Tumor levels of the mediators of ErbB2-driven anoikis resistance correlate with breast cancer relapse in patients receiving trastuzumab-based therapies.

PURPOSE: Patients with ErbB2/Her2 oncoprotein-positive breast cancers often receive neoadjuvant therapies (NATs) containing the anti-ErbB2 antibody trastuzumab. Tumors that are still present after NATs are resected, and patients continue receiving trastuzumab. These cancers are associated with high relapse risk. Whether relapse will occur cannot be presently reliably predicted. The ability to make such predictions could improve disease management. We found previously that ErbB2 blocks breast tumor cell anoikis, apoptosis induced by cell detachment from the extracellular matrix, by downregulating the pro-apoptotic protein Irf6 and upregulating the anti-apoptotic protein Epidermal Growth Factor Receptor (EGFR) in the cells and, thus, promotes their three-dimensional growth. We now tested whether tumor levels of these proteins before and after NATs correlate with patients' relapse-free survival (RFS) and overall survival (OS). METHODS: We selected archival breast tumor samples collected from 37 women with ErbB2-positive stages II and III breast cancer before and after NATs. We used immunohistochemistry to test whether levels of the indicated proteins in respective tumors correlate with RFS and OS. RESULTS: We observed that the presence of high Irf6 levels in the tumors following NATs correlated with reduced RFS and OS. Perhaps not by coincidence, we noticed that trastuzumab-sensitive ErbB2-positive breast cancer cells selected for the ability to overproduce exogenous Irf6 in culture acquired trastuzumab resistance. Finally, EGFR presence in patients' tumors before or after NATs was associated with decreased RFS and OS. CONCLUSIONS: This study could help identify patients with ErbB2-positive tumors that are at increased risk of disease relapse following NATs.

A pilot study of urinary microRNA as a biomarker for urothelial cancer.

OBJECTIVE: MicroRNAs (miRNAs) are part of a class of small ribonucleic acid (RNAs). They are important regulatory molecules, involved in several cell processes, such as developmental timing, stem cell division and apoptosis. Dysregulated miRNAs have been identified in several human malignancies, including bladder cancer tissue samples, and may confer a "tumour signature" that can be exploited for diagnostic purposes. We report on a prospective pilot study investigating the diagnostic capability of miRNAs in the urine of patients with urothelial cancer. METHODS: Voided urine samples were collected from patients with urothelial carcinoma just prior to bladder tumour resection, as well as age-matched healthy control patients. Pathology demonstrated both low- and high-grade cancer. Total RNA was isolated and quantitative reverse transcriptase-polymerase chain reaction was performed on the RNA extracts using primers for 4 miRNAs shown previously to be dysregulated in solid urothelial carcinomas with RNU6B as the endogenous control. Standard urine cytology was performed on all samples in a blinded fashion. RESULTS: Two miRNAs of interest were dysregulated in the urine from cancer patients with miR-125b showing an average 10.42-fold decrease (p < 0.01) and miR-126 showing an average 2.70-fold increase (p = 0.30) in the cancer samples compared to the normal controls. The sensitivity and specificity of the cytology on the same urine samples were 50% and 80%, respectively. Using these 2 miRNAs only, a decision-tree prediction model was generated for a validation cohort of patients yielding a specificity of 100% and a sensitivity of 80%. DISCUSSION: This preliminary study of candidate urinary miRNA in patients with low- and high-grade urothelial cancer demonstrated a significantly improved diagnostic accuracy over cytology. These results provide rationale for further studies on discovery and validation of candidate miRNAs in voided urine and may potentially lead to the development of a non-invasive and sensitive test for bladder cancer diagnosis and prognosis.

The microRNA-200 family is upregulated in endometrial carcinoma.

BACKGROUND: MicroRNAs (miRNAs, miRs) are small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. MicroRNAs are dysregulated in cancer and may play essential roles in tumorigenesis. Additionally, miRNAs have been shown to have prognostic and diagnostic value in certain types of cancer. The objective of this study was to identify dysregulated miRNAs in endometrioid endometrial adenocarcinoma (EEC) and the precursor lesion, complex atypical hyperplasia (CAH). METHODOLOGY: We compared the expression profiles of 723 human miRNAs from 14 cases of EEC, 10 cases of CAH, and 10 normal proliferative endometria controls using Agilent Human miRNA arrays following RNA extraction from formalin-fixed paraffin-embedded (FFPE) tissues. The expression of 4 dysregulated miRNAs was validated using real time reverse transcription-PCR. RESULTS: Forty-three miRNAs were dysregulated in EEC and CAH compared to normal controls (p<0.05). The entire miR-200 family (miR-200a/b/c, miR-141, and miR-429) was up-regulated in cases of EEC. CONCLUSIONS: This information contributes to the candidate miRNA expression profile that has been generated for EEC and shows that certain miRNAs are dysregulated in the precursor lesion, CAH. These miRNAs in particular may play important roles in tumorigenesis. Examination of miRNAs that are consistently dysregulated in various studies of EEC, like the miR-200 family, will aid in the understanding of the role that miRNAs play in tumorigenesis in this tumour type.

Herpes Simplex Virus Hepatitis in an Immunocompetent Adult: A Fatal Outcome due to Liver Failure.

Objective. To present a case of a healthy 41-year-old female who developed fulminant hepatic failure leading to death. The cause of hepatic failure identified on postmortem exam was herpes simplex virus hepatitis. Design. Observation of a single patient. Setting. Intensive care unit of a tertiary care university teaching hospital in Canada. Patient. 41-year-old previously healthy female presenting with a nonspecific viral illness and systemic inflammatory response syndrome. Intervention. The patient was treated with intravenous fluids and broad-spectrum antibiotics. On the second day of admission, she was found to have elevated transaminases, and, over 48 hours, she progressed to fulminant liver failure with disseminated intravascular coagulopathy, refractory lactic acidosis, and shock. She progressed to respiratory failure requiring intubation and mechanical ventilation. She was started on N-acetylcysteine, a bicarbonate infusion, hemodialysis, and multiple vasopressors and inotropes. Measurements and Main Results. Despite treatment, the patient died roughly 70 hours after her initial presentation to hospital. Her postmortem liver biopsy revealed herpes simplex virus hepatitis as her cause of death. Conclusions. Herpes simplex virus must be considered in all patients presenting with liver failure of unknown cause. If suspected, prompt treatment with acyclovir should be initiated.