oncologic Department complied with the appropriate safety standards and 78% was reassured about their concerns during the medical interview, but 41% was worried of being at higher risk of infection upon entry into the Oncology Department and 53 3% felt being at greater risk of infection because of chemotherapy treatment in general The majority of the participants (62 2%) felt that postponing cancer treatment could reduce its efficacy, however 80% declared they did not feel abandoned at the time of treatment delay 79 4% of the attendees felt more worried for their underlying disease in this emergency situation, but the mood worsened only for 34 2% of the participants Conclusions: Our survey reveals that Oncology Departments have been considered worthy of the emergency in terms of safety standards and care management by cancer patients However, the majority of attendees perceived the mutual negative influence between their underlying oncologic disease and risk of Sars-CoV-2 infection and manifested concerns about their health condition highlighting the need for special measures to ensure safe continuity of care Legal entity responsible for the study: Universita Politecnica delle Marche- AOU Ospedali Riuniti di Ancona Funding: Has not received any funding Disclosure: All authors have declared no conflicts of interest

Objective: We built and externally validated a nomogram for predicting the overall survival (OS) probability of advanced gastric cancer patients receiving second-line treatment. Methods: The nomogram was developed on a set of 320 Italian patients and validated on two independent sets (295 Italian and 172 Korean patients). Putative prognostic variables were selected using a random forest model and included in the multivariable Cox model. The nomogram’s performance was evaluated by calibration plot and C index. Results: ECOG performance status, neutrophils to lymphocytes ratio, and peritoneal involvement were selected and included into the multivariable model. The C index was 0.72 (95% CI 0.68–0.75) in the development set, 0.69 (95% CI 0.65–0.73) in the Italian validation set, but only 0.57 (95% CI 0.52–0.62) in the Korean set. While Italian calibrations were quite good, the Korean one was poor. Regarding 6-month OS predictions, calibration was best in both Caucasian cohorts and worst the in Asian one. Conclusions: Our nomogram may be a useful tool to predict 3- or 6-month OS in Caucasian gastric cancer patients eligible for second-line therapy. Based on three easy-to-collect variables, the Gastric Life nomogram may help clinicians improve patient selection for second-line treatments and assist in clinical trial enrollment.

Although lactate dehydrogenase (LDH) serum levels, indirect markers of angiogenesis, are associated with a worse outcome in several tumours, their prognostic value is not defined in pancreatic cancer. Moreover, high levels are associated even with a lack of efficacy of tyrosine kinase inhibitors, contributing to explain negative results in clinical trials. We assessed the role of LDH in advanced pancreatic cancer receiving sorafenib. Seventy-one of 114 patients included in the randomised phase II trial MAPS (chemotherapy plus or not sorafenib) and with available serum LDH levels, were included in this analysis. Patients were categorized according to serum LDH levels (LDH ≤ vs.> upper normal rate). A significant difference was found in progression free survival (PFS) and in overall survival (OS) between patients with LDH values under or above the cut-off (PFS: 5.2 vs. 2.7 months, p = 0.0287; OS: 10.7 vs. 5.9 months, p = 0.0021). After stratification according to LDH serum levels and sorafenib treatment, patients with low LDH serum levels treated with sorafenib showed an advantage in PFS (p = 0.05) and OS (p = 0.0012). LDH appears to be a reliable parameter to assess the prognosis of advanced pancreatic cancer patients, and it may be a predictive parameter to select patients candidate to receive sorafenib.

When it comes to cancer treatment, few have been as difficult as renal cell carcinoma (RCC). Many patients present with advanced or unresectable disease, and up to 30% of patients who have initiall...

Radiofrequency ablation (RFA) is an effective local treatment for curative intent in patients with cirrhosis of the liver and hepatocellular carcinoma (HCC) with diameter

Highlights • Natural history of biliary cancers metastatic to bone • The role of skeletal events in patients with biliary cancer • Biliary cancer and bone metastases: role of bisphosphonates

Background: Sorafenib is recommended for the treatment of advanced-stage hepatocellular carcinoma (HCC). Nonetheless, it is expensive, effective in few patients, and may cause significant adverse effects. Therefore, accurate selection of patients is needed. In a previous study, we constructed a simple scoring system to predict patients’ outcomes based on the occurrence of sorafenib adverse effects. Objective: The present study aimed to validate this scoring system in a real-life cohort of HCC patients. Patients and Methods: Clinical records of 279 outpatients treated with sorafenib in eight Italian centers were retrospectively analyzed. Adverse effects considered to calculate the score were skin toxicity, diarrhea, and arterial hypertension, occurring during the first month of therapy. For each adverse effect, 1 point was assigned if present; and 0 points if absent (resulting in a total score between 0 and 3). Results: Median overall survival (OS) was 10.8months and median time to progression (TTP) was 5.1months. At multivariate analysis, performance status, α-fetoprotein (AFP), and Child-Pugh score were independently associated with TTP and OS. A progressive increase of OS and TTP was observed in patients with scores from 0 to 3 (p&nbsp

Purpose In 2015, we published a study on a small series of patients with hepatocellular carcinoma (HCC) treated chronically with metformin for type II diabetes mellitus (DM2) who showed a poorer response to sorafenib. The aim of the present study was to validate the prognostic significance of metformin in HCC patients treated with sorafenib, providing a biological rationale for the mechanism of resistance to sorafenib in patients on chronic metformin therapy, and to clarify the role of sirtuin-3 (SIRT-3), a protein involved in metabolic diseases and acknowledged as a tumour suppressor in HCC, in this resistance. Patients and methods We analysed 279 patients consecutively treated with sorafenib for the clinical analysis. Of the 86 (30%) patients with DM2, 52 (19%) were on chronic treatment with metformin and 34 (12%) with insulin. We included 43 patients with HCC for the biological study: 19 (44.1%) were diabetic and 14 (73.7%) of these received metformin for DM2. SIRT-3 expression was investigated by immunohistochemistry (IHC) in formalin-fixed and paraffin-embedded (FFPE) samples. Results In HCC patients undergoing chronic treatment with metformin, the use of sorafenib was associated with poor progression-free survival (PFS) and overall survival (OS) (1.9 and 6.6 months, respectively) compared to 3.7 months and 10.8 months, respectively, for patients without DM2 and 8.4 months and 16.6 months, respectively, for patients on insulin (P

Introduction: The microsatellite-instable gastric cancer subtype, because of its supposed high antigenic potential, is a promising candidate for immunotherapy. We analyzed if the presence of a defective mismatch repair (MMR) system is associated with other markers of immune response and their relationship with outcome in advanced gastric cancer patients. Methods: We analyzed the relationship between clinical outcome and MMR status, the presence of tumor-infiltrating lymphocytes (TIL), lymphocytosis, and neutrophil-to-lymphocyte ratio (NLR) in metastatic gastric cancer patients treated with a chemotherapy doublet in the first-line setting. Other stratification factors were sex, age, Eastern Cooperative Oncology Group performance status, adjuvant/neoadjuvant chemotherapy, metastatic sites, and histotype. Results: One hundred three patients were eligible for analysis. Defective MMR was found in 15 patients (14%), TILs were found in 18 patients (17%), lymphocytosis was found in 24 patients (23%), and high NLR was found in 75 patients (72%). Significant correlations were found between defective MMR and TIL positivity (p=0.0004), between defective MMR and lymphocytosis (p=0.0062), between defective MMR and low NLR (p=0.000069), and between TIL positivity and lymphocytosis (p=0.000147). All factors had a statistically significant impact on overall survival, although on multivariate analysis only defective MMR (p=0.0001) and TIL positivity (p=0.0192) maintained their independent prognostic role. Similar results were observed for progression-free survival, with defective MMR (p=0.0001) and TIL positivity (p=0.0195) maintaining their prognostic role on multivariate analysis. Conclusions: Our analysis confirms the favorable prognosis of metastatic gastric cancer patients with a defective MMR system and suggests that expression of TILs might also be linked to better outcome. Because of the correlation between defective MMR status and measures of immune system activity, this group of patients would be the best candidates for novel immunotherapy-based therapies.

Introduction: Tumour-associated inflammation is involved with the development of genitourinary cancers. A growing understanding of the interactions between immune cells and cancer provides the basis for immunomodulating approaches.Area covered: Immunotherapies targeting immune checkpoints and tumour-associated antigens are providing a new approach in patients with prostate and bladder cancer and renal cell carcinoma. The possibility to integrate such therapeutic agents in the current scenario, both in sequential or combined approaches, relies on a comprehension of the pro-tumourigenic activity of the immune system and the mechanisms of cancer-related immunosuppression.Expert commentary: Treatment of genitourinary cancers is being revolutionized by the recent development of new immunotherapeutic approaches. The next step will be the identification of the sequences or combinations between novel and effective immunotherapies and currently approved targeted agents and chemotherapies.

The number of anti-angiogenic drugs who demonstrated activity in metastatic colorectal cancer patients is arising but there is still much debate on which is the optimal use of this class of agents, with particular emphasis given on when (meant as in which line of treatment) and how (meant as in duration of treatment). We sampled the data of randomised phase II-III trials employing this type of drugs, with particular emphasis on trying to "highlight" situations where anti-angiogenetic treatment could provide most benefit. The review displays all relevant clinical data regarding the use of anti-angiogenic drugs in metastatic colorectal cancer and comments on potential implications of these trials in everyday clinical practice. © 2014 Elsevier Ltd.

Background In two retrospective studies we analyzed endothelial-derived nitric oxide synthase (eNOS) and angiopoietin-2 (ANGPT2) polymorphisms, and patients with eNOS-786CC+TC genotype and ANGPT2rs55633437 GG genotypes had significantly higher median PFS and OS compared to those with other genotypes. On the basis of these preliminary results, our aim was to validate in a prospective study these data in patients with HCC treated with sorafenib (S). Methods The primary outcomes were PFS. 160 total sample size was planned with the aim to confirm a HR of 0.58. Event-time distributions were estimated using the Kaplan-Meier method and survival curves were compared using the log-rank test Results 165 patients were prospectively enrolled in the study between 03/2015 and 06/2018. Median OS was 13.1 months and median PFS was 4.2 months. We confirmed that eNOS-786 CC+CT genotype was significantly associated with a higher median PFS (2.4 vs 5.9 months, HR 0.43, 95% CI 0.26-0.70 p = 0.0007) and OS (15.7 vs 8.6 months, HR 0.38, 95% CI 0.24-0.60 p Conclusions Our Italian multicenter, prospective study met its primary and secondary end points, and we confirmed that eNOS-786 CC+CT genotype may be capable of identifying a subset of HCC patients who have a higher median OS and PFS. For the first time in ten years of sorafenib research our study confirms the prognostic role of a biological marker in a prospective study. Clinical trial identification NCT02786342. Legal entity responsible for the study University of Modena. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

e15663 Background: For over ten years the most stimulating results in systemic therapy for advanced HCC derived from the use of sorafenib (S). But in the last two years several drugs, in particular other multikinase inhibitors like lenvatinib (L), regorafenib (R), cabozantinib (C), proved to be effective both as an alternative or a sequential therapy to sorafenib. In this widened and rapidly increased scenario, without any head-to-head trial, clinicians struggle to define the best drug and the best treatment sequence. Aim of the first part of this project is to evaluate the activity of different treatment sequences in HCC cell lines to pave the way to a future clinical trial investigating their efficacy. Methods: Compounds of S, R, L and C were dissolved in DMSO and aliquoted. HepG2 cell line, obtained from ECACC (Salisbury, UK), was seeded at the density of 3 x 104 cells/ml. After 24 h of incubation, compounds or vehicle (DMSO) were added. Treatments were performed in single administration and six replicates were carried out for each dose. At 48h post-treatment, cells were fixed and stained with acid solution. The absorbance was measured at 520 nm using an ELISA reader (BioTek Instruments, USA). The assay was also performed with the sequences of: S-R, S-C, L-R, L-C (first line treatments for 48h followed by the second compound for 48h). Higher doses than the minimum inhibiting one were tested. Results: S showed superior activity than L as first line compound. In the sequence assay S-C and S-R seems to have the best results in terms of cell viability. After L the best compound appears to be R. See table. Conclusions: Our results showed relevant variations in cell viability with different drug sequences. Already planned analyses in the RISE-HEP project in vivo and in humans are mandatory to confirm which sequence would have the highest efficacy.[Table: see text]

4075 Background: In the ePHAS study we analyzed three eNOSpolymorphisms and at univariate analysis, patients with eNOS-786 -TTgenotype had significantly shorter median Progression Free Survival (PFS) and Overall Survival (OS) compared to those with other genotypes. On the basis of these preliminary results, our aim is to validate in a prospective study this data in patients with HCC treated with sorafenib. Methods: This is a prospective Italian multicenter study, that includes 141 HCC patients receiving sorafenib. We analyzed eNOS-786and itwas analyzed by Real Time PCR in relation to the primary end point (OS). Event-time distributions were estimated using the Kaplan-Meier method and survival curves were compared using the log-rank test. Results: 141 HCC patients (122 males and 19 females), prospectively treated with sorafenib from May 2015 to September 2018 were included. Median age was 69 years (range 28-88 years). 120 patients had Child-Pugh A and 21 had Child-Pugh B7. 43 had BCLC-B and 98 patients had BCLC-C. Atunivariate analysis, we confirmed that eNOS-786 TT genotype were significantly associated with a lower median OS than the other genotypes (8.8 vs 15.7 months, HR 1.69, 95% CI 1.02-2.83 p=0.0424). Following adjustment for clinical covariates (age, gender, etiology, BCLC stage, serum α-FP level, MELD score), multivariate analysis confirmed eNOS- 786 and BCLC stage as the independentsprognostic factors predicting OS (TTvsTC+CC; HR: 2.39, 95% CI 1.14-5.03 p=0.0211; C vs B;2.23, 95% CI 1.44-4.77 p=0.039). Conclusions: Our prospective study confirms the prognostic role of eNOS-786 in advanced HCC patients treated with sorafenib. Clinical trial information: NCT02786342.

INTRODUCTION: In this review, we analyzed the current literature about cetuximab to clarify its role in the treatment of pancreatic cancer. Using single-agent gemcitabine has been the standard treatment for more than 15 years for advanced pancreatic cancer. The attempts at improving the results by combining it with several other drugs, such as fluorouracil, cisplatin, irinotecan, oxaliplatin, or pemetrexed produced no clear survival benefit. Recently, however, new combination chemotherapy regimens (e.g., FOLFIRINOX, nab-paclitaxel plus gemcitabine) achieved a significant survival benefit compared to gemcitabine alone.AREAS COVERED: Epidermal growth factor receptor (EGFR) transmembrane glycoprotein has been demonstrated to be overexpressed in pancreatic cancer, and it correlates with more advanced disease, poor survival, and the presence of metastases. Therefore, inhibition of the EGFR signaling pathway could be an attractive therapeutic target in this tumor. Although several combinations of EGFR inhibitors with chemotherapy demonstrate inhibition of tumor-induced angiogenesis, tumor cell apoptosis, and regression in xenograft models, these benefits remain to be confirmed.EXPERT OPINION: The encouraging results from preclinical and early clinical studies with cetuximab in pancreatic cancer were not confirmed in a Phase III trial. Cetuximab failed to demonstrate improved patient outcome when paired with various chemotherapeutic regimens and/or other biological agents.

Advances in surgical and medical treatments have significantly changed the management of colorectal cancer liver metastases (CRCLMs). In particular, new drugs and modern combination chemotherapy regimens, together with the improvement of surgical techniques, allow a potentially curative approach in an increasing number of patients. Nevertheless, there is no strong evidence for an optimal treatment strategy for CRCLMs, mainly because of the extensive heterogeneity in the patients. In fact, although we consider them a population, they represent different clinical and biological subtypes requiring different approaches. Furthermore, results from different studies in this setting may be difficult to interpret, also because the definitions of different patient subgroups are unclear and overlapping. In this review we discuss the results of clinical trials evaluating the role of chemotherapy in the multimodal management of CRCLMs, in either the pre- or postoperative setting. Then we identify three main categories of CRCLM patients, providing clinical recommendations for each.

The encouraging results in immunotherapy for melanoma also led the way for translational and clinical research about immune-related mechanisms possibly relevant for gastrointestinal tumours. It is in fact now evident that the immune checkpoint modulation and in particular cell-mediated immune-response through programmed cell death-1 (PD-1) and the cytotoxic T-lymphocyte antigen-4 (CTLA4) receptors along with the regulatory T cells activity all have a relevant role in gastrointestinal cancers as well. This review aims to explore the state of the art of immunotherapy for gastrointestinal tumours, deepening recent scientific evidence regarding anti PD-1/PDL-1 and anti CTLA4 monoclonal antibodies, peptide based vaccine, DNA based vaccine, and pulsed dendritic cells, either alone or in combination with other antineoplastic medical therapy and locoregional treatments. Considering the non-negligible toxicity profile deriving from such a treatment approach, predictive biomarkers of response to immunotherapy in gastrointestinal cancer are also urgently needed in order to better select the patients’ group with the highest likelihood of benefit.

BACKGROUND:The potential clinical impact of aspirin use beyond its canonical indications is a novel matter of scientific debate. In patients with metastatic colorectal cancer failing all available options, regorafenib and TAS 102 represent the only chance of treatment. Although effective, these therapeutic options bring along a not-negligible burden in terms of economic costs and toxicity. In this setting, the indication to use aspirin in combination with chemotherapy would potentially represent a medical revolution under the economic and toxicity profile.PATIENTS AND METHODS:We assessed the role of aspirin in patients with metastatic colorectal cancer who failed all previous treatments and were receiving capecitabine as a salvage option before the introduction of regorafenib and TAS-102.RESULTS:Sixty-six patients were eligible. Twenty patients (30%) were on incidental treatment with aspirin for cardiovascular diseases. Twelve (60%) partial responses were seen in patients on treatment with aspirin, compared with 3 (6%) partial responses in the remaining patients (P = .00007). Sixteen patients on aspirin (80%) obtained disease control versus 14 (30%) patients who were not on aspirin (P = .000377). The median progression-free survival for patients receiving treatment with aspirin was 6.5 months versus 3.3 months for patients who were not on aspirin (hazard ratio, 0.48; 95% confidence interval, 0.30-0.79; P = .0042). A significantly improved overall survival was also evident in aspirin users (median overall survival, 14.7 vs. 8.7 months, respectively; hazard ratio, 0.43; 95% confidence interval, 0.26-0.72; P = .0023).CONCLUSION:Aspirin may improve the clinical outcome of heavily pre-treated patients with metastatic colorectal cancer receiving chemotherapy. Further studies are necessary before application in the clinical practice.Copyright © 2016 Elsevier Inc. All rights reserved.KEYWORDS:Aspirin; Capecitabine; Chemotherapy; Colon cancer; Salvage treatment

// Andrea Casadei Gardini 1 , Emanuela Scarpi 2 , Luca Faloppi 3, 4 , Mario Scartozzi 4 , Nicola Silvestris 5 , Daniele Santini 6 , Giorgio de Stefano 7 , Giorgia Marisi 8 , Francesca V. Negri 9 , Francesco Giuseppe Foschi 10 , Martina Valgiusti 1 , Giorgio Ercolani 11, 12 , Giovanni Luca Frassineti 1 1 Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS, Meldola, Italy 2 Unit of Biostatistics and Clinical Trials, IRST IRCCS, Meldola, Italy 3 Department of Medical Oncology, Ospedale Generale Provinciale di Macerata ASUR Marche AV3, Macerata, Italy 4 Department of Medical Oncology, University Hospital Cagliari, Cagliari, Italy 5 Medical Oncology Unit, Cancer Institute “Giovanni Paolo II”, Bari, Italy 6 Medical Oncology Department, University Campus Bio-Medico, Via Alvaro del Portillo, Rome, Italy 7 Infectious Diseases and Interventional Ultrasound Unit, D. Cotugno Hospital, Naples, Italy 8 Biosciences Laboratory, IRST IRCCS, Meldola, Italy 9 Medical Oncology Unit, University Hospital, Parma, Italy 10 DPT Internal Medicine, Faenza Hospital, Faenza, AUSL Romagna, Forli, Italy 11 Department of General Surgery, Morgagni-Pierantoni Hospiatal, AUSL Romagna, Forli, Italy 12 Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy Correspondence to: Andrea Casadei Gardini, email: andrea.casadei@irst.emr.it Keywords: systemic immune-inflammation index, inflammation, biomarker, hepatocellular carcinoma, neutrophil-to-lymphocyte ratio Received: June 21, 2016 Accepted: August 15, 2016 Published: August 24, 2016 ABSTRACT We evalueted a systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) with the aim to explored their prognostic value in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib. 56 advanced HCC patients receiving sorafenib were available for our analysis. Lymphocyte, neutrophil and platelet were measured before beginning of treatment and after one month. Patient with SII ≥ 360 showed lower median PFS (2.6 vs. 3.9 months, P < 0.026) and OS (5.6 vs. 13.9 months, P = 0.027) with respect to patients with SII < 360. NLR ≥ 3 had a lower median PFS (2.6 vs. 3.3 months, P < 0.049) but not OS (5.6 vs. 13.9 months, P = 0.062) than those with NLR < 3. After adjusting for clinical covariates SII and NLR remained an independent prognostic factor for OS. The SII and NLR represent potential prognostic indicator in patients with advanced HCC treated with sorafenib.

Background: Sorafenib is a multi-targeted kinase inhibitor with a demonstrated activity in renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC), and it is currently used for the treatment of these pathologies. Ongoing clinical trials are studying its activity in other malignancies, such as non-small-cell lung cancer (NSCLC). However, no biological marker is known to define either the sensitivity or resistance to the drug. Case presentation: Here we report a case of a patient with two synchronous tumors, HCC and NSCLC, with metastases in the contralateral lung and bone. The patient was treated with gemcitabine as first line, with a resulting progressive disease after two months, and then with sorafenib at standard dosage in the second line setting. After 6 months of treatment CT scan showed a partial response in the primary lesion of the lung, complete response of the metastasis in the contralateral lung, and stability of HCC. The patient had progression in the lung, liver and bone after 13 months of therapy. A molecular characterization of NSCLC and HCC lesions was performed, revealing a BRAF exon 11 mutation (G469V) only in NSCLC. We hypothesize that the response observed in NSCLC lesions could be due to the presence of BRAF mutation, and that this alteration could be responsible in determining sorafenib sensitivity. Conclusions: Results observed in this case encourage further research on the activity of sorafenib in both HCC and NSCLC, based on the presence of BRAF mutation. This could lead to a selection of HCC patients to be treated with this drug, and could help identify a novel treatment strategy for BRAF-mutated NSCLC patients.

Regorafenib monotherapy is a potential option for metastatic colorectal cancer patients. However, the lack of predictive factors and the severe toxicities related to treatment have made its use in clinical practice challenging. Polymorphisms of VEGF and its receptor (VEGFR) genes might regulate angiogenesis and thus potentially influence outcome during anti-angiogenesis treatment such as regorafenib. Aim of our study was to evaluate the role of VEGF and VEGFR genotyping in determining clinical outcome for colorectal cancer patients receiving regorafenib. We retrospectively collected clinical data and samples (tumour or blood) of 138 metastatic colorectal cancer patients treated with regorafenib. We analysed the correlation of different VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs) with patients’ progression-free survival (PFS) and overall survival (OS). Results from angiogenesis genotyping showed that only VEGF-A rs2010963 maintained an independent correlation with PFS and OS. Among clinical factors only ECOG PS was independently correlated with OS, whereas no correlation with PFS was evident. Grouping together those results allowed further patients stratification into 3 prognostic groups: favourable, intermediate and unfavourable. VEGF-A rs2010963 genotyping may represent an important tool for a more accurate selection of optimal candidates for regorafenib therapy.

LDH may represent an indirect marker of neo-angiogenesis and worse prognosis in many tumour types. We assessed the correlation between LDH and clinical outcome for biliary tract cancer (BTC) patients treated with first-line chemotherapy. Overall, 114 advanced BTC patients treated with first-line gemcitabine and cisplatin were included. Patients were divided into two groups (low vs. high LDH), according to pre-treatment LDH values. Patients were also classified according to pre- and post-treatment variation in LDH serum levels (increased vs. decreased). Median progression free survival (PFS) was 5.0 and 2.6 months respectively in patients with low and high pre-treatment LDH levels (p = 0.0042, HR = 0.56, 95% CI: 0.37–0.87). Median overall survival (OS) was 7.7 and 5.6 months (low vs. high LDH) (p = 0.324, HR = 0.81, 95% CI: 0.54–1.24). DCR was 71% vs. 43% (low vs. high LDH) (p = 0.002). In 38 patients with decreased LDH values after treatment, PFS and OS were respectively 6.2 and 12.1 months, whereas in 76 patients with post-treatment increased LDH levels, PFS and OS were respectively 3.0 and 5.1 months (PFS: p = 0.0009; HR = 0.49; 95% IC: 0.33–0.74; OS: p

// Andrea Casadei Gardini 1, * , Giorgia Marisi 2, * , Luca Faloppi 3 , Emanuela Scarpi 4 , Francesco Giuseppe Foschi 5 , Massimo Iavarone 6 , Gianfranco Lauletta 7 , Jody Corbelli 8 , Martina Valgiusti 1 , Floriana Facchetti 6 , Cristina della Corte 6 , Luca Maria Neri 9 , Stefano Tamberi 8 , Stefano Cascinu 3 , Mario Scartozzi 10 , Dino Amadori 1 , Oriana Nanni 4 , Elena Tenti 1 , Paola Ulivi 2, ** , Giovanni Luca Frassineti 1, ** 1 Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy 2 Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy 3 Department of Medical Oncology, Azienda Ospedaliero Universitaria Ospedali Riuniti, Universita Politecnica delle Marche, Ancona, Italy 4 Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy 5 DPT Internal Medicine, Faenza Hospital, AUSL Romagna, Faenza, Italy 6 A.M.&A. Migliavacca Center for Liver Disease, 1st Division of Gastroenterology, Fondazione IRCCS Ca' Granda Maggiore Hospital, University of Milan, Milan, Italy 7 Department of Biomedical Sciences and Human Oncology, Internal Medicine “G. Baccelli”, University of Bari “A. Moro”, Bari, Italy 8 Department of Medical Oncology, Faenza Hospital, AUSL Romagna, Faenza, Italy 9 Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy 10 Department of Medical Oncology, University Hospital Cagliari, Cagliari, Italy * These first authors contributed equally to this work ** These authors have contributed equally to this work Correspondence to: Giorgia Marisi, e-mail: giorgia.marisi@irst.emr.it Keywords: hepatocellular carcinoma, endothelial nitric oxide synthase, single nucleotide polymorphisms, biomarkers, angiogenesis Received: February 08, 2016 Accepted: March 28, 2016 Published: April 4, 2016 ABSTRACT Sorafenib may reduce endothelial nitric oxide synthase (eNOS) activity by inhibiting vascular endothelial growth factor receptors (VEGF-R), leading to a decrease in nitric oxide production. In the Italian multicenter ePHAS ( eNOS polymorphisms in HCC and sorafenib) study, we analyzed the role of eNOS polymorphisms in relation to clinical outcome in patients with hepatocellular carcinoma (HCC) receiving sorafenib. Our retrospective study included a training cohort of 41 HCC patients and a validation cohort of 87 HCC patients, all undergoing sorafenib treatment. Three eNOS polymorphisms ( eNOS -786T>C, eNOS VNTR 27bp 4a/b and eNOS +894G>T) were analyzed by direct sequencing or Real Time PCR in relation to progression-free survival (PFS) and overall survival (OS) (log-rank test). In univariate analysis, training cohort patients homozygous for eNOS haplotype (HT1:T-4b at eNOS -786/ eNOS VNTR) had a lower median PFS (2.6 vs. 5.8 months, P < 0.0001) and OS (3.2 vs. 14.6 months, P = 0.024) than those with other haplotypes. In the validation set, patients homozygous for HT1 had a lower median PFS (2.0 vs. 6.7 months, P < 0.0001) and OS (6.4 vs. 18.0 months, P < 0.0001) than those with other haplotypes. Multivariate analysis confirmed this haplotype as the only independent prognostic factor. Our results suggest that haplotype HT1 in the eNOS gene may be capable of identifying a subset of HCC patients who are resistant to sorafenib.