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Background: Scientific data provide the evidence that secondary K-RAS mutations do not occur during anti-epidermal growth factor receptor therapy in colorectal cancer patients. This multicenter phase II prospective study aims to investigate the activity of a retreatment with a cetuximab-based therapy. Patients and methods: We enrolled 39 irinotecan-refractory patients who had a clinical benefit after a line of cetuximab- plus irinotecan-based therapy and then a progression of disease for which underwent a new line chemotherapy and finally, after a clear new progression of disease, were retreated with the same cetuximab- plus irinotecan-based therapy. Results: Median number of therapeutic lines before accrual was 4. Median interval time between last cycle of first cetuximab-based therapy and first cycle of the retreatment was 6 months. Overall response rate was 53.8% with 19 partial responses (48.7%) and 2 complete responses (5.1%). Disease stabilization was obtained in 35.9% of patients and progression in four patients (10.2%). Median progression-free survival was 6.6 months. The correlation between skin toxicity during first cetuximab therapy and during cetuximab rechallenge was significant (P = 0.01). Conclusion: Rechallenge with the same cetuximab-based therapy may achieve a new important clinical benefit further delaying the progression of disease and improving the therapeutic options. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Dietary restrictions, including fasting (or long-term starvation), calorie restriction (CR), and short-term starvation (STS), are considered a strong rationale that may protect against various diseases, including age-related diseases and cancer. Among dietary approaches, STS, in which food is not consumed during designed fasting periods but is typically not restricted during designated feeding periods, seems to be more suitable, because other dietary regimens involving prolonged fasting periods could worsen the health conditions of cancer patients, being they already naturally prone to weight loss. Until now, the limited amount of available data does not point to a single gene, pathway, or molecular mechanism underlying the benefits to the different dietary approaches. It is well known that the healthy effect is mediated in part by the reduction of nutrient-related pathways. The calorie restriction and starvation (long- and short-term) also suppress the inflammatory response reducing the expression, for example, of IL-10 and TNF-α, mitigating pro-inflammatory gene expression and increasing anti-inflammatory gene expression. The dietary restriction may regulate both genes involved in cellular proliferation and factors associated to apoptosis in normal and cancer cells. Finally, dietary restriction is an important tool that may influence the response to chemotherapy in preclinical models. However, further data are needed to correlate dietary approaches with chemotherapeutic treatments in human models. The aim of this review is to discuss the effects of various dietary approaches on the cancer progression and therapy response, mainly in preclinical models, describing some signaling pathways involved in these processes.

Steroid nuclear receptors are known to be involved in the regulation of epithelial-mesenchymal transition process with important roles in invasion and metastasis initiation. Androgen receptor (AR) has been extensively studied, but its role in relation to breast cancer patient prognosis remains to be clarified. AR/ER ratio has been reported to be an unfavorable prognostic marker in early primary breast cancer, but its role in the patients with advanced disease has to be cleared. We retrospectively analyzed ER, PgR, and AR expression on a case series of 159 specimens of primary BC samples by using immunohistochemistry and 89 patients of these had luminal tumors for which AR and ER expression and survival data were available. For twenty-four patients both primary and metastatic tumors were available. A significantly shorter overall survival was observed in primary tumors with AR/PgR ratio ≥ 1.54 (HR = 2.27; 95% CI 1.30-3.97; p = 0.004). Similarly OS was significantly shorter when ER/PgR ratio ≥2 in primary tumors (HR = 1.89; 95% CI 1.10-3.24; p = 0.021). The analysis of the 24 patients who had biomarker determinations both in primary tumors and metastasis showed a better OS when AR/ER ratio in the metastasis was ≥ 0.90 (p = 0.022). Patients with a high AR/ER ratio in primary tumor that remained high in the metastasis had better prognosis in terms of OS (p = 0.011). Despite we suggested that the ratios AR/ER and AR/PgR could be used to identify patients with different prognosis, their real value needs to be better clarified in different BC settings through prospective studies.

Objectives Brain metastases are common among patients with non-squamous non-small-cell lung cancer (NSCLC) and result in a poor prognosis. Consequently, such patients are often excluded from clinical trials. In Italy an expanded access program (EAP) was used to evaluate nivolumab efficacy and safety in this subpopulation outside a clinical trial. Materials and methods In this EAP, nivolumab was available for patients with non-squamous NSCLC in progression after at least one systemic treatment for stage IIIB/IV disease. Nivolumab 3 mg/kg was administered intravenously every 2 weeks. Patients with brain metastases could be included if they were asymptomatic, neurologically stable and either off corticosteroids or on a stable or decreasing dose of ≤10 mg/day prednisone. Results 409 out of 1588 patients included had asymptomatic or controlled brain metastases. A median of 7 doses (range 1–45) were delivered. Median follow-up was 6.1 months (range 0.1–21.9). The disease control rate was 39%: 4 patients had a complete response, 64 a partial response and 96 showed stable disease. At baseline, 118 patients were on corticosteroids and 74 were undergoing concomitant radiotherapy. The median overall survival in this subpopulation was 8.6 months (95% CI: 6.4–10.8). 337 discontinued treatment for various reasons, 23 (7%) of whom due to adverse events, in line with that observed in the overall population and in previous studies. Conclusions Our results confirm that nivolumab is active in non-squamous NSCLC patients with brain metastases, despite their poor prognosis. Its safety profile is also concordant with results in the EAP overall population and in patients with other malignancies.

Breast cancer is the most frequent carcinoma and second most common cause of cancer-related mortality in postmenopausal women. The acquisition of somatic mutations represents the main mechanism through which cancer cells overcome physiological cellular signaling pathways (e.g., PI3K/Akt/mTOR, PTEN, TP53). To date, diagnosis and metastasis monitoring is mainly carried out through tissue biopsy and/or re-biopsy, a very invasive procedure limited only to certain locations and not always feasible in clinical practice. In order to improve disease monitoring over time and to avoid painful procedure such as tissue biopsy, liquid biopsy may represent a new precious tool. Indeed, it represents a basin of “new generation” biomarkers that are spread into the bloodstream from both primary and metastatic sites. Moreover, elevated concentrations of circulating tumor DNA (ctDNA) as well as circulating tumor cells (CTCs) have been found in blood plasma of patients with various tumor types. Nowadays, several new approaches have been introduced for the detection and characterization of CTCs and ctDNA, allowing a real-time monitoring of tumor evolution. This review is focused on the clinical relevance of liquid biopsy in breast cancer and will provide an update concerning CTCs and ctDNA utility as a tool for breast cancer patient monitoring during the course of disease.

The diagnosis and treatment of hepatocellular carcinoma (HCC) underwent a huge advancement in the last years. Recently, microRNAs (miRNAs) have been also studied to provide a new tool for early diagnosis of high risk patients, for prognostic classification to identify those patients who benefit cancer treatment and for predictive definition to select the right targeted drug. In this review we revised all the available data obtained to explore the role of miRNAs in HCC. This analysis led to identification of miRNAs which could gain a diagnostic, prognostic or predictive role. The results of studies on miRNAs involved in HCC are initial and far from providing scientific evidences to translate into clinical practice. We propose a classification of these miRNAs, that we could name HepatomiRNoma as a whole. Anyway prospective studies have to be designed to clarify the real clinical impact of this new tool. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

The RAS-related signalling cascade has a fundamental role in cell. It activates differentiation and survival. It is particularly important one of its molecules, B-RAF. B-RAF has been a central point for research, especially in melanoma. Indeed, it lacked effective therapeutic weapons since the early years of its study. Molecules targeting B-RAF have been developed. Nowadays, two classes of molecules are approved by FDA. Multi-target molecules, such as Sorafenib and Regorafenib, and selective molecules, such as Vemurafenib and Dabrafenib. Many other molecules are still under investigation. Most of them are studied in phase 1 trials. Clinical studies correlate B-RAF inhibitors and QT prolongation. Though this cardiovascular side effect is not common using these drugs, it must be noticed early and recognize its signals. Indeed, Oncologists and Cardiologists should work in cooperation to prevent lethal events, such as fatal arrhythmias or sudden cardiac death. These events could originate from an uncontrolled QT prolongation.

Gastric cancer remains one of the most common malignancies worldwide. Despite the significant advances in surgical treatment and multimodality strategies, prognosis has modestly improved over the last two decades. Locoregional relapse remains one of the main issues and the combined chemoradiation treatment seems to be one of the preferred approaches. However, more than ten years after the hallmark INT-0116 trial, minimal progress has been made both in terms of effectiveness and toxicity. Moreover, new regimens added to combined therapy failed to prove favourable results. Herein, we attempt a thorough literature review comparing pros and cons of all relative studies and potential bias, targeting well-designed future approaches.

Objective: The vast majority of pancreatic cancers occurs sporadically. The discovery of frequent variations in germline gene copy number can significantly influence the expression levels of genes that predispose to pancreatic adenocarcinoma. We prospectively investigated whether patients with sporadic pancreatic adenocarcinoma share specific gene copy number variations (CNVs) in their germline DNA. Patients and methods: DNA samples were analyzed from peripheral leukocytes from 72 patients with a diagnosis of sporadic pancreatic adenocarcinoma and from 60 controls using Affymetrix 500K array set. Multiplex ligation-dependent probe amplification (MLPA) assay was performed using a set of self-designed MLPA probes specific for seven target sequences. Results: We identified a CNV-containing DNA region associated with pancreatic cancer risk. This region shows a deletion of 1 allele in 36 of the 72 analyzed patients but in none of the controls. This region is of particular interest since it contains the YTHDC2 gene encoding for a putative DNA/RNA helicase, such protein being frequently involved in cancer susceptibility. Interestingly, 82.6% of Sicilian patients showed germline loss of one allele. Conclusions: Our results suggest that the YTHDC2 gene could be a potential candidate for pancreatic cancer susceptibility and a useful marker for early detection as well as for the development of possible new therapeutic strategies.

Malignant pleural mesothelioma (MPM) is an aggressive tumor of the pleura with a poor prognosis. The most active first-line regimens are platinum compounds and pemetrexed. There is no standard second-line treatment in MPM. Advances in the understanding of tumor molecular biology have led to the development of several targeted treatments, which have been evaluated in clinical trials. Unfortunately none of the explored targeted treatments can currently be recommended as routine treatment in MPM. We reviewed the biological pathways involved in MPM, the clinical trials about targeted therapy, and possible related mechanisms of resistance. We suggest that specific genetic markers are needed as targets of selective therapy. By this way the selection of patients based on the molecular profile may facilitate a therapeutic strategy that allows the use of the most appropriate drug for each patient. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

Colorectal cancer (CRC) is one of the leading causes of cancer-related death. Surgery, radiotherapy and chemotherapy have been till now the main therapeutic strategies for disease control and improvement of the overall survival. Twenty-five per cent (25%) of CRC patients have clinically detectable liver metastases at the initial diagnosis and approximately 50% develop liver metastases during their disease course. Twenty-thirty per cent (20%-30%) are CRC patients with metastases confined to the liver. Some years ago various studies showed a curative potential for liver metastases resection. For this reason some authors proposed the conversion of unresectable liver metastases to resectable to achieve cure. Since those results were published, a lot of regimens have been studied for resectability potential. Better results could be obtained by the combination of chemotherapy with targeted drugs, such as anti-VEGF and anti-EGFR monoclonal antibodies. However an accurate selection for patients to treat with these regimens and to operate for liver metastases is mandatory to reduce the risk of complications. A multidisciplinary team approach represents the best way for a proper patient management. The team needs to include surgeons, oncologists, diagnostic and interventional radiologists with expertise in hepatobiliary disease, molecular pathologists, and clinical nurse specialists. This review summarizes the most important findings on surgery and systemic treatment of CRC-related liver metastases.

The adenocarcinoma of the lung has recently shown peculiar molecular characteristics, which relate with both carcinogenesis and response to targeted drugs. Several molecular alterations have been defined as "driver mutations". These are responsible for both the initiation and maintenance of the malignancy. The epidermal growth factor receptor (EGFR) pathway is the main regulator of cell function and cancer development. It has a widely defined role in the occurrence of driver mutations. Up till now EGFR gene mutations, KRAS gene mutations and EML4-ALK fusion genes are the most widely recognized alterations involved in both the biology and the clinical management of lung adenocarcinoma. In this review we report the molecular bases that have led to the clinical application of the detection for such genetic impairments. Subsequently we discuss the clinical studies regarding the prognostic role and the predictive value for response to anti-EGFR tyrosine kinase inhibitors (TKI) of the same mutations. We also provide a potential algorithm as a guide in the choice of the best treatment for patients with adenocarcinoma.

The recent advances in identification of the molecular mechanisms related to tumorigenesis and angiogenesis, along with the understanding of molecular alterations involved in renal cell carcinoma (RCC) pathogenesis, has allowed the development of several new drugs which have revolutionized the treatment of metastatic renal cell carcinoma (mRCC). This process has resulted in clinically significant improvements in median overall survival and an increasing number of patients undergoes two or even three lines of therapy. Therefore, it is necessary a long-term perspective of the treatment: planning a sequential and personalized therapeutic strategy to improve clinical outcome, the potential to achieve long-term response, and to preserve quality of life (QOL), minimizing treatment-related toxicity and transforming mRCC into a chronically treatable condition. Because of the challenges still encountered to draw an optimal therapeutic sequence, the main focus of this article will be to propose the optimal sequencing of existing, approved, oral targeted agents for the treatment of mRCC using evidence-based data along with the knowledge available on the tumor behavior and mechanisms of resistance to anti-angiogenic treatment to provide complementary information and to help the clinicians to maximize the effectiveness of targeted agents in the treatment of mRCC.

// Francesco Passiglia 1, * , Giuseppe Bronte 1, * , Viviana Bazan 1, * , Clara Natoli 2 , Sergio Rizzo 1 , Antonio Galvano 1 , Angela Listi 1 , Giuseppe Cicero 1 , Christian Rolfo 3 , Daniele Santini 4 , Antonio Russo 1 1 Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy 2 Department of Medical, Oral and Biotechnological Sciences, University “G. D’Annunzio”, Chieti, Italy 3 Phase I- Early Clinical Trials Unit, Oncology Department and Multidisciplinary Oncology Center Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium 4 Medical Oncology Department, Campus Biomedico, University of Rome, Rome, Italy * These authors have contributed equally to this work Correspondence to: Antonio Russo, e-mail: antonio.russo@usa.net Keywords: PD-L1, predictive biomarker, immunotherapy, anti-PD1/PD-L1 MoAbs, NSCLC Received: December 03, 2015 Accepted: February 11, 2016 Published: February 22, 2016 ABSTRACT Background: Clinical trials of immune checkpoints modulators, including both programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) inhibitors, have recently shown promising activity and tolerable toxicity in pre-treated NSCLC patients. However the predictive role of PD-L1 expression is still controversial. This pooled analysis aims to clarify the association of clinical objective responses to anti PD-1/PD-L1 monoclonal antibodies (MoAbs) and tumor PD-L1 expression in pre-treated NSCLC patients. Methods: Data from published studies, that evaluated efficacy and safety of PD-1/PD-L1 inhibitors in pre-treated NSCLC patients, stratified by tumor PD-L1 expression status (immunohistochemistry, cut-off point 1%), were collected by searching in PubMed, Cochrane Library, American Society of Clinical Oncology, European Society of Medical Oncology and World Conference of Lung Cancer, meeting proceedings. Pooled Odds ratio (OR) and 95% confidence intervals (95% CIs) were calculated for the Overall Response Rate (ORR) (as evaluated by Response Evaluation Criteria in Solid Tumors, version 1.1), according to PD-L1 expression status. Results: A total of seven studies, with 914 patients, were eligible. Pooled analysis showed that patients with PD-L1 positive tumors (PD-L1 tumor cell staining ≥1%), had a significantly higher ORR, compared to patients with PD-L1 negative tumors (OR: 2.44; 95% CIs: 1.61-3.68). Conclusions: PD-L1 tumor over-expression seems to be associated with higher clinical activity of anti PD-1/PD-L1 MoAbs, in pre-treated NSCLC patients, suggesting a potential role of PD-L1 expression, IHC cut-off point 1%, as predictive biomarker for the selection of patients to treat with immune-checkpoint inhibitors.

// Giuseppe Bronte 1, * , Tindara Franchina 2, * , Massimiliano Alu 3, * , Giovanni Sortino 1 , Claudia Celesia 1 , Francesco Passiglia 1 , Giuseppina Savio 3 , Agata Laudani 3 , Alessandro Russo 2 , Antonio Picone 2 , Sergio Rizzo 1 , Michele De Tursi 4 , Elisabetta Gambale 4 , Viviana Bazan 1 , Clara Natoli 4 , Livio Blasi 3 , Vincenzo Adamo 2 , Antonio Russo 1 1 Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy 2 Medical Oncology Unit-AOOR Papardo-Piemonte, Messina and Department of Human Pathology, University of Messina, Messina, Italy 3 Medical Oncology Unit, A.R.N.A.S. Civico, Palermo, Italy 4 Department of Medical, Oral and Biotechnological Sciences, University “G. D'Annunzio”, Chieti, Italy * These authors contributed equally to this work Correspondence to: Antonio Russo, email: antonio.russo@usa.net Keywords: non-small-cell lung cancer, EGFR, tyrosine kinase inhibitor, chemotherapy Received: January 21, 2016 Accepted: February 28, 2016 Published: March 16, 2016 ABSTRACT Background: Second-line treatment for advanced non-small-cell lung cancer (NSCLC) patients includes monotherapy with a third-generation cytotoxic drug (CT) or a tyrosine kinase inhibitor (TKI). These options are the actual standard for EGFR wild-type (WT) status, as patients with EGFR mutations achieve greater benefit by the use of TKI in first-line treatment. Some clinical trials and meta-analyses investigated the comparison between CT and TKI in second-line, but data are conflicting. Methods: We designed a retrospective trial to gather information about TKI sensitivity in comparison with CT. We selected from clinical records patients treated with at least 1 line of CT and at least 1 line of TKI. We collected data about age, sex, performance status, comorbidity, smoking status, histotype, metastatic sites, EGFR status, treatment schedule, better response and time-to-progression (TTP) for each line of treatment and overall survival (OS). Results: 93 patients met selection criteria. Mean age 66,7 (range: 46–84). M/F ratio is 3:1. 39 EGFR-WT and 54 EGFR-UK. All patients received erlotinib or gefitinib as second-line treatment or erlotinib as third-line treatment. No TTP differences were observed for both second-line (HR:0,91; p = 0,6333) and third-line (HR:1.1; p = 0,6951) treatment (TKI vs CT). A trend of a benefit in OS in favor of 3rd-line TKI (HR:0,68; p = 0,11). Conclusions: This study explores the role of TKIs in EGFR non-mutated NSCLC patients. OS analysis highlights a trend to a benefit in patients who received TKI in third-line, even if this result is statistically non-significant. Further analysis are needed to find an explanation for this observation.

Genetic changes involved in the metaplastic progression from squamous esophageal mucosa toward Barrett's metaplasia and adenocarcinoma are almost unknown. Several evidences suggest that some miRNAs are differentially expressed in Barrett's esophagus (BE) and esophageal adenocarcinoma. Among these, miR-143, miR-145, miR-194, miR-203, miR-205, miR-215 appear to have a key role in metaplasia and neoplastic progression. The aim of this study was to analyze deregulated miRNAs in serum and esophageal mucosal tissue biopsies to identify new biomarkers that could be associated with different stages of esophageal disease. Esophageal mucosal tissue biopsies and blood samples were collected and analyzed for BE diagnosis. Quantitative Real-time PCR was used to compare miRNA expression levels in serum and 60 disease/ normal-paired tissues from 30 patients diagnosed with esophagitis, columnar-lined oesophagus (CLO) or BE. MiRNA expression analysis showed that miR-143, miR-145, miR-194 and miR-215 levels were significantly higher, while miR-203 and miR-205 were lower in BE tissues compared with their corresponding normal tissues. Esophageal mucosa analysis of patients with CLO and esophagitis showed that these miRNAs were similarly deregulated but to a lesser extent keeping the same trend and CLO appeared as intermediate step between esophagitis and BE. Analysis on circulating miRNA levels confirmed that miR-194 and miR-215 were significantly upregulated in both BE and CLO compared to esophagitis, while miR-143 was significantly upregulated only in the Barrett group. These findings suggest that miRNAs may be involved in neoplastic/ metaplastic progression and miRNA analysis might be useful for progression risk prediction as well as for monitoring of BE/CLO patients.

Clinical trials investigated the potential role of both KRAS and BRAF mutations, as prognostic biomarkers, in colorectal cancer (CRC) patients who underwent surgical treatment of CRC-related liver metastases (CLM), showing conflicting results. This meta-analysis aims to review all the studies reporting survival outcomes (recurrence free survival (RFS), and/or overall survival (OS)) of patients undergoing resection of CLM, stratified according to KRAS and/or BRAF mutation status. Background: Clinical trials investigated the potential role of both KRAS and BRAF mutations, as prognostic biomarkers, in colorectal cancer (CRC) patients who underwent surgical treatment of CRC-related liver metastases (CLM), showing conflicting results. This meta-analysis aims to review all the studies reporting survival outcomes (recurrence free survival (RFS), and/or overall survival (OS)) of patients undergoing resection of CLM, stratified according to KRAS and/or BRAF mutation status. Materials and methods: Data from all published studies reporting survival outcomes (RFS and/or OS) of CRC patients who received resection of CLM, stratified by KRAS and/or BRAF mutation status were collected, according to the PRISMA guidelines. Pooled HRs were calculated for both the OS and/or RFS. Results: Seven eligible trials (1403 patients) were included. Pooled analysis showed that KRAS mutations predicted a significantly worse both RFS (HR: 1.65; 95% CI: 1.23-2.21) and OS (HR: 1.86; 95% CI: 1.51-2.30) in patients who underwent surgical resection of CLM. BRAF mutations were also associated with a significantly worse OS (HR: 3.90; 95% CI: 1.96-7.73) in this subgroup of patients. Conclusions: This meta-analysis suggests both KRAS and BRAF mutations as poor, prognostic biomarkers, associated with worse survival outcomes, in patients undergoing hepatic resection of CLM.

Introduction: The therapeutic options for NSCLC are limited barring targeted drugs, such as EGFR tyrosine-kinase inhibitors and anaplastic lymphoma kinase inhibitors, for patients bearing oncogenic mutations. Platinum-based chemotherapy remains the best strategy for most patients. New targeted drugs, including mAbs and small molecules, are currently under clinical investigation for treating NSCLC patients. Areas covered: The authors of this article focus on farletuzumab, a mAb targeting folate receptor, which has been studied in ovarian cancer and various other malignancies. In this review, the authors review its potential as therapy for NSCLC, because of the biological rationale provided by the expression of folate receptor a in most of lung adenocarcinoma. The authors provide details of farletuzumab's mechanism of action and discuss the results from completed Phase I and Phase II clinical trials. They also highlight ongoing trials. Expert opinion: There are an increasing number of treatment options for NSCLC and it is hoped that farletuzumab could be added to them. That being said, further evidence for its use with NSCLC patients is still needed. It could have a synergic effect with pemetrexed, because these two drugs have a similar target, namely the folate pathway. This combined action could provide an improved efficacy, although there are some concerns about increased toxicity. However, the authors do note that the combination of farletuzumab with other cytotoxic drugs has not been shown to increase toxicity alone.

Microbial communities that colonize in humans are collectively described as microbiome. According to conservative estimates, about 15% of all types of neoplasms are related to different infective agents. However, current knowledge is not sufficient to explain how the microbiome contributes to the growth and development of cancers. Large and thorough studies involving colonized, diverse and complex microbiome entities are required to identify microbiome as a potential cancer marker and to understand how the immune system is involved in response to pathogens. This article reviews the existing evidence supporting the enigmatic association of transformed microbiome with the development of cancer through the immunological modification. Ascertaining the connection between microbiome and immunological responses with risk of cancer may direct to explaining significant advances in the etiology of cancer, potentially disclosing a novel paradigm of research for the management and prevention of cancer.

Nessuno

Introduction: The identification of cell membrane-bound molecules with a relevant role in cancer cell survival prompted the development of moAbs to block the related pathways. In the last few years, the number of approved moAbs for cancer treatment has constantly increased. Many of these drugs significantly improved the survival outcomes in patients with solid tumours. Areas covered: In this review, all the FDA-approved moAbs in solid tumours have been described. This is an update of moAbs available for cancer treatment nowadays in comparison with the moAbs approved until few years ago. The moAbs under development are also discussed here. Expert opinion: The research on cancer antigens as therapeutic targets led to an expanding scenario of available treatment options in non-haematological malignancies. In a few years, the number of approved drugs has increased rapidly. Some of these agents are actually on label in combination with standard chemotherapy. Only some of them can be delivered as monotherapy. The research on these new drugs is addressing both the identification of further target molecules in key cancer-related pathways and the improvement of drug effectiveness by changing the affinity and the selectivity of a moAb relative to its target.

Since a chance for cure was found out in metastatic colorectal cancer (mCRC) patients undergoing a resection of liver and lung metastases, high tumor shrinkage by chemotherapy regimens and their combination with targeted agents have been addressed in potentially resectable mCRC. However, most mCRC patients cannot reach this opportunity because of tumor burden or metastatic sites. For these patients a salvage systemic therapy could be offered to prolong survival. To date, a huge number of clinical trials provided some evidences for the achievement of this goal. A lot of chemotherapeutic regimens in combination with biological therapies are now available. We tried to propose a simple way to choose the best options and to plan an optimal sequence of treatments. This tool could help the oncologists worldwide to better and easily manage mCRC patients who need salvage systemic therapy.

Gefitinib and erlotinib are the two anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) approved for treatment of advanced NSCLC patients. These drugs target one of the most important pathways in lung carcinogenesis and are able to exploit the phenomenon of 'oncogene addiction', with different efficacy according to EGFR gene mutational status in tumor samples. Gefitinib has been approved only for EGFR mutation bearing patients regardless the line of treatment, while erlotinib is also indicated in patients without EGFR mutation who undergo second- or third-line treatment. Some studies evaluated the main differences between these drugs both for direct comparison and to improve their sequential use. In particular, toxicity profile resulted partially different, and these observations may be explained by several molecular and pharmacoldnetic features. Therefore, this review integrates preclinical data with clinical evidences of TKIs to guide the optimization of currently available treatments in advanced NSCLC patients. (C) 2013 Published by Elsevier Ireland Ltd.

Immunotherapy has been studied for many years in lung cancer without significant results, making the majority of oncologists quite skeptical about its possible application for non-small cell lung cancer treatment. However, the recent knowledge about immune escape and subsequent cancer immunoediting has yielded the development of new strategies of cancer immunotherapy, heralding a new era of lung cancer treatment. Cancer vaccines, including both whole-cell and peptide vaccines have been tested both in early and advanced stages of non-small cell lung cancer. New immunomodulatory agents, including anti-CTLA4, anti-PD1/PDL1 monoclonal antibodies, have been investigated as monotherapy in metastatic lung cancer. To date, these treatments have shown impressive results of efficacy and tolerability in early clinical trials, leading to testing in several large, randomized Phase III trials. As these results will be confirmed, these drugs will be available in the near future, offering new exciting therapeutic options for lung cancer treatment.

Many targeted drugs have been studied to target the molecular pathways involved in the development of gastrointestinal cancers. Anti-VEGF, anti-EGFR agents, and recently also multi-kinase inhibitor regorafenib, have already been available for the treatment of metastatic colorectal cancer patients. To date, Her-2 positive, gastric cancer patients, are also treated with trastuzumab, while the multi-targeted inhibitor, sorafenib, represents the standard treatment for hepatocellular carcinoma patients. Finally, sunitinib and everolimus, have been approved for the treatment of the neuroendocrine gastroenteropancreatic tumors. Actually a great number of further drugs are under preclinical and clinical development. The aim of this review is to provide a comprehensive overview of the state of art, focusing on the new emerging strategies in the personalized treatment of gastrointestinal tumors.

Introduction: Several new targeted agents with anti-angiogenic properties have been developed recently, including vandetanib, sunitinib, sorafenib, bevacizumab and others. Tumor development, progression, metastasis are strongly linked to angiogenesis. Targeted agents like bevacizumab, a monoclonal antibody which targets VEGF, have been fully developed in several solid tumors. These new agents strongly advocate that targeting angiogenesis is one of the best approaches for cancer therapy. Areas covered: Those agents that target additional pro-angiogenic intracellular signaling pathways beyond VEGF signaling have also the potential to contribute to anticancer therapies. The authors present here nintedanib (BIBF 1120), a triple angiokinase inhibitor. It targets not only VEGFRs, but also FGFR and PDGFR. All the available clinical information regarding Phase I - II trials and the toxicity and efficacy of BIBF 1120 both as single agent and in combination with cytotoxic agents in non-small cell lung cancer (NSCLC) is reviewed and discussed here. Expert opinion: Up till now, Phase I and II trials with nintedanib showed an improvement for survival of advanced NSCLC patients. Tolerability profile seems to be acceptable in these clinical trials. However, Phase III trials are mandatory to translate these findings into clinical practice. The research for predictive biomarkers could improve the success of these anti-angiogenic agents.

Introduction: Among gastrointestinal cancers, colorectal and gastric neoplasms are the most frequent. The development of new targeted drugs improved the efficacy of systemic therapy in advanced stages of those malignancies. Areas covered: This review highlights the main biological processes implicated in gastrointestinal cancer development and progression, such as angiogenesis and epidermal growth factor receptor (EGFR) signaling pathway. On these bases, anti-EGFR and anti-vascular endothelial growth factor (VEGF) monoclonal antibodies in colorectal and gastric cancer are discussed. Data about further monoclonal antibodies in development are also reported. Expert opinion: The use of monoclonal antibodies in colorectal and gastric cancers showed the best outcomes when combined with chemotherapy, even though single agent anti-EGFR antibodies seem active in particular setting of metastatic colorectal cancer (CRC) patients. It is not well defined whether the addition of anti-VEGF and anti-EGFR to chemotherapy could improve outcome in those patients susceptible to CRC-related metastases resection. Little and conflicting data are available about the role of these drugs in adjuvant setting. Tests are available to select patients with higher probability to get benefit from these treatments. Further biomarkers need to be evaluated to improve this selection and achieve "tailorization" of systemic therapy. © 2013 Informa UK, Ltd.

Recently, the hypothesis that colorectal tumors originate from a subpopulation of cells called ‘cancer stem cells' (CSCs) or tumor-initiating cells, which exhibit stem-like features, has been confirmed experimentally in various human cancers. Several studies have confirmed the existence of colorectal CSCs (CRCSCs) and have demonstrated that this rare cell population can be isolated by the expression of specific cell surface biomarkers. MicroRNAs (miRNAs) are a class of small non-coding RNAs, which are crucial for post-transcriptional regulation of gene expression and participate in a wide variety of biological functions, including development, cell proliferation, differentiation, metabolism and signal transduction. Moreover, new evidences suggest that miRNAs could contribute to preserve stemness of embryonic stem cells and could be involved in maintaining stemness of CSCs. Recent studies have begun to outline the role of miRNAs in regulation of CRCSCs. This review aims to summarize the recent advancement about the roles of miRNAs in CRCSCs that may represent a step forward in understanding the molecular mechanisms and the possible approaches for colorectal cancer therapy.

Copyright: © 2013 Fanale D, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. MicroRNAs (MiRNAs) are involved in the regulation of several biological processes such as development, differentiation, metabolism, apoptosis and proliferation. Recently, it has been shown that deregulated expression of miRNAs are present in different human cancers, suggesting a potential role in carcinogenesis [1,2]. Recent evidence suggests that miRNAs may represent potential new therapeutic approaches in patients with drug resistance and drug induced toxicity [3]. MiRNAs may have therapeutic applications through two mechanisms. The first strategy involves the inhibition of oncogenic miRNAs by using miRNA antagonists (anti-miRNAs) resulting in up-regulation of genes that would be silenced by deregulated miRNAs. The second strategy involves the restoration in expression levels of tumor suppressor microRNA with miRNA mimics [1]. To date, several studies have shown that miRNA mimics and antimiRNAs may be useful to restore normal gene networks in different cancer cell lines and animal models, suggesting a new potential role in anti-cancer therapy.

Previously, it has been reported that hypoxia causes increased mutagenesis and alteration in DNA repair mechanisms. In 2005, an interesting study showed that hypoxia-induced decreases in BRCA1 expression and the consequent suppression of homologous recombination may lead to genetic instability. However, nothing is yet known about the involvement of BRCA2 in hypoxic conditions in breast cancer. Initially, a cell proliferation assay allowed us to hypothesize that hypoxia could negatively regulate the breast cancer cell growth in short term in vitro studies. Subsequently, we analyzed gene expression in breast cancer cell lines exposed to hypoxic condition by microarray analysis. Interestingly, genes involved in DNA damage repair pathways such as mismatch repair, nucleotide excision repair, nonhomologous end-joining and homologous recombination repair were downregulated. In particular, we focused on the BRCA2 downregulation which was confirmed at mRNA and protein level. In addition, breast cancer cells were treated with dimethyloxalylglycine (DMOG), a cell-permeable inhibitor of both proline and asparaginyl hydroxylases able to induce HIF-1αstabilization in normoxia, providing results comparable to those previously described. These findings may provide new insights into the mechanisms underlying genetic instability mediated by hypoxia and BRCA involvement in sporadic breast cancers.

The modern approach for metastatic colorectal cancer (mCRC) patients is based on the identification of oncogenic pathways, which could be targeted by specific molecules. Vascular endothelial growth factor (VEGF)- and epithelial growth factor receptor (EGFR)-related pathways represent the most important biological mechanisms for cancer development and progression. However, the most significant results by VEGF and EGFR targeting could be achieved through the combination of these drugs with standard chemotherapeutic regimens. These strategies aim to improve the resectability of liver and lung metastases. For those patients who cannot be eligible for metastases resection, a 'continuum of care' has been proposed as the best option. This strategy includes the sequential delivery of various regimens with different targeted drugs. For this reason the choice of the pathway to target, that is, VEGF or EGFR, is not a real dilemma since both these molecules would be targeted during the mCRC natural history. To date, a selection by KRAS mutational status is mandatory to identify those patients with higher probability of benefit from anti-EGFR monoclonal antibodies. In this case VEGF targeting is the only way to choose. New molecules are under evaluation to widen these treatment options.

Objectives: The rapid fatality of pancreatic cancer is, in large part, the result of diagnosis at an advanced stage in the majority of patients. Identification of individuals at risk of developing pancreatic adenocarcinoma would be useful to improve the prognosis of this disease. There is presently no biological or genetic indicator allowing the detection of patients at risk. Our main goal was to identify copy number variants (CNVs) common to all patients with sporadic pancreatic cancer. Methods: We analyzed gene CNVs in leukocyte DNA from 31 patients with sporadic pancreatic adenocarcinoma and from 93 matched controls. Genotyping was performed with the use of the GeneChip Human Mapping 500K Array Set (Affymetrix). Results: We identified 431 single nucleotide polymorphism (SNP) probes with abnormal hybridization signal present in the DNA of all 31 patients. Of these SNP probes, 284 corresponded to 3 or more copies and 147 corresponded to 1 or 0 copies. Several cancer-associated genes were amplified in all patients. Conversely, several genes supposed to oppose cancer development were present as single copy. Conclusions: These data suggest that a set of 431 CNVs could be associated with the disease. This set could be useful for early diagnosis.

Objective: miRNAs are attractive molecules for cancer treatment, including colon rectal cancer (CRC). We investigate on the molecular mechanism by which miR-182 could regulate thrombospondin-1 (TSP-1) expression, a protein down-regulated in CRC and inversely correlated with tumor vascularity and metastasis. Background: MicroRNAs are small non-coding RNAs that regulate the expression of different genes, involved in cancer progression, angiogenesis and metastasis. miR-182, over-expressed in colorectal cancer (CRC), has like predictive target thrombospondin-1 (TSP-1), a protein inversely correlated with tumor vascularity and metastasis that results downregulated in different types of cancer including CRC. Results: We found that TSP-1 increased after transfection with anti-miR-182 and we showed that miR-182 targets TSP-1 3'UTR-mRNA in both cells. Moreover, we observed that anti-miR-182 did not induce significant variation of Egr-1 expression, but affected the nuclear translocation and its binding on tsp-1 promoter in HCT-116. Equally, Sp-1 was slightly increased as total protein, rather we found a nuclear accumulation and its loading on the TSP-1 promoter in HT-29 transfected with anti-miR-182. Conclusion: Our data suggest that miR-182 targets the anti-angiogenic factor TSP-1 and that anti-miR-182 determines an upregulation of TSP-1 expression in colon cancer cells. Moreover, anti-miR-182 exerts a transcriptional regulatory mechanism of tsp-1 modulating Egr-1 and Sp-1 function. Anti-miR-182 could be used to restore TSP-1 expression in order to contrast angiogenic and invasive events in CRC.

Use of anti-epidermal growth factor receptor (anti-EGFR) agents has yielded significant advances in the treatment of patients with metastatic colorectal cancer. In fact these drugs, which include the monoclonal antibodies cetuximab and panitumumab, can be delivered both as a single agent and in combination with chemotherapy, achieving better survival and quality of life and in some cases also resectability of metastases. However, these agents can result in the development of toxicities that are usually different from those observed with chemotherapy alone. For the management of these adverse effects, proper knowledge is mandatory. Skin toxicity is the most frequent adverse effect. Other toxicities can be observed, such as hypomagnesemia, gastrointestinal toxicity, and thromboembolic events. Severe infusion reactions can be life-threatening. For these reasons a review of anti-EGFR-drug-related toxicity is useful for clinical practice.

Esophageal adenocarcinoma originates from columnar metaplastic epithelium of the distal esophagus. Various steps for this carcinogenetic process are known. Before the onset of high-grade dysplasia and adenocarcinoma, endoscopic surveillance is possible. However, because of the high cost of long-term surveillance, predictive factors for cancer are being evaluated to identify subjects with metaplasia who have a higher risk of developing malignancy. Molecular changes seem suitable for this purpose, but could require a high resource expenditure. While trying to identify the best predictive factors for cancer risk, molecular changes and differences in miRNA expression profile between the various steps leading to cancer could help to clarify Barrett's carcinogenesis. In this attempt to find a molecular explanation for the onset of esophageal adenocarcinoma, it is still difficult to understand whether the molecular changes are causes or effects of the neoplastic phenotypic modifications.

Introduction: miRNAs are noncoding RNAs that target specific mRNA with subsequent regulation of particular genes, implicated in various biological processes. In cancer, miRNAs could show a different expression from normal tissues. miRNAs have a role as oncogenes when they target tumor suppressor genes and similarly they are tumor suppressors when they target oncogenes. Areas covered: In this review, areas covered include the role of miRNAs in cancer diagnosis, prognosis and research for achievement of therapeutic strategies implicating miRNAs in oncology. As biogenesis of miRNAs is fundamental to understand their usefulness, this has also been discussed. Both miRNA expression profiles in cancer tissues and miRNA levels in peripheral blood were studied for improvement in the management of cancer patients. Expert opinion: miRNAs have the potential for better understanding of tumor biology, but could also provide clinical advancement in management and therapy of various malignancies. The possibility of miRNA detection in peripheralblood would allow an eager expansion of their application in variousclinical settings for cancer. The applicability of miRNA expression profiles still needs to be defined

Introduction: The use of monoclonal antibodies is one of the strategies for targeting the specific key points of the main pathways of cancer growth and survival, but only a few antibodies have offered a clear clinical benefit in the treatment of non-haematological malignancies. Areas covered: This review summarizes the general properties of monoclonal antibodies, including structure, nomenclature and production techniques. The antibodies approved for use in clinical practice for the treatment of non-haematological tumors and those antibodies still being developed in this setting are briefly described. The types of antibody fragments are also reported. Expert opinion: Monoclonal antibodies were initially developed in order to avoid the cytotoxic effects of chemotherapy on healthy tissues. However antibodies have not yet replaced chemotherapy agents, since the combination of both kinds of drugs have usually appeared to achieve higher benefit compared with chemotherapy alone. The research for the development of new monoclonal antibodies aims to identify further targets and to provide innovative antibody constructs.

Bortezomib is a proteasome inhibitor. It targets the ubiquitin-proteasome pathway with subsequent inhibition of the degradation of proteins involved in cell cycle regulation and cancer cell survival. The best known molecular mechanism concerns the inhibition of IkappaB breakdown and the related stabilization of NFkappaB, thus preventing its translocation to the nucleus for the activation of downstream pathways. Bortezomib is the only drug in this class which has been approved for clinical use. It has shown an efficient antitumor effect in a phase III clinical trial (APEX) involving relapsed multiple myeloma patients. Response rate, time to progression and overall survival have been improved in patients treated with bortezomib and dexamethasone compared to dexamethasone alone. These results have induced several researchers to suggest preclinical and clinical studies for the application of bortezomib in solid tumors. Preclinical data have proved useful in the identification of several of the biological processes implicated, including cell cycle arrest at the G2/M phase, upregulation of p21, apoptosis regulation, microvessel density reduction, overcoming chemotherapy resistance. The clinical results obtained so far with the use of bortezomib in patients with solid malignancies are still not sufficient for the introduction of the drug into clinical practice. Furthermore, the results obtained with the use of bortezomib combined with cytotoxic drugs have not proved any more satisfactory than those obtained with bortezomib used as a single agent. Other preclinical studies are required in order to reach a clearer understanding of the relevance of bortezomib in the therapy of solid tumors.

Laura Ottini1, Carlo Capalbo2, Piera Rizzolo1, Valentina Silvestri1, Giuseppe Bronte3, Sergio Rizzo3, Antonio Russo31Department of Experimental Medicine, “Sapienza” University of Rome, Rome, Italy; 2Medical Oncology, IDI-IRCCS, Rome, Italy; 3Department of Surgical and Oncological Sciences, Section of Medical Oncology, University of Palermo, Palermo, ItalyAbstract: Although rare, male breast cancer (MBC) remains a substantial cause for morbidity and mortality in men. Based on age frequency distribution, age-specific incidence rate pattern, and prognostic factor profiles, MBC is considered similar to postmenopausal breast cancer (BC). Compared with female BC (FBC), MBC cases are more often hormonal receptor (estrogen receptor/progesterone receptor [ER/PR]) positive and human epidermal growth factor receptor 2 (HER2) negative. Treatment of MBC patients follows the same indications as female postmenopausal with surgery, systemic therapy, and radiotherapy. To date, ER/PR and HER2 status provides baseline predictive information used in selecting optimal adjuvant/neoadjuvant therapy and in the selection of therapy for recurrent or metastatic disease. HER2 represents a very interesting molecular target and a number of compounds (trastuzumab [Herceptin®; F. Hoffmann-La Roche, Basel, Switzerland] and lapatinib [Tykerb®, GlaxoSmithKline, London, UK]) are currently under clinical evaluation. Particularly, trastuzumab, a monoclonal antibody which selectively binds the extracellular domain of HER2, has become an important therapeutic agent for women with HER2-positive (HER2+) BC. Currently, data regarding the use of trastuzumab in MBC patients is limited and only few case reports exist. In all cases, MBC patients received trastuzumab concomitantly with other drugs and no severe toxicity above grade 3 was observed. However, MBC patients that would be candidate for trastuzumab therapy (ie, HER2+/ER+ or HER2+/ER- MBCs) represent only a very small percentage of MBC cases. This is noteworthy, when taking into account that trastuzumab is an important and expensive component of systemic BC therapy. Since there is no data supporting the fact that response to therapy is different for men or women, we concluded that systemic therapy in MBC should be considered on the same basis as for FBC. Particularly in male patients, trastuzumab should be considered exclusively for advanced disease or high-risk HER2+ early BCs. On the other hand, lapatinib (Tykerb), a novel oral dual tyrosine kinase inhibitor that targets both HER2 and epidermal growth factor receptor, may represent an interesting and promising therapeutic agent for trastuzumab-resistant MBC patients.Keywords: target therapy, trastuzumab, lapatinib

The relationship between sex steroids and cancer has been studied for more than a century. Using an original intact cell analysis, we investigated sex steroid metabolism in a panel of human cancer cell lines, either hormone responsive or unresponsive, originating from human breast, endometrium, and prostate. We found that highly divergent patterns of steroid metabolism exist and that the catalytic preference (predominantly reductive or oxidative) is strictly associated with the steroid receptor status of cells. We explored intra-tissue concentrations and profiles of estrogens in a set of human breast tumors as compared to normal mammary tissues, also in relation to their estrogen receptor status. In particular, we showed that, with hydroxyestrogens representing the majority of all tissue estrogens, concentrations of individual metabolites, as well as their ratios, significantly differ when comparing normal tissue with cancer tissues or when they are related to the overall survival of cancer patients. © 2004 New York Academy of Sciences.