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Introduction: About 90% of cholangiocarcinomas are adenocarcinomas with glandular or tubular structures lined by epithelial cells, with no bile production and with a variable degree of differentiation, arising in the background of desmoplastic stroma. The remaining 10% is represented by rarer histological variants of which there is little knowledge regarding the biological behavior, molecular characterization, and sensitivity to the various possible therapies, including molecular-based treatments. Such rare tumors are described only in case reports or small retrospective series because of their exclusion from clinical trials. This national initiative, here presented, aims to address the following knowledge gap: a) how much does histological diversity translate into clinical manifestation variety? b) are those chemotherapy regimens, recommended for conventional biliary tract cancers, potentially active in rare variants?Therefore, epidemiological, pathological, and clinical characterization of series of rare biliary histotypes/variants, for which therapeutic and follow-up data are available, will be collected., Methods: An Italian task force on rare tumors of the biliary tract (IRaBiCa) has been created, whose initiative is a multicenter retrospective study involving 34 Italian cancer centers.Clinical data from approximately 100 patients will be collected and analyzed. Continuous variables will be presented as median ± standard deviation, while categorical variables will be expressed in terms of frequency. Kaplan-Maier analyses will be used to compare disease free, progression free and overall survival, according to the different histotypes., Conclusions: We expect to gather novel data on rare histotypes of biliary tract cancer that will be useful to support their molecular and immunological characterization., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: LR reports consulting fees from AstraZeneca, Basilea, Bayer, BMS, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Jazz Pharmaceuticals, Lilly, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho Oncology, Zymeworks; lecture fees from AstraZeneca, Bayer, Eisai, Gilead, Incyte, Ipsen, Merck Serono, Roche, Sanofi, Servier; travel expenses from AstraZeneca; research grants (to Institution) from Agios, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Zymeworks.NS reports consulting fees from MSD, Bristol Myers Squibb, GSK.MN:Travel expenses from AstraZeneca, speaker honorarium from Accademia della Medicina and Incyte; honoraria from Sandoz, Medpoint SRL, Incyte and Servier for editorial collaboration. Consultant honoraria from EMD Serono, Basilea Pharmaceutica, Incyte, MSD Italia, Servier, Astrazeneca and TaihoAll other authors have nothing to declare

Colorectal cancer (CRC) is one of the most common malignancies and a relevant cause of cancer-related deaths worldwide. Dysregulation of microRNA (miRNA) expression has been associated with the development and progression of various cancers, including CRC. Among them, miR-221 emerged as an oncogenic driver, whose high expression is associated with poor patient prognosis. The present study was conceived to investigate the anti-CRC activity of miR-221 silencing based on early clinical data achieved from a first-in-human study by our group. Going back from bedside to bench, we demonstrated that LNA-i-miR-221 reduces cell viability, induces apoptosis in vitro , and impairs tumor growth in preclinical in vivo models of CRC. Importantly, we disclosed that miR-221 directly targets TP53BP2, which, together with TP53INP1, is known as a positive regulator of the TP53 apoptotic pathway. We found that (1) both these genes are overexpressed following miR-221 inhibition, (2) the strong anti-tumor activity of LNA-i-miR-221 was selectively observed on TP53 wild-type cells, and (3) this activity was reduced in the presence of the TP53-inhibitor Pifitrin-α. Our data pave the way to further investigations on TP53 functionality as a marker predictive of response to miR-221 silencing, which might be relevant for clinical applications., Competing Interests: P.Tagliaferri, M.T.D.M., and P.Tassone are inventors of patents (US 9,404,111 B2; EPO 2943570; C.C.I.A.A. 0001429326) and applied for PCT/IB2023/055010, which are owned by Magna Græcia University, Catanzaro, Italy. All other authors declare no competing interests., (© 2024 The Author(s).)

Background: Long-term survival induced by anticancer treatments discloses emerging frailty among breast cancer (BC) survivors. Trastuzumab-induced cardiotoxicity (TIC) is reported in at least 5% of HER2+BC patients. However, TIC mechanism remains unclear and predictive genetic biomarkers are still lacking. Interaction between systemic inflammation, cytokine release and ADME genes in cancer patients might contribute to explain mechanisms underlying individual susceptibility to TIC and drug response variability. We present a single institution case series to investigate the potential role of genetic variants in ADME genes in HER2+BC patients TIC experienced., Methods: We selected data related to 40 HER2+ BC patients undergone to DMET genotyping of ADME constitutive variant profiling, with the aim to prospectively explore their potential role in developing TIC. Only 3 patients ("case series"), who experienced TIC, were compared to 37 "control group" matched patients cardiotoxicity-sparing. All patients underwent to left ventricular ejection fraction (LVEF) evaluation at diagnosis and during anti-HER2 therapy. Each single probe was clustered to detect SNPs related to cardiotoxicity., Results: In this retrospective analysis, our 3 cases were homogeneous in terms of clinical-pathological characteristics, trastuzumab-based treatment and LVEF decline. We identified 9 polymorphic variants in 8 ADME genes (UGT1A1, UGT1A6, UGT1A7, UGT2B15, SLC22A1, CYP3A5, ABCC4, CYP2D6) potentially associated with TIC., Conclusion: Real-world TIC incidence is higher compared to randomized clinical trials and biomarkers with potential predictive value aren't available. Our preliminary data, as proof of concept, could suggest a predictive role of pharmacogenomic approach in the identification of cardiotoxicity risk biomarkers for anti-HER2 treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The identification of biomarkers for predicting inter-individual sorafenib response variability could allow hepatocellular carcinoma (HCC) patient stratification. SNPs in angiogenesis- and drug absorption, distribution, metabolism, and excretion (ADME)-related genes were evaluated to identify new potential predictive biomarkers of sorafenib response in HCC patients. Five known SNPs in angiogenesis-related genes, including VEGF-A , VEGF-C , HIF-1a , ANGPT2 , and NOS3 , were investigated in 34 HCC patients (9 sorafenib responders and 25 non-responders). A subgroup of 23 patients was genotyped for SNPs in ADME genes. A machine learning classifier method was used to discover classification rules for our dataset. We found that only the VEGF-A (rs2010963) C allele and CC genotype were significantly associated with sorafenib response. ADME-related gene analysis identified 10 polymorphic variants in ADH1A (rs6811453), ADH6 (rs10008281), SULT1A2/CCDC101 (rs11401), CYP26A1 (rs7905939), DPYD (rs2297595 and rs1801265), FMO2 (rs2020863), and SLC22A14 (rs149738, rs171248, and rs183574) significantly associated with sorafenib response. We have identified a genetic signature of predictive response that could permit non-responder/responder patient stratification. Angiogenesis- and ADME-related genes correlation was confirmed by cumulative genetic risk score and network and pathway enrichment analysis. Our findings provide a proof of concept that needs further validation in follow-up studies for HCC patient stratification for sorafenib prescription.

Background: Carboplatin is still the cornerstone of the first-line treatment in advanced Epithelial Ovarian Cancer (aEOC) management and the clinical response to platinum-derived agents remains the major predictor of long-term outcomes., Patient and Methods: We aimed to identify the best treatment of the aEOC in terms of efficacy and safety, considering all treatment phases. A systematic literature search has been done to compare all treatments in aEOC population. Randomized trials with available survival and safety data published in the 2011-2022 timeframe were enclosed. Only trials reporting the BRCA or HRD (Homologous Recombination Deficiency) status were considered., Data Extraction and Synthesis: A ranking of treatment schedules on the progression-free survival (PFS) endpoint was performed. The random-effect model was used to elaborate and extract data. The Network Meta-Analysis (NMA) by Bayesian model was performed by STATA v17. Data on PFS were extracted in terms of Hazard ratio with relative confidence intervals., Results: This NMA involved 18 trials for a total of 9105 patients. Within 12 treatment groups, we performed 3 different sensitivity analyses including "all comers" Intention to Treat (ITT) population, BRCA-mutated (BRCAm), and HRD subgroups, respectively. Considering the SUCRA-reported cumulative PFS probabilities, we showed that in the ITT population, the inferred best treatment was niraparib plus bevacizumab with a SUCRA of 96.7. In the BRCAm subgroup, the best SUCRA was for olaparib plus chemotherapy (96,9). The HRD population showed an inferred best treatment for niraparib plus bevacizumab (SUCRA 98,4). Moreover, we reported a cumulative summary of PARPi toxicity, in which different 3-4 grade toxicity profiles were observed, despite the PARPi "class effect" in terms of efficacy., Conclusions: Considering all aEOC subgroups, the best therapeutical option was identified as PARPi plus chemotherapy and/or antiangiogenetic agents, suggesting the relevance of combinatory approaches based on molecular profile. This work underlines the potential value of "chemo-free" regimens to prolong the platinum-free interval (PFI)., Competing Interests: Declaration of Competing Interest All authors declare that they have no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The rapid development of novel therapeutic options for advanced hepatocellular carcinoma (aHCC) has generated some uncertainty about the rational choice of the systemic upfront treatment. So far, a variety of therapeutic strategies have been investigated, including the combination of immunecheckpoint inhibitors and anti -VEGF. To identify the treatment that should be preferred as front-line approach, we compared the efficacy and toxicity of a variety of therapeutic strategies. With this aim, we performed a systematic review and a meta-analysis of randomized clinical trials. OS, PFS, ORR and tolerability outcomes were considered, and for each outcome the treatment ranking was evaluated by the surface under the cumulative rankings (SUCRAs). Combination of Camrelizumab + Rivoceranib scored the best in OS, followed by Sintilimab + Bevacizumab, whereas Lenvatinib + Pembrolizumab showed higher probability to be the best treatment in PFS and Sintilimab + Bevacizumab performed best in ORR. Finally, Durvalumab is the most tolerated treatment., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background: We developed a 13-mer locked nucleic acid (LNA) inhibitor of miR-221 (LNA-i-miR-221) with a full phosphorothioate (PS)-modified backbone. This agent downregulated miR-221, demonstrated anti-tumor activity against human xenografts in mice, and favorable toxicokinetics in rats and monkeys. Allometric interspecies scaling allowed us to define the first-in-class LNA-i-miR-221 safe starting dose for the clinical translation., Methods: In this first-in-human, open-label, dose-escalation phase 1 trial, we enrolled progressive cancer patients (aged ≥ 18 years) with ECOG 0-2 into 5 cohorts. The treatment cycle was based on a 30-min IV infusion of LNA-i-miR-221 on 4 consecutive days. Three patients within the first cohort were treated with 2 cycles (8 infusions), while 14 patients were treated with a single course (4 infusions); all patients were evaluated for phase 1 primary endpoint. The study was approved by the Ethics Committee and Regulatory Authorities (EudraCT 2017-002615-33)., Results: Seventeen patients received the investigational treatment, and 16 were evaluable for response. LNA-i-miR-221 was well tolerated, with no grade 3-4 toxicity, and the MTD was not reached. We recorded stable disease (SD) in 8 (50.0%) patients and partial response (PR) in 1 (6.3%) colorectal cancer case (total SD + PR: 56.3%). Pharmacokinetics indicated non-linear drug concentration increase across the dose range. Pharmacodynamics demonstrated concentration-dependent downregulation of miR-221 and upregulation of its CDKN1B/p27 and PTEN canonical targets. Five mg/kg was defined as the recommended phase II dose., Conclusions: The excellent safety profile, the promising bio-modulator, and the anti-tumor activity offer the rationale for further clinical investigation of LNA-i-miR-221 (ClinTrials.Gov: NCT04811898)., (© 2023. The Author(s).)

Carboplatin is the cornerstone of ovarian cancer (OC) treatment, while platinum-response, dependent on interindividual variability, is the major prognostic factor for long-term outcomes. This retrospective study was focused on explorative search of genetic polymorphisms in the Absorption, Distribution, Metabolism, Excretion (ADME) genes for the identification of biomarkers prognostic/predictive of platinum-response in OC patients. Ninety-two advanced OC patients treated with carboplatin-based therapy were enrolled at our institution. Of these, we showed that 72% of patients were platinum-sensitive, with a significant benefit in terms of OS ( p = 0.001). We identified an inflammatory-score with a longer OS in patients with lower scores as compared to patients with the maximum score ( p = 0.001). Thirty-two patients were genotyped for 1931 single nucleotide polymorphisms (SNPs) and five copy number variations (CNVs) by the DMET Plus array platform. Among prognostic polymorphisms, we found a potential role of UGT2A1 both as a predictor of platinum-response ( p = 0.01) and as prognostic of survival ( p = 0.05). Finally, we identified 24 SNPs related to OS. UGT2A1 correlates to an "inflammatory-score" and retains a potential prognostic role in advanced OC. These data provide a proof of concept that warrants further validation in follow-up studies for the definition of novel biomarkers in this aggressive disease.

Background: The incidence of Merkel cell carcinoma (MCC), a rare form of skin cancer with a poor prognosis, has increased in Italy in recent decades. Avelumab, an anti-programmed death ligand 1 monoclonal antibody, is approved for the treatment of metastatic MCC (mMCC) based on the results of the phase 2 JAVELIN Merkel 200 trial. The global avelumab expanded access program (EAP) was designed to provide compassionate use of avelumab prior to approval for patients with mMCC who had limited treatment options. We report findings from a subgroup of Italian patients enrolled in the avelumab EAP., Methods: Eligible patients had mMCC and progressive disease following ≥ 1 prior line of chemotherapy or were ineligible for chemotherapy or clinical trial participation. Patients received avelumab 10 mg/kg intravenously every 2 weeks. Treating physicians were provided with an initial 3-month supply of avelumab; resupply was permitted if the patient achieved a complete response, partial response, stable disease, or other clinical benefit per physician assessment. Safety and efficacy data for the EAP were reported at the treating physician's discretion., Results: Between April 1, 2016, and September 14, 2018, 109 requests for avelumab were received from Italy, and 102 were approved. All but 1 of the approved patients had received ≥ 1 prior line of therapy. At data cutoff (March 22, 2019), 95 patients had been supplied with avelumab and response data were available for 55 patients. The objective response rate in response-evaluable patients was 29.1%, including 6 patients (10.9%) who achieved a complete response and 10 patients (18.2%) who achieved a partial response; in the total population supplied with avelumab (n = 95), the proportion who had an objective response was 16.8%. The median duration of treatment in responding patients was 9.7 months (range, 3.5-41.7 months). The most frequently reported treatment-related adverse events were infusion-related reaction (single preferred term; n = 3 [3.2%]) and pyrexia (n = 2 [2.1%])., Conclusions: Results from Italian patients enrolled in the avelumab EAP are consistent with the findings of the JAVELIN Merkel 200 trial and confirm the efficacy and safety of avelumab treatment in this population.

Background: GOLFIG is a chemo-immunotherapy regimen established in preclinical models that combines gemcitabine + FOLFOX (fluoropyrimidine backbone coupled to oxaliplatin) poly-chemotherapy with low-dose s. c. recombinant interleukin-2 (rIL-2) and granulocyte-macrophage colony stimulating factor (GM-CSF). Promising antitumor effects in metastatic colorectal cancer (mCRC) patients were obtained in previous phase II and III trials. Here we report the results of 15 years of follow-up. Methods: This is a multi-institutional retrospective analysis including 179 mCRC patients receiving GOLFIG regimen between June 2002 and June 2018. Sixty-two of them received the treatment as frontline (enrolled in the GOLFIG-2 phase III trial) and 117 as second/third line (49 enrolled in the GOLFIG-1 phase II trial and 68 as compassionate use). One hundred twelve patients showed a primary left side and 67 a primary right side; K/N-ras mutational status was available in 74 cases, and an activating mutation was detected in 33. Kaplan-Meier and Cox regression analyses were carried out to relate PFS and OS with different parameters. Results: Overall, we recorded a mean PFS and OS of 15.28 (95% CI: 10.36-20.20) and 24.6 (95% CI: 19.07-30.14) months, respectively, with 14 patients surviving free of progression for 10 years. This regimen, in our updated survey of the GOLFIG-2 trial, confirmed superiority over FOLFOX in terms of PFS (hazard ratio (HR) = 0.58, p = 0.006) with a trend to a longer OS (HR = 0.69, P = 0.06) in the first line. Our analysis also confirmed significant antitumor activity in pre-treated patients, reporting a mean PFS and OS of 12.55 (95% CI: 7.19-17.9) and 20.28 (95% CI: 14.4-26.13) months, respectively. Immune-related adverse events (irAEs) were recorded in 24% of the cases and were related to a longer survival (HR = 0.36; P = 0.0001). Finally, patients' outcome was not correlated to sex, sidedness, and MT-K/N-ras. Conclusions: The GOLFIG regimen is a reliable underestimated therapeutic option in pre-treated mCRC patients and offers a strong rationale to design further trials., (Copyright © 2019 Caraglia, Correale, Giannicola, Staropoli, Botta, Pastina, Nesci, Caporlingua, Francini, Ridolfi, Mini, Roviello, Ciliberto, Agostino, Strangio, Azzarello, Nardone, Falzea, Cappabianca, Bocchetti, D'Arrigo, Tripepi, Tassone, Addeo, Giordano, Pirtoli, Francini and Tagliaferri.)

Introduction: Carboplatin is the milestone of epithelial ovarian cancer (EOC) treatment, thus response to platinum is the major prognostic factor. Among platinum-sensitive patients, 40% carry a germline or somatic BRCA1/2 mutation. In this scenario a new class of drugs, the PARP inhibitors (PARPis), produced a significant improvement in long-term disease control. In order to make an aggregate evaluation of the impact of these agents, we performed a systematic review and meta-analysis., Patients and Methods: Clinical trials were selected by searching "Pubmed" database and abstracts from major cancer meetings. We considered the January 2008 - April 2018 time frame. Progression free survival (PFS) was the primary end-point, toxicities were secondary end-points. Hazard ratios (HRs) of PFS, with confidence intervals, and risk ratios of grade 3-4 toxicity rates, were extracted from retrieved studies and included in the current analysis. Meta-analysis was carried out by the fixed and random effect models. We conducted this meta-analysis to also compare indirectly the efficacy of different PARPis in EOC patients., Results: Five randomized trials for a total of 1839 patients were selected and included in the final analysis. In particular, we evaluated a BRCA-mutant cohort (871 patients) with a pooled HR 0.25 (95%CI 0.21-0.31) and the BRCA-wild type cohort (836 patients) with a pooled HR 0.41 (95%CI 0.31-0.55), respectively. Regarding safety profile, no significant differences were detected in all grade toxicities, however, taking into account 3-4 grade toxicities and SAEs (severe adverse events), we show that rucaparib-treated patients reported major abdominal pain events, while niraparib-treated patients were associated with the highest percentage of haematological toxicities, hypothesizing a drug effect for the safety analysis. In the indirect comparisons, significant differences were not detected on PFS for the different agents., Conclusions: We confirm a significant benefit in survival outcome of PARPis for EOC patients with a "class effect" on the bases of narrow CI and indirect comparisons in the different groups. Therefore, we underline that this strategy is of special value in BRCA-mutated patients because genetic testing allows best patient selection for all PARPis with the added value of individualized prevention in familiars., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: At present, there is uncertainty on the best systemic treatment in first-line setting for RAS wild-type (WT) metastatic colorectal cancer (mCRC) patients. Indeed, several chemotherapy and biologics combinations showed an improvement on survival. We performed a systematic review with a pair-wise and bayesan meta-analysis to rank the best strategy for these patients., Methods: A systematic literature search through March 2017 was performed to evaluate the association between several treatment combinations and overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and toxicity rate (TR) in RAS WT mCRC patients. Data were extracted from studies and pooled using the random-effect model for pair-wise meta-analyses and bayesan model for network meta-analysis (NMA)., Results: Eight studies with a total of 2518 individuals were included in the meta-analyses. Pooled analyses for subgroups stratified by type of schedule and tumor location demonstrated that anti-EGFR + doublet had the best OS when compared to doublet ± bevacizumab (0.767; 95%CI, 0.695-0.846; P < 0.0001). This benefit is limited to LSCC when compared to a doublet-based schedule and doublet + bevacizumab (HRs, 0.692; 95%CI, 0.596-0.804; P < 0.001; 0.706; 95%CI, 0.584-0.854; P < 0.001; respectively). No significant differences are detected in PFS, whereas the cetuximab-based regimens showed the highest ORR and TR. In NMA our ranking showed the best performance for FOLFOX + panitumumab., Conclusions: Our study indicates that FOLFOX + panitumumab has the major probability to provide an improvement of survival with a good safety profile in patients with RAS WT mCRC with an added value from selection based on sidedness., (Copyright © 2018 Elsevier B.V. All rights reserved.)

TSPP is an anticancer poly-epitope peptide vaccine to thymidylate synthase, recently investigated in the multi-arm phase Ib TSPP/VAC1 trial. TSPP vaccination induced immune-biological effects and showed antitumor activity in metastatic colorectal cancer (mCRC) patients and other malignancies. Progression-free and overall survival of 41 mCRC patients enrolled in the study correlated with baseline levels of CEA, immune-inflammatory markers (neutrophil/lymphocyte ratio, CRP, ESR, LDH, ENA), IL-4 and with post-treatment change in p-ANCA and CD56 dim CD16 bright NKs ( p < 0.04). A subset of 19 patients with activating k-ras mutations showed a different immune-inflammatory response to TSPP as compared to patients with k-ras/wt and a worse outcome in term of PFS ( p = 0.048). In patients with k-ras/mut, inflammatory markers lost their predictive value and their survival directly correlated with the baseline levels of IL17/A over the median value ( p = 0.01). These results provide strong hints for the design of further clinical trials aimed to test TSPP vaccination in mCRC patients., Competing Interests: CONFLICTS OF INTEREST All the authors declare no conflicts of interest

Despite major therapeutic advancements, multiple myeloma (MM) is still incurable and relapsed/refractory multiple myeloma (RRMM) remains a challenge; the rational choice of the most appropriate regimen in this setting is currently undefined. We performed a systematic review and 2 standard pairwise meta-analyses to evaluate the efficacy of regimens that have been directly compared with bortezomib or immunomodulatory imide drugs (IMiDs) in head-to-head clinical trials and a network meta-analysis (NMA) to determine the relevance of each regimen on the basis of all the available direct and indirect evidence. Sixteen trials were included in the pairwise meta-analyses, and 18 trials were included in the NMA. Pairwise meta-analyses showed that a 3-drug regimen (bortezomib- or IMiD-based) was superior to a 2-drug regimen in progression-free-survival (PFS) and overall response rate (ORR). NMA showed that an IMiD backbone associated with anti-MM monoclonal antibodies (mAbs) (preferably) or proteasome inhibitors had the highest probability of being the most effective regimen with the lowest toxicity. The combination of daratumumab, lenalidomide, and dexamethasone ranked as the first regimen in terms of activity, efficacy, and tolerability according to the average value between surface under the cumulative ranking curve of PFS, overall survival, ORR, complete response rate, and safety. This is the first NMA comparing all currently available regimens evaluated in published randomized trials for the treatment of RRMM, but our results need to be interpreted taking into account differences in their patient populations. Our analysis suggests that IMiDs plus new anti-MM mAb-containing regimens are the most active therapeutic option in RRMM., Competing Interests: Conflict-of-interest disclosure: The authors declare no competing financial interests.

Multiple myeloma (MM) is closely dependent on cross-talk between malignant plasma cells and cellular components of the inflammatory/immunosuppressive bone marrow milieu, which promotes disease progression, drug resistance, neo-angiogenesis, bone destruction and immune-impairment. We investigated the relevance of inflammatory genes in predicting disease evolution and patient survival. A bioinformatics study by Ingenuity Pathway Analysis on gene expression profiling dataset of monoclonal gammopathy of undetermined significance, smoldering and symptomatic-MM, identified inflammatory and cytokine/chemokine pathways as the most progressively affected during disease evolution. We then selected 20 candidate genes involved in B-cell inflammation and we investigated their role in predicting clinical outcome, through univariate and multivariate analyses (log-rank test, logistic regression and Cox-regression model). We defined an 8-genes signature (IL8, IL10, IL17A, CCL3, CCL5, VEGFA, EBI3 and NOS2) identifying each condition (MGUS/smoldering/symptomatic-MM) with 84% accuracy. Moreover, six genes (IFNG, IL2, LTA, CCL2, VEGFA, CCL3) were found independently correlated with patients' survival. Patients whose MM cells expressed high levels of Th1 cytokines (IFNG/LTA/IL2/CCL2) and low levels of CCL3 and VEGFA, experienced the longest survival. On these six genes, we built a prognostic risk score that was validated in three additional independent datasets. In this study, we provide proof-of-concept that inflammation has a critical role in MM patient progression and survival. The inflammatory-gene prognostic signature validated in different datasets clearly indicates novel opportunities for personalized anti-MM treatment.

Objectives: The current gold-standard for the first-line treatment in IIIb/IV stages of epithelial ovarian cancer (EOC) is the combination of carboplatin and paclitaxel plus bevacizumab in some countries. In the era of personalized medicine, there is still uncertainty on the impact of several molecularly targeted agents, which have been investigated for the management of this disease. To shed light on the actual role of targeted therapy in EOC, a systematic review and meta-analysis was performed., Methods: Clinical trials were selected by searching "Pubmed" database and abstracts from major cancer meetings within the time-frame of January 2004-June 2015. The endpoints were survival outcome and response rate (RR). Hazard ratios (HRs) of survival outcomes, with confidence intervals and odds-ratios (ORs) of RR, were extracted from retrieved studies and used for current analysis. Meta-analysis was carried out by random effect model., Results: 30 randomized trials for a total of 10,530 patients were selected and included in the final analysis. A benefit in terms of OS (pooled HR 0.915; 95%CI 0.840-0.997; p=0.043), particularly for anti-angiogenetic agents (HR 0.872; 95%CI 0.761-1.000; p=0.049), has been demonstrated for targeted therapy. Moreover, a significant advantage in platinum-resistant subgroup in term of PFS (HR 0.755; 95%CI 0.624-0.912; p=0.004) was found., Conclusions: This systematic review and meta-analysis provide the first evidence that targeted therapy is potentially able to translate into improved survival of EOC patients, with a major role played by anti-angiogenetic drugs. The role of target therapy is underlined in the platinum-resistant setting that represents the "pain in the neck" in EOC management.

Although significant therapeutic improvement has been achieved in the last 10 years, the survival of metastatic colorectal cancer patients remains in a range of 28 to 30 months. Presently, systemic treatment includes combination chemotherapy with oxaliplatin and/or irinotecan together with a backbone of 5-fluorouracil/levofolinate, alone or in combination with monoclonal antibodies to VEGFA (bevacizumab) or EGF receptor (cetuximab and panitumumab). The recent rise of immune checkpoint inhibitors in the therapeutic scenario has renewed scientific interest in the investigation of immunotherapy in metastatic colorectal cancer patients. According to our experience and view, here, we review the immunological strategies investigated for the treatment of this disease, including the use of tumor target-specific cancer vaccines, chemo-immunotherapy and immune checkpoint inhibitors.

Aim: A systematic review and meta-analysis from literature has been performed to assess the impact of targeted therapy in advanced pancreatic cancer., Methods: By searching different literature databases and major cancer meetings proceedings, data from all randomized clinical trials designed to investigate molecular targeted agents in the treatment of advanced pancreatic cancer were collected. The time-frame between January 2007 and March 2015 was selected. Data on predefined end-points, including overall survival, progression-free survival in terms of Hazard Ratio and response-rate were extracted and analyzed by a random effects model. Pooled data analysis was performed according to the DerSimonian and Laird test. The occurrence of publication bias was investigated through Begg's test by visual inspection of funnel plots., Results: Twenty-seven randomized clinical trials for a total of 8205 patients were selected and included in the final analysis. A significant benefit was demonstrated for anti-EGFR agents on overall survival (HR = 0.880; 95% confidence interval (CI) 0.797-0.972; p = 0.011). In the pooled analysis no benefit on overall survival (OS: pooled HR = 0.957; 95%CI 0.900-1.017; p = 0.153), or progression-free survival (PFS: pooled HR = 0.908; 95%CI 0.817-1.010; p = 0.075) for targeted-based therapies as compared to conventional treatments could be demonstrated. No advantage was reported in response-rate (OR for RR = 1.210; 95%CI 0.990-1.478; p = 0.063). Begg's funnel plot showed no evidence of publication bias., Conclusion: The use of molecular targeted agents does not translate into clinical benefit. Therefore, our work highlights the need to identify predictive factors for patient selection and rationally designed clinical trials., (Copyright © 2016 IAP and EPC. Published by Elsevier India Pvt Ltd. All rights reserved.)

Objectives: To prospectively investigate the occurrence of postinfectious functional gastrointestinal disorders (FGIDs), diagnosed according to the Rome III criteria, in children with acute diarrhea of different infectious etiology., Study Design: This was a prospective cohort multicenter study. Children 4-17 years of age presenting with acute diarrhea who tested positive for an enteric infection were recruited within 1 month from the episode and matched with control subjects of similar age and sex. Symptoms were evaluated with a validated questionnaire for FGIDs at the time of enrollment in the study and after 3 and 6 months., Results: A total of 64 patients (36 boys; median age 5.3 years; age range 4.1-14.1 years) were recruited, 32 subjects in each arm. Infections included rotavirus (56.8%), salmonella (30%), adenovirus (6.6%), norovirus (3.3%), and Giardia lamblia (3.3%). FGIDs were significantly more common in exposed patients compared with controls within 1 month from acute diarrhea (40.6% vs 12.5% [P = .02, relative risk (RR) = 1.9]), 3 months (53% vs 15.6% [P = .003, RR = 2.2]), and 6 months (46.8% vs 15.6% [P = .01, RR = 1.9]) later. No correlation was found between different etiologies, age, or sex, and any type of FGIDs. Among exposed children, abdominal pain-related FGIDs were significantly more frequent compared with controls after 6 months from infection (P = .04, RR = 1.7)., Conclusion: This prospective cohort multicenter study supports postinfectious FGIDs as a true entity in children. There seems to be a significant increase in abdominal pain-related FGIDs after acute diarrhea in children within 1 month and 3 and 6 months later., (Copyright © 2015 Elsevier Inc. All rights reserved.)

It is still uncertain if targeted therapy-based regimens in advanced gastric cancer actually produce survival benefit. To shed light on this important question, we performed a systematic review and meta-analyses on each relevant targeted-pathway. By searching literature databases and proceedings of major cancer meetings in the time-frame 2005-2014, 22 randomized clinical trials exploring targeted therapy for a total of 7022 advanced gastric cancer patients were selected and included in the final analysis. Benefit was demonstrated for antiangiogenic agents in terms of overall survival (HR 0.759; 95%CI 0.655-0.880; p < 0.001). Conversely no benefit was found for EGFR pathway (HR 1.077; 95%CI 0.847-1.370; p = 0.543). Meta-analysis of HER-2 pathway confirmed improvement in terms of survival outcome, already known for this class of drugs (HR 0.823; 95%CI 0.722-0.939; p = 0.004). Pooled analysis demonstrated a significant survival benefit (OS: HR 0.823; PFS: HR 0.762) with acceptable tolerability profile for targeted-based therapies as compared to conventional treatments. This finding conflicts with the outcome of most individual studies, probably due to poor trial design or patients selection. In conclusion, our findings demonstrate a significant survival benefit for targeted therapy in its whole, which can be ascribed to anti-angiogenic and anti-HER2 agents.

Ovarian cancer is the leading cause of death among gynecological tumors. Carboplatin/paclitaxel represents the cornerstone of front-line treatment. Instead, there is no consensus for management of recurrent/progressive disease, in which pegylated liposomal doxorubicin (PLD) ± carboplatin is widely used. We performed a systematic review and metaanalysis to evaluate impact of PLD-based compared with no-PLD-based regimens in the ovarian cancer treatment. Data were extracted from randomized trials comparing PLD-based treatment to any other regimens in the January 2000-January 2013 time-frame. Study end-points were overall survival (OS), progression free survival (PFS), response rate (RR), CA125 response, and toxicity. Hazard ratios (HRs) of OS and PFS, with 95% CI, odds ratios (ORs) of RR and risk ratios of CA125 response and grade 3-4 toxicity, were extracted. Data were pooled using fixed and random effect models for selected endpoints. Fourteen randomized trials for a total of 5760 patients were selected and included for the final analysis, which showed no OS differences for PLD-based compared with other regimens (pooled HR: 0.94; 95% CI: 0.88-1.02; P = 0.132) and a significant PFS benefit of PLD-based schedule (HR: 0.91; 95% CI: 0.86-0.96; P = 0.001), particularly in second-line (HR: 0.85; 95% CI: 0.75-0.91) and in platinum-sensitive (HR: 0.83; 95% CI: 0.74-0.94) subgroups. This work confirmed the peculiar tolerability profile of this drug, moreover no difference was observed for common hematological toxicities and for RR, CA125 response. PLD-containing regimens do not improve OS when compared with any other schedule in all phases of disease. A marginal PFS advantage is observed only in platinum-sensitive setting and second-line treatment.

The GOLFIG-2 phase III trial was designed to compare the immunobiological activity and antitumor efficacy of GOLFIG chemoimmunotherapy regimen with standard FOLFOX-4 chemotherapy in frontline treatment of metastatic colorectal cancer (mCRC) patients. This trial was conceived on the basis of previous evidence of antitumor and immunomodulating activity of the GOLFIG regimen in mCRC. GOLFIG-2 is a multicentric open/label phase III trial (EUDRACT: 2005-003458-81). Chemo-naive mCRC patients were randomized in a 1:1 ratio to receive biweekly standard FOLFOX-4 or GOLFIG [gemcitabine (1000 mg/m(2), day 1); oxaliplatin (85 mg/m(2), day 2); levofolinate (100 mg/m(2), days 1-2), 5-fluorouracil (5-FU) (400 mg/m(2) in bolus followed by 24 h infusion at 800 mg/m(2),days 1-2), sc. GM-CSF (100 μg, days 3-7); sc. aldesleukin (0·5 MIU bi-daily, days 8-14 and 17-30)] treatments. The study underwent early termination because of poor recruitment in the control arm. After a median follow-up of 43.83 months, GOLFIG regimen showed superiority over FOLFOX in terms of progression-free survival [median 9·23 (95% confidence interval (CI), 6·9-11.5) vs. median 5.70 (95% CI, 3.38-8.02) months; hazard ratio (HR): 0.52 (95% CI, 0.35-0.77), P=0·002] and response rate [66.1% (95% CI, 0.41-0.73) vs. 37·0% (95% CI, 0.28-0.59), P=0.002], with a trend to longer survival [median 21.63 (95% CI, 18.09-25.18) vs. 14.57 mo (95% CI, 9.07-20.07); HR: 0·79 (95% CI, 0.52-1.21); P=0.28]. Patients in the experimental arm showed higher incidence of non-neutropenic fever (18.5%), autoimmunity signs (18.5%), an increase in the number of monocytes, eosinophils, CD4(+) T lymphocytes, natural killer cells, and a decrease in immunoregulatory (CD3(+)CD4(+)CD25(+)FoxP3(+)) T cells. Taken together, these findings provide proof-of-principle that GOLFIG chemoimmunotherapy may represent a novel reliable option for first-line treatment of mCRC.

Bevacizumab is a humanized anti-VEGF monoclonal antibody able to produce clinical benefit in advanced non-squamous non-small-cell lung cancer (NSCLC) patients when combined to chemotherapy. At present, while there is a rising attention to bevacizumab-related adverse events and costs, no clinical or biological markers have been identified and validated for baseline patient selection. Preclinical findings suggest an important role for myeloid-derived inflammatory cells, such as neutrophils and monocytes, in the development of VEGF-independent angiogenesis. We conducted a retrospective analysis to investigate the role of peripheral blood cells count and of an inflammatory index, the neutrophil-to-lymphocyte ratio (NLR), as predictors of clinical outcome in NSCLC patients treated with bevacizumab plus chemotherapy. One hundred and twelve NSCLC patients treated with chemotherapy ± bevacizumab were retrospectively evaluated for the predictive value of clinical or laboratory parameters correlated with inflammatory status. Univariate analysis revealed that a high number of circulating neutrophils and monocytes as well as a high NLR were associated with shorter progression-free survival (PFS) and overall survival (OS) in bevacizumab-treated patients only. We have thus developed a model based on the absence or the presence of at least one of the above-mentioned inflammatory parameters. We found that the absence of all variables strongly correlated with longer PFS and OS (9.0 vs. 7.0 mo, HR: 0.39, p = 0.002; and 20.0 vs. 12.0 mo, HR: 0.29, p < 0.001 respectively) only in NSCLC patients treated with bevacizumab plus chemotherapy. Our results suggest that a baseline systemic inflammatory status is marker of resistance to bevacizumab treatment in NSCLC patients.

Background: Ovarian cancer (OC) is the sixth most common cancer in women. Currently, carboplatin/paclitaxel ± bevacizumab is the cornerstone of front-line treatment. Conversely, the therapeutic options for recurrent or progressive disease are not well defined. For platinum-sensitive patients the best therapeutic approach is still a re-challenge with a platinum-based regimen. Pegylated liposomal doxorubicin (PLD), is considered one of the most active therapeutic options for recurrent or progressive OC. In this retrospective mono-institutional analysis, we evaluated the impact of PLD on the outcome of OC patients., Patients and Methods: We performed the retrospective study on a cohort of 108 patients with histologically confirmed serous papillary OC, followed at our Institution between 2001 and 2011. 80 patients were in stage III/IV and 55 of them received a second-line treatment. Thirty patients were treated with PLD. Both groups (PLD-treated versus PLD-untreated) underwent a median of 3 treatment lines and were prognostically balanced. The median follow-up was 60 months. Survival endpoints, toxicity and correlations between patients' baseline characteristics and treatment efficacy were evaluated., Results: Patients who had undergone PLD treatment (PLD group) showed a median overall survival (OS) of 45 months as compared to 65 months of patients not treated with PLD (PLD-free group) (HR 2.50 [0.95-6.67; p = 0.06]). Moreover, the median progression-free survival was 6 months in the PLD group versus 10 months in the PLD-free group (HR 1.75 [0.94-3.34; p = 0.07]). The overall objective response rate in II line treatment was 43% (13% in PLD group versus 57% in PLD-free group). Furthermore, we investigated survival endpoints in platinum-refractory patients who received PLD at least once during the course of disease. No OS advantage was achieved by PLD administration when compared to other therapeutic options (30 versus 32 months; HR 1.16 [0.31-4.34; p = 0.81]). No difference in term of toxicity was observed among different groups., Conclusions: No evidence of superiority if PLD was compared to alternative agents was found in this analysis, particularly in the platinum-refractory setting. Our findings indicate a modest therapeutic activity of PLD in OC. Analysis of cost/benefit of PLD in OC is eagerly awaited.

Background: Pancreatic cancer is the fourth leading cause of cancer-related death worldwide. Gemcitabine is the mainstay treatment for advanced disease. However, almost all up-to-date trials, that evaluated the benefit of gemcitabine-combination schedules, failed to demonstrate an improvement in overall survival (OS). In this study, we performed a systematic review and a meta-analysis of randomised clinical trials (RCTs) to investigate the efficacy and safety of gemcitabine-based combination regimens as compared to gemcitabine alone in the management of pancreatic cancer., Methods: Clinical trials were collected by searching different databases (PubMed, Embase and the Central Registry of Controlled Trials of the Cochrane Library) and abstracts from major cancer meetings. We considered period ranging from January 1997 to January 2012. Primary end-point was OS, secondary end-points were response rate (RR), disease control rate (DCR) and safety. Hazard ratios (HRs) of OS, odds-ratios (ORs) of RR, DCR and risk ratios of grade 3-4 toxicity rates (TRs), were extracted as presented in retrieved studies and used for statistical analysis. Meta-analytic estimates were derived using random-effects model., Findings: Thirty-four trials for a total of 10,660 patients were selected and included in the final analysis. The analysis showed that combination chemotherapy confers benefit in terms of OS (HR: 0.93; 95% confidence interval (CI): 0.89-0.97; p=0.001). ORs for both RR and DCR demonstrated a significant advantage for combination therapy (OR for RR: 0.60, 95%CI: 0.47-0.76, p<0.001; OR for DCR: 0.79; 95%CI: 0.66-0.93; p=0.006). Toxicities were more frequent with the combination treatment and significance in terms of risk ratio was reached for diarrhoea (0.53, 95%CI: 0.36-0.79), nausea (0.74, 95%CI: 0.56-0.96), neutropenia (0.71, 95%CI: 0.59-0.85) and thrombocytopenia (0.57, 95%CI: 0.43-0.75)., Interpretation: The combination chemotherapy as compared to gemcitabine alone significantly improves OS in advanced pancreatic cancer (APC). However, this advantage is marginal whereas the treatment-related toxicity is increased, suggesting the use of gemcitabine-based combination regimens only in selected patient populations. New prospective trials, based on translational approaches and innovative validated biomarkers, are eagerly awaited on this topic., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Nanoparticle albumin bound paclitaxel (nab-paclitaxel) represents the first nanotechnology-based drug in cancer treatment. We discuss the development of this innovative compound and report the recent changing-practice results in breast and pancreatic cancer. A ground-breaking finding is the demonstration that nab-paclitaxel can not only enhance the activity and reduce the toxicity of chromophore-diluted compound, but also exert activity in diseases considered refractory to taxane-based treatment. This is the first clinical demonstration of major activity of nanotechnologically modified drugs in the treatment of human neoplasms.

Liver metastases are a common event in patients with colorectal cancer. Surgical resection, if feasible, produces a survival benefit. We performed a systematic review of randomized clinical trials (RCT) and meta-analysis to address the question if current available studies support the use of systemic chemotherapy as an adjunct to surgery in resected/resectable patients. The search was based on major databases (Pubmed, CancerLit, Embase, Medscape and Cochrane) of published literature and selecting abstracts from major cancer meetings. We performed a literature for the January 1982-May 2010 time frame. The hazard ratios (HRs), with confidence intervals, as presented in retrieved studies, referred to the disease- and/or progression-free (DFS and/or PFS) and overall survival (OS) were extracted. The meta-analysis was carried out by the fixed-effect and the random-effects model. Three studies randomizing combined treatment vs. surgery alone for a total of 666 patients (642 evaluable for survival analysis) were selected and included in the final analysis. Evidence for chemotherapy-induced benefit in terms of both DFS (pooled HR, 0.71; CI, 0.582-0.878; p=0.001) and PFS (pooled HR, 0.75; CI, 0.620-0.910; p=0.003) was demonstrated. However, our meta-analysis failed to demonstrate a significant advantage of combined treatment in terms of OS (pooled HR, 0.743; CI, 0.527-1.045; p=0.088). Chemotherapy combined with surgical resection of colorectal liver metastases improves DFS and PFS whereas the benefit in OS is not demonstrated on the basis of the available results of RCTs. New prospective trials in the era of targeted therapy are eagerly awaited on this specific topic.

Recent findings have disclosed the role of UDP-glucuronosyltransferase (UGT) 1A1*28 on the haematological toxicity induced by irinotecan (CPT-11), a drug commonly used in the treatment of metastatic colorectal cancer (mCRC). We investigated the pharmacogenomic profile of irinotecan-induced gastrointestinal (GI) toxicity by the novel drug-metabolizing enzyme and transporter (DMET) microarray genotyping platform. Twenty-six mCRC patients who had undergone to irinotecan-based chemotherapy were enrolled in a case (patients experiencing ≥ grade 3 gastrointestinal, (GI) toxicity) - control (matched patients without GI toxicity) study. A statistically significant difference of SNP genotype distribution was found in the case versus control group. The homozygous genotype C/C in the (rs562) ABCC5 gene occurred in 6/9 patients with GI toxicity versus 1/17 patients without GI toxicity (P=0.0022). The homozygous genotype G/G in the (rs425215) ABCG1 was found in 7/9 patients with GI toxicity versus 4/17 patients without GI toxicity (P=0.0135). The heterozygous genotype G/A in the 388G>A (rs2306283) OATP1B1/SLCO1B1 was found in 3/9 patients with grade ≥ 3 GI toxicity vs. 14/17 patients without GI toxicity (P=0.0277). DNA extracted from peripheral blood cells was genotyped by DMET Plus chip on Affymetrix array system. Genotype association was calculated by Fisher's exact test (two tailed) and relevant SNPs were further analyzed by direct sequencing. We have identified 3 SNPs mapping in ABCG1, ABCC5 and OATP1B1/SLCO1B1 transporter genes associated with GI toxicity induced by irinotecan in mCRC patients expanding the available knowledge of irinogenomics. The DMET microarray platform is an emerging technology for easy identification of new genetic variants for personalized medicine.