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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.

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. © 2014 Landes Bioscience.

Bevacizumab is a humanized anti-VeGF monoclonal antibody able to produce clinical beneit 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 identiied and validated for baseline patient selection. preclinical indings suggest an important role for myeloid-derived inlammatory 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 inlammatory index, the neutrophil-tolymphocyte ratio (nLR), as predictors of clinical outcome in nsCLC patients treated with bevacizumab plus chemotherapy. one hundred twelve nsCLC patients treated with chemotherapy ± bevacizumab were retrospectively evaluated for the predictive value of clinical or laboratory parameters correlated with inlammatory 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 inlammatory 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 inlammatory status is marker of resistance to bevacizumab treatment in nsCLC patients. © 2013 Landes Bioscience.

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. © 2012 Elsevier Ltd. All rights reserved.

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.

// Pierpaolo Correale 1 , Cirino Botta 2 , Nicoletta Staropoli 3 , Valerio Nardone 4 , Pierpaolo Pastina 4 , Cristina Ulivieri 5 , Claudia Gandolfo 6 , Tatiana Cosima Baldari 5 , Stefano Lazzi 7 , Domenico Ciliberto 3 , Rocco Giannicola 1 , Antonella Fioravanti 8 , Antonio Giordano 9 , Silvia Zappavigna 10 , Michele Caraglia 9, 10 , Pierfrancesco Tassone 2, 3, 10 , Luigi Pirtoli 4 , Maria Grazia Cusi 6 and Pierosandro Tagliaferri 3 1 Unit of Medical Oncology, Grand Metropolitan Hospital Bianchi Melacrino Morelli, Reggio-Calabria, Italy 2 Medical Oncology Unit, AUO Mater Domini, Magna Graecia University, Catanzaro, Italy 3 Department of Experimental and Clinical Medicine, Magna Graecia University , Catanzaro, Italy 4 Unit of Radiotherapy, Department of Surgery, Medicine and Neurological Science, Siena University Hospital, Siena, Italy 5 Department of Science of Life, Siena University, Siena, Italy 6 Microbiology and Virology Unit, Department of Medical Biotechnology, Siena University, Siena, Italy 7 Unit of Pathology, Department of Surgery, Medicine and Neurological Science, Siena University Hospital, Siena, Italy 8 Unit of Rheumatology, Department of Clinical Medicine and Immunologic Sciences, University of Siena, Siena, Italy 9 Department of Biotechnology, Temple University, Sbarro Foundation, Philadelphia, Pennsylvania, USA 10 Department of Precision Medicine, University of Campania L. Vanvitelli, Naples, Italy Correspondence to: Pierosandro Tagliaferri, email: tagliaferri@unicz.it Pierpaolo Correale, email: correalep@yahoo.it Keywords: bio-markers; cancer vaccine; colorectal cancer; K-ras; thymidylate synthase Received: August 24, 2017 Accepted: February 21, 2018 Published: April 17, 2018 ABSTRACT 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.

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.

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.

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.

// Nicoletta Staropoli 1, * , Domenico Ciliberto 1, * , Silvia Chiellino 1 , Francesca Caglioti 1 , Teresa Del Giudice 1 , Simona Gualtieri 1 , Angela Salvino 1 , Alessandra Strangio 1 , Cirino Botta 1 , Sandro Pignata 2 , Pierfrancesco Tassone 1, * , Pierosandro Tagliaferri 1, * 1 Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy 2 Department of Gynecologic and Urologic Oncology, Fondazione Pascale, National Cancer Institute of Naples, Naples, Italy * These authors have contributed equally to this work Correspondence to: Pierosandro Tagliaferri, email: tagliaferri@unicz.it Keywords: ovarian cancer, targeted therapy, systemic chemotherapy, systematic review, meta-analysis Received: May 01, 2016 Accepted: September 25, 2016 Published: October 13, 2016 ABSTRACT 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.

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.

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.

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/m2, day 2); levofolinate (100 mg/m2, days 1-2), 5-fluorouracil (5-FU) (400 mg/m2 in bolus followed by 24 h infusion at 800 mg/m2,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. 14.57mo (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 proofof- principle that GOLFIG chemoimmunotherapy may represent a novel reliable option for first-line treatment of mCRC. Copyright © 2014 by Lippincott Williams & Wilkins.

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.

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.

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 versus 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.