Accurate test for aggressive prostate cancer steps closer with genetic study

Urology

Rsearchers behind a new genetic study led by the University of Pittsburgh School of Medicine, PA, suggest their findings will lead to a more accurate test for aggressive prostate cancer and new ways to treat it.

Writing about their work in the American Journal of Pathology, the team explains how they found prostate cancerpatients with certain genetic mutations have a 91% chance of their cancer coming back.

Senior author Jian-Hua Luo, a professor of pathology at Pitt School of Medicine who specializes in researching the genome and gene expression of cancers, and particularly how prostate cancers become invasive, says:

“Being able to say, with such certainty, that a patient is nearly guaranteed to see a recurrence of his prostate cancer means that doctors and patients can elect to be more aggressive in treating the cancer, knowing that the benefits likely outweigh the risks.”

He suggests eventually such a finding could lead to a genetic therapy that cures prostate cancer, and adds:

“With this discovery, we’re at the tip of the iceberg in terms of possibilities for improving patient outcomes.”

Prostate cancer treatment can be worse than the disease

Prostate cancer is the second most common cancer in men (after skin cancer) and the second leading cause of cancer death in American men, behind only lung cancer.

According to the American Cancer Society, about 1 man in 7 will be diagnosed with prostate cancer during his lifetime.

However, despite this high rate of disease, few men diagnosed with it develop the aggressive type that spreads, which poses a problem for treatment, as Prof. Luo explains:

“In some cases, this can make the treatment more dangerous than the disease, so doctors need more accurate tests to tell them which patients would most benefit from aggressive therapies, such as surgery, radiation andchemotherapy.”

Study found 8 ‘hybrid genes’ or ‘fusion transcripts’ strongly linked to prostate cancer

For the study, the team sequenced the genomes of tissue samples taken from the prostates of five men whose prostate cancer recurred, and compared them with the genomes of tissue samples from men without cancer.

In the tissue of the men with prostate cancer recurrence, they found 76 hybrid genes that are often linked to cancer. After further tests, 8 of these hybrid genes were found to be strongly linked to prostate cancer.

The hybrid genes are known as “fusion transcripts” that are formed from previously separate genes. These are often linked to cancer.

The team then looked for the 8 hybrid genes in 289 prostate tissue samples from men treated at three centers, with clinical follow-up ranging from 1 to 15 years after surgery.

The analysis showed that 91% of the patients (69 out of 76) who tested positive for any of the hybrid genes experienced prostate cancer recurrence, metastases, and/or died of prostate cancer after surgery. Also, three of the hybrid genes were only found in tissue samples from patients who experienced recurrence or died from prostate cancer.

However, of the prostate cancer patients who did not carry any of the genes, only 37% (58 out of 157) experienced recurrence, metastases or died of prostate cancer.

The researchers say the findings suggest formation of the hybrid genes may underlie the aggressive behavior of prostate cancer.

Subject to successful clinical trials, Prof. Luo expects the test to be available to patients in a few years. He says there are also plans to further investigate the hybrid genes most strongly linked to prostate cancer. This could one day lead to treatments that stop the cancer by changing or stopping the mutations.

Funds for the study came from the National Institutes of Health, the American Cancer Society and the University of Pittsburgh Cancer Institute.

Meanwhile, in May 2014, Medical News Today learned about research from the University of Tampere in Finland that established the feasibility of diagnosing prostate cancer using an eNose. The team found the eNose results were comparable to those obtained from prostate specific antigen tests.

Written by Catharine Paddock PhD

 

After spinal cord injury, transplanted stem cells help prevent bladder fibrosis

Urology

A team of researchers from Korea and Canada have found that transplantation of B10 cells (a stable immortalized human bone marrow derived mesenchymal stem cell line; B10 hMSC) directly into the bladder wall of mice modeled with spinal cord injury (SCI) helped inhibit the development of bladder fibrosis and improved bladder function by promoting the growth of smooth muscle cells in the bladder.

The study will be published in a future issue of Cell Transplantation and is currently freely available on-line as an unedited early e-pub.

Spinal cord injury (SCI) can cause severe lower urinary tract dysfunction and conditions such as overactive bladder, urinary retention and increased bladder thickness and fibrosis. HMSCs, multipotent cells that can differentiate into a variety of cell types, including bone cells, cartilage cells, and fat cells, have been transplanted into injured spinal cords to help patients regain motor function.

In this study, mice receiving the B10 hMSCs injected directly into the bladder wall experienced improved bladder function while an untreated control group did not.

“Human MSCs can secrete growth factors,” said study co-author Seung U. Kim of the Division of Neurology at the University of British Columbia Hospital, Vancouver, Canada. “In a previous study, we showed that B 10 cells secrete various growth factors including hepatocyte growth factor (HGF) and that HGF inhibits collagen deposits in bladder outlet obstructions in rats more than hMSCs alone. In this study, the SCI control group that did not receive B10 cells showed degenerated spinal neurons and did not recover. The B10-injected group appeared to have regenerated bladder smooth muscle cells.”

Four weeks after the onset of SCI, the treatment group received the B10 cells transplanted directly into the bladder wall. To track the transplanted B10 cells via magnetic resonance imaging (MRI), the researchers labeled them with fluorescent magnetic particles.

“HGF plays an essential role in tissue regeneration and angiogenesis and acts as a potent antifibrotic agent,” explained Kim.

The researchers concluded that local injection, rather than systemic intravenous injection, was preferred because systemic injection caused the hMSCs to be localized in the pulmonary capillary bed.

Voiding function was assessed at four weeks post-transplantation and MRI “showed clear hypointense signal induced by the labeled cells”. When the bladders of the transplanted group were harvested they were found to have improved smooth muscle cells and reduced collagen deposition.

The researchers concluded that MSC-based cell transplantation may be a novel therapeutic strategy for bladder dysfunction in patients with SCI.

“This study provides potential evidence that an human stable immortalized MSC line could be useful in the treatment of spinal cord injury-related problems such as bladder dysfunction.” said Dr. David Eve, associate editor of Cell Transplantation and Instructor at the Center of Excellence for Aging & Brain Repair at the University of South Florida. “Further studies to elucidate the mechanisms of action and the long term effects of the cells, as well as confirm the optimal route of administration, will help to illuminate what the true benefit of these cells could be.”

http://www.medicalnewstoday.com/releases/282059.php

Picture courtesy of https://twitter.com/BioheartInc

 

 

Catheter-associated urinary tract infections significantly reduced by electronic alerts

Urology_Nephrology

A Penn Medicine team has found that targeted automated alerts in electronic health records significantly reduce urinary tract infections in hospital patients with urinary catheters. In addition, when the design of the alert was simplified, the rate of improvement dramatically increased.

The alerts help physicians decide whether their patients need urinary catheters in the first place and then alert them to reassess the need for catheters that have not been removed within a recommended time period. The electronic alert, developed by medical researchers and technology experts at the Perelman School of Medicine at the University of Pennsylvania, is the subject of a study published in the September issue of Infection Control and Hospital Epidemiology.

Approximately 75 percent of urinary tract infections acquired in the hospital are associated with a urinary catheter, which is a tube inserted into the bladder through the urethra to drain urine. According to the Centers for Disease Control and Prevention, 15 to 25 percent of hospitalized patients receive urinary catheters during their hospital stay. As many as 70 percent of urinary tract infections in these patients may be preventable using infection control measures such as removing no longer needed catheters resulting in up to 380,000 fewer infections and 9,000 fewer deaths each year.

“Our study has two crucial, applicable findings,” said the Penn study’s lead author Charles A. Baillie, MD, an internal medicine specialist and fellow in the Center for Clinical Epidemiology and Biostatistics at Penn Medicine. “First, electronic alerts do result in fewer catheter-associated urinary tract infections. Second, the design of the alerts is very important. By making the alert quicker and easier to use, we saw a dramatic increase in the number of catheters removed in patients who no longer needed them. Fewer catheters means fewer infections, fewer days in the hospital, and even, fewer deaths. Not to mention the dollars saved by the health system in general.”

In the first phase of the study, two percent of urinary catheters were removed after an initial “off-the-shelf” electronic alert was triggered (the stock alert was part of the standard software package for the electronic health record). Hoping to improve on this result in a second phase of the study, Penn experts developed and used a simplified alert based on national guidelines for removing urinary catheters they had previously published with the CDC. Following introduction of the simplified alert, the proportion of catheter removals increased more than seven-fold to 15 percent.

The study also found that catheter associated urinary tract infections decreased from an initial rate of .84 per 1,000 patient days to .70 per 1,000 patient-days following implementation of the first alert and .50 per 1,000 patient days following implementation of the simplified alert. Among other improvements, the simplified alert required two mouse clicks to submit a remove-urinary-catheter order compared to seven mouse clicks required by the original alert.

The study was conducted among 222,475 inpatient admissions in the three hospitals of the University of Pennsylvania Health System between March 2009 and May 2012. In patients’ electronic health records, physicians were prompted to specify the reason (among ten options) for inserting a urinary catheter. On the basis of the reason selected, they were subsequently alerted to reassess the need for the catheter if it had not been removed within the recommended time period based on the reason chosen.

Women’s health units had the highest proportion of alerts that led to a remove-urinary-catheter order and critical care units saw the lowest proportion of alerts leading to a remove order.

“As more hospitals adopt electronic health records, studies such as ours can help point the way toward improved patient care,” said senior author Craig Umscheid, MD, MSCE, assistant professor of Medicine and Epidemiology and director of Penn’s Center for Evidence-based Practice. “Thoughtful development and deployment of technology solutions really can make a difference. In this study, we learned that no two alerts are alike, and that changes to an alert’s usability can dramatically increase its impact.”

Several studies have already shown that reminder systems to limit the use and duration of urinary catheters can lower catheter infection rates. However, the majority of these have used non-computerized reminders, such as written reminders or stickers. The current Penn study is one of the largest to examine the impact of electronically generated alerts. In addition to the size of the study, a second strength is its multi-year duration. Most prior studies relied on a brief study period, and several studies observed an increase in catheter use when the relatively brief intervention had ended.

http://www.medicalnewstoday.com/releases/281479.php

 

 

 

Atypical antipsychotic drug use increases risk for acute kidney injury

Nephrology_Urology

Atypical antipsychotic drug use is associated with an increased risk for acute kidney injury (AKI) and other adverse outcomes, according to a study being published in Annals of Internal Medicine.

Each year, millions of older adults are prescribed atypical antipsychotic drugs (quetiapine, risperidone, and olanzapine) to manage behavioral symptoms of dementia, which is not an approved indication. This type of off-label use has raised safety concerns, as these atypical antipsychotics are known to cause AKI. Researchers compared medical records for 97,777 adults aged 65 or older who received a new outpatient prescription for an oral atypical antipsychotic drug against a matched cohort of patients who had not received such a prescription to determine the risk for AKI and other adverse outcomes.

Persons who had received a prescription for any three atypical antipsychotic drugs in the previous 90 days had an elevated risk for hospitalization with AKI. The drugs were also associated with increased risk for hypotension, acute urinary retention, and death. The findings support current safety concerns regarding the use of these drugs in older adults.

Study: Atypical Antipsychotic Drugs and the Risk for Acute Kidney Injury and Other Adverse Outcomes in Older Adults: A Population-Based Cohort Study, Y.J. Hwang, S.N. Dixon, J.P. Reiss, R. Wald, C.R. Parikh, S. Gandhi, S.Z. Shariff, N. Pannu, D.M. Nash, F. Rehman, and A.X. Garg, Annals of Internal Medicine, doi: 10.7326/M13-2796, published 18 August 2014.

http://www.medicalnewstoday.com/releases/281206.php

 

 

Enzyme lost in 100 percent of kidney tumors analyzed

Urology_Nephrology

In an analysis of small molecules called metabolites used by the body to make fuel in normal and cancerous cells in human kidney tissue, a research team from the Perelman School of Medicine at the University of Pennsylvania identified an enzyme key to applying the brakes on tumor growth. The team found that an enzyme called FBP1 – essential for regulating metabolism – binds to a transcription factor in the nucleus of certain kidney cells and restrains energy production in the cell body. What’s more, they determined that this enzyme is missing from all kidney tumor tissue analyzed. These tumor cells without FBP1 produce energy at a much faster rate than their non-cancer cell counterparts. When FBP1 is working properly, out-of-control cell growth is kept in check.

The new study, published online this week in Nature, was led by Celeste Simon, PhD, a professor of Cell and Developmental Biology and the scientific director for the Abramson Family Cancer Research Institute at Penn.

Clear cell renal cell carcinoma (ccRCC), the most frequent form of kidney cancer, is characterized by elevated glycogen (a form of carbohydrate) and fat deposits in affected kidney cells. This over-storage of lipids causes large clear droplets to accumulate, hence the cancer’s name.

In the last decade, ccRCCs have been on the rise worldwide. However, if tumors are removed early, a patient’s prognosis for five-year survival is relatively good. If expression of the FBP1 gene is lost, patients have a worse prognosis.

“This study is the first stop in this line of research for coming up with a personalized approach for people with clear cell renal cell carcinoma-related mutations,” says Simon, also an investigator with the Howard Hughes Medical Institute.

A Series of Faulty Reactions

The aberrant storage of lipid in ccRCC results from a faulty series of biochemical reactions. These reactions, called the Kreb’s cycle, generate energy from carbohydrates, fats, and proteins in the form of ATP. However, the Kreb’s cycle is hyperactive in ccRCC, resulting in enhanced lipid production. Renal cancer cells are associated with changes in two important intracellular proteins: elevated expression of hypoxia inducible factors (HIFs) and mutations in the von Hippel-Lindau (VHL) encoded protein, pVHL. In fact, mutations in pVHL occur in 90 percent of ccRCC tumors. pVHL regulates HIFs, which in turn affect activity of the Kreb’s cycle.

Although much is already known about metabolic pathways and their role in cancer, there are still important questions to be answered. For example, kidney-specific VHL deletion in mice does not elicit clear cell-specific tumor formation, suggesting that additional mechanisms are at play. Toward answering that hunch, recent large-scale sequencing analyses have revealed the loss of several epigenetic enzymes in certain types of ccRCCs, suggesting that changes within the nucleus also account for kidney tumor progression.

To complement genetic studies revealing a role for epigenetic enzymes, the team evaluated metabolic enzymes in the 600-plus tumors they analyzed. The expression of FBP1 was lost in all kidney cancer tissue samples examined. They found FBP1 protein in the cytoplasm of normal cells, where it would be expected to be active in glucose metabolism. But, they also found FBP1 in the nucleus of these normal cells, where it binds to HIF to modulate its effects on tumor growth. In cells without FBPI, the team observed the Warburg effect – a phenomenon in which malignant, rapidly growing tumor cells go into overdrive, producing energy up to 200 times faster than their non-cancer-cell counterparts.

This unique dual function of FBP1 explains its ubiquitous loss in ccRCC, distinguishing FBP1 from previously identified tumor suppressors that are not consistently inhibited in all tumors. “And since FBP1 activity is also lost in liver cancer, which is quite prevalent, FBP1 depletion may be generally applicable to a number of human cancers,” notes Simon.

Next steps, according to the researchers, will be to identify other metabolic pathways to target, measure the abundance of metabolites in kidney and liver cancer cells to determine FBP1’s role in each, and develop a better mouse model for preclinical studies.

Picture Credit: Credit: Bo Li and Brian Keith, Perelman School of Medicine, University of Pennsylvania.

http://www.medicalnewstoday.com/releases/279893.php

 

 

 

Nanoparticles used to enhance chemotherapy

Nephrology_Urology_Radiology

University of Georgia researchers have developed a new formulation of cisplatin, a common chemotherapydrug, that significantly increases the drug’s ability to target and destroy cancerous cells.

Cisplatin may be used to treat a variety of cancers, but it is most commonly prescribed for cancer of the bladder, ovaries, cervix, testicles and lung. It is an effective drug, but many cancerous cells develop resistance to the treatment.

Shanta Dhar, assistant professor of chemistry in the UGA Franklin College of Arts and Sciences, and Rakesh Pathak, a postdoctoral researcher in Dhar’s lab, constructed a modified version of cisplatin called Platin-M, which is designed to overcome this resistance by attacking mitochondria within cancerous cells. They published their findings recently in the Proceedings of the National Academy of Sciences.

“You can think of mitochondria as a kind of powerhouse for the cell, generating the energy it needs to grow and reproduce,” said Dhar, a member of the UGA Cancer Center and principal investigator for the project. “This prodrug delivers cisplatin directly to the mitochondria in cancerous cells. Without that essential powerhouse, the cell cannot survive.”

Sean Marrache, a graduate student in Dhar’s lab, entrapped Platin-M in a specially designed nanoparticle 1,000 times finer than a human hair that seeks out the mitochondria and releases the drug. Once inside, Platin-M interferes with the mitochondria’s DNA, triggering cell death.

Dhar’s research team tested Platin-M on neuroblastoma – a cancer commonly diagnosed in children-that typically originates in the adrenal glands. In preliminary experiments using a cisplatin-resistant cell culture, Platin-M nanoparticles were 17 times more active than cisplatin alone.

“This technique could become a treatment for a number of cancers, but it may prove most useful for more aggressive forms of cancer that are resistant to current therapies,” said Pathak.

Both Dhar and Pathak caution that their experimental results are preliminary and they must do more work before Platin-M enters any clinical trials. However, their early results in mouse models are promising, and they are currently developing safety trials in larger animals.

“Cisplatin is a well-studied chemotherapy, so we hope our unique formulation will enhance its efficacy,” said Dhar, who is also a member of UGA’s Nanoscale Science and Engineering Center, Center for Drug Discovery, and Regenerative Bioscience Center. “We are excited about these early results, which look very promising.”

 

http://www.medicalnewstoday.com/releases/279303.php

Picture courtesy of www.sciencedaily.com

 

 

 

“Big data” technique improves monitoring of kidney transplant patients

Urology_Nephrology

A new data analysis technique could radically improve monitoring of kidney transplant patients, according to new research published this week in PLOS Computational Biology.

The research, carried out by a team comprising physicists, chemist and clinicians at the University of Leeds, provides a method for making sense out of the huge number of clues about a kidney transplant patient’s prognosis contained in their blood.

By applying a sophisticated “big data” analysis to the samples, scientists were able to process hundreds of thousands of variables into a single parameter to indicate how a kidney transplant was faring. This allowed them to predict poor function of a kidney after only two days in cases that may not have been previously detected as failing until weeks after transplant.

These extra few days are vital in the early stages after transplant and would give doctors a better chance to intervene to save the transplant and improve patient recovery periods. In some cases, the team were able to predict failure from patients’ blood samples taken before the transplant operation.

Dr Sergei Krivov, in the University of Leeds’ Astbury Center, said: “If you put a blood sample through Nuclear Magnetic Resonance analysis you get data down to the molecular level. You can identify chemical fingerprints left behind by specific cellular processes and you get a very large number of different parameters in those samples that vary with the outcome for a patient.

“These are vital clues. But, if you have got thousands of variables all moving in different ways in a complex system, how does a doctor bring all that information together and decide what to do? It is not possible to do this with the human mind; there are just too many variables. We have to do it with computers and find a way to weigh those variables and produce an intelligible output describing where, overall, the patient is heading.”

The study, which analysed data from daily blood samples from 18 patients immediately before and in a week-long period after kidney transplants, showed that it was possible to pick out pieces of information that varied with the overall likelihood of a patient either rejecting a kidney or recovering kidney function.

Given enough data, the technique could even be used to quantify very complex and extended processes affecting the whole population.

http://www.medicalnewstoday.com/releases/278531.php