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Abstract Recently, in Hepatocellular carcinoma (HCC) setting, the use of metformin has been associated to a trend toward worse response rate, overall survival and progression free survival in patients who received immunotherapy. The study population included individuals from both Eastern and Western regions with a confirmed diagnosis of HCC and receiving first line treatment with Atezolizumab plus bevacizumab or Lenvatinib. Univariate and multivariate analyses were performed by Cox proportional. For the analysis, patients were stratified based on their use of concomitant medication or not. At the time of database lock, 319 deaths were observed: 209 in the Lenvatinib cohort, 110 in the Atezolizumab plus bevacizumab cohort. In the Atezolizumab plus Bevacizumab arm, 50 (16.5%) patients were on chronic metformin use. At the univariate analysis for OS, patients who used metformin showed significantly shorter OS compared to patients who did not use metformin (HR 1.9, 95% CI 1.1–3.2). Multivariate analysis confirmed that patients in metformin group had significantly shorter OS compared to patients in no-metformin group (HR 1.9; 95% CI 1.1–3.1). At the univariate analysis for PFS, patients in metformin group had significantly shorter PFS compared to patients in no-metformin group (HR 1.6, 95% CI 1.0–2.6). Multivariate analysis confirmed that patients in metformin group had significantly shorter PFS compared to patients in no-metformin group (HR 1.7; 95% CI 1.1–2.7; p = 0.0147). No differences were reported in terms of ORR and DCR between patients in metformin group and those in no-metformin group. In the Lenvatinib cohort, 65 (15%) patients were recorded to chronically use metformin. No statistically significant differences in terms of both OS and PFS were found between patients in metformin group and patients in no-metformin group. This analysis unveils a negative prognostic role associated with metformin use specifically within the Atezolizumab plus Bevacizumab group.

Background and purpose: To assess feasibility, toxicity and outcome of moderately hypofractionated radiotherapy concomitant to capecitabine after induction chemotherapy for advanced pancreatic cancer. Materials and methods: Patients with advanced pancreatic cancer without distant progression after induction chemotherapy (CHT) were considered. Radiochemotherapy (RCT) consisted of 44.25 Gy in 15 fractions to the tumor and involved lymph-nodes concomitant to capecitabine 1250 mg/m2/day. Feasibility and toxicity were evaluated in all pts. Overall survival (OS), progression free survival (PFS), distant PFS (DPFS) and local PFS (LPFS) were assessed only in stage III patients. Results: 254 patients, 220 stage III, 34 stage IV, were treated. Median follow up was 19 months. Induction CHT consisted of Gemcitabine (35 patients), or drug combination (219 patients); median duration was 6 months.Four patients (1.6 %) did not complete RT (1 early progression, 3 toxicity), median duration of RT was 20 days, 209 patients (82 %) received ≥ 75 % of capecitabine dose.During RCT G3 gastrointestinal toxicity occurred in 3.2% of patients, G3-G4 hematologic toxicity in 5.4% of patients. Subsequently, G3, G4, G5 gastric or duodenal lesions occurred in 10 (4%), 2 (0.8%) and 1 patients (0.4%), respectively.Median PFS, LPFS, and DPFS were 11.9 months (95 % CI:11.4–13), 16 months (95 % CI:14.2–17.3) and 14.0 months (95 % CI:12.6–146.5), respectively.Median OS was 19.5 months (95 % CL:18.1–21.3). One- and two-year survival were 85.2 % and 36 %, respectively. Conclusions: The present schedule of hypofractionated RT after induction CHT is feasible with acceptable toxicity rate and provides an outcome comparable with that achievable with standard doses and fractionation.

AbstractSmall bowel adenocarcinoma (SBA) is a rare tumor with an unfavorable prognosis, and due to its rarity, few studies on its treatment are available. Chemotherapy remains the standard of treatment in advanced disease. Recently immunotherapy has demonstrated to be a valid therapeutic option for many solid tumors. We reviewed the data published in literature to understand the impact of immunotherapy in this cancer.

Introduction The impact of etiology on response to immunotherapy in advanced hepatocellular carcinoma (HCC) is being debated, with contrasting findings between early and recent post-hoc analyses of IMbrave-150 and metanalyses of clinical trials of PD-1/PD-L1 blockers. As a results, it is not clear whether the first-line systemic treatment atezolizumab plus bevacizumab is equally effective in viral and non-viral patients. Methods We retrospectively analyzed 885 HCC patients treated with first-line A + B from multiple centers from Eastern and Western countries, 53.9% having viral and 46.1% non-viral etiology. Baseline clinical and laboratory characteristics were analyzed with uni- and multi-variate models to explore potential differences on overall survival (OS), time to progression (TTP), disease control rates based on etiology and to identify putative prognostic factors in etiology subgroups. Treatment toxicities and access to second-line treatments and outcomes were also reported and compared between etiologies. Results Overall, no statistically significant differences were found in OS (mOS: viral 15.9 months; non-viral 16.3 months), TTP (mTTP: viral 8.3 months; non-viral 7.2 months), and disease control rates (DCR: viral 78.1%; non-viral 80.8%) based on etiology. Prognostic factors of survival and progression were mainly shared between viral and non-viral etiologies, including alpha-fetoprotein, aspartate transaminase, neutrophil-to-lymphocyte ratio (NLR) and ALBI score. Exploratory analyses highlighted a possible stronger association of immunological factors, i.e. NLR and eosinophil count, to treatment outcomes in viral patients. The toxicity profile, the access to and type of second-line treatments and their outcome in terms of OS almost overlap in the two etiology subgroups. Conclusion Atezolizumab plus bevacizumab efficacy does not vary according to underlying etiology of HCC in a multicenter, real-world population, matching recent post-hoc findings from the IMbrave-150 trial. Preliminary analyses suggest that some prognostic factors differ between viral and non-viral patients, potentially due to biological and immunological differences. Prospective and comparative trials stratifying by etiology are warranted to validate these findings and guide clinical practice.

Abstract Adjuvant chemotherapy recommendations for ER+/HER2− early-stage breast cancers (eBC) involve integrating prognostic and predictive information which rely on physician judgment; this can lead to discordant recommendations. In this study we aim to evaluate whether Oncotype DX improves confidence and agreement among oncologists in adjuvant chemotherapy recommendations. We randomly select 30 patients with ER+/HER2− eBC and recurrence score (RS) available from an institutional database. We ask 16 breast oncologists with varying years of clinical practice in Italy and the US to provide recommendation for the addition of chemotherapy to endocrine therapy and their degree of confidence in the recommendation twice; first, based on clinicopathologic features only (pre-RS), and then with RS result (post-RS). Pre-RS, the average rate of chemotherapy recommendation is 50.8% and is higher among junior (62% vs 44%; p

Abstract IDH1-mutated cholangiocarcinomas (CCAs) are an interesting group of neoplasia with particular behavior and therapeutic implications. The aim of the present work is to highlight the differences characterizing IDH1m and IDH1wt CCAs in terms of genomic landscape. 284 patients with iCCA treated for resectable, locally advanced or metastatic disease were selected and studied with the FOUNDATION Cdx technology. A comparative genomic analysis and survival analyses for the most relevant altered genes were performed between IDH1m and IDH1wt patients. Overall, 125 patients were IDH1m and 122 IDH1wt. IDH1m patients showed higher mutation rates compared to IDH1wt in CDKN2B and lower mutation rates in several genes including TP53, FGFR2, BRCA2, ATM, MAP3K1, NOTCH2, ZNF703, CCND1, NBN, NF1, MAP3 KI3, and RAD21. At the survival analysis, IDH1m and IDH1wt patients showed no statistically differences in terms of survival outcomes, but a trend in favor of IDH1wt patients was observed. Differences in prognostic values of the most common altered genes were reported. In surgical setting, in IDH1m group the presence of CDKN2A and CDKN2B mutations negatively impact DFS, whereas the presence of CDKN2A, CDKN2B, and PBRM1 mutations negatively impact OS. In advanced setting, in the IDH1m group, the presence of KRAS/NRAS and TP53 mutations negatively impact PFS, whereas the presence of TP53 and PIK3CA mutations negatively impact OS; in the IDH1wt group, only the presence of MTAP mutation negatively impact PFS, whereas the presence of TP53 mutation negatively impact OS. We highlighted several molecular differences with distinct prognostic implications between IDH1m and IDH1wt patients.

Background: The results of the phase III ClarIDHy trial led to the FDA approval of ivosidenib as a therapeutic option for patients with locally advanced or metastatic cholangiocarcinoma (CCA) harboring isocitrate dehydrogenase 1 (IDH1) mutations. We recently published the first data on the use of ivosidenib in a real-world setting. Objective: Here we report the updated survival results of 11 patients with locally advanced or metastatic IDH1-mutated CCA who received ivosidenib in clinical practice. Patients and methods: Patients treated with ivosidenib as second- and third-line treatments for advanced CCA have been collected with the aim to evaluate the survival outcomes. A molecular study has been performed by next generation sequencing essay. Results: Overall, 11 patients were included. After a median follow-up of 13.7 months, median progression-free survival from the start of treatment with ivosidenib was 4.4 months (95% CI: 2.0–5.8), whereas median overall survival was 15 months (95% CI: 6.6–15.0) regardless of treatment line. Disease control rate was 63%, with two patients achieving a partial response (18%). Eighteen percent of patients experienced at least one treatment-related adverse events (AEs), but no grade ⩾3 was reported. The most frequently observed grade 2 AEs were prolonged QT interval and hypomagnesemia. A molecular profiling was performed on 8 out of 11 patients, highlighting TP53, BAP1, CDKN2A, and CDKN2B as the most common co-altered genes in these patients. Conclusion: The present update confirms the results of our previous real-world experience on the use of ivosidenib in IDH1-mutated CCA. Real-world evidence on larger numbers of patients is needed to confirm our findings.

Gastric cancer (GC) is recognized as one of the most common deadly malignancies worldwide and about 40–50% of patients present at diagnosis with an unresectable disease due to a locally advanced or already metastatic condition. Recently, therapeutic options for management of metastatic GC (mGC) have been approved allowing a potential improvement of patient cancer treatment response and also an establishment of a continuum of care for this aggressive disease. This report is the result of a literature review by an expert panel. The aim of this document is to provide evidence, wherever it is lacking, to provide expert opinion directed at strategic management of mGC, and in particular aspect at practical management where appropriate guidelines are not available. Treatment landscape with new therapeutic strategies for third line and beyond, role of imaging, prognostic factors, symptoms, and markers as well as the importance of multidisciplinary approach particularly the nutritional aspects are discussed.

Introduction: In the REFLECT trial, lenvatinib was found to be non-inferior compared to sorafenib in terms of Overall Survival. Here, we analyze the effects of lenvatinib in the real-life experience of several centers across the world, and to identify clinical factors that could be significantly associated with survival outcomes. Methods: The study population derived from retrospectively collected data of HCC patients treated with lenvatinib. The overall cohort included Western and Eastern populations from 23 centres in five countries. Results: We included 1325 patients with HCC and treated with lenvatinib in our analysis. Median OS was 16.1 months. Overall response rate was 38.5%. Multivariate analysis for OS highlighted that HBsAg positive, NLR >3 and AST >38 were independently associated with poor prognosis in all models. Conversely, NAFLD/NASH related aetiology was independently associated with good prognosis. Median progression free survival was 6.3 months. Multivariate analysis for Progression Free survival revealed that NAFLD/NASH, BCLC, NLR and AST as independent prognostic factors for progression free survival. A proportion of 75.2% of patients suffered from at least one adverse effect during the study period. Multivariate analysis exhibited that the appearance of decreased appetite Grade ≥ 2 versus Grade 0-1 as an independent prognostic factor for worse Progression Free Survival. 924 patients on 1325 progressed during lenvatinib (69.7%), and 827 of them had a follow-up over two-months from the beginning of second line treatment. From first line therapy the longest median OS was obtained with the sequence lenvatinib and immunotherapy (47.0 months), followed by TACE (24.7 months), ramucirumab (21.2 months), sorafenib (15.7 months), regorafenib (12.7 months) and best supportive care (10.8 months). Conclusions: Our study confirms in a large and global population of patients with advanced HCC not candidate to locoregional treatment the OS reported in the registration study and a high response rate with lenvatinib.

Targeting tumor-driven angiogenesis is an effective strategy in the management of metastatic colorectal cancer (mCRC); however, the choice of second-line therapy is complicated by the availability of several drugs, the occurrence of resistance and the lack of validated prognostic and predictive biomarkers. This review examines the use of angiogenesis-targeted therapies for the second-line management of mCRC patients. Mechanisms of resistance and anti-placental growth factor agents are discussed, and the role of aflibercept, a recombinant fusion protein consisting of portions of human vascular endothelial growth factor receptor (VEGFR)-1 and VEGFR-2, is highlighted. The novel mechanism of action of aflibercept makes it a useful second-line agent in mCRC patients progressing after oxaliplatin-based chemotherapy, as well as in those with resistance after bevacizumab.

Background: Malnutrition is common in cancer patients, particularly in those affected by gastrointestinal malignancies, and negatively affects treatment tolerance, survival, functional status, and quality of life (QoL). Nutritional support, including supplemental parenteral nutrition (SPN), has been recommended at the earliest opportunity in malnourished cancer patients. The limited available evidence on the efficacy of SPN in gastrointestinal cancer patients is positive, particularly with regards to QoL, body composition, and energy intake, but the evidence on survival is still scanty. Furthermore, studies regarding the early administration of SPN in combination with nutritional counseling from the beginning of first-line chemotherapy (CT) are lacking. We hypothesize that early systematic SPN in combination with nutritional counseling (NC), compared with NC alone, can benefit patients with previously untreated metastatic gastric cancer at nutritional risk undergoing first-line CT. Methods: The aim of this pragmatic, multicenter, randomized (1:1), parallel-group, open-label, controlled clinical trial is to evaluate the efficacy in terms of survival, weight maintenance, body composition, QoL and feasibility of cancer therapy of early systematic SNP. This is in combination with NC, compared with NC alone, in treatment-naïve metastatic gastric cancer patients at nutritional risk undergoing first-line CT. Discussion: Malnutrition in oncology remains an overlooked problem. Although the importance of SPN in gastrointestinal cancer patients has been acknowledged, no studies have yet evaluated the efficacy of early SPN in metastatic gastric patients undergoing CT. The present study, which guarantees the early provision of nutritional assessment and support to all the enrolled patients in accordance with the recent guidelines and recommendations, could represent one of the first proofs of the clinical effectiveness of early intensive nutritional support in cancer patients undergoing CT. This study could stimulate further large randomized trials in different cancer types, potentially resulting in the improvement of supportive care quality. Trial registration: This study is registered on ClinicalTrials.gov: NCT03949907.

BACKGROUND AND AIMS:The present study aims to investigate the role of the prognostic nutritional index (PNI) on survival in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib. METHODS:This multicentric study included a training cohort of 194 HCC patients and three external validation cohorts of 129, 76 and 265 HCC patients treated with Sorafenib, respectively. The PNI was calculated as follows: 10 × serum albumin (g/dL) + 0.005 × total lymphocyte count (per mm3). Univariate and multivariate analyses were performed to investigate the association between the covariates and the overall survival (OS). RESULTS:A PNI cut-off value of 31.3 was established using the ROC analysis. In the training cohort, the median OS was 14.8 months (95% CI 12-76.3) and 6.8 months (95% CI 2.7-24.6) for patients with a high (>31.3) and low ( 70 years (p< 0.0038) were independent prognostic factors for OS. By performing the same multivariate analysis of the training cohort, the PNI 31.3 was found to be an independent prognostic factor for predicting OS in all the three validation cohorts. CONCLUSIONS:PNI represents a prognostic tool in advanced HCC treated with first-line Sorafenib. It is readily available and low-cost, and it could be implemented in clinical practice in patients with HCC.

Abstract Background Concurrent chemo-radiation (CT-RT) is a standard therapy for squamous cell carcinoma of anal canal. Different clinical and biological factors may potentially affect outcome. We investigated the prognostic role of baseline hemoglobin (Hb) in a cohort of anal cancer patients submitted to CT-RT with 5-fluorouracil and mitomycin C. Methods Up to 161 patients with clinical stage T1-T4/N0-N3/M0 were treated. Response was assessed at 6 weeks and thereafter at 3, 6 and 12 months. Two different approaches were used:a)simultaneous integrated boost following RTOG 05-29 indications;b)first sequence of 45Gy/25 fractions to the pelvis followed by 9–14.4 Gy/5–8 fractions to the macroscopic disease. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Results On multivariate analysis, pre-treatment Hb level had a significant correlation to OS (HR:0.53;95% CI:0.33–0.87; p = 0.001), but not to PFS (HR:0.78;95% CI:0.53–1.15; p = 0.12) Patients with pre-treatment Hb ≥ 12 g/dl had 5-year PFS and OS of 82.2%, compared to 29.3% and 32.8% for those below the threshold. The likelihood to achieve a complete remission increased by 5.6% for every single-unit (g/dl) increase in baseline Hb level over 11 g/dl. On multivariate analysis, response to treatment had a significant correlation to PFS (incomplete vs complete response – HR:5.43;95% CI:2.75–10.7; p

IntroductionPancreatic ductal adenocarcinoma is associated to dismal prognosis despite the use of palliative chemotherapy, partly due to the lack of knowledge of biological processes underlying disease progression. Exosomes have been identified as biomarkers sources in different cancer types. Aim of the study was to analyse the contents of circulating exosomes in patients with pancreatic cancer who received palliative chemotherapy.Patients and methodsPatients were submitted to blood sample collection before chemotherapy (T0) and after 3 months (T3). We quantified by an ELISA-based technique specific proteins of cancer-derived exosomes (CD44,CD44v6,EpCAM,CD9,CD81,Tspan8,Integrin α6,Integrin β4,CD24,CXCR4). We correlated the baseline levels of these factors and changes between T3 and T0 and survival outcomes. Survival analyses were performed by Kaplan-Meier method. Correlation was assessed by log-rank test and level of statistical significance was set at 0.05. Multivariate analysis was performed by logistic regression analysis.ResultsNineteen patients were enrolled. EpCAM T0 levels and increased EpCAM levels from T0 to T3 were those mostly associated with differences in survival. Patients having higher EpCAM had median progression free survival (PFS) of 3.18vs7.31 months (HR:2.82,95%CI:1.03-7.73,p = 0.01). Overall survival (OS) was shorter for patients having higher EpCAM (5.83vs16.45 months,HR:6.16,95%CI:1.93-19.58,p = 0.0001) and also response rates (RR) were worse (20%vs87%,p = 0.015). EpCAM increase during treatment was associated with better median PFS (2.88vs7.31 months,HR:0.24,95%CI:0.04-1.22,p = 0.003). OS was also better (8.75vs11.04 months, HR:0.77,95%CI:0.21-2.73,p = 0.66) and RR were 60%vs20% (p = 0.28). Among clinical factors that might determine changes on PFS and OS, only ECOG PS was associated to significantly worse PFS and OS (p = 0.0137andConclusionsPancreatic cancer patients exosomes express EpCAM, whose levels change during treatment. This represents a useful prognostic factor and also suggests that future treatment modalities who target EpCAM should be tested in pancreatic cancer patients selected by exosome EpCAM expression.

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.

Herein we evaluate the involvement of the TRPV2 channel, belonging to the Transient Receptor Potential Vanilloid channel family (TRPVs), in development and progression of different tumor types. In normal cells, the activation of TRPV2 channels by growth factors, hormones, and endocannabinoids induces a translocation of the receptor from the endosomal compartment to the plasma membrane, which results in abrogation of cell proliferation and induction of cell death. Consequently, loss or inactivation of TRPV2 signaling (e.g., glioblastomas), induces unchecked proliferation, resistance to apoptotic signals and increased resistance to CD95-induced apoptotic cell death. On the other hand, in prostate cancer cells, Ca2+-dependent activation of TRPV2 induced by lysophospholipids increases the invasion of tumor cells. In addition, the progression of prostate cancer to the castration-resistant phenotype is characterized by de novo TRPV2 expression, with higher TRPV2 transcript levels in patients with metastatic cancer. Finally, TRPV2 functional expression in tumor cells can also depend on the presence of alternative splice variants of TRPV2 mRNA that act as dominant-negative mutant of wild-type TRPV2 channels, by inhibiting its trafficking and translocation to the plasma membrane. In conclusion, as TRP channels are altered in human cancers, and their blockage impair tumor progression, they appear to be a very promising targets for early diagnosis and chemotherapy.

Relevant heterogeneity exists among Postgraduate Schools in Medical Oncology, also within the same country. In order to provide a comprehensive overview of the landscape of Italian Postgraduate Schools in Medical Oncology, the Italian Association of Medical Oncology (AIOM) undertook an online survey, inviting all the residents to describe their daily activities and to express their overall satisfaction about their programs.A team composed of five residents and three consultants in medical oncology prepared a 38 items questionnaire that was published online in a reserved section, accessible through a link sent by e-mail. Residents were invited to anonymously fill in the questionnaire that included the following sub-sections: quality of teaching, clinical and research activity, overall satisfaction.Three-hundred and eleven (57%) out of 547 invited residents filled in the questionnaire. Two-hundred and twenty-three (72%) participants declared that attending lessons was frequently difficult and 153 (49%) declared they did not gain substantial improvement in their knowledge from them. Fifty-five percent stated that they did not receive lessons on palliative care. Their overall judgment about didactic activity was low in 63% of the interviewed. The satisfaction for clinical activity was in 86% of cases good: 84% recognized that, during the training period, they acquired a progressive independence on patients' management. About research activity, the majority (79%) of participants in the survey was actively engaged in managing patients included in clinical trials but the satisfaction level for the involvement in research activities was quite low (54%). Overall, 246 residents (79%) gave a positive global judgment of their Medical Oncology Schools.The landscape of Italian Postgraduate Schools in Medical Oncology is quite heterogeneous across the country. Some improvements in the organization of teaching and in the access to research opportunity are needed; the perception about clinical activity and the overall judgment of the programs are quite satisfactory.

Hyponatraemia has been reported with targeted therapies in cancer patients. Aim of the study was to perform an up-to-date meta-analysis in order to determine the incidence and relative risk (RR) in cancer patients treated with these agents.The scientific literature regarding hyponatraemia was extensively reviewed using MEDLINE, PubMed, Embase and Cochrane databases. Eligible studies were selected according to PRISMA statement. Summary incidence, RR, and 95% Confidence Intervals were calculated using random-effects or fixed-effects models based on the heterogeneity of selected studies.4803 potentially relevant trials were identified: of them, 13 randomized phase III studies were included in this meta-analysis. 6670 patients treated with 8 targeted agents were included: 2574 patients had hepatocellular carcinoma, whilst 4096 had other malignancies. The highest incidences of all-grade hyponatraemia were observed with the combination of brivanib and cetuximab (63.4) and pazopanib (31.7), while the lowest incidence was reported by afatinib (1.7). The highest incidence of high-grade hyponatraemia was reported by cetuximab (34.8), while the lowest incidences were reported by gefitinib (1.0). Summary RR of developing all-grade and high-grade hyponatraemia with targeted agents was 1.36 and 1.52, respectively. The highest RRs of all-grade and high-grade hyponatraemia were associated with brivanib (6.5 and 5.2, respectively). Grouping by drug category, the RR of high-grade hyponatraemia with angiogenesis inhibitors was 2.69 compared to anti-Epidermal Growth Factor Receptors agents (1.12).Treatment with biological therapy in cancer patients is associated with a significant increased risk of hyponatraemia, therefore frequent clinical monitoring should be emphasized when managing targeted agents.

With a median survival of 9-11 months, advanced gastric cancer represents one of the most aggressive neoplastic disease in western Countries. Radical surgery is considered the cornerstone for any curative procedure, however only a relatively small proportion of resected cases can be considered cured after surgery. In the last few years research data suggested that advanced gastric cancer can be classified into 2 distinct clinical categories: locally advanced (nonmetastatic, non resectable) and metastatic. While the therapeutic goal in the metastatic setting is palliation and survival improvement, in locally advanced cases one of the main goals of the treatment should be response with the aim to make resectable what was unresectable. The introduction of docetaxel for the treatment of advanced gastric cancer represented then a crucial step forward for the cure of this disease with an improvement in both survival and response rate. In this article we reviewed past and ongoing trials using docetaxel in gastric cancer with the aim to delineate a possible effective strategy for the treatment of this tumour

Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved for the treatment of metastatic renal cell carcinoma (mRCC). We aimed to assess the association between the baseline values and treatmentrelated modifications of total serum cholesterol (C), triglycerides (T), body mass index (BMI), fasting blood glucose level (FBG) and blood pressure (BP) levels and the outcome of patients treated with everolimus for mRCC.177 patients were included in this retrospective analysis. Time to progression (TTP), clinical benefit (CB) and overall survival (OS) were evaluated.Basal BMI was significantly higher in patients who experienced a CB (p=0,0145). C,T and C+T raises were significantly associated with baseline BMI (p=0.0412, 0.0283 and 0.0001). Median TTP was significantly longer in patients with T raise compared to patients without T (10 vs 6, p=0.030), C (8 vs 5, p=0.042) and C+T raise (10.9 vs 5.0, p=0.003). At the multivariate analysis, only C+T increase was associated with improved TTP (p=0.005). T raise (21.0 vs 14.0, p=0.002) and C+T increase (21.0 vs 14.0, p=0.006) were correlated with improved OS but were not significant at multivariate analysis.C+T raise is an early predictor for everolimus efficacy for patients with mRCC.

BackgroundBone is an uncommon site of metastasis in patients with advanced hepatocellular carcinoma (HCC). Therefore, there are few studies concerning the natural history of bone metastasis in patients with HCC.Patients and methodsData on clinicopathology, survival, skeletal-related events (SREs), and bone-directed therapies for 211 deceased HCC patients with evidence of bone metastasis were statistically analyzed.ResultsThe median age was 70 years; 172 patients were male (81.5%). The median overall survival was 19 months. The median time to the onset of bone metastasis was 13 months (22.2% at HCC diagnosis); 64.9% patients had multiple bone metastases. Spine was the most common site of bone metastasis (59.7%). Most of these lesions were osteolytic (82.4%); 88.5% of them were treated with zoledronic acid. At multivariate analysis, only the Child Score was significantly correlated with a shorter time to diagnosis of bone metastases (p = 0.001, HR = 1.819). The median survival from bone metastasis was 7 months. At multivariate analysis, HCC etiology (p = 0.005), ECOG performance status (p = 0.002) and treatment with bisphosphonate (p = 0.024) were associated with shorter survival after bone disease occurrence. The site of bone metastasis but not the number of bone lesions was associated with the survival from first skeletal related event (SRE) (p = 0.021) and OS (p = 0.001).ConclusionsThis study provides a significant improvement in the understanding the natural history of skeletal disease in HCC patients. An early and appropriate management of these patients is dramatically needed in order to avoid subsequent worsening of their quality of life.

Abstract Maspin (mammary serine protease inhibitor), is a member of the serine protease inhibitor/non‐inhibitor superfamily. Its expression is down‐regulated in breast, prostate, gastric and melanoma cancers but over‐expressed in pancreatic, gallbladder, colorectal, and thyroid cancers suggesting that maspin may play different activities in different cell types. However, maspin expression seems to be correlated with better prognosis in prostate, bladder, lung, gastric, colorectal, head and neck, thyroid and melanoma cancer. In breast and ovarian cancer maspin significance is associated with its subcellular localization: nucleus maspin expression correlates with a good prognosis, whilst in pancreatic cancer it predicts a poor prognosis. Since tumor metastasis requires the detachment and invasion of tumor cells through the basement membrane and stroma, a selectively increased adhesion by the presence of maspin may contribute to the inhibition of tumor metastasis. Furthermore the different position of maspin inside the cell or its epigenetic modifications may explain the different behavior of the expression of maspin between tumors. The expression of maspin might be useful as a prognostic and possibly predictive factor for patients with particular types of cancer and data can guide physicians in selecting therapy. Its expression in circulating tumor cells especially in breast cancer, could be also useful in clinical practice along with other factors, such as age, comorbidities, blood examinations in order to select the best therapy to be carried out. Focusing on the malignancies in which maspin showed a positive prognostic value, therapeutic approaches studied so far aimed to re‐activate a dormant tumor suppressor gene by designed transcription factors, to hit the system that inhibits the expression of maspin, to identify natural substances that can determine the activation and the expression of maspin or possible “molecules binds” to introduce maspin in cancer cell and gene therapy capable of up‐regulating the maspin in an attempt to reduce primarily the risk of metastasis. Further studies in these directions are necessary to better define the therapeutic implication of maspin.

Clinical data indicate that prognostic stratification of radically resected colorectal cancer based on disease stage only may not be always be adequate. Preclinical findings suggest that cancer stem cells may influence the biological behaviour of colorectal cancer independently from stage: objective of the study was to assess whether a panel of stemness markers were correlated with clinical outcome in resected stage II and III colon cancer patients. A panel of 66 markers of stemness were analysed and thus patients were divided into two groups (A and B) with most patients clustering in a manner consistent with different time to relapse by using a statistical algorithm. A total of 62 patients were analysed. Thirty-six (58%) relapsed during the follow-up period (range 1.63-86.5 months). Twelve (19%) and 50 (81%) patients were allocated into group A and B, respectively. A significantly different median relapse-free survival was observed between the 2 groups (22.18 vs 42.85 months, p=0.0296). Among of all genes tested, those with the higher "weight" in determining different prognosis were CD44, ALCAM, DTX2, HSPA9, CCNA2, PDX1, MYST1, COL1A1 and ABCG2. This analysis supports the idea that, other than stage, biological variables, such as expression levels of colon cancer stem cell genes, may be relevant in determining an increased risk of relapse in resected colorectal cancer patients.

BACKGROUND: Recently, a new classification for gastric cancer (GC) has been proposed, based on Lauren's histology and on anatomic tumour location, identifying three subtypes of disease: type 1 (proximal non diffuse GC), type 2 (diffuse GC) and type 3 (distal non diffuse GC). Aim of our analysis was to compare clinical outcome according to different GC subtypes (1,2,3) in metastatic GC patients receiving first-line chemotherapy. PATIENTS AND METHODS: Advanced GC pts treated with a first-line combination chemotherapy were included in our analysis. Pts were divided in three subgroups (type 1, type 2 and type 3) as previously defined. RESULTS: A total of 248 advanced GC pts were included: 45.2% belonged to type 2, 43.6% to type 3 and 11.2% to type 1. Patients received a fluoropyrimidine-based chemotherapy doublet or three drugs regimens including a platinum derivate and a fluoropyrimidine with the addition of an anthracycline, a taxane or mytomicin C. RR was higher in type 1 pts (RR = 46.1%) and type 3 (34,3%) compared to type 2 (20,4%), (p = 0.015). Type 2 presented a shorter PFS, median PFS = 4.2 months, compared to type 1, mPFS = 7.2 months, and type 3, mPFS = 5.9 months (p = 0.011) and also a shorter OS (p = 0.022). CONCLUSIONS: Our analysis suggests that GC subtypes may be important predictors of benefit from chemotherapy in advanced GC patients. Future clinical trials should take in account these differences for a better stratification of patients.

In many tumor types serum lactate dehydrogenase (LDH) levels is an indirect marker of tumor hypoxia, neo-angiogenesis and worse prognosis. However data about hepatocellular carcinoma (HCC) are lacking in the clinical setting of patients undergoing transarterial-chemoembolization (TACE) in whom hypoxia and neo-angiogenesis may represent a molecular key to treatment failure. Aim of our analysis was to evaluate the role of LDH pre-treatment levels in determining clinical outcome for patients with HCC receiving TACE. One hundred and fourteen patients were available for our analysis. For all patients LDH values were collected within one month before the procedure. We divided our patients into two groups, according to LDH serum concentration registered before TACE (first: LDH≤450 U/l 84 patients; second: LDH>450 U/l 30 patients). Patients were classified according to the variation in LDH serum levels pre- and post-treatment (increased: 62 patients vs. decreased 52 patients). No statistically significant differences were found between the groups for all clinical characteristics analyzed (gender, median age, performance status ECOG, staging systems). In patients with LDH values below 450 U/l median time to progression (TTP) was 16.3 months, whereas it was of 10.1 months in patients above the cut-off (p = 0.0085). Accordingly median overall survival (OS) was 22.4 months and 11.7 months (p = 0.0049). In patients with decreased LDH values after treatment median TTP was 12.4 months, and median OS was 22.1 months, whereas TTP was 9.1 months and OS was 9.5 in patients with increased LDH levels (TTP: p = 0.0087; OS: p

In radically resected gastric cancer the possibility to predict the site of relapse could be clinically relevant for the selection of post-surgical management. We previously showed that specific tumour integrins genotypes are independently associated with either peritoneal or hematogenous metastases (ITGA and ITGV). Recently VEGF and VEGF-R polymorphisms have been demonstrated to potentially affect tumour angiogenesis and the metastatic process in gastric cancer. We then investigated the role of VEGFs and VEGF-R genotyping in determining either peritoneal carcinosis or hematogenous metastases in radically resected gastric cancer patients. Tumour genotyping for integrins (ITGA and ITGV) was also performed according to our previous findings. Genotyping for VEGF-A, VEGF-C, VEGFR-1,2,3 and ITGA and ITGV was carried out on pT4a radically resected gastric tumours recurring with either peritoneal-only carcinosis or hematogenous metastases. 101 patients fulfilled the inclusion criteria: 57 with peritoneal carcinomatosis only and 44 with hematogenous spread only. At multivariate analysis, intestinal histology and the AC genotype of rs699947 (VEGFA) showed to independently correlate with hematogenous metastases (p = 0.0008 and 0.008 respectively), whereas diffuse histology and the AA genotype of rs2269772 (ITGA) independently correlated with peritoneal-only diffusion (p =

Transitional cell carcinoma (TCC) of the bladder is one of the most common malignancies of genitourinary tract. Patients with bladder cancer need a life-long surveillance, directly due to the relatively high recurrence rate of this tumor. The use of cystoscopy represents the gold standard for the followup of previously treated patients. Nevertheless, several factors, including cost and invasiveness, render cystoscopy not ideal for routine controls. Advances in the identification of specific alterations in the nuclear structure of bladder cancer cells have opened novel diagnostic landscapes. The members of nuclear matrix protein family BLCA-1 and BLCA-4, are currently under evaluation as bladder cancer urinary markers. They are involved in tumour cell proliferation, survival, and angiogenesis. In this paper, we illustrate the role of BLCA-1 and BLCA-4 in bladder carcinogenesis and their potential exploitation as biomarkers in this cancer.

The authors wish to make the following corrections to this paper [1]: [...]