MRI-Robot Helps Target Cancer

MRI (magnetic resonance imaging) has recently been demonstrated to help in the diagnosis of prostate cancer, especially in men with a prior negative biopsy or those meeting criteria for active surveillance (See our prior blog on MRI and Active Surveillance). Traditionally prostate biopsies are performed with ultrasound imaging – which is great at targeting the prostate, but not necessarily for finding prostate cancer. Fusing MRI and ultrasound imaging is a recent advance that has helped urologists make use of the precision of MRI for finding tumors and the targeting of ultrasound to sample them.

Fusing MRI and ultrasound images can be complex and does not always work perfectly. If the tumor could be targeted with MRI, the extra step of fusion could be avoided. However, MRI machines make use of extremely strong magnets and metal instruments cannot be near the machine when it is turned on. This makes it impossible to use metal needles or machines with any metal components (including electrical wiring).

Researchers at Johns Hopkins, led by Dan Stoianovici, PhD, Director of the Urology Robotics Program, have developed a completely MRI-compatible robot to target the prostate and cancers within it. The robot makes use of pneumatic system composed of rubber and plastic tubing, screws and gears to manipulate a MRI-compatible needle to target the prostate. "The robotic device mounts on the MRI table alongside the patient. The physician selects a suspicious region that the MRI has shown, and the robot automatically guides the needle to target and presets the depth of insertion."

"To the best of our knowledge, this is the only robot approved by the FDA to operate in the MR environment in general, not only for the prostate."

The MR-bot (MRI-robot) has been approved by the Food and Drug Administration (FDA) and Insitutional Review Board (IRB) of Johns Hopkins for a clinical trial in humans. Urologists Mohamad Allaf, MD and Ashley Ross, MD, PhD, perform the biopsies. The first few cases indicate that robotic biopsy is safe and feasible.


With more precise imaging and techniques, urologists may continue to improve the precision of prostate biopsies. This work was awarded best paper of the Engineering and Urology Society of the American Urological Association.


Read more about the MrBOT at: http://urobotics.urology.jhu.edu/projects/MrBot/





Portions of this story were extracted from "First-Ever MRI Robot Targets Potential Cancer Sites for Biopsy" in Discovery: Volume XI, Winter 2015 by the Patrick C. Walsh Prostate Cancer Research Fund.

Getting closer to an “quantitative” diagnosis of prostate cancer

Histomorphometry is the study of the microscopic organization and structure of tissue in a quantitative manner under the microscope. This process was briefly described in a prior blog, and often involves computer-assisted technology to provide objective measures cellular architecture to aide in diagnosis – a process that is often based on subjective classification of microscopic features.

Most cancers, prostate cancer included, are diagnosed by a pathologist – who examines tissue under a microscope to determine the presence and aggressiveness of a cancer. The future of digital pathology will likely use prostate cancer quantitative histomorphometry using computer-assisted scanned image features and may serve as a new and innovative predictive tool to improve determination of aggressive phenotypes of cancer. In prior work, Dr. Robert Veltri, PhD, of the Brady Urological Institute, demonstrated that a special "spectrophotometer" microscope was accurate and capable of predicting stage, recurrence and progression of prostate cancer when examining portions of prostate cancer slides.[1] 

An original, high-powered image of prostate cancer (a) is segmented into areas of individual nuclei (b), classified into individual sets (c) and segmented by the computer-alogorithm.  From Ali etal [2].

With collaborator, Anant Madabhushi, PhD, and his team at Case Western Reserve University, Dr. Veltri is working to develop new techniques to examine the entire slide image in a high-throughput process. These novel tools could form the basis of future software tools to conduct, in cooperation with the pathologist, automated, rapid and reproducible identification and quantification of tissue histology morphologic and molecular events – enabling machine-based predictions of tumor aggressiveness and outcomes such as recurrence, metastasis and survival.

 
In a recent experiment, Drs. Veltri and Madabhushi examined 80 prostate cancers looking at a variety of cellular features. Through a complex computer algorithm termed adaptive active contour scheme (AdACM), they were able to distinguish features of nuclei, gland architecture, and texture and then identify the best features to discriminate Gleason grade patterns. Using these features, AdACM was able to distinguish Gleason score patterns with an accuracy of 86%.[2]

Different computer-generated features to model architecture of prostate cancer in a core of tissue from a prostate biopsy. From Ali etal [2].

This is just some of the exciting research ongoing at the Brady Urological Institute at Johns Hopkins that will improve the way we diagnose and treat prostate cancer.

 
[1] Ali S, Veltri R, Epstein JI, Christudass C, Madabhushi A.Adaptive energy selective active contour with shape priors for nuclear segmentation and gleason grading of prostate cancer.Med Image Comput Comput Assist Interv. 2011;14(Pt 1):661-9.

[2] Ali S, Veltri R, Epstein JI, Christhunesa Christudass CS, Madabhushi A. Selective Invocation of Shape Priors for Deformable Segmentation and Morphologic Classification of Prostate Cancer Tissue Microarrays. CMIG, December, 2014. dx.doi.org/10.1016/j.compmedimag.2014.11.001

MRI Improves the “Misclassification” of Men with Prostate Cancer Undergoing Active Surveillance

While prostate cancer remains one of 

Active surveillance for prostate cancer: What is it and is it right for me? PART ONE ALL CANCERS ARE NOT CREATED EQUAL PART TWO WHAT DOES IT ENTAIL

the most common cancers  in men in the US, many patients are diagnosed with indolent (or benign-behaving) prostate cancer – cancers that will not affect a man's longevity and do not require treatment. This blog has previously covered the basics of active surveillance (see inset). Over a ten year period of active surveillance, approximately one third of men will undergo a treatment for their prostate cancer. The majority of those men, approximately 70%, elected treatment due to an increased volume of cancer or Gleason score > 6 – indicating the presence of more aggressive cancer.[1] Determining who has high-grade or aggressive prostate cancer at the outset can be challenging based on traditional biopsy techniques. Dr. H. Ballentine Carter, MD, Professor of Urology and Director of the Active Surveillance Program at the Brady Urological Institute explains,

"Misclassification is the problem of relying on a prostate biopsy, which samples only a small fraction of the prostate, to reflect the biology of the entire gland. If a diagnosis of low-grade prostate cancer is made on the prostate biopsy and the patient chooses active surveillance, the risk that a higher-grade, more aggressive cancer is present within the prostate can range from 10 to 30 percent."

MRI (Magnetic resonance imaging) makes use of high-powered magnets and their influence on molecules like water (H2O) to image the body. Multi-parametric MRI (mpMRI) uses complex computer algorithms to differentiate benign from malignant tissue and has demonstrated promise in better identifying patients suitable for active surveillance. This technology relies on three characteristics of prostate cancer cells:

1. Prostate cancer cells are abnormal and can emit MRI signals different than normal tissue
2. Because cancer cells are disorganized relative to normal prostate tissue, surrounding water diffuses through cancerous tissue differently than through normal prostate
3. Cancers form with new blood vessels, these new blood vessels create abnormal diffusion of contrast materials through cancer and normal tissue

In addition, some prostate cancers can hide in areas of the prostate difficult to reach with a standard, transrectal ultrasound-guided biopsy. By assessing all of these characteristics and viewing these "hard to reach places," mpMRI can detect prostate cancers missed on biopsy.

In a recent study of 96 men on active surveillance at Johns Hopkins, Carter, with radiology colleagues Sayed Dianat and Kasia Macura, found that men with a mpMRI abnormality had a cancer 41% of the time, compared to 8% of men with a normal mpMRI. This resulted in a 65% lower risk of adverse pathology on subsequent biopsy if an active surveillance patient had a normal mpMRI.[2] 
"Our group demonstrated that when mpMRI suggested the absence of prostate cancer in a particular area of the prostate, there was a high probability that cancer was absent on multiple biopsies taken from these negative mpMRI areas."

"We are now using mpMRI routinely to help select the most appropriate candidates for active surveillance, and to help reduce the frequency of biopsies."

Therefore, mpMRI can help identify men who truly have low-risk prostate cancer, reducing the "misclassification" of these men and decreasing the number of biopsies needed in the future.

Portions of this story were extracted from "Making Active Surveillance Safer" in Discovery: Volume XI, Winter 2015 by the Patrick C. Walsh Prostate Cancer Research Fund.

 
[1] Tosoian JJ, Trock BJ, Landis P, Feng Z, Epstein JI, Partin AW, Walsh PC, Carter HB. Active surveillance program for prostate cancer: an update of the Johns Hopkins experience. J Clin Oncol. 2011 Jun 1;29(16):2185-90. doi: 10.1200/JCO.2010.32.8112. Epub 2011 Apr 4. http://jco.ascopubs.org/content/29/16/2185.long
[2] Dianat SS, Carter HB, Pienta KJ, Schaeffer EM, Landis PK, Epstein JI, Trock BJ, Macura KJ. Magnetic Resonance-invisible Versus Magnetic Resonance-visible Prostate Cancer in Active Surveillance: A Preliminary Report on Disease Outcomes. Urology. 2015 Jan;85(1):147-54. doi: 10.1016/j.urology.2014.06.085. Epub 2014 Oct 16. http://www.goldjournal.net/article/S0090-4295(14)00915-7/abstract

“Lighting up” Prostate Cancer

Prostate cancer is notoriously difficult to image. In fact, traditional imaging technologies like CT (computerized tomography) and ultrasound are useless for clinically-localized disease (cancer still in the prostate). These technologies can find the prostate, but cannot reliably distinguish cancer from normal prostate gland. Recently, improvements in MRI (magnetic resonance imaging) have made this technology more useful for the diagnosis of localized prostate cancer. While the role of MRI in localized prostate cancer is being determined, the only useful imaging technologies are for patients with advanced and metastatic disease. For instance, CT scan (or MRI) can detect enlarged lymph nodes and nuclear medicine (bone) scans can find cancer that has spread to bones.

Even PET (positron emission tomography) imaging – which can detect many other cancers – is useless in prostate cancer. PET imaging makes use of a labelled glucose molecule that is taken up by rapidly dividing and growing cancer cells. Unfortunately prostate cancer is slow growing and does not pick up the glucose molecule to make it detectable.

Martin Pomper, MD, PhD

Researchers at the Brady Urological Institute and Johns Hopkins may be onto a new way to image prostate cancer using molecular genetics and PET imaging. Martin Pomper, MD, PhD, works with nanoparticle imaging technologies that preferentially bind to prostate cancer cells and emit a signal that can be detected. Instead of using a glucose pathway, Dr. Pomper has developed a nanoparticle that binds to PSMA (prostate specific membrane antigen), a protein overexpressed on prostate cancer cells. The nanoparticle sensor "only becomes activated when it encounters malignant cells, but not normal tissue, so that cancer and its metastases can be detected anywhere in the body."

PSMA-based PET imaging of a mouse model with prostate cancer tumor (yellow arrow) implanted
in the forearm of the mouse. The urinary system (kidneys, kid; bladder, bl) are also visualized in the
early imaging as the molecule is filtered by the urine. From Chen et al. [1]

Over several years, Dr. Pomper has worked to refine the molecule and technology used to image prostate cancer in the prostate and around the body. His work has been published in Nature Medicine and Cancer Research. Stay tuned as in human studies are in progress.

 
Portions of this story were extracted from "Molecular-Genetic Imaging Shows Individual Prostate Cancer Cells" in Discovery: Volume XI, Winter 2015 by the Patrick C. Walsh Prostate Cancer Research Fund.


 

 
[1] Chen Y, Pullambhatla M, Foss CA, Byun Y, Nimmagadda S, Senthamizhchelvan S, Sgouros G, Mease RC, Pomper MG. 2-(3-{1-Carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid, [18F]DCFPyL, a PSMA-based PET imaging agent for prostate cancer. Clin Cancer Res. 2011 Dec 15;17(24):7645-53. doi: 10.1158/1078-0432.CCR-11-1357. Epub 2011 Oct 31.

New Urine Test Shows Promise for Bladder Cancer

The majority of the 300,000 bladder cancers detected in the US each year are non-invasive bladder cancers, and, in general, are not dangerous. However, most of these patients will have recurrences and some will develop muscle-invasive, potentially fatal bladder cancer. Predicting who will "progress" to invasive disease is almost impossible and surveillance involves invasive testing including cystoscopy and biopsies of the bladder. 

Trinity J. Bivalacqua. MD, PhD

Trinity J. Bivalacqua, MD, PhD, Director of Urologic Oncology at the Brady Urological Institute explains, "Because of the high rate of tumor recurrence, we have to perform frequent follow-up cystoscopy procedures, but this results in an unacceptable rate of invasive procedures and ballooning costs." A new urine test developed at Johns Hopkins may become part of the arsenal in detecting new and recurrent bladder cancer.

Mutations in the promoter of the telomerase reverse transcriptase (TERT) gene have been demonstrated in upwards of 66% of muscle-invasive urothelial cancers of the bladder and is the most frequently mutated gene in advanced bladder cancers.[1,2] George Netto, MD, a genitourinary pathologist at Johns Hopkins states, "These are the most common genetic alterations ever identified in early bladder cancer."

The TERT promoter gene.  From Kinde et al. [3].

George Netto, MD

Researchers from the Brady Urological Institute, including Drs. Bivalacqua and Netto with collaborators from the Ludwig Cancer Research team, investigated 76 patients with a variety of bladder cancers. The looked at TERT mutations in early tumors from these patients and in follow-up urine samples as they monitored these patients for progression. They found a high rate of TERT promoter mutations in most (approximately 75%) tumors, including both papillary and flat lesions; and tumors of low- and high-grade nature. More importantly, among patients whose tumors harbored TERT promoter mutations, the same mutations were present in follow-up urines in seven of eight patients that recurred but in none of the six patients that did not recur – indicating that TERT may be a strong indicator of patients likely to recur!

"These exciting results strongly support the potential future analysis of TERT promoter mutations as a urine test that can facilitate the early diagnosis of bladder cancer, before it spreads deep into the bladder wall, in patients at high risk for disease progression. The test will also give us a non-invasive alternative to the many follow-up procedures we currently need to monitor our patients for recurrence of bladder cancer. This test has great potential to save many lives."

This work was published in Cancer Research.[3]

The story was extracted from:

"Urine Test Detects New, Recurrent Bladder Cancer" in Johns Hopkins Urology: News for Physicians, Winter 2015 by Johns Hopkins Medicine.

"Can Urine Test Can Detect Bladder Cancer Early" in Discovery: Volume XI, Winter 2015 by the Patrick C. Walsh Prostate Cancer Research Fund.

 
[1] Horn S, Figl A, Rachakonda PS, Fischer C, Sucker A, Gast A, et al. TERT promoter mutations in familial and sporadic melanoma. Science 2013;339:959–61.
[2] Killela PJ, Reitman ZJ, Jiao Y, Bettegowda C, Agrawal N, Diaz LA Jr., et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci U S A 2013;110:6021–6.
[3] Kinde I, Munari E, Faraj SF, Hruban RH, Schoenberg M, Bivalacqua T, Allaf M, Springer S, Wang Y, Diaz LA Jr, Kinzler KW, Vogelstein B, Papadopoulos N, Netto GJ. TERT promoter mutations occur early in urothelial neoplasia and are biomarkers of early disease and disease recurrence in urine. Cancer Res. 2013 Dec 15;73(24):7162-7. doi: 10.1158/0008-5472.CAN-13-2498. Epub 2013 Oct 11.

Noncoding RNAs and RNA therapeutics in prostate cancer

There is a new frontier in cancer and biology which focuses on the non-conventional role and use of RNAs. RNA stands for ribonucleic acid. Traditionally RNA has been viewed as a simple messenger that translates genetic information from our DNA (deoxyribonucleic acid) into proteins that are used by the cells in our body. Over the last several decades, however, new roles for RNA have been discovered that go well beyond the simple beauty of protein coding. For instance, there are segments of RNA that do not carry a code for a protein, but instead act by influencing how the information in DNA and RNA is used. These segments are called "non-coding" RNA segments. In addition to these natural non-coding RNAs, new techniques have been evolved to artificially generate RNAs as novel cancer diagnostic, prognostic and therapeutic agents. Here we review some of these new discoveries and technologies, including long noncoding RNAs, microRNAs and RNA aptamers, and how they are being applied to prostate cancer research at the Brady Urological Institute.

In a cell, DNA is "translated" by RNA into proteins that can be used by the cell throughout the body.
From http://exploringorigins.org/rna.html

It is incredible to think that it has only been 50 years since the genetic code was cracked [1]. These breakthrough discoveries taught us how information locked in DNA sequences can code for the specific synthesis of protein components in cells, tissues and organisms. In fact, much of our understanding about cancer biology today stems from the discovery of mutations (or alterations) in protein-coding genes, and how the resulting protein products can drive cancer development, progression, and metastasis [2]. Importantly, these critical discoveries may only be the tip of the iceberg. It is estimated that coding genes (the genes which code for the ~20,000 human proteins) only account for ~1.5% of the three BILLION nucleotides of sequence information in the human genome. Within the last decade a major effort has begun to identify and characterize the other types of codes that exist in the remaining 98.5% of the human genome [3].

One class of genes which do not code for protein products are called noncoding RNAs (ncRNAs). This gene class includes long noncoding RNAs (lncRNAs) and microRNAs (miRNAs), both of which have been implicated in cancer [4, 5]. Long noncoding RNAs are over 200 nucleotides (or building blocks of DNA and RNA) in length and may perform a variety of functions which include the regulation of DNA organizational density in chromosomes and the regulation of gene expression. The exact mechanisms of lncRNAs are diverse, and most have not yet been fully characterized. MicroRNAs, on the other hand, are smaller RNAs which primarily function as RNA interference agents, to block the synthesis of proteins encoded by specific coding genes. The 1998 discovery of this fundamental RNA interference pathway was so instrumental in biology and medicine that it quickly led to a Nobel Prize in 2006 [6].

 

Long non-coding RNA: PCA3

In the field of urology, there is one well known long non-coding RNA called PCA3 (also known as DD3). This RNA was originally discovered at the Brady Urological Institute in the laboratory of William Isaacs, through a molecular biology screen designed to find genes that are differentially expressed in healthy and cancerous prostate tissues [7]. Surprisingly, PCA3 did not appear to encode for a protein. Thus, it could not be detected by traditional laboratory assays such as ELISA or immunohistochemistry. Moreover, as such a unique noncoding RNA at the time, it had been difficult to determine its biological function. In fact, the specific function of PCA3 in prostate cancer remains unclear. Nonetheless, it has become a useful new RNA-based marker in the urine of potential prostate cancer patients [8-10]. The high prostate cancer specificity of PCA3 can be helpful in predicting or negating the presence of prostate cancer in a patient with a high PSA, but an initially negative biopsy. In addition to PCA3, several other lncRNAs are being studied around the world in prostate cancer biology. These include PCGEM1, PCAT1, and SchLAP1 [11].

 

MicroRNA: miR-21

MicroRNAs are the physically smaller class of ncRNAs. They too have been broadly studied in prostate and other cancers. Currently, there are over 1,000 known human microRNAs, each of which is predicted to regulate hundreds to thousands of protein coding genes [12]. MicroRNAs can regulate gene expression because they contain small pieces of genetic code that block the synthesis of RNA-encoding proteins – they do this by forming double-stranded RNA structures (similar to DNA) that prevent the information from being passed along [6]. This complex network of gene expression and microRNA gene regulation has been described as a possible buffering system to balance the diversity of ongoing gene expression and to fine-tune pathway activities [13].
A number of miRNAs have been observed to be differentially expressed in healthy versus cancerous tissues. Moreover, the forced expression or inhibition of specific miRNAs has been found to contribute to cancer cell growth and survival. We recently discovered that a series of microRNAs are involved in the androgen receptor signaling pathway, which is the major target of androgen deprivation therapies (ADT) for men with advanced prostate cancer. The expression of one microRNA, miR-21, was found to stimulate prostate cancer growth and to be sufficient to cause castration resistance [14, 15]. Other studies, by Angelo De Marzo's laboratory, have identified miR-26a and miR-26b, as possible signaling molecules in prostate cancer initiation and progression [16]. Dr. Ted Schaeffer's laboratory has also bioinformatically studied how miRNAs may regulate the complex gene expression patterns that occur during prostate development and early prostate carcinogenesis [17].
In addition to these functional studies, our group has recently investigated three miRNAs that have been previously reported to be differentially expressed in prostate cancer. The goal was to determine the association of miRNA expression with prostate cancer recurrence after surgery. The levels of these three miRNAs were measured in tumor tissue from 118 archived radical prostatectomy tumor specimens, for which we had long-term follow up for disease recurrence. The samples were matched by patient age, race, stage, and Gleason grade, but only half eventually recurred after surgery. The results of the study found that lower levels of one miRNA, miR-221, were associated with a higher risk of disease recurrence after surgery [18]. These preliminary results suggest that miR-221 may be useful in primary prostate cancer prognosis; however, these findings must be validated by several independent studies and with larger patient populations. In addition to the above mentioned miRNAs, several other miRNAs are being globally studied in prostate cancer biology [11]. These include miR-125, miR-141, miR-34a, miR-101, miR-15/16, and miR-106b.

 

RNA aptamers:

Additional classes of RNA are being applied to prostate cancer experimental therapeutics research here at the Brady. What separates these RNAs from the above discussed RNAs is that they are artificial in nature; in other words they are manmade and are not naturally found in the wild. The first type of molecule is known as an RNA aptamer [19]. These RNA-based molecules can be selected from high diversity libraries, starting with over 10¹⁴ (a quadrillion) different aptamer molecules, to identify a few specific aptamers that tightly bind to a target protein or cellular component, much in the same way that a key fits tightly into a lock [20, 21]. Importantly, because these aptamer molecules are manmade, they can be modified so that they can be applied as stable pharmacologic agents. For example, there is one RNA aptamer that is clinically approved and applied for the treatment of macular degeneration [22]. In 2002, we reported the development of new RNA aptamers that can target prostate cancer cells through an abundant cell surface protein called PSMA (Prostate Specific Membrane Antigen) [23]. These aptamers were reported as nucleotide sequences, which could then be easily read and synthesized by other investigators interested in developing prostate-targeted agents. A series of promising aptamer-targeted research strategies were then reported by many independent laboratories using the described prostate-targeted aptamer sequences. One approach combined the PSMA-targeting RNA aptamers with another artificial RNA-based agent, called small interfering RNAs or siRNA [24, 25]. These small interfering RNAs act through the natural RNA interference pathway, described above, to bind and degrade the messenger RNA of a specific gene, ultimately inhibiting its protein synthesis [6]. In this way a cancer promoting pathway can be selectively shut down in prostate cancer cells. Our laboratory, in collaboration with Ted DeWeese and the Department of Radiation Oncology and Molecular Radiation Sciences at Johns Hopkins, has taken this aptamer-targeted RNA interference approach to target DNA repair pathways in prostate cancer cells [26]. The goal is to selectively make prostate cancer cells more susceptible to ionizing radiation therapy, by inhibiting their ability to repair radiation-induced DNA damage, while sparing non-prostatic cells and tissues from similar radiation sensitization. The results of these studies have been promising and new research is ongoing. Although, it is important to note that these studies are currently experimental in nature and are not yet ready for use in the clinic.

In summary, a new frontier in RNA-based research and therapeutics is rapidly developing. There are many opportunities to exploit these RNAs and pathways in prostate cancer research, diagnostics, prognostics, and therapeutics. Our research teams at the Brady are exploring these cutting edge fields for new discoveries.

 
This blog was written by Shawn Lupold, PhD, Associate Professor of Urology and Oncology; Co-Director of the Sidney Kimmel Comprehensive Cancer Center Prostate Cancer Program; and member of Radiation Oncology and Molecular Radiation Sciences and Johns Hopkins Institute for NanoBioTechnology.

 

 

 

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10. Crawford, E.D., et al., Diagnostic performance of PCA3 to detect prostate cancer in men with increased prostate specific antigen: a prospective study of 1,962 cases. J Urol, 2012. 188(5): p. 1726-31.
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26. Ni, X., et al., Prostate-targeted radiosensitization via aptamer-shRNA chimeras in human tumor xenografts. J Clin Invest, 2011. 121(6): p. 2383-90.

Looking to Identify Men with High-Risk Prostate Cancer Early

Robert Veltri, PhD

Some men are diagnosed with small, low-risk prostate cancers and choose active surveillance. "However, some of these low-risk cancers may harbor molecular or other very subtle nuclear morphological features of size & shape in more aggressive cancer," says Robert Veltri, Ph.D., Associate Professor of Urology and Director of the Fisher Biomarker and Repository Laboratory at the Johns Hopkins University School of Medicine. "If these men could be identified early, we could eradicate their cancer when the disease burden is low." Morphologic features refer to the size, shape and consistency of the nucleus (or center) of a given cell.

The red flags that signal more aggressive disease early-on are extremely tiny, for example, subtle nuclear morphological alterations within the cancer cell, or differences in the levels of specific cancer-related proteins. Veltri, working with Brady Urology Institute urologists, Alan Partin, M.D., Ph.D. and H. Ballentine Carter, M.D.; and a world's expert pathologist, Jonathan I. Epstein, MD, has used highly sophisticated methods to analyze very small prostate biopsy tissue samples for ways of identifying men who appear to have more aggressive disease. Dr. Veltri is looking for a "signature" of aggressive disease that can be spotted at a diagnostic biopsy and his research is funded by the Early Detection Research Network of the National Cancer Institute and a Department of Defense.

Morphology versus morphometry for adenoma assessment. Morphometric measurements performed by quantitative, digitalized assessment of histopathology slides compared with regular pathology assessment through the microscope.  From http://www.medscape.com/viewarticle/703573_5 

Previously, Dr. Veltri demonstrated that DNA content of cancer cells and the levels of (-7)ProPSA (a precursor molecule to PSA) in biopsy tissue could predict those men selected for active surveillance that would fail.[1] Currently, he is seeking a morphologic and molecular "signature" to separate less aggressive from more aggressive prostate cancer. Veltri has analyzed 80 cases of prostate cancer that were stratified by Gleason score and also biopsy samples from 70 men on active surveillance who turned out to have aggressive cancer, and from 70 men who had mild, slow-growing disease, and came up with a test.

"The results indicate we have developed an integrated, quantitative histomorphic and molecular biomarker-based predictor for the early detection of clinically more aggressive prostate cancer," he says. These preliminary results were reported by Dr. Guangjing Zhu, a post-doctoral fellow at the annual American Association for Cancer Research's annual meeting San Diego.

 
[1] Isharwal S, Makarov DV, Sokoll LJ, Landis P, Marlow C, Epstein JI, Partin AW, Carter HB, Veltri RW. ProPSA and diagnostic biopsy tissue DNA content combination improves accuracy to predict need for prostate cancer treatment among men enrolled in an active surveillance program. Urology. 2011 Mar;77(3):763.e1-6. doi: 10.1016/j.urology.2010.07.526. Epub 2011 Jan 8.

Hopkins Researchers Contribute to "Molecular Family History" for Prostate Cancer

Two of the biggest risk factors for prostate cancer are family history and ancestry. Men of Northern European and African descent have the highest risk of being diagnosed with cancer and aggressive prostate cancer, while a number of studies demonstrate that Asian men may have a lower risk of prostate cancer. Recent improvements in technology make assessment of a person's genome (or genetic code) more facile and affordable. One such method examines SNP (single nucleotide polymorphisms) as they vary from person-to-person and group-to-group. This is a method of "DNA fingerprinting" used by many forensic investigators. Evaluating SNP over a large population can provide data to locate changes in the genome that put a population at risk of prostate cancer. A number of studies have examined SNP in populations of European descent, African-Americans, Japanese and Latino patients.[1-7]

A recent study, in which researchers from Johns Hopkins participated, combined data from a number of these populations to find common genetic causes of prostate cancer around the world. The study combined data on over 87,000 men and found 23 new genetic variants that increase a man's risk of prostate cancer. These variants are found in "non-coding" portions of the genome – DNA regions that regulate genes rather than actually make proteins in the body. It is believed that these variants in the genome explain 33% of the familial risk of prostate cancer.

William Isaacs, PhD and Alan Partin, MD, PhD

William B. Isaacs, PhD, Professor of Urology and Oncology led the Hopkins initiative with Chairman of the Brady Urological Institute, Alan W. Partin, MD, PhD. Dr. Partin commented, "Inheriting any single one of these genetic variants has only a small effect of prostate cancer risk. However, a subset of men will inherit many of these variants, putting them at substantially increase risk for the disease, from three to six times the population average. Men with these risk levels may benefit from disease screening at earlier ages."

Dr. Isaacs states, 

the identification of prostate cancer-related SNPS could serve as a "molecular family history" to enable better screening guidelines and therapies.

The entire manuscript can be found in the March, 2014 issue of Nature Genetics.[1]


Al Olama, A.A., et al., A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer. Nat Genet, 2014. advance online publication.

Quotations from this blog are from the press release, "Large Study Reveals New Genetic Variants that Raise Risk for Prostate Cancer," from Johns Hopkins Medicine and Vanessa Wasta.

REFERENCES
[1] Eeles, R.A. et al. Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array. Nat. Genet. 45, 385–391 (2013).
[2] Eeles, R.A. et al. Multiple newly identified loci associated with prostate cancer susceptibility. Nat. Genet. 40, 316–321 (2008).
[3] Gudmundsson, J. et al. Genome-wide association and replication studies identify four variants associated with prostate cancer susceptibility. Nat. Genet. 41, 1122–1126 (2009).
[4] Schumacher, F.R. et al. Genome-wide association study identifies new prostate cancer susceptibility loci. Hum. Mol. Genet. 20, 3867–3875 (2011).
[5] Thomas, G. et al. Multiple loci identified in a genome-wide association study of prostate cancer. Nat. Genet. 40, 310–315 (2008).
[6] Cheng, I. et al. Evaluating genetic risk for prostate cancer among Japanese and Latinos. Cancer Epidemiol. Biomarkers Prev. 21, 2048–2058 (2012).
[7] Haiman, C.A. et al. Characterizing genetic risk at known prostate cancer susceptibility loci in African Americans. PLoS Genet. 7, e1001387 (2011).

Brady Presentations at the Mid-Atlantic American Urological Association Meeting, 2014

The Mid-Atlantic Section of the American Urological Association has met annually since 1941. This year the meeting is in Baltimore and offers the opportunity for urologists in practice, small and large hospitals to meet, share ideas and build lasting relationships. This year the Brady Urological Institute is well-represented. Some of the highlights include:

Arthur L. Burnett, MD, MBA

• A special topic lecture by Arthur Burnett on the "Efficacy of Early Penile Rehabilitation Following Radical Prostatectomy: Myth or Reality," Thursday, 3pm.
• Point/Counterpoint sessions led by:
  • Stephen Schatz on Endoscopic Management of BPH, Friday, 10:45am
  • Trinity Bivalacqua on BCG Refractory Superficial Bladder Cancer, Friday, 4:00pm
• Video Case Discussion of laparoscopic and robotic complications by Christian Pavlovich and Misop Han

In addition, faculty members, research fellows and residents will be giving over 25 podium and poster presentations over the course of three days. 

A full schedule of the Brady events are listed below.
To see the full listing of presentations and abstracts click here. 

ThurSDAY, September 18

SCIENTIFIC SESSION 1: 2-3pm

6. Percent Lymph Node Involvement Predicts Mortality after Inguinal Lymph Node Dissection for Penile Cancer. Mark W. Ball, Joan Ko, Deborah Kaye, George Netto, Stephania Bezerra, Arthur L Burnett, Trinity Bivalacqua.

MODERATED POSTER SESSION 1: 2-3pm

MP7.     Sickle Cell Disease in Priapism: Disparities in Care? Gregory A. Joice, Max Kates, Nikolai Sopko, Johanna Hannan, Trinity Bivalacqua.
MP9. Quantification of Feulgen Stain (DNA) Nuclear Morphometry Predicts Prostate Cancer Aggressiveness. Aniq ur rehman Gajdhar, Guangjing Zhul, James E. Verdone, Christine Davis, Jonathan I. Epstein, Robert W. Veltri.
MP11.     A Human Prostatic Bacterial Isolate Alters the Prostatic Microenvironment and Accelerates Prostate Cancer Progression. Brian W. Simonsl, Nicholas M. Durham, Tullia Bruno, Joseph Grosso, Anthony Schaeffer, Ashley E. Ross, Paula Hurley, David M. Berman, Charles G. Drakel, Praveen Thumbikaf, Edward M. Schaeffer.

DISPLAY POSTERS: 2P-8P

P5. Rnaseh2a Roles In Regulating Prostate Cancer Cell Cycle And Survival. Zhenhua Huang, Sr., Edward Schaeffer, Sr., Ashley Ross.
P15. Priapism Impact Profile (PIP) Questionnaire: Development and Initial Evaluation. Arthur L Burnett, Uzoma A. Anele, Irene N. Trueheart.
P17. Identification of Men With The Highest Risk of Early Disease Recurrence After Radical Prostatectomy. Debasish Sundi, Vinson Wang, Phillip M. Pierorazio, Misop Han, Alan W. Partin, Phuoc Tran, Ashley E. Ross, Trinity Bivalacqua.
P19. Robotic Retroperitoneal Lymph Node Dissection for Clinical Stage I NSGCT: Initial Study of Feasibility and Comparative Analysis. Mark W. Ball, GautamJayram, MichaelA. Gorin, Phillip M. Pierorazio, Mohamad E. Allaf.
P20. Grade Reclassification on Active Surveillance: Age Matters. Jeffrey Tosoian, Bruce Trock, Max Kates, Patricia Landis,Jonathan I. Epstein, H. Ballentine Carter.
P23. National Resource Utilization In Radical Cystectomy For Bladder Cancer. Jen Jane Liu, Nilay Gandhi, Christian Pavlovich, Trinity Bivalacqua.
P24. Glycolysis Is Necessary For Cell Motility And Cytoskeleton Remodeling In Epithelial To Mesenchymal Transition In Prostate Cancer Cells. Takumi Shiraish P,Jessie Huang, James E. Verdone, James Hernandez', Steven M. Mooney, StevenS. An, Kennth J. Pienta.
P25. Predicting the Risk of Non Organ Confined Prostate Cancer When Perineural Invasion Is Found on Biopsy. Michael A. Gorin, Heather Chalfin, Jonathan I. Epstein, Zhaoyong Feng, Alan W. Partin, Bruce Trock.
P27. Secondary Re Closure in Classic Bladder Exstrophy: The Johns Hopkins Experience. Brian M. Inouye, Heather N. DiCarlo, Ezekiel E. Young, Ali Tourchi,John Gearhart.

SPECIAL TOPIC LECTURE: 3-345p

"Efficacy of Early Penile Rehabilitation Following Radical Prostatectomy: Myth or Reality" -- Presenter: Arthur Burnett, M.D.

SCIENTIFIC SESSION 2: 330-4pm

8. 5-year Analysis of A MultiInstitutional, Prospective Clinical Trial of Delayed Intervention And Surveillance For Small Renal Masses: The Dissrm Registry. Phillip M. Pierorazio, MichaelA. Gorin, Mark W. Ball, Bruce Trock, Mohamad E. Allaf.
14. Do PreBiopsy Rectal Swabs for FluoroquiQolone Resistance Reduce Prostate BiopsyRelated Infections? Jason E. Michaud, Aniq Gajdhar, Lucinda Robinson, Stephen M. Schatz, Pravin K. Rao, E. James Wright, Christian P. Pavlovich.

MODERATED POSTER SESSION 2: 3:45-4-45pm

MP14. Phenotypic Heterogeneity in Small Renal Masses. Mark W. Ball, Stephania Bezerra, Michael A. Gorin, Christian P. Pavlovich, Phillip M. Pierorazio, George]. Netto, Mohamad E. Allaf.
MP16. Risk Factors for IntraProstatic Incision Into Malignant Glands at Radical Prostatectomy Nathaniel Readal, SungWoo Park, Bruce Trock, Elizabeth Humphreys, Jonathan I. Epstein, Alan W. Partin, Misop Han.
MP17. Predict Prostate Cancer Aggression with Multiple Biomarkers Using a Novel Quantitative Tissue Immunoassay. Guangjing Zhul, Zhi Uu, Christhunesa S. Christudass,Jonathan I. Epstein, Hui Zhang, Joon Yong Chung, Stephen M. Hewitt, Robert W. Veltri.
MPI5. Erectile Dysfunction after Recurrent Ischemic Priapism in Patients With and Without Sickle Cell Disease: A Characterization and Comparative Analysis of Risk Factors. Uzoma A. Anele, Irene N. Trueheart, Arthur L Burnett.
MP22. The Financial Impact of Robotic Technology for Partial and Radical Nephrectomy. Max Kates, Mark W. Ball, Hiten D. Patel, Michael A. Gorin, PhillipP. Pierorazio, Mohamad E. Allaf.
MP24. Increased a actin and TGFj31 Levels in Bladder Exstrophy Smooth Muscle Cells. Ezekiel E. Young', Eric Z Massanyi, Heather DiCarlo, Brian Inouye, John P. Gearhart, Larissa A. Shimoda.

FRIDAY, September 19

SCIENTIFIC SESSION 3: 745-9am

21. Long:-term Erectile Function Outcomes of Patients In A Randomized Controlled Trial of Nightly Vs OnDemand Penile Rehabilitation With Sildenafil After Nerve sparing Radical Prostatectomy. Nilay M. Gandhi, Lynda Z. Mettee, Zhaoyong Feng, Bruce Trock, Christian P. Pavlovich.
22. Variability in Medicare Utilization and Payment Among Urologists. Joan S. Ko, Heather Chalfin, Bruce Trock, Zhaoyong Feng, Elizabeth Humphreys, Sung-Woo Park, H. Ballentine Carter, Misop Han.

POINT-COUNTERPOINT: 1045-1130am

Endoscopic Management of Benign Prostatic Hyperplasia (BPH):Greenlight KTP laser vs. Bipolar TURP -- Moderator: Stephen Schatz, MD
Greenlight KTP: Gregg Eure, M.D. Urology of Virginia, Virginia Beach, VA
Bipolar TURP: William Jaffe, M.D. Penn Presbyterian Medical Center, Philadelphia, PA

VIDEO CASE PANEL DISCUSSION: 2-3pm

Management of Intraoperative Laparoscopic and Robotic Complications (or what to do when the sh.. hits the fan)
Moderators: Misop Han, M.D., Johns Hopkins Hospital, Baltimore, MD; Christian Pavlovich, M.D., Johns Hopkins, Baltimore, MD
Panelists:
David Chen, M.D., Fox Chase Cancer Center, Rockledge, PA
Costas Lallas, M.D., Thomas Jefferson University, Philadelphia, PA
Thomas Jarrett, M.D., George Washington University, Washington, DC

SCIENTIFIC SESSION 4: 3-4pm

25. Robotic Simple Prostatectomy for Symptomatic Large-Gland BPH: Safety, Feasibility, and Comparative Analysis. Mark W. Ball, GautamJayram, Christian P. Pavlovich, Misop Han.
28. Neoadjuvant Chemotherapy Prediction of Extravesical Cancer Control Based Off Pathologic Staging. Nilay M. Gandhi, Alex Baras,Jen Jane-Uu, Mark Schoenberg, George Netto, Trinity Bivalacqua.
30. African American Race is Associated with Adverse Oncologic Outcomes Following Prostatectomy: LongrTerm Follow Up. Farzana Faisal, Debasish Sundi, Ashley     Ross, Elizabeth R Humphreys, Alan W. Partin, Misop Han, Edward M. Schaeffer.

POINT-COUNTERPOINT: 4-445pm

BCG Refractory Superficial Bladder Cancer: Early Cystectomy vs.Salvage Intravesical Therapy
Moderators: Matthew Kaag, M.D., Penn State Hershey Medical Center, Hershey, PA
Early Cystectomy: Thomas Guzzo, M.D., University of Pennsylvania, Philadelphia, PA
Salvage Intravesical Therapy: Trinity Bivalacqua, M.D., Ph.D., Johns Hopkins Medical Center, Baltimore, MD

Defining the Immune Response in Cavernous Nerve Injury after Radical Prostatectomy

Schematic cross section in the mid-prostate demonstrating the
neurovascular bundle (NVB) and technique of high-anterior
release to prevent "traction" nerve injury.  From Nielsen etal,
High Anterior Release of the Levator Fascia Improves
Sexual Function Following Open Radical Retropubic
Prostatectomy, Journal of Urology, 182 (2), 2008.

The discovery of neurovascular bundle and the establishment of nerve-sparing radical prostatectomy enabled preservation of erectile function after radical prostatectomy (RP) [1,2,3]. Nonetheless, 9%-86% of men undergoing RP will still experience some degree of erectile dysfunction (ED) following RP [4]. A major cause of post-operative ED following RP is cavernous nerve (CN) injury from surgical maneuvers. Traditionally CN injury was believed to be caused by direct transection, crush injury or electrical injury from cautery. More recently, surgical "maneuvers" such as excessive traction or torque have been implicated in CN injury. Therefore, mitigating CN injury and CN regeneration are keys to regain potency.

The immune system is believed to play a major role in repair mechanisms following CN injury. Inhibiting inflammation and the inflammatory response may prevent injury and neurological deficits. In addition, genes involved in injury and repair of the major pelvic ganglion (MPG, the source of the nerves that control erections) in response to CN injury may serve as therapeutic targets for new medications or treatments. Several significant molecular themes have been identified in the immune mechanism of CN injury including transcriptional regulation, chemokines, oxidative stress, apoptosis, and inflammatory cytokines. A number of these cytokines, including tumor necrosis factor alpha (TNF-α), transforming growth factor beta (TGF-β), and chemokines related to macrophage induction including monocyte chemoattractant protein-1 (MCP-1) have been investigated as therapeutic targets. A prior study from the Brady Urological Institute led by Johanna Hannan, PhD, demonstrated a temporal increase in neuroinflammation in the MPG following CNI that was mediated by cytokines (TNF-α, TGF-β) and macrophages (M1 and M2) that may result deleterious effects on neuronal cell survival and nerve regeneration.[6] To further investigate these mechanisms, it is hypothesized that an increase in TNF-α in the MPG and subsequent neuroinflammation contribute to impaired CN regeneration.

Model of cavernous nerve injury in the male rat.
From pelvipharm.com.

To test this hypothesis, researchers at the Brady Urological Institute have created and use an animal model to investigate post-operative ED following RP – the male rat with bilateral cavernous injury (BCNI) [5]. Under general anesthesia, a rat's prostate is exposed via mid-line abdominal incision. The CN and the major pelvic ganglion (MPG), which projects the CN, are located posterolataral to the prostate. To create a rat with BCNI, the CN of each side is crushed with forceps.

A total of six MPGs were harvested from 3 control rats and cultured in Matrigel® with (n = 3) or without TNF-α (20 ng/mL, n=3). Neurite outgrowth length was measured 48 and 72 hours after culture and indicates the animals ability to regenerate injured nerves. We measured the longest neurites in each area (25-40 neurites / MPG) and compared the averages to evaluate the effect of exogenous TNF-α on neurite outgrowth from MPGs.

Average neurite lengths of MPGs cultured with TNF-α at 48 and 72 hours were significantly shorter than those of the control group (329±12.2 μm and 384±13.1 μm, p<0.01 at 48 hours; 369±14.5 and 462±20.0 μm, p<0.01 at 72 hours) (Figure 1). These results demonstrate that exogenous TNF-α treatment inhibits neurite outgrowth from MPGs.

Average neurite lengths of the control groups and the groups cultured with TNF-α at 48 hours
(A) and at 72 hours (B) after culture. * indicates significant difference.

Interestingly, neurite outgrowth patterns were different between the 2 groups. Neurites of the control group tended to grow equally, while neurites of the TNF-α group did not (Figure 2.).

Representative images of neurite outgrowth patterns. (A) Neurites of the control group grew equally. (B) Neurite lengths of the TNF-α were either as long as the average length of the control group or much shorter than that.

In the TNF-α group, some neurites were as long as the average length of the control group and others were much shorter than that. In order to demonstrate this difference of neurite outgrowth patterns quantitatively, we measured all the neurites measurable and made histograms of neurite lengths. Histograms of the control group showed almost normal distribution. On the other hand, histograms of the TNF-α group showed heavy-tailed distribution (Figure 3.).

The histograms of the neurite lengths in the control group and the TNF-α group at
(A) 48 hours and at (B) 72hours. The control group showed almost normal distribution, while the
histograms of the TNF-α group showed heavy-tailed distribution.

Variances of each group were calculated and compared. There was no significant difference of the variances between the 2 groups at 48 hours but the variance of the TNF-α group was significantly larger than the control group's at 72 hours (Figure 4).

The variances of the neurite lengths in the control group and the TNF-α group at
(A) 48 hours and at (B) 72hours. * indicates significant difference.

SUMMARY

This study provides additional evidence that exogenous TNF-α inhibits neurite outgrowth inhibition from the MPG. This suggests that TNF-α inhibition may be a future therapeutic target to prevent post-operative ED following RP. In addition, this study indicates that exogenous TNF-α does not inhibit all the neurites from MPGs. Accordingly, TNF-α may inhibit specific types of neurites, such as parasympathetic nerves. Further investigation is required to clarify the types of neurites inhibited by TNF-α.


This blog was written by Hotaka Matsui, a post-doctoral research fellow and graduate of the National Institute of Public Health in Japan. This work is the result of collaborative work with Johanna L. Hannan, Xiaopu Liu and Trinity J. Bivalacqua and is supported by the National Institute of Health (NIH) R03 Grant DK101701-01.

 

 

 
References:
[1]    Walsh PC and Donker PJ: Impotence following radical prostatectomy: insight into etiology and prevention. J Urol 1982;128:492.
[2]    Walsh PC: The discovery of the cavernous nerves and development of nerve sparing radical retropubic prostatectomy. J Urol 2007;177:1632.
[3]    Walsh PC, Lepor H and Eggleston JC: Radical prostatectomy with preservation of sexual function: anatomical and pathological considerations. Prostate 1983;4:473.
[4]    Burnett AL, Aus G, Canby-Hagino ED et al. Erectile function outcome reporting after clinically localized prostate cancer treatment. J Urol 2007;178:597.
[5]    Hannan JL, Kutlu O, Stopak BL et al. Valproic acid prevents penile fibrosis and erectile dysfunction in cavernous nerve-injured rats. J Sex Med 2014;11(6):1442
[6]    Hannan JL, Weyne E, Albersen M et al. Cavernous nerve injury induced temporal increase in neuroinflammation and cytokine induction in the major pelvic ganglion of the rat. American Urological Association Annual Meeting 2014. Orlando, FL. MP43-10

A New Test May Change the Meaning of a “Negative” Prostate Biopsy

Nearly one million men undergo prostate biopsy yearly in the US. 750,000 (3 in 4) of these biopsies are histologically found to be negative for evidence of prostate cancer by microscopic analysis. Other data suggest that of these 750,000 negative biopsies, 25% (187,000) actually have cancer in the prostate that the initial biopsy might have missed. A new tissue assay (made by ConfirmMDx) 

From MDxHealth.com

looks at the methylation (alteration of the DNA) of three genes to predict that cancer may have been missed and that a repeat biopsy should be recommended. The test relies on the concept that a "halo" of DNA-alterations (methylation) occurs around a foci of cancer within the prostate. With the ability to search for DNA-abnormalities in the "halo," this test effectively increases the size of each biopsy and decreases the likelihood of missing a prostate cancer.

Jonathan I. Epstein, MD

The multicenter DOCUMENT (Detection of Cancer Using Methylated Events in Negative Tissue) study was conducted with 350 PSA-screened men from five major urologic centers, including Johns Hopkins University, Cleveland Clinic Foundation, Lahey Clinic, University of California Los Angeles and East Virginia Medical School. The study involved patients with an initial negative index prostate biopsy who had high-risk variables (e.g. High Grade PIN, Atypia high PSA, etc…) and compared this tissue methylation assay results to cancer detection in subsequent repeat biopsy within 24 months. Index and repeat biopsy tissues were subjected to blinded, centralized pathology review by Jonathan Epstein, MD, Reinhard Professor of Urologic Pathology and Director of Surgical Pathology at Johns Hopkins. The ConfirmMDx for Prostate Cancer test, was used to analyze the DNA from 3,687 negative tissue cores from the index prostate biopsy for epigenetic abnormalities. The study confirmed the previously published results using the same ConfirmMDx for Prostate Cancer test as a significant, independent predictor (odds ratio = 2.85) for the risk of prostate cancer in a repeat biopsy, outperforming standard clinical risk factors such as age, prostate specific antigen (PSA), digital rectal exam (DRE), and pathology in multivariate logistic regression analysis. In addition, the high negative predictive value of the epigenetic assay was confirmed (88%).[1]

Alan W. Partin, MD, PhD

Dr. Alan Partin, MD, PhD, Chairman of the Brady Urological Institute and Urologist-in-Chief at Johns Hopkins Hospital comments, 

"The DOCUMENT study validates the three-gene epigenetic assay as a better predictor of risk for the presence of occult cancer than any other factor in the clinic today. Results from this study provide further clinical evidence that the epigenetic test delivers actionable information to help guide urologists on the decision for repeat prostate biopsy."

"DOCUMENT was a pivotal validation study, demonstrating that the test's high negative predictive value and odds ratio are robust and reproducible in different cohorts of patients," stated Dr. Epstein. "The importance of this blinded, multicentered study is that it validated the performance of the test using predetermined analytical cutoff values in a population of U.S. patients undergoing routine PSA screening for prostate cancer."

The entire manuscript appears in the April 18, 2014 Edition of the Journal of Urology. Click here of follow the link below to read the entire manuscript.

Partin AW, Van Neste L, Klein EA, Marks LS, Gee JR, Troyer DA, Rieger-Christ K, Jones JS, Magi-Galluzzi C, Mangold LA, Trock BJ, Lance RS, Bigley JW, Van Criekinge W, Epstein JI. Clinical Validation of an Epigenetic Assay to Predict Negative Histopathological Results in Repeat Prostate Biopsies. J Urol. 2014 Apr 18. pii: S0022-5347(14)03341-2. doi: 10.1016/j.juro.2014.04.013.


 
[1] Stewart GD, Van Neste L, Delvenne P, Delrée P, Delga A, McNeill SA, O'Donnell M, Clark J, Van Criekinge W, Bigley J, Harrison DJ. Clinical utility of an epigenetic assay to detect occult prostate cancer in histopathologically negative biopsies: results of the MATLOC study. J Urol. 2013 Mar;189(3):1110-6. doi: 10.1016/j.juro.2012.08.219. Epub 2012 Oct 8.