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MicroRNAs have Diagnostic and Prognostic Potential in Urinary Bladder Cancer

German researchers have identified four biomarkers that correctly determine malignancy of urinary bladder cancers and contribute to the accurate prediction of patient outcomes. Their results are published in the September issue of The Journal of Molecular Diagnostics.

Current prognosticators of bladder cancer, such as tumor grade, stage, size, and number of foci, have limited usefulness for clinicians since they do not accurately reflect clinical outcomes. Therefore, investigators have been searching for new biomarkers with better diagnostic and prognostic capabilities. Focusing on the role of microRNAs (miRNAs), small non-coding RNAs, researchers have identified four miRNAs that together perfectly discriminated between nonmalignant and malignant tissue, including one alone that classified 81% of the samples correctly. Levels of two miRNAs correlated with overall survival time.

Urinary bladder cancer is the fourth most common cancer in the West. According to the National Cancer Institute, it is estimated that in the United States 72,570 individuals will be diagnosed with and 15,210 will die of cancer of the urinary bladder in 2013. At presentation, in 75% of patients the cancers are confined to the mucosa or submucosa (known as non-muscle invasive bladder cancer, NMIBC), whereas in 25% of cases the cancers have already invaded nearby muscle (muscle-invasive bladder cancer, MIBC).

In a series of experiments, investigators analyzed bladder tissue from patients with NMIBC, MIBC, and nonmalignant bladders. After screening 723 miRNAs by microarray, they selected a subset of 15 distinctively deregulated miRNAs for further validation by real-time quantitative PCR. Seven miRNAs were found to be up-regulated, and eight were down-regulated in malignant bladder tissue samples compared to healthy tissue. Four miRNAs were expressed differently in bladder cancers that invaded muscle compared to those that did not. With one exception, no correlation was found between tumor stage and miRNA levels.

When all 15 of the selected miRNAs were considered together, they correctly classified 100% of tissues as either normal or malignant. Further analysis identified four miRNAs that led to 100% correct classification, and one miRNA (miR-130b) that by itself had an 81% accuracy rate. “These results underline the great potential of miRNAs to serve as diagnostic markers, as previously noted for other urological tumors,” says lead investigator Klaus Jung, MD, the Department of Urology at the University Hospital Charité, Berlin and the Berlin Institute for Urologic Research.

The investigators found that tumor grading could not be correlated with overall survival. Yet, they were able to find two miRNAs that significantly correlated with survival: miR-141 and miR-205. miR-141 showed a trend (P=0.08) of being able to stratify patients with muscle-invasive tumors into two groups with different overall survival times. “This finding could be of clinical importance, but these results must be interpreted cautiously,” says Dr. Jung. “However, previously published studies underline the possible prognostic potential of miRNAs to predict progression and disease-specific or overall survival in bladder cancer patients.”

miRNAs are small non-coding RNAs that contain between 19 and 24 nucleotides. miRNAs regulate gene expression by degrading messenger RNAs or impairing their translation. In recent years there has been a growing interest in miRNAs as potential diagnostic and/or prognostic biomarkers in cancers and other diseases.

Study: miRNA Profiling Identifies Candidate miRNAs for Bladder Cancer Diagnosis and Clinical Outcome [Journal of Molecular Diagnostics]

Source: Elsevier

Clarient, A GE Healthcare Company, Introduces First Lab Developed Test To Assess Multiple Proteins at Single-Cell Level

GE Healthcare recently announced the introduction by Clarient Diagnostic Services, a GE Healthcare Company, of the first lab developed test using MultiOmyx™, a ground-breaking new pathology platform which uses proprietary methodology to assess multiple proteins from a single tissue section at a single-cell level. This test, now available, offers an aid to a pathologist’s diagnosis of CD30-positive lymphoma cases with difficult morphology or otherwise insufficient tissue to adequately evaluate the case.

“In many instances, suspected lymphoma cases are not straightforward, and sample tissue size inadequacy issues further complicate the matter,” said Lawrence Weiss, MD, Medical Director of Clarient. “In difficult to call diagnoses, MultiOmyx gives me great confidence in making the diagnosis and relieves me from the concern of running out of tissue. If I only have a small amount of tissue, I do not have to sacrifice or choose between important markers – I can assess them all.”

The Hodgkin Lymphoma (HL) Profile by MultiOmyx helps to assess nine unique antibodies (CD30, CD15, CD20, CD45, PAX5, OCT2, BOB1, CD3, and CD79A) on a single formalin fixed paraffin embedded tissue section to aid in differential diagnosis of Classical HL.

In clinical validation, this single slide assay called the Hodgkin Lymphoma Profile by MultiOmyx demonstrated high levels of accuracy, diagnostic reproducibility and repeatability, and high sensitivity of all immunofluorescent stains in comparison to traditional immunohistochemistry performed on the same samples. The correlation study identified unique cases where MultiOmyx demonstrated improved performance.

“Traditional pathology uses multiple slices from paraffin-fixed tumor samples and examines them slide by slide, which is less efficient and effective,” said Carrie Eglinton Manner, CEO, Clarient. “Using a single slide may save time, uses significantly less tissue and may provide a more consistent result. Since different parts of a tumor sample can act differently and because less tissue is required, pathologists can access the most accurate and broad tumor analysis available, while eliminating today’s need to prioritize tests due to limited tissue availability.”

The relevance of the MultiOmyx technology was recently confirmed in a clinical paper written by a team of scientists from GE Global Research published in Proceedings of the National Academy of Sciences (PNAS). The paper details the different ways GE is using image data to visualize cancer and the relationship between different biomarkers and the tumor environment and suggests the technology could be broadly applicable to problems in basic biological research, drug discovery and development and companion and clinical diagnostics.

“MultiOmyx provides clinicians and researchers with a novel biomarker multiplexing method to understand biological context in a way that is not possible with other technologies that disrupt the tissue histology. Once cells are removed from the context of their overall microenvironment with other methods valuable information is lost,” said Christine Kuslich, PhD, Chief Science Officer, In Vitro Diagnostics, GE Life Sciences. “MultiOmyx uniquely facilitates the ability to visualize multiple biological pathways, local immune response as well as heterogeneity of expression within regions of interest on a cell-by-cell basis from a single tissue section maintaining tissue context.”

The platform uses fluorescence to provide quantitative analysis of antibodies and allows for up to 60 proteins to be examined on a single tissue sample. It creates a “digital map” of the tumor, giving each cell an “address” and allowing for a clear graphic representation of protein expression. Matching this map to known biosignatures gives researchers a more accurate representation of the exact characteristics of the tumor and may provide clinicians with a clearer view to aid the diagnosis. It also allows them to identify patterns in the tissue by analyzing each cell and biomarker individually, or as a cluster, and thus get a level of understanding of the biological process that could not be achieved via traditional methods.

Study: Highly multiplexed single-cell analysis of formalin-fixed, paraffin-embedded cancer tissue

Source: Business Wire

ColoMarker: Convenient, Low-cost, Early Stage Colon Cancer Blood Test Reports Validation

EDP Biotech, the US-based developer of a blood test to detect the early stages of colon cancer called ColoMarker™, recently announced its plans to commercialize the product and bring the new technology to market. Unlike other diagnostic tests currently in development, the ColoMarker test detects a level of CA11-19 antigen, a specific protein molecule found in the bloodstream. While every human being produces this protein, elevated levels in the bloodstream suggest the presence of colon cancer.

Recent third party validation of ColoMarker™, demonstrating test accuracy of 95 percent, has positioned EDP Biotech to pursue market launch in the near future. To EDP’s knowledge, no other routine sandwich ELISA technology identifies 95 percent of early stage colorectal cancer in blood.

EDP Biotech has partnered with Corgenix Medical Corporation to manufacture ColoMarker™. Corgenix is a world leader in the development and manufacturing of specialized diagnostic kits for more than 20 years. EDP is also aggressively pursuing CE Mark and fully anticipates approval and subsequent commercialization in Europe by the end of this year, followed by a strategic path towards FDA approval.

“We developed ColoMarker because of the critical need to detect cancer at its earliest stages,” says Tom Boyd, CEO of EDP Biotech. “This validation confirms that our technology has strong potential to save thousands of lives each year through early stage detection, and it’s our goal to make it available to diagnostic oncology labs and accessible to medical professionals throughout the world.”

ColoMarker™ has proven to be effective in identifying elevated levels of a biomarker in the bloodstream in 95 percent of early stage colorectal cancers, when the disease is most treatable and survival rates are highest. To date, physicians have relied primarily on colonoscopies and fecal occult blood testing (FOBT) to identify potential cases of early stage colon cancer.

A critical part of EDP Biotech’s research and development of the ColoMarker technology has been the involvement and consultation of some of the world’s most recognized experts in this field:

  • Dr. Gene Overholt – inventor of the scope for colonoscopies and recognized worldwide as the “father of the colonoscopy”
  • Dr. Herbert Fritsche – one of the world’s leading experts on cancer biomarkers and former Chief of Clinical Chemistry at MD Anderson Cancer Center
  • Dr. John Costanzi – internationally-known and considered a leading expert in the treatment of cancer

Recently Dr. Donald Wheeler – author, professor, statistician and renowned quality control expert – also joined EDP Biotech’s scientific advisory board as the company approaches commercialization.

Source: Business Wire

C2N Diagnostics Announces Collaborative Research Agreement with Cambridge Isotopes

C2N Diagnostics (C2N) recently announced that it has signed a collaborative research and a global, exclusive supplier agreement with Cambridge Isotope Laboratories, Inc (CIL). The partnership guarantees C2N’s future access to mass quantities of highly enriched stable isotopes at predictable prices. These stable isotopes are key reagents to C2N’s platform of Stable Isotope Labeling Kinetic (SILK™)-based biomarkers. Such biomarkers are showing considerable promise to detect early Alzheimer’s pathology (i.e., well before the onset of clinical symptoms) as well as to measure treatment responsiveness in preclinical and clinical drug studies.

C2N gains a research partner in CIL that is the premier manufacturer in the world of stable isotopes used in clinical research and diagnostic applications. Under terms of the agreement, C2N receives from CIL an upfront payment, commercial milestone fees, future supply guarantees of stable isotopes at predictable prices, and large quantities of GMP-grade stable isotope (13C6) labeled leucine (L-Leucine). The L-Leucine will be used in future upcoming clinical validation studies involving C2N’s SILK™-based tests. CIL also commits to making significant investment in its own infrastructure and manufacturing processes. This will ensure CIL’s ability to meet the future demand of stable isotopes that will incorporate into C2N’s tests

“We spent considerable time evaluating the options available to C2N for obtaining access to stable isotopes used in our SILK™ tests. The logistics of having adequate supply of these reagents to enable disease screening on large numbers of at-risk individuals are far from trivial. We concluded that CIL is the best-positioned company in the world to meet our future expected demands in terms of both material quantity and material quality,” stated Dr. Joel B. Braunstein, C2N’s CEO. “Stable isotopes are non-radioactive, perfectly safe for people to consume and to the environment, and offer great sensitivity for tracking the in vivo metabolism of proteins implicated in diseases like Alzheimer’s. This makes them highly desirable diagnostic reagents. As we expand the use of our SILK™-based biomarkers beyond research services and into clinical diagnostic applications, CIL will be an instrumental partner to help us qualify our test kits and to produce L-Leucine under GMP scaled-up conditions.”

Dr. Joel Bradley, CIL’s CEO, commented, “By focusing on ways to diagnose and treat early Alzheimer’s disease, C2N is tackling one of the most important challenges in modern medicine. The company is making encouraging progress toward its ultimate goal of offering a convenient screening test for early Alzheimer’s that can be administered in the ambulatory setting. At CIL, we acknowledge the social and commercial impact of C2N’s efforts. For this reason, CIL is privileged and delighted to assist C2N with its development activities and to become C2N’s exclusive supplier of stable isotopes.”

Source: C2N Diagnostics

Study Published in The Journal of Clinical Oncology Demonstrates Advantages of NanoString’s Prosigna Breast Cancer Assay

NanoString Technologies, Inc. (NASDAQ: NSTG), a provider of life science tools for translational research and molecular diagnostic products, recently announced that the TransATAC clinical validation study for its Prosigna Breast Cancer Prognostic Gene Signature Assay, which is based on the PAM50 gene signature, was published in the Journal of Clinical Oncology (JCO). This study, portions of which were initially presented at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium, evaluated the ability of three breast cancer tests to predict risk of distant recurrence after endocrine therapy in postmenopausal women with hormone receptor-positive (HR+) early-stage breast cancer. The authors of the study concluded that the PAM50-based assay provides more prognostic information in endocrine treated patients with HR+ node negative disease than Oncotype DX®, with better differentiation of intermediate and high-risk groups.

The study included 1,017 samples from the landmark ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial of postmenopausal women with HR+ early-stage breast cancer treated with five years of endocrine therapy. The study was performed on RNA extracted from tumor samples by Genomic Health, Inc. for validation of the Oncotype DX® Breast Cancer Assay. The goals of the TransATAC study were to determine if the PAM50 gene signature added prognostic information to clinical-pathological variables and to compare the performance of the PAM50 risk of recurrence (ROR) score, the Oncotype DX recurrence score (RS), and the IHC4 score, derived from immunohistochemical assessment of ER, PR, HER2 and Ki67 genes, in indicating risk of distant recurrence after endocrine therapy. All primary and secondary endpoints of the study were met.

Authors of the study reported that the PAM50 ROR score added prognostic information about the risk of 10-year distant recurrence in addition to that provided by standard clinical-pathological variables in the analysis of all patients studied (p < 0.001). Similar results were achieved in all three prospectively defined clinically important subsets of patients: node-negative (p < 0.001), node-positive (p = 0.002), and HER2-negative (p < 0.001). In addition, the study reported that patients with Luminal A subtype had a lower risk of recurrence than those with the Luminal B subtype further supporting the biological differences between these groups. The authors also concluded that the PAM50 ROR score provided more prognostic information than the widely used Oncotype DX RS. Compared to Oncotype DX RS, PAM50 ROR score categorized fewer patients as intermediate-risk and more as high-risk when using prospectively defined risk cutoffs for low, intermediate and high risk of <10%, 10% to 20% and >20% estimated risk of recurrence, respectively. Moreover, the authors concluded that the PAM50 ROR score provided at least as much information as the IHC4 and may provide more information than IHC4 in the node negative/HER2 negative patient group.

“The publication of the TransATAC study is an important milestone in our ongoing effort to enable genomic testing for breast cancer in local laboratories worldwide,” said Brad Gray, President and Chief Executive Officer of NanoString Technologies. “We look forward to discussing the results and conclusions of this study with oncologists, pathologists, and payers in the European Union and other countries that recognize the CE Mark, as we continue with our commercial launch in those regions.”

Study: Comparison of PAM50 Risk of Recurrence Score With Oncotype DX and IHC4 for Predicting Risk of Distant Recurrence After Endocrine Therapy

Source: Business Wire