plasma matrix metalloprotease 9 correlates with blood lymphocytosis leukemic cell invasiveness and prognosis in b cell chronic lymphocytic leukemia

The complex biology underlying chronic lymphocytic leukemia cell migration and tissue invasiveness is not yet completely understood and might provide novel predictive markers and therapeutic targets. A total of 36 patients out of treatment from at least 3 months were enrolled and followed up for a median period of 44.2 months (range: 4.4-99.2). Matrix metalloprotease 9 and tissue inhibitor of metalloproteases 1 plasma levels and production/release from lymphoid cells were measured by zymography and enzyme-linked immunosorbent assay (ELISA) analysis. Malignant and normal lymphocyte mobility and matrix-degradation capability were studied using a Boyden chamber system, with and without autologous plasma. Free matrix metalloprotease 9 plasma levels were related with blood lymphocytosis, especially in more advanced stages (p = 0.003), and higher concentrations were associated with an increased disease progression risk (hazard ratio = 9.0, 95% confidence interval = 1.5-13.8). Leukemic cells expressed and secreted very little matrix metalloprotease 9. On the contrary, normal lymphocytes derived from the same leukemic patients showed matrix metalloprotease 9 intracellular levels that were lower in subjects with higher blood lymphocytosis (p = 0.024) and more advanced stages (p = 0.03); the released quantities were inversely associated with matrix metalloprotease 9 plasma concentrations (p = 0.035). Leukemic cells had a reduced spontaneous mobility and matrix-degradation capability that were stimulated by autologous plasma (p = 0.001) and normal lymphocytes (p = 0.005), respectively. Matrix metalloprotease 9 affected cell invasiveness depending on concentration and disease stage. In conclusion, chronic lymphocytic leukemia cells have a reduced mobility, matrix-degradation capability, and matrix metalloprotease 9 production compared to their own autologous normal lymphocytes. They are exposed to matrix metalloprotease 9 of prevalently systemic origin whose higher levels are associated with both leukemic and normal lymphocyte accumulation in the peripheral blood and have a negative prognostic value

Targeted therapies for advanced and metastatic adenocarcinoma of the gastroesophageal junction: is there something new?

Despite improvements in systemic chemotherapy (CT), the prognosis of metastatic adenocarcinoma of the gastroesophageal junction remains poor. Over the years, new targeting agents have become available and were tested, with or without CT, in first or subsequent lines of therapy. The epidermal growth factor receptor family was targeted with monoclonal antibodies (MoAbs) (trastuzumab, cetuximab, panitumumab) and tyrosin kinase inhibitors (TKIs) (lapatinib, erlotinib, gefitinib). Only trastuzumab, in combination with cisplatin and fluoropyrimidines, significantly improved overall survival (OS) in first-line therapy (13.8 vs. 11.1 months). Angiogenesis also was targeted with MoAbs (bevacizumab and ramucirumab); ramucirumab, a vascular endothelial growth factor-receptor 2 antagonist, enhanced OS in two phase III studies in the first (9.6 vs. 7.4 months) and subsequent lines of treatment (5.2 vs. 3.8 months), while the bevacizumab study was negative. TKIs (sunitinib, sorafenib, regorafenib, apatinib) were tested in this setting in phase II studies in the second/third line, only showing modest antitumor activity. The hepatocyte growth factor receptor (MET) was targeted in untreated patients in a phase III trial with MoAb rilotumumab, with or without CT, but the study was stopped because of mortality excess in the rilotumumab arm. Mammalian target of rapamycin (MTOR) pathway inhibition with everolimus was tested in pretreated patients in a placebo-controlled phase III trial who failed to improve OS (5.4 vs. 4.3 months). In conclusion, considering the modest survival gain obtained overall, the high cost of these therapies and the quality of life issue must be primarily considered in treating these patients

An individual patient-data meta-analysis of metronomic oral vinorelbine in metastatic non-small cell lung cancer

MOV is an active and well-tolerated chemotherapy in metastatic NSCLC and is a manageable therapy in frail patients

Germ line polymorphisms as predictive markers for pre-surgical radiochemotherapy in locally advanced rectal cancer: A 5-year literature update and critical review

Locally advanced rectal cancer is currently treated with pre-surgical radiotherapy and chemotherapy. Approximately one-half of patients obtain a relevant shrinkage/disappearance of tumour, with major clinical advantages. The remaining patients, in contrast, show no benefit and possibly need alternative treatment. To provide the best therapeutic option for each individual patient, predictive markers have been widely researched. This review was undertaken to evaluate recent progress made in this field. A systematic literature search was performed using PubMed and Scopus database, focused on germ line gene polymorphisms as biomarkers and response and toxicity as outcomes. Because an exhaustive previous review was available describing findings up to 2008, we restricted our analysis to the last 5 years. Ten original research articles were found, reporting promising results for some candidate genes in drug metabolism (TYMS, MTHFR), DNA repair (XRCC1, OGG1, CCND1) and inflammation (SOD2, TGFB1)/immunity (IL13) pathways, but with no firm conclusion. All the studies had small sample size and were defined as exploratory. This review highlights pivotal molecular, clinical, genetic and statistical issues in the investigation of genetic polymorphisms as outcome predictors for rectal cancer and offers suggestions for future development. What emerges is a clear need for new proposals, especially in view of the increasing evidence for tumour-host and gene-gene interactions during anticancer treatment, together with stronger adherence to proper methodological requirements

Telomere shortening and PCDH10 promoter methylation in colorectal cancer mucosae

Background: telomerase activity and telomere length (TL) have important implications in several human diseases.Telomere shortening is associated with colorectal carcinogenesis. Recent studies also showed that protocadherin 10(PCDH10) plays a critical role in cancer cell growth, by negatively regulating telomerase activity. PCDH10isfrequently downregulated by promoter DNA methylation. The aim of this study was to investigate whether PCDH10promoter methylation was associated with TL in colorectal cancer (CRC). Methods: DNA was extracted from 35 CRC and 35 adjacent normal tissues with Gentra Purgene Kit (Qiagen, Hilden,Germany). A quantitative methylation-specific PCR (MSP) based method was used to analyze a selected CpG site inPCDH10promoter. TL was evaluated with qPCR and expressed as telomere to single copy gene (T/S) ratio.Differences were assessed with Mann-Whitney test or Wilcoxon signed-ranks test when appropriate, whilstcorrelation analyses were performed with Spearman\u2019s test. Diagnostic performance was calculated with receiveroperating characteristics (ROC) curve analysis. The level of statistical significance was set at p <0.05. Results: we found that TL was significantly lower in CRC than in adjacent non-cancerous tissues (p=0.0005). Thearea under the ROC curve (AUC) for TL was 0.759 (95% Confidence Interval: 0.643-0.875, p=0.0002). AberrantPCDH10promoter methylation was detected in 100% of CRC tissues but in none of paired non-cancerous tissues.The median methylation rate in CRC tissues was 55.7% (range: 6.1-97.8%). TL was negatively correlated withPCDH10promoter methylation (r=-0.42, p=0.0002). Conclusions: these results suggest a pivotal role of telomere shortening and PCDH10methylation in CRC tissues.TL may be seen as a potential biomarker in CRC diagnostics

Tolerance to the repolarization effects of ‘oorac‘ox-sotalol during long-term treatment

Aims To establish whether tolerance to the QT effect could ensue during maintenance treatment with rac-sotalol

Plasma expression levels of circulating miR-21 are not useful for diagnosing and monitoring colorectal cancer

BACKGROUND: Recent evidence suggests that microRNAs play an important role in cancer diagnostics. We assessed plasma microRNA-21 levels in patients with colorectal cancer (CRC) at different stages and in patients with benign polyps.METHODS: Plasma levels of miR-21 were assessed by quantitative reverse transcription polymerase chain reaction assay in plasma samples of 76 CRC patients and in 20 patients with benign polyps. Differences between groups were evaluated with Mann-Whitney and Kruskal-Wallis tests.RESULTS: No significant differences of miR-21 plasma levels were observed between CRC patients and subjects with benign polyps (p > 0.05). Also, no significant differences were found between CRC patients with advanced (III-IV) or early cancer stages (I-II) (p > 0.05).CONCLUSIONS: These results do not support the hypothesis that circulating miR-21 expression is increased in adenoma-carcinoma-advanced carcinoma sequence. Accordingly, plasma miR-21 assessment does not appear to be a useful biomarker for diagnosing and staging CRC