Quantification of fibrosis by collagen proportionate area predicts hepatic decompensation in hepatitis C cirrhosis

Background It is unclear whether the course of cirrhosis and its prognosis are related to the amount of collagen in the liver. Aim To determine whether fibrosis, assessed by collagen proportionate area (CPA) in patients with compensated cirrhosis, is associated with the presence of oesophageal varices, and predict disease decompensation during the follow-up period. Methods We prospectively evaluated 118 consecutive patients with compensated cirrhosis to correlate fibrosis, assessed by CPA in liver biopsies, with the presence of oesophageal varices (OV) and with the rate of liver decompensation (LD) development during a median follow-up of 72 months. Results At baseline 38 (32.2%) patients had OV and during the follow-up (median 72 months, IQR 47–91), 17 patients (14.4%) developed LD. The mean CPA value was different in patients with and without OV (14.8 5.9% vs. 21.6 9.5%, P < 0.001). The best CPA cut-off for OV by area under the receiver operating characteristic (AUROC) was ≥14% and with multivariate logistic analysis CPA was the only variable associated with OV (OR: 28.32, 95% CI: 6.30–127.28; P < 0.001). By AUROC analysis the best CPA cut-off to predict LD was 18.0%. By Cox regression multivariate analysis CPA ≥18% (HR: 3.99, 95% CI: 1.04–11.45; P = 0.036), albumin (HR: 0.12, 95% CI: 0.04–0.43; P = 0.001) and presence of OV (HR: 8.15, 95% CI: 2.31– 28.78; P = 0.001) were independently associated with LD. Conclusion Quantification of fibrosis by collagen proportionate area allows identification of patients with compensated HCV cirrhosis with a higher likelihood of clinically relevant portal hypertension and a higher risk of decompensation

Anti-endothelin drugs in solid tumors

Importance of the field: The endothelin (ET) axis, which includes the biological functions of ETs and their receptors, has played a physiological role in normal tissue, acting as a modulator of vasomotor tone, tissue differentiation and development, cell proliferation and hormone production. Interestingly, it also functions in the growth and progression of various tumors. Several researchers have identified the blockade of the ET-1 receptor as a promising therapeutic approach. Areas covered in this review: The clinical investigation of an orally bioavailable ET antagonist, atrasentan, in prostate cancer, is encouraging. In this neoplasia, it has shown antitumor activity, bone metastasis control and amelioration of cancer-related pain but improvement in time to progression and overall survival has still not been demonstrated. The clinical trials of other ET antagonists are reported. Literature research was performed by Pubmed and Pharmaprojects. What the reader will gain: A comprehensive view about the use of atrasentan in the treatment of castration-resistant prostate cancer (CRPC) is provided together with the scientific rationale based on the function of ET and its receptor in various cancer development mechanisms. Take home message: Atrasentan seems to be active in CRPC, although strong scientific evidence is still to be found. Interesting clinical findings regard zibotentan

Beyond evidence-based data: Scientific rationale and tumor behavior to drive sequential and personalized therapeutic strategies for the treatment of metastatic renal cell carcinoma

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 evidencebased 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

Circulating miR-22, miR-24 and miR-34a as Novel Predictive Biomarkers to Pemetrexed-Based Chemotherapy in Advanced Non-Small Cell Lung Cancer

Pemetrexed has been widely used in patients with advanced non-small cell lung cancer (NSCLC). The clinical relevance of polymorphisms of folate pathway genes for pemetrexed metabolism have not been fully elucidated yet. The aim of this study was to evaluate the expression levels of circulating miR-22, miR-24, and miR-34a, possibly involved in folate pathway, in NSCLC patients treated with pemetrexed compared with healthy controls and to investigate their impact on patient clinical outcomes. A total of 22 consecutive patients with advanced NSCLC, treated with pemetrexed-based chemotherapy and 27 age and sex matched healthy controls were included in this preliminary analysis. miR-22, miR-24, and miR-34a targets were identified by TargetScan 6.2 algorithm, validating the involvement of these microRNAs in folate pathway. MicroRNAs were isolated from whole blood and extracted with miRNAeasy Mini Kit (Qiagen). miRNA profiling was performed using Real-Time PCR. SPSS 17 was used to data analysis. miR-22, miR-24, and miR-34a were found upregulated (P<0.05) in NSCLC patients versus healthy controls. Higher expression levels were recorded for miR-34a. Nevertheless, significantly higher miR-22 expression was observed in patients developing progressive disease (P=0.03). No significant associations with clinical outcome were recorded for miR-24 and miR-34a. Albeit preliminary, these data support the involvement of miR-22, miR-24, and miR-34a in advanced NSCLC. The correlation between high expression of miR-22 in whole blood and the lack of response in pemetrexed treated NSCLC patients indicates that miR-22 could represent a novel predictive biomarker for pemetrexed-based treatment

A Phase II Trial of Fixed-Dose Rate Gemcitabine plus Capecitabine in Metastatic/Advanced Biliary Tract Cancer Patients

Background: This phase II trial was conducted to determine the activity and safety of the combination of fixed-dose rate (FDR) gemcitabine and capecitabine in metastatic biliary tract cancer (BTC) patients. Methods: Patients with unresectable BTC who had pathologically confirmed adenocarcinoma, no prior chemotherapy, Eastern Cooperative Oncology Group (ECOG) performance status 641 and measurable disease were enrolled. Treatment consisted of FDR gemcitabine at 800 mg/m 2 on days 1 and 8 every 21 days with capecitabine administered orally b.i.d. in equal doses (650 mg/m 2 b.i.d.) for 14 days (28 doses). Results: Between May 2005 and February 2009, 30 patients were enrolled. The median age was 67 years (45-76) and there were 14 males. Thirty patients were evaluable for response and toxicity. A total of 221 cycles were administered (median 7, range 2-16). One patient achieved complete response and 7 patients achieved partial response, giving an overall response rate of 26.7% in the intention-to-treat population. Twelve patients (40.0%) had stable disease. The median progression-free survival was 6.33 months. The median overall survival was 10.8 months. Grade 3/4 neutropenia and thrombocytopenia were noted in 13 and 7% of the patients, respectively. Grade 2/3 nonhematologic toxicities were asthenia (54% of patients), diarrhea (17%), stomatitis (23%) and hand-foot syndrome (7%). There was no treatment-related death. The drugs taken were skipped at least once in 45% of the patients and the dose was reduced in 26% of them. Conclusions: The combination of FDR gemcitabine and capecitabine in this 3-week cycle is safe and seems to have a good activity in advanced biliary cancer

Monoclonal antibodies for the treatment of non-haematological tumours: Update of an expanding scenario

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

Nintedanib in NSCLC: Evidence to date and place in therapy

The treatment of advanced non-small cell lung cancer (NSCLC) is currently driven by the detection of targetable oncogenic drivers, i.e. epidermal growth factor receptor, echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase, etc. Those patients who are wildtype for known and valuable oncogenes can receive standard chemotherapy as first-line treatment, with the possibility of adding bevacizumab. With regard to second-line treatment, nintedanib can improve the efficacy of docetaxel. Nintedanib is a tyrosine kinase inhibitor targeting three angiogenesis-related transmembrane receptors. The usefulness of nintedanib as an anticancer agent for NSCLC has been proved by both preclinical and clinical phase I and II trials; however, its approval for the use in clinical practice has been possible because of the positive results of the LUME-Lung 1 trial (nintedanib + docetaxel versus docetaxel alone) in terms of progression-free survival and overall survival, and a manageable tolerability profile. Therefore, the good results seen in the clinical trials with nintedanib in the second-line setting for NSCLC patients with adenocarcinoma subtype are encouraging enough to recommend it in clinical practice

Targeting of immunosuppressive myeloid cells from glioblastoma patients by modulation of size and surface charge of lipid nanocapsules

Background: Myeloid derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) are two of the major players involved in the inhibition of anti-tumor immune response in cancer patients, leading to poor prognosis. Selective targeting of myeloid cells has therefore become an attractive therapeutic strategy to relieve immunosuppression and, in this frame, we previously demonstrated that lipid nanocapsules (LNCs) loaded with lauroyl-modified gemcitabine efficiently target monocytic MDSCs in melanoma patients. In this study, we investigated the impact of the physico-chemical characteristics of LNCs, namely size and surface potential, towards immunosuppressive cell targeting. We exploited myeloid cells isolated from glioblastoma patients, which play a relevant role in the immunosuppression, to demonstrate that tailored nanosystems can target not only tumor cells but also tumor-promoting cells, thus constituting an efficient system that could be used to inhibit their function. Results: The incorporation of different LNC formulations with a size of 100 nm, carrying overall positive, neutral or negative charge, was evaluated on leukocytes and tumor-infiltrating cells freshly isolated from glioblastoma patients. We observed that the maximum LNC uptake was obtained in monocytes with neutral 100 nm LNCs, while positively charged 100 nm LNCs were more effective on macrophages and tumor cells, maintaining at low level the incorporation by T cells. The mechanism of uptake was elucidated, demonstrating that LNCs are incorporated mainly by caveolae-mediated endocytosis. Conclusions: We demonstrated that LNCs can be directed towards immunosuppressive cells by simply modulating their size and charge thus providing a novel approach to exploit nanosystems for anticancer treatment in the frame of immunotherapy.[Figure not available: see fulltext.