RxPG News : Bladder

Increased production of a microRNA resulted in better response to chemotherapy

Thu, 30 Jun 2011 17:27:41 PST

( from http://www.rxpgnews.com ) Researchers at the UC Davis Cancer Center have discovered a way of sensitizing muscle-invasive bladder cancer cells so that they succumb to the toxic effects of chemotherapy. The finding adds to mounting evidence that tiny strands of RNA — called microRNA — play key roles in some of the deadliest types of cancer.

In the current study, published online June 28 in International Journal of Cancer, researchers boosted the production of a microRNA found in bladder cancer cell lines — encoded for by the gene miR-34a — and found that this resulted in more of the cells being killed by cisplatin, a chemotherapy drug used to treat many types of cancer.

"When we took the bladder cancer cell lines and activated miR-34a, they were more responsive to chemotherapy," said Ralph deVere White, UC Davis Cancer Center director and professor of urology.

The study establishes, for the first time, a link between sensitivity of bladder cancer cells to chemotherapy and the expression of miR-34a. It suggests that miR-34a may be used as a predictor of response to chemotherapy, as well as a target for new drugs.

Currently, about 50 percent of patients with advanced bladder cancer will survive five years after diagnosis. Although clinical trials have demonstrated that chemotherapy before surgery can improve survival rates, it is rarely used because fewer than 50 percent of patients will respond favorably. Without knowing which patients will improve as a result of chemotherapy, physicians are generally reluctant to use a treatment that can cause their patients to suffer significant side effects.

"So, now we have to prove that it works to predict chemotherapy response in patients," deVere White said. To that end, UC Davis has entered into a partnership with Israel-based Rosetta Genomics to develop a microRNA profile for muscle-invasive bladder cancer that may be used to predict response to chemotherapy.

As part of the current study, deVere White and his colleagues studied 27 patients and found that many who expressed lower levels of miR-34a subsequently did not respond to the combined chemotherapy-surgery treatment. Because the finding was not statistically significant, however, further work in this area is needed.

The team also studied tumor samples taken from eight of the patients who did not respond to chemotherapy. They compared the expression of miR-34a before and after chemotherapy.

"We wanted to see, if you looked at the patient's tissue before chemotherapy, were there differentially expressed microRNAs in the patients who responded to the drugs versus those that didn't respond," deVere White explained.

The team found that expression of miR-34a increased after treatment in only two of the eight cases, suggesting that gene expression levels remained low during treatment and confirming the link between low gene expression and failure to respond to treatment.

"The combined data indicate that the elevation of miR-34a expression levels prior to chemotherapy would be of benefit to muscle-invasive bladder cancer patients, particularly in a setting of low mi-R-34a expression," the authors write.

Since their discovery in 1993, microRNAs have been found to be involved in a number of types of cancer, heart disease and diseases of the nervous system. In 2007, deVere White was part of a team that identified miR-125b, a gene that encodes for a microRNA that jump starts prostate cancer cell growth midway through the disease process, eventually causing it to become fatal.

The microRNA studied here was also recently found to play a role in medulloblastoma, an aggressive type of brain cancer. MicroRNAs, which are usually 22 to 33 nucleotides in length, are known as post-transcriptional regulators. That means they work by turning genes on or off during the part of the protein synthesis process that involves making a strand of RNA from a DNA template. The human genome encodes for an estimated 1,000 microRNAs.

According to the authors, future studies involving miR-34a will focus on testing its ability to increase sensitivity to chemotherapy and analysis of miR-34a expression in patients with muscle-invasive bladder cancer. With the currently low chemotherapy success rate and poor five-year survival rate for patients with this disease, "such studies are clearly warranted," the authors write.

"If we can prove what is causing chemotherapy resistance in patients with muscle-invasive bladder cancer, American ingenuity will come up with ways to overcome it," predicted deVere White.

Selenium May Prevent Some Bladder Cancers

Mon, 08 Dec 2008 15:19:11 PST

( from http://www.rxpgnews.com ) Selenium, a trace element found in grains, nuts and meats, may help prevent high-risk bladder cancer.

Dartmouth Medical School researchers compared selenium levels in 767 individuals newly diagnosed with bladder cancer with the levels of 1,108 individuals from the general population.

Findings showed an inverse association between selenium and bladder cancer among women, some smokers and those with p53 positive bladder cancer.

In the entire study population, there was no inverse association between selenium and bladder cancer, but women -, moderate smokers - and those with p53 positive cancer - had significant reductions in bladder cancer with higher rates of selenium.

'There are different pathways by which bladder cancer evolves and it is thought that one of the major pathways involves alterations in the p53 gene,' said study co-author Margaret Karagas, professor of community and family medicine of the Norris Cotton Cancer Centre at Dartmouth.

'Bladder cancers stemming from these alternations are associated with more advanced disease,' she said, according to a release of the Cancer Centre.

While other studies have shown a similar association between selenium and bladder cancer among women, this study is one of the first to show an association between selenium and p53 positive bladder cancer.

'Ultimately, if it is true that selenium can prevent a certain subset of individuals, like women, from developing bladder cancer, or prevent certain types of tumours such as those evolving through the p53 pathway, from developing, it gives us clues about how the tumours could be prevented in the future and potentially lead to chemopreventive efforts,' Karagas said.

The study was published in the December issue of Cancer Prevention Research.

Bacon may increase bladder cancer risk

Fri, 01 Dec 2006 14:25:15 PST

( from http://www.rxpgnews.com ) New York, Dec 1 - People who eat bacon sandwich at least five times a week are likely to be at 59 percent more risk of developing bladder cancer than those who do not, says a study.

Bacon by definition is cured and smoked pork. In the US, the cut most commonly used is pork belly, preferably the belly meat from the back closest to the loin.

Researchers at the Harvard School of Public Health in Boston looked at data for 136,000 people and found that people who ate bacon at least five times a week were 59 percent more likely to develop the disease, reports the online edition of BBC.

People who frequently ate skinless chicken had a 52 percent greater risk, researchers said in the study that appeared in the American Journal of Clinical Nutrition.

Nitrosamines, chemicals often found in processed meats and in particularly high levels in bacon, are known to be carcinogenic in high quantities. Heterocyclic amines, also known carcinogens, form when meat is cooked at high temperatures.

Compared with skinless chicken, cooked chicken with skin is known to contain a smaller amount of heterocyclic amines, the researchers said.

'More research is needed before we can say for sure whether or not eating bacon in particular affects bladder cancer risk,' said Emma Knight, the science information manager at Cancer Research UK.

'For now, our advice remains to eat a balanced diet that is low in fat, processed and red meat, and rich in vegetables, fruit and fibre,' Knight added.

Surgery should occur within 3 months of diagnosis of bladder carcinoma

Tue, 28 Mar 2006 21:02:00 PST

( from http://www.rxpgnews.com ) Bladder cancer patients whose surgery was delayed for more than three months after their diagnosis were more likely to die from their disease than patients whose surgery was performed sooner, according to a study by researchers at the University of Michigan Comprehensive Cancer Center.

The study, published in the April Journal of Urology, looked at 214 patients diagnosed with muscle-invasive bladder cancer and treated with radical cystectomy, an operation in which the bladder is removed. The researchers found that patients whose surgery was delayed more than 93 days from the date of diagnosis had worse survival rates compared to patients whose surgery occurred in fewer than 93 days.

Thirty-nine percent of patients without a delay died, while 54 percent of patients with a delay died. The patients whose surgery was delayed lived on average only one year, and their three-year survival rate was 38 percent, compared to a three-year survival rate of 51 percent for patients whose surgery was not delayed.

The time from diagnosis to surgery ranged from four days to 175 days, with 26 patients having a delay of more than 93 days, roughly three months. The most common reason for delay was scheduling issues. Less frequent reasons were patients seeking multiple opinions, misdiagnosis or patients reluctant to be treated. Patient indecision was not a common cause of lengthy delays.

"Most of these causes for delaying surgery are potentially reversible, and physicians despite busy schedules and the need for second opinions need to be diligent about coordinating appointments and information in a timely way," says lead study author Cheryl Lee, M.D., director of the bladder cancer program at the U-M Comprehensive Cancer Center and assistant professor of urology at the U-M Medical School.

The researchers believe a delay in treatment could cause micrometastases, cancer cells that spread through the body but in small quantities that cannot be detected by standard imaging techniques. The short survival less than a year among patients whose surgery was delayed more than 93 days is similar to survival for bladder cancer patients in which it is known the cancer has spread.

Some causes of treatment delay were unavoidable and irreversible, such as the patient being too old for surgery or having other medical conditions that rule out surgery.

Cystectomy is standard treatment for bladder cancer that has invaded the nearby muscle. Typically, five-year survival rates after surgery are as high as 80 percent.

This year, an estimated 61,420 Americans will be diagnosed with bladder cancer and 13,000 will die from it, according to the American Cancer Society. The disease affects men three times more often than women.

Urinary Protein NMP22 Can Help Detect Bladder Cancer Recurrence

Sat, 21 Jan 2006 21:38:00 PST

( from http://www.rxpgnews.com ) Measurement of a certain protein in urine can increase the ability to detect bladder cancer recurrence, with test results available during the patients visit, according to a study in the January 18 issue of JAMA.

Bladder cancer is the fifth most common malignancy in the United States, according to background information in the article. In 2005, there were an estimated 63,210 new cases and more than 13,000 deaths. There are 500,000 patients in the United States with a history of bladder cancer, making its prevalence higher than that of lung cancer. The probability of recurrence ranges from 50 percent to 90 percent, depending on stage, grade, and number of primary tumors. Consequently, rigorous surveillance is advocated. A combination of methods is used to monitor patients at risk of recurrent bladder cancer because no single procedure is 100 percent sensitive. Cystoscopy (visual examination of the bladder with a medical instrument) is a standard approach but can fail to detect some bladder cancers. Cytologic (cell) analysis of urine frequently is used as an adjunctive test, but can have poor sensitivity and variability in interpreting results.

H. Barton Grossman, M.D., of the M. D. Anderson Cancer Center, Houston, and colleagues investigated the clinical utility of a noninvasive urine test, which can be used in the physicians office, for the protein NMP22, as an aid in detecting recurrent cancer in patients with a history of bladder cancer. The researchers compared its usefulness with that of voided urine cytology, which must be analyzed in a clinical laboratory. The study, conducted from September 2001 to February 2002, included 23 academic, private practice, and hospital facilities in 9 U.S. states and enrolled 668 patients with a history of bladder cancer. Prior to undergoing cystoscopy, patients provided a urine sample for analysis of NMP22 protein and for cytology testing.

Bladder cancer was diagnosed in 103 patients. Cystoscopy alone identified 91.3 percent of the cancers. The combination of cystoscopy with the NMP22 assay detected 99.0 percent of the malignancies. The NMP22 assay detected 8 of 9 cancers that were not visualized during initial cystoscopy, including 7 that were high-grade. The sensitivity and specificity of the NMP22 test alone were 49.5 percent and 87.3 percent, respectively. Cytology based on voided urine detected only 3 of the malignancies missed during initial cystoscopy and did not significantly increase the sensitivity of cystoscopy (94.2 percent).

The authors conclude, "When combined with cystoscopy, the NMP22 test improves the detection of recurrence in patients with a history of bladder cancer."

Telomerase activity in urine useful for detecting bladder cancer in men

Wed, 26 Oct 2005 23:21:00 PST

( from http://www.rxpgnews.com ) Measurement of an enzyme level (telomerase activity) in urine appears useful for detection of bladder cancer in men, according to a study in the October 26 issue of JAMA.

The incidence of human bladder cancer has greatly increased over the last few decades, with more than 60,000 new cases diagnosed each year in the United States alone, and now represents the 4th most common malignancy in men and the 10th most common in women, according to background information in the article. At present, about 20 percent of patients die each year, but when the disease is diagnosed and treated in the early stage, the chances of survival are good, indicating the importance of a timely and accurate diagnosis.

Established approaches for detecting bladder cancer are either invasive and costly or have limited sensitivity, highlighting the need for the development of a noninvasive, reliable, and simple test to increase the rate of detection of bladder cancer. Among the markers investigated for this purpose has been telomerase (a certain enzyme) activity in urine.

Maria Aurora Sanchini, M.Sc., of Morgagni-Pierantoni Hospital, Forlì, Italy, and colleagues conducted a study to define the diagnostic accuracy of different telomerase activity cutoff values in terms of sensitivity and specificity. The study included 218 men (84 healthy individuals and 134 patients at first diagnosis of histologically confirmed bladder cancer), recruited between March 2003 and November 2004 in Italy. Urine telomerase activity was determined using a highly sensitive telomeric repeat amplification protocol (TRAP) assay. Urine samples were processed for cytological (cell) diagnosis and TRAP assay. The diagnosis of bladder cancer was based on bioptic and cystoscopic examinations (direct visual examination of the urinary tract). The performance of the TRAP assay to detect urine telomerase activity was compared to urine cytology as an aid to early cancer detection.

Using a 50 arbitrary enzymatic unit (AEU) cutoff value, in the overall series, there was 90 percent sensitivity and 88 percent specificity. Specificity increased to 94 percent for individuals aged 75 years or younger. The same predictive capacity of telomerase activity levels was observed for patients with low-grade tumors or with negative cytology results. The sensitivity of urine telomerase activity in detecting bladder tumors was similar in the subgroups of patients with different tumor grades at all AEU cutoff values. In particular, at 50 AEUs the sensitivity was 93 percent, 87 percent, and 89 percent for grades 1, 2, and 3, respectively.

"The test we developed requires a small amount of urine; is noninvasive, inexpensive, and easy to perform; and permits a quantitative evaluation of telomerase activity in cellular extracts from urine. Furthermore, it is objective, reproducible, and specific and is not reliant on the expertise of the cytopathologist. Indeed, one important advantage of this test is its proven ability to also identify low-grade tumors, which often escape detection, thus largely contributing to false-negatives in cytologic examination," the researchers write.

"However, notwithstanding the validated optimal diagnostic accuracy of the test, it is not recommended for use in routine screening programs because of the low incidence of bladder cancer, and should be aimed at high-risk subgroups. Specifically, smokers have about a 3-fold increased risk of developing bladder cancer compared with nonsmokers," the authors add.

"In conclusion, we believe that our telomerase activity urine assay, with the reliability verified in pilot and confirmatory studies, represents a promising and potentially important contribution to the early diagnosis of bladder carcinoma, in particular for high-risk subgroups. Further prospective studies on larger patient populations are needed to assess the promising diagnostic role of urinary telomerase and to define the ability of this assay to detect low-grade tumors and disease recurrence before it becomes clinically evident, which is especially important in a tumor characterized by a high relapse rate."

FDA Clearance to Initiate Chemophase Clinical Trial for Superficial Bladder Cancer

Thu, 11 Aug 2005 23:28:00 PST

( from http://www.rxpgnews.com ) Halozyme Therapeutics, Inc.(Amex: HTI), a biopharmaceutical company focused on the development and commercialization of recombinant human enzymes, today announced it has received clearance from the U.S. Food and Drug Administration (FDA) for its Chemophase(TM) Investigational New Drug (IND)application. The initial clinical protocol under this IND is a Phase I study designed to evaluate a single intravesical administration of Chemophase along with mitomycin in patients with superficial bladder cancer.

"We are thrilled to be able to begin our Chemophase study," said Jonathan Lim, MD, Halozyme's Chairman and CEO. "This novel therapeutic biologic is being developed to enhance the delivery of chemotherapy. Based on the promising pre-clinical data gathered to date, and the previous clinical work done with bovine hyaluronidase in bladder cancer, co-delivery of Chemophase may increase the penetration of mitomycin throughout the tumor and reach residual tumor cells that otherwise might develop into recurrent tumors. We are excited about potentially bringing this therapeutic into the clinic in the fourth quarter, which will represent another important milestone for Halozyme."

According to data from the American Cancer Society, National Cancer Institute, American Urological Association, and Southwest Oncology Group Study, over 180,000 patients present with new or recurrent cases of superficial bladder cancer in the US every year, all of whom would be potential candidates for Chemophase in the event it is approved as first line treatment with mitomycin. The clinical protocol has received Institutional Review Board approval, and the Phase 1 study will enroll up to ten patients to obtain five evaluable patients with superficial bladder cancer. The
objectives of the Chemophase clinical trial are to determine the safety, tolerability and pharmacokinetics of Chemophase administered intravesically with mitomycin.

Broccoli compounds may help in bladder cancer

Fri, 29 Jul 2005 18:17:00 PST

( from http://www.rxpgnews.com ) Researchers have isolated compounds from the vegetable broccoli that they believe may help prevent or slow the progress of bladder cancer.

The current work builds on a major study conducted six years ago by Harvard and Ohio State universities that found that men who ate two or more half-cup servings of broccoli per week had a 44 percent lower incidence of bladder cancer compared to men who ate less than one serving each week.

We're starting to look at which compounds in broccoli could inhibit or decrease the growth of cancerous cells, said Steven Schwartz, a study co-author and a professor of food science and technology at Ohio State University .

Knowing that could help us create functional foods that benefit health beyond providing just basic nutrition.

Some 63,000 people will be diagnosed with bladder cancer this year, according to the American Cancer Society. And more than 13,000 with the disease will die.

The researchers isolated compounds called glucosinolates from broccoli sprouts. During chopping, chewing and digestion, these phytochemicals morph into nutritional powerhouses called isothiocyanates compounds that the scientists believed play a role in inhibiting cancer.

Their hunch was right, at least in the laboratory experiments. There, isothiocyanates hindered the growth of bladder cancer cells. And the most profound effect was on the most aggressive form of bladder cancer they studied.

The researchers presented their findings on July 18 in New Orleans at the annual Institute of Food Technologists meeting.

They first extracted and measured the levels of glucosinolates from broccoli sprouts. They then used a process that uses enzymes to convert the glucosinolates to isothiocyanates.

While young sprouts naturally have higher concentrations of these phytochemicals than full-grown broccoli spears, eating the spears also provides health benefits, Schwartz said.

He and his colleagues treated two human bladder cancer cell lines and one mouse cell line with varying amounts of glucosinolates and isothiocyanates. Even though glucosinolates are converted to isothiocyanates, the researchers wanted to know if the former would have any effect on controlling the growth of cancer cells.

It didn't.

However, the isothiocyanates decreased proliferation in all three cell lines. The strongest effect was on the most aggressive of these lines human invasive transitional cell carcinoma.

The researchers aren't sure what caused this effect, or exactly how these compounds keep cancer cells from proliferating. But they are looking into it.

There's no reason to believe that this is the only compound in broccoli that has an anti-cancer effect, said Steven Clinton, a study co-author and an associate professor of hematology and oncology at Ohio State. There are at least a dozen interesting compounds in the vegetable.

We're now studying more of those compounds to determine if they work together or independently, and what kind of effects they have on cancer cells, he added.

Broccoli isn't the only cruciferous veggie with health benefits, the researchers say. The plant's kin, which include cabbage, cauliflower, Brussels sprouts and kale, may all contain similar disease-fighting phytochemicals.

It's too early to suggest just how much broccoli or other cruciferous vegetables should be eaten to stave off or slow down the progression of bladder cancer. Still, they are an important part of the diet.

Cruciferous veggies have an effect on other types of cancer, too, Schwartz said. We already know that they contain compounds that help detoxify carcinogens. We're thinking more along the lines of progression and proliferation, such as once cancer starts, is there a way to slow it down?

He and Clinton conducted the study with Ohio State colleagues Robin Rosselot, a graduate student in food science and technology and Qingguo Tian, a research associate also in food science and technology.

More dependable, less expensive tool to detect bladder cancer earlier

Wed, 16 Feb 2005 19:42:00 PST

( from http://www.rxpgnews.com ) Physicians now have a more dependable, less expensive tool to help detect bladder cancer earlier.

Researchers at The University of Texas M. D. Anderson Cancer Center found that a simple test that can be administered and read in the doctor's office was three times more effective than a conventional laboratory test for detecting bladder cancer.

In a study published in the February 16 issue of the Journal of the American Medical Association, researchers tested the NMP22 tumor marker assay in 1,331 patients at high risk for bladder cancer. Researchers determined through cystoscopy that 79 of the 1,331 patients examined had bladder cancer. The NMP22 assay was positive in 55 percent of the cases (44 out of 79 cases) while the conventional cytology test detected about 16 percent of malignancies (12 out of 76 cases).

This demonstrated that the NMP22 test was significantly more sensitive than cytology, or the conventional laboratory test, says H. Barton Grossman, M.D., professor in M. D. Anderson's Department of Urology and the study's lead author.

"Our challenge is to improve the detection of bladder cancer," says Grossman. "This test is easy and may save lives."

He cautions, however, that NMP22 should not be used alone to detect bladder cancer, but should be combined with bladder examination (cystoscopy) to provide an accurate diagnosis.

"No single procedure is 100 percent sensitive, so a combination of procedures is recommended," Grossman says.

The findings are seen as an advance in screening for bladder cancer, Grossman says, which is the fifth most common cancer in the United States. Five-year survival is 95 percent for cancer caught early, but it is much lower for the 25 percent of bladder tumors that are advanced when first diagnosed. It is estimated that more than 60,000 people living in the U.S. will be diagnosed with bladder cancer this year; 13,000 are predicted to die of the disease.

Grossman led a team of researchers at M. D. Anderson and 23 academic, private practice, and veterans' facilities in 10 states who enrolled patients into the clinical trial that examined the effectiveness of these different diagnostic tests.

Patients enrolled in the trial were suspected of having bladder cancer because they had evidence of blood in their urine and met some of the risk factors associated with the disease, which include a history of smoking, exposure to certain chemicals, being over age 40 and painful and frequent urination. Tobacco use is the most common risk factor, accounting for about 50 percent of bladder cancer, Grossman says.

To conduct the study, a sample of urine collected from the patients was divided in half, and one part was used for the NMP22 test. The rest was used for a cytology test, which is the screening method physicians traditionally use. The cytology test looks for abnormal cells in the urine and must be sent to outside laboratories for evaluation. Patients may wait as long as a week to receive these results, according to Grossman, while the results of the NMP22 test can be read within 30 to 50 minutes in the doctor's office.

The patients also received a cystoscopy, which uses a flexible endoscope to examine the bladder. This low-risk procedure can be performed under local anesthesia in a doctor's office and is considered the "gold standard" of diagnostic tests, but can fail to detect some bladder cancers, says Grossman.

In this study, the researchers looked at the sensitivity as well as the specificity of cytology versus the NMP22 test. Sensitivity refers to how frequently the test picked up the existence of cancer; specificity refers to whether the test detected cancer that truly existed, and not false positives.

Although NMP22 was more sensitive in this study, cytology was more specific (99 percent versus 86 percent), meaning that the number of false positives was higher for the NMP22 test. Still, the authors say "the high specificity of cytology is offset by low sensitivity, ambiguous test results, expense, and time lag to obtain reports."