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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.

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.

Treatment-related neurotoxicity is a common side effect in cancer patients. However, few data are available regarding the risk of several neurotoxicities in patients treated with immune checkpoint inhibitors. The MOUSEION-02 study is an up-to-date meta-analysis aimed at assessing the risk of peripheral neuropathy, peripheral sensory neuropathy, and headache in cancer patients receiving immunotherapy and immuno-oncology combinations. Patients receiving immunotherapy (as monotherapy or in combination with other anticancer agents) showed lower risk of all-grade peripheral neuropathy (RR, 0.50; 95% CI, 0.35���0.70) and all-grade peripheral sensory neuropathy (RR, 0.49; 95% CI, 0.30���0.79). Similarly, in patients treated with immune checkpoint inhibitor monotherapy, we observed lower risk of all-grade peripheral neuropathy (RR, 0.05; 95% CI, 0.03���0.10) and all-grade peripheral sensory neuropathy (RR, 0.11; 95% CI, 0.05���0.23). No differences were observed in terms of all-grade headache. Although the results of this meta-analysis should be interpreted with caution due to several issues, our study draws attention to immunotherapy-related neurotoxicity with the aim of maximizing clinical outcomes of cancer patients experiencing these not uncommon, and yet poorly studied, adverse events.

The primary endpoint of MOUSEION-01 was to assess overall survival (OS) in male and female patients receiving immune checkpoint inhibitors versus control treatments, calculating the pooled OS Hazard Ratio (HR) and 95 % Confidence Interval (CI) in both groups. 37 randomized phase III studies and 22646 patients (16382 men and 6264 women) were included. In patients treated with immunotherapy (as monotherapy or in combination with other agents), the pooled OS HR was 0.78 (0.75-0.82) and 0.77 (95 % CI, 0.72-0.83) in male and female subjects, respectively. The pooled HR for OS in male patients treated with single-agent immunotherapy versus control was 0.77 (95 % CI, 0.70-0.85), while this benefit was smaller in female patients (HR, 0.81; 95 % CI, 0.73-0.9). Our findings highlight that high-quality trials accounting for potential confounders are needed before being able to suggest a real effect of the patient's gender on immune checkpoint inhibitors efficacy in different settings.

Background Biliary tract cancers (BTC) are rare but highly aggressive tumours with poor prognosis, usually detected at advanced stages. Herein, we aimed at identifying BTC-specific DNA methylation alterations. Methods Study design included statistical power and sample size estimation. A genome-wide methylation study of an explorative cohort (50 BTC and ten matched non-tumoral tissue samples) has been performed. BTC-specific altered CpG islands were validated in over 180 samples (174 BTCs and 13 non-tumoral controls). The final biomarkers, selected by a machine-learning approach, were validated in independent tissue (18 BTCs, 14 matched non-tumoral samples) and bile (24 BTCs, five non-tumoral samples) replication series, using droplet digital PCR. Results We identified and successfully validated BTC-specific DNA methylation alterations in over 200 BTC samples. The two-biomarker panel, selected by an in-house algorithm, showed an AUC > 0.97. The best-performing biomarker (chr2:176993479-176995557), associated with HOXD8, a pivotal gene in cancer-related pathways, achieved 100% sensitivity and specificity in a new series of tissue and bile samples. Conclusions We identified a novel fully efficient BTC biomarker, associated with HOXD8 gene, detectable both in tissue and bile by a standardised assay ready-to-use in clinical trials also including samples from non-invasive matrices.

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.

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 synthaseThis 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 forA total of 165 patients were enrolled between March 2016 and June 2018.The INNOVATE study met the primary endpoint, confirming that patients with advanced HCC with

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.

Background Clustered protocadherins (PCDHs) map in tandem at human chromosome 5q31 and comprise three multi-genes clusters: α-, β- and γ-PCDH. The expression of this cluster consists of a complex mechanism involving DNA hub formation through DNA-CCTC binding factor (CTCF) interaction. Methylation alterations can affect this interaction, leading to transcriptional dysregulation. In cancer, clustered PCDHs undergo a mechanism of long-range epigenetic silencing by hypermethylation. Results In this study, we detected frequent methylation alterations at CpG islands associated to these clustered PCDHs in all the solid tumours analysed (colorectal, gastric and biliary tract cancers, pilocytic astrocytoma), but not hematologic neoplasms such as chronic lymphocytic leukemia. Importantly, several altered CpG islands were associated with CTCF binding sites. Interestingly, our analysis revealed a hypomethylation event in pilocytic astrocytoma, suggesting that in neuronal tissue, where PCDHs are highly expressed, these genes become hypomethylated in this type of cancer. On the other hand, in tissues where PCDHs are lowly expressed, these CpG islands are targeted by DNA methylation. In fact, PCDH-associated CpG islands resulted hypermethylated in gastrointestinal tumours. Conclusions Our study highlighted a strong alteration of the clustered PCDHs methylation pattern in the analysed solid cancers and suggested these methylation aberrations in the CpG islands associated with PCDH genes as powerful diagnostic biomarkers. Electronic supplementary material The online version of this article (10.1186/s13148-019-0695-0) contains supplementary material, which is available to authorized users.

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.

Sirtuins (SIRT), first described as nicotinamide adenine dinucleotide (NAD + )-dependent type III histone deacetylases, are produced by cells to support in the defense against chronic stress conditions such as metabolic syndromes, neurodegeneration, and cancer. SIRT-3 is one of the most studied members of the mitochondrial sirtuins family. In particular, its involvement in metabolic diseases and its dual role in cancer have been described. In the present review, based on the evidence of SIRT-3 involvement in metabolic dysfunctions, we aimed to provide an insight into the multifaceted role of SIRT-3 in many solid and hematological tumors with a particular focus on hepatocellular carcinoma (HCC). SIRT-3 regulatory effect and involvement in metabolism dysfunctions may have strong implications in HCC development and treatment. Research literature widely reports the relationship between metabolic disorders and HCC development. This evidence suggests a putative bridge role of SIRT-3 between metabolic diseases and HCC. However, further studies are necessary to demonstrate such interconnection.

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.

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third leading cause of cancer deaths. microRNAs (miRNAs) are evolutionary conserved small non-coding RNA that negatively regulate gene expression and protein translation. Recent evidences have shown that they are involved in many biological processes, from development and cell-cycle regulation to apoptosis. miRNAs can behave as tumor suppressor or promoter of oncogenesis depending on the cellular function of their targets. Moreover, they are frequently dysregulated in HCC. In this review we summarize the latest findings of miRNAs regulation in HCC and their role as potentially diagnostic and prognostic biomarkers for HCC. We highlight development of miRNAs as potential therapeutic targets for HCC.

Although new treatment modalities changed the global approach to hepatocellular carcinoma (HCC), this disease still represents a medical challenge. Currently, the therapeutic stronghold is sorafenib, a tyrosine kinase inhibitor (TKI) directed against the vascular endothelial growth factor (VEGF) family. Previous observations suggested that polymorphisms of VEGF and its receptor (VEGFR) genes may regulate angiogenesis and lymphangiogenesis and thus tumour growth control. The aim of our study was to evaluate the role of VEGF and VEGFR polymorphisms in determining the clinical outcome of HCC patients receiving sorafenib. From a multicentre experience 148 samples (tumour or blood samples) of HCC patients receiving sorafenib were tested for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs). Patients' progression-free survival (PFS) and overall survival (OS) were analysed. At univariate analysis VEGF-A alleles C of rs25648, T of rs833061, C of rs699947, C of rs2010963, VEGF-C alleles T of rs4604006, G of rs664393, VEGFR-2 alleles C of rs2071559, C of rs2305948 were significant predictors of PFS and OS. At multivariate analysis rs2010963, rs4604006 and BCLC (Barcelona Clinic Liver Cancer) stage resulted to be independent factors influencing PFS and OS. Once prospectively validated, the analysis of VEGF and VEGFR SNPs may represent a clinical tool to better identify HCC patients more likely to benefit from sorafenib. On the other hand, the availability of more accurate predictive factors could help avoiding unnecessary toxicities to potentially resistant patients who may be optimal candidates for different treatments interfering with other tumour molecular pathways.