Hsa-miR-375 is a predictor of local control in early stage breast cancer

Background: A long-term analysis by the Early Breast Cancer Trialist Group (EBCTG) revealed a strong correlation between local control and cancer-specific mortality. MicroRNAs (miRs), short (20-25 nucleotides) non-coding RNAs, have been described as prognosticators and predictors for breast cancer in recent years. The aim of the current study was to identify miRs that can predict local control after breast conserving therapy (BCT) in early stage breast cancer. Results: Clinical data of 46 early stage breast cancer patients with local relapse after BCT were selected from the institutional database. These patients were matched to 101 control patients showing identical clinical features but without local relapse. The study was conducted in two steps. (1) In the pilot study, 32 patients (16 relapses versus 16 controls) were screened for the most de-regulated microRNAs (= candidate microRNAs) in a panel of 1250 miRs by microarray technology. Eight miRs were found to be significantly de-regulated. (2) In the validation study, the candidate microRNAs were analyzed in an independent cohort of 115 patients (30 relapses versus 85 controls) with reverse transcription quantitative polymerase chain reaction (RT-qPCR). From these eight candidates, hsa-miR-375 could be validated. Its median fold change was 2.28 (Mann-Whitney U test, corrected p value = 0.008). In the log-rank analysis, high expression levels of hsa-miR-375 correlated with a significantly higher risk of local relapse (p = 0.003). In a multivariate analysis (forward stepwise regression) including established predictors and prognosticators, hsa-miR-375 was the only variable that was able to distinguish the statistical significance between relapse and control groups (raw p value = 0.000195 HR = 0.76, 95 % CI 0.66-0.88;corrected p value = 0.005). Conclusions: Hsa-miR-375 predicts local control in patient with early stage breast cancer, especially in estrogen receptor alpha (ER-alpha)-positive patients. It can therefore serve as an additional molecular marker for treatment choice independently from known predictors and prognosticators. Validation in larger prospective studies is warranted

Loss of PTEN/MMAC1 activity is a rare and late event in the pathogenesis of nephroblastomas.

Recent genetic investigations of nephroblastomas point to an activation of the Wnt pathway. Data indicate however that activation might be partly due to cross talk of different signaling pathways including the tumor suppressor gene PTEN (phosphatase and tensin homolog on chromosome 10). Therefore, we examined expression and chromosomal aberrations of PTEN in nephroblastomas of different subtypes and the corresponding nephrogenic rests. Loss of heterozygosity was analyzed by high-resolution melting analysis of 4 different single nucleotide polymorphisms. Results were confirmed by sequence analysis of the polymerase chain reaction products. In addition, an intragenic insertion-deletion polymorphism of the PTEN gene was investigated. Protein expression was assessed by immunohistochemistry. Twenty-two nephroblastomas and their corresponding nephrogenic rests were included in the study. In the high-resolution melting analysis, 15 samples were homozygous, 6 were heterozygous, and for 1 sample results could not be obtained for technical reasons. None of the samples showed loss of heterozygosity. Nineteen of the tumors and corresponding nephrogenic rests were also examined immunohistochemically. All tumors showed cytoplasmic positivity, with the exception of 1 tumor that showed complete loss of staining. In 1 tumor, the epithelial component showed distinct cytoplasmic staining, whereas the immature muscle and hyaline cartilage were negative. All nephrogenic rests exhibited positive cytoplasmic staining of all components. Our results establish that inactivation of PTEN is a rare and late event in the pathogenesis of nephroblastomas

Activation of beta-catenin is a late event in the pathogenesis of nephroblastomas and rarely correlated with genetic changes of the APC gene.

[en] AIMS: Activation of β-catenin has been identified as a possible mechanism for the development of nephroblastomas. In our study we investigated whether this activation occurs already in precursor lesions of nephroblastomas, called nephrogenic rests (NRs). Inactivation of the adenomatous polyposis coli (APC) protein is an important regulatory mechanism of activating β-catenin. We clarified the role of APC by assessing loss of heterozygosity (LOH) and possible mutations within the genomic region. METHODS: Activation of β-catenin was examined by immunohistochemistry identifying nuclear translocation. Two polymorphic loci of the APC gene were investigated for LOH and sequence analysis was performed for the mutation cluster region of the APC gene on formalin fixed, paraffin embedded samples. RESULTS: Four of the 18 nephroblastomas available for immunohistochemistry exhibited nuclear staining of β-catenin, but none of the NRs. Analysis of LOH revealed 14 homozygous samples, 10 heterozygous tumours and six tumours exhibiting LOH of the APC gene. One blastema-type nephroblastoma showed nuclear localisation of β-catenin in conjunction with LOH of the APC gene. Analysis of 12 nephroblastomas revealed no sequence aberration. CONCLUSION: Our results indicate that nuclear activation of β-catenin is a late event in the tumorigenesis of nephroblastomas coinciding in some tumours with LOH of the APC gene

Capecitabine in combination with bendamustine in pretreated women with HER2-negative metastatic breast cancer: results of a phase II trial (AGMT MBC-6)

BACKGROUND: Bendamustine, a medication approved for the treatment of indolent non-Hodgkin lymphoma, has already shown anticancer activity in metastatic breast cancer (MBC). Here, we present the results of a phase II trial of bendamustine in combination with capecitabine in pre-treated patients with MBC. PATIENTS AND METHODS: AGMT MBC-6 is a multicentre, open-label, single-arm phase II study in HER2-negative MBC. All patients were pre-treated with anthracyclines and/or taxans and had measurable disease. Patients received per os 1000 mg/m(2) capecitabine twice daily on days 1 to 14 in combination with 80 mg/m(2) bendamustine intravenously on days 1 and 8 of a 3-week cycle for a maximum of eight cycles, followed by a capecitabine maintenance therapy. The primary endpoint was overall response rate (ORR). RESULTS: From September 2013 to May 2015, 40 patients were recruited in eight Austrian centres. The median age was 60 years (range 29-77). Twenty-five per cent of patients had triple-negative breast cancer (TNBC) and 93% showed visceral involvement. With 17 partial and one complete remission, ORR was 46%. Median progression-free survival (PFS) was 7.5 months [95% confidence interval (CI) 6.1-10.7]. The most common non-haematological adverse events (AEs) of grade 3 were hand-foot syndrome (13%), fatigue (10%), nausea (8%), and dyspnoea (8%). One grade 4 non-haematological AE (hepatic failure) and three grade 4 haematological AEs (neutropenia) were observed. One patient died of restrictive cardiomyopathy, in which a relationship to capecitabine cannot be excluded, but seems unlikely. CONCLUSION: The combination of capecitabine and bendamustine shows promising efficacy and moderate toxicity. Further evaluation of this drug combination is warranted.The clinical trial AGMT MBC-6 was registered at ClinicalTrials.gov, (https://clinicaltrials.gov/; identifier: NCT01891227)

DNA methylation signatures predicting bevacizumab efficacy in metastatic breast cancer

Background: Biomarkers predicting response to bevacizumab in breast cancer are still missing. Since epigenetic modifications can contribute to an aberrant regulation of angiogenesis and treatment resistance, we investigated the influence of DNA methylation patterns on bevacizumab efficacy. Methods: Genome-wide methylation profiling using the Illumina Infinium HumanMethylation450 BeadChip was performed in archival FFPE specimens of 36 patients with HER2-negative metastatic breast cancer treated with chemotherapy in combination with bevacizumab as first-line therapy (learning set). Based on objective response and progression-free survival (PFS) and considering ER expression, patients were divided in responders (R) and non-responders (NR). Significantly differentially methylated gene loci (CpGs) with a strong change in methylation levels (>0.15 or <-0.15) between R and NR were identified and further investigated in 80 bevacizumab-treated breast cancer patients (optimization set) and in 15 patients treated with chemotherapy alone (control set) using targeted deep amplicon bisulfite sequencing. Methylated gene loci were considered predictive if there was a significant association with outcome (PFS) in the optimization set but not in the control set using Spearman rank correlation, Cox regression, and logrank test. Results: Differentially methylated loci in 48 genes were identified, allowing a good separation between R and NR (odds ratio (OR) 101, p<0.0001). Methylation of at least one cytosine in 26 gene-regions was significantly associated with progression-free survival (PFS) in the optimization set, but not in the control set. Using information from the optimization set, the panel was reduced to a 9-gene signature, which could divide patients from the learning set into 2 clusters, thereby predicting response with an OR of 40 (p<0.001) and an AUC of 0.91 (LOOCV). A further restricted 3-gene methylation model showed a significant association of predicted responders with longer PFS in the learning and optimization set even in multivariate analysis with an excellent and good separation of R and NR with AUC=0.94 and AUC=0.86, respectively. Conclusion: Both a 9-gene and 3-gene methylation signature can discriminate between R and NR to a bevacizumab-based therapy in MBC and could help identify patients deriving greater benefit from bevacizumab.(VLID)251037

Neurologic Factors in Female Sexual Function and Dysfunction

Sexual dysfunction affects both men and women, involving organic disorders, psychological problems, or both. Overall, the state of our knowledge is less advanced regarding female sexual physiology in comparison with male sexual function. Female sexual dysfunction has received little clinical and basic research attention and remains a largely untapped field in medicine. The epidemiology of female sexual dysfunction is poorly understood because relatively few studies have been done in community settings. In the United States, female sexual dysfunction has been estimated to affect 40% of women in the general population. Among the elderly, however, it has been reported that up to 87% of women complain of sexual dissatisfaction. Several studies have shown that the prevalence of female sexual arousal disorders correlates significantly with increasing age. These studies have shown that sexual arousal and frequency of coitus in the female decreases with increasing age. The pathophysiology of female sexual dysfunction appears more complex than that of males, involving multidimensional hormonal, neurological, vascular, psychological, and interpersonal aspects. Organic female sexual disorders may include a wide variety of vascular, neural, or neurovascular factors that lead to problems with libido, lubrication, and orgasm. However, the precise etiology and mechanistic pathways of age-related female sexual arousal disorders are yet to be determined. In the past two decades, some advances have been made in exploring the basic hemodynamics and neuroregulation of female sexual function and dysfunction in both animal models and in human studies. In this review, we summarize neural regulation of sexual function and neurological causes of sexual dysfunction in women

The 70-Gene Prognostic Signature for Korean Breast Cancer Patients

Purpose: A 70-gene prognostic signature has prognostic value in patients with node-negative breast cancer in Europe. This diagnostic test known as “MammaPrint TM (70-gene prognostic signature)” was recently validated and implementation was feasible. Therefore, we assessed the 70-gene prognostic signature in Korean patients with breast cancer. We compared the risk predicted by the 70-gene prognostic signature with commonly used clinicopathological guidelines among Korean patients with breast cancer. We also analyzed the 70-gene prognostic signature and clinicopathological feature of the patients in comparison with a previous validation study. Methods: Forty-eight eligible patients with breast cancer (clinical T1-2N0M0) were selected from four hospitals in Korea. Fresh tumor samples were analyzed with a customized microarray for the 70-gene prognostic signature. Concordance between the risk predicted by the 70-gene prognosti

Low aerobic mitochondrial energy metabolism in poorly- or undifferentiated neuroblastoma

<p>Abstract</p> <p>Background</p> <p>Succinate dehydrogenase (SDH) has been associated with carcinogenesis in pheochromocytoma and paraganglioma. In the present study we investigated components of the oxidative phosphorylation system in human neuroblastoma tissue samples.</p> <p>Methods</p> <p>Spectrophotometric measurements, immunohistochemical analysis and Western blot analysis were used to characterize the aerobic mitochondrial energy metabolism in neuroblastomas (NB).</p> <p>Results</p> <p>Compared to mitochondrial citrate synthase, SDH activity was severely reduced in NB (n = 14) versus kidney tissue. However no pathogenic mutations could be identified in any of the four subunits of SDH. Furthermore, no genetic alterations could be identified in the two novel SDH assembly factors SDHAF1 and SDH5. Alterations in genes encoding nfs-1, frataxin and isd-11 that could lead to a diminished SDH activity have not been detected in NB.</p> <p>Conclusion</p> <p>Because downregulation of other complexes of the oxidative phosphorylation system was also observed, a more generalized reduction of mitochondrial respiration seems to be present in neuroblastoma in contrast to the single enzyme defect found in hereditary pheochromocytomas.</p