In a randomized, double-blind phase 2 study, an intravaginal probiotic composed of Lactobacillus crispatus CTV-05 (Lactin-V, Osel Inc) reduced the rate of recurrent urinary tract infection (rUTI) in UTI-prone women by roughly one half, which compares favorably with historical data on antimicrobial prophylaxis, the researchers say.
They add that larger trials are warranted to see whether use of vaginal Lactobacillus could replace long-term antimicrobial preventive treatments in women susceptible to rUTI.
The study was published online April 15 and in the May 15 print issue of Clinical Infectious Diseases.
UTIs are common in women and frequently recur, Ann Stapleton, MD, from the University of Washington in Seattle, and colleagues note in their report. It has been shown, they add, that women with rUTIs often have alterations in vaginal microbiota, including depletion of lactobacilli.
A phase 1 study of Lactobacillus crispatus CTV-05 showed that the probiotic can be given as a vaginal suppository with minimal adverse effects to healthy women with a history of rUTI. In the phase 2 study, 100 premenopausal women (median age, 21 years) with a history of rUTI received antimicrobials for acute UTI and then were randomly assigned to receive eitherLactobacillus crispatus CTV-05 or placebo vaginal suppository gelatin capsules administered once daily for 5 days, followed by once weekly for 10 weeks.
"We found that Lactin-V reduced the risk of rUTI approximately as effectively as antimicrobial prophylaxis, achieved high-level vaginal colonization in most women, and was well tolerated," Dr. Stapleton and colleagues report.
According to the investigators, culture-confirmed rUTI occurred in 7 (15%) of 48 of women who received Lactobacillus crispatus CTV-05 compared with 13 (27%) of 48 women who received placebo (relative risk [RR], .5; 95% confidence interval [CI], .2 - 1.2).
A high level of vaginal colonization with L crispatus throughout follow-up was associated with a significant reduction in rUTI only among women receiving Lactobacillus crispatus CTV-05 (RR for Lactin-V, .07; RR for placebo, 1.1; P < .01).
The safety profile of the probiotic mirrored that seen in the phase 1 study. Adverse effects were reported by 56% of women receiving Lactobacillus crispatus CTV-05 and 50% of those receiving placebo. The most common adverse effects included vaginal discharge or itching or moderate abdominal discomfort.
A novel aspect of this study, the authors say, is the application of quantitative polymerase chain reaction to assess vaginal microbiota after UTI. This enabled them to define sentinel changes in vaginal microbiota with or without the Lactobacillus crispatus CTV-05 probiotic.
Using quantitative polymerase chain reaction to assess L crispatus colonization in women in both study groups, the researchers say, allowed them to distinguish the natural recovery of the vaginal microbiota after UTI, as may have potentially occurred in the placebo group, from specific effects attributable to the probiotic.
What was "striking," the investigators add, was that placebo-treated women often had high concentrations of vaginal L crispatus during follow-up, yet this failed to protect them from rUTI (RR, 1.1; 95% CI, .4 - 3.1). In contrast, women who received Lactobacillus crispatus CTV-05 and achieved high colonization were protected from rUTI (RR, .07; 95% CI, .02 - .3; P < .01).
"Lactin-V after treatment for acute UTI," they conclude, "confers a significant advantage over repopulation of the vaginal microbiota with endogenous L. crispatus."
"Ongoing studies in our group are directed at understanding the mechanisms of protection in vivo and optimizing this prophylactic regimen," they note.
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BRCA2 MUTATION LINKED TO BETTER SURVIVAL IN OVARIAN CANCER PATIENTS
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Ovarian cancer patients with the BRCA2 gene mutation are more likely to survive their disease than those with the BRCA1 mutation and those without either mutation.
After adjustment for stage, grade, histology and age at diagnosis, BRCA1 carriers showed a modest nonsignificant survival advantage (hazard ratio [HR], 0.84; P = .12). However, BRCA2 carriers showed a marked improvement in survival, compared with noncarriers (HR, 0.57; P = 6 ×10–4).
The data were presented here at the American Association for Cancer Research 102nd Annual Meeting.
"This is the first solid evidence that BRCA2 carriers show a distinct clinical course from BRCA1 carriers," said lead author Kelly Bolton, MPhil, a predoctoral candidate at the National Cancer Institute.
"Our findings don't have any immediate impact on clinical practice, but they do have important implications for both clinical prediction and trial design — particularly for clinical trials," explained Ms. Bolton.
The next step is to try to understand the mechanism driving these survival differences. "There is some evidence from in vitro work and some retrospective clinical studies that suggest that response to chemotherapy may be different between carriers and noncarriers," she said. "There could also be biological differences that exist that we are not yet aware of between BRCA1 andBRCA2 carriers and noncarriers that are driving this association."
Rare germline mutations in the breast and ovarian cancer predisposition genes BRCA1 and BRCA2 are present in about 10% to 15% of ovarian cancer patients, but are quite uncommon in the general population. Both genes play key roles in DNA damage repair, but appear to have distinct, although often complementary, functions, Ms. Bolton pointed out. Breast and ovarian cancer risks differ between the 2 carrier groups, and mutation-specific effects have been suggested for both.
Possible Treatment Implications
Survival among ovarian cancer patients is quite variable, noted Ellen Goode, PhD, associate professor of epidemiology at the Mayo Clinic in Rochester, Minnesota. "BRCA1 and BRCA2 are 2 genes that increase the risk of ovarian cancer."
"But what hasn't been definitively shown until now is that once you have ovarian cancer, if you are a carrier of one of these genes, that will affect your survival," she told Medscape Medical News. Dr. Goode was not involved in the study.
This study shows that there is a difference in outcome that could lead to variables in treatment. "It could be that we need more tailored chemotherapy, depending on BRCA status," she said.
It is still premature to consider testing all ovarian cancer patients for BRCA status, explained Dr. Goode, but it should be considered on an individual basis. "Testing for BRCA is very expensive, so it is not something that is feasible on a large scale," she said.
"If a woman has a family history of the disease and has already been tested, it is probably something that should be taken into account at this point," she added.
"In terms of chemotherapy regimens, a good next analysis would be to stratify women by carrier status," said Dr. Goode. "In the future, I think that this information will prove useful in terms of treatment."
Survival Advantage for BRCA2 Carriers
In this study, Ms. Bolton and colleagues conducted a large multicenter study to investigate the impact of germline BRCA1 andBRCA2 mutations on ovarian cancer survival.
The cohort consisted of 3531 women with invasive epithelial ovarian cancer, of whom 1178 were BRCA1 carriers, 367 were BRCA2carriers, and 1986 were noncarriers. The team analyzed survival-time data obtained from 24 studies conducted in the United States, Europe, Israel, and Asia. The main analysis excluded patients who had not or who were likely to have not received platinum-based therapy.
BRCA1 and BRCA2 carriers were more likely than noncarriers to present with advanced-stage disease, high-grade tumors, and serous disease. The authors also observed that BRCA1 carriers tended to be younger than noncarriers at diagnosis (P = 2 × 10–9), and that BRCA2 carriers were slightly older at diagnosis (P = .002).
In terms of tumor stage, grade, and histology, there was no difference between BRCA1 and BRCA2 carriers, but there was a difference in age at diagnosis (P = 2 × 10–14). In an unadjusted analysis, neither BRCA1 nor BRCA2 carriers differed from noncarriers in overall survival (BRCA1 HR, 1.02; P = .77; BRCA2 HR, 0.89; P = .36). However, after adjustment for baseline characteristics, differences in the 3 groups emerged. For noncarriers, 5-year survival was 36%, for BRCA1 carriers it was 46%, and for BRCA2 carriers it was 61%.
The survival differences that were observed between BRCA1 and BRCA2 carriers could be related to differences in tumor biology or chemosensitivity, the authors note.
After adjustment for stage, grade, histology and age at diagnosis, BRCA1 carriers showed a modest nonsignificant survival advantage (hazard ratio [HR], 0.84; P = .12). However, BRCA2 carriers showed a marked improvement in survival, compared with noncarriers (HR, 0.57; P = 6 ×10–4).
The data were presented here at the American Association for Cancer Research 102nd Annual Meeting.
"This is the first solid evidence that BRCA2 carriers show a distinct clinical course from BRCA1 carriers," said lead author Kelly Bolton, MPhil, a predoctoral candidate at the National Cancer Institute.
"Our findings don't have any immediate impact on clinical practice, but they do have important implications for both clinical prediction and trial design — particularly for clinical trials," explained Ms. Bolton.
The next step is to try to understand the mechanism driving these survival differences. "There is some evidence from in vitro work and some retrospective clinical studies that suggest that response to chemotherapy may be different between carriers and noncarriers," she said. "There could also be biological differences that exist that we are not yet aware of between BRCA1 andBRCA2 carriers and noncarriers that are driving this association."
Rare germline mutations in the breast and ovarian cancer predisposition genes BRCA1 and BRCA2 are present in about 10% to 15% of ovarian cancer patients, but are quite uncommon in the general population. Both genes play key roles in DNA damage repair, but appear to have distinct, although often complementary, functions, Ms. Bolton pointed out. Breast and ovarian cancer risks differ between the 2 carrier groups, and mutation-specific effects have been suggested for both.
Possible Treatment Implications
Survival among ovarian cancer patients is quite variable, noted Ellen Goode, PhD, associate professor of epidemiology at the Mayo Clinic in Rochester, Minnesota. "BRCA1 and BRCA2 are 2 genes that increase the risk of ovarian cancer."
"But what hasn't been definitively shown until now is that once you have ovarian cancer, if you are a carrier of one of these genes, that will affect your survival," she told Medscape Medical News. Dr. Goode was not involved in the study.
This study shows that there is a difference in outcome that could lead to variables in treatment. "It could be that we need more tailored chemotherapy, depending on BRCA status," she said.
It is still premature to consider testing all ovarian cancer patients for BRCA status, explained Dr. Goode, but it should be considered on an individual basis. "Testing for BRCA is very expensive, so it is not something that is feasible on a large scale," she said.
"If a woman has a family history of the disease and has already been tested, it is probably something that should be taken into account at this point," she added.
"In terms of chemotherapy regimens, a good next analysis would be to stratify women by carrier status," said Dr. Goode. "In the future, I think that this information will prove useful in terms of treatment."
Survival Advantage for BRCA2 Carriers
In this study, Ms. Bolton and colleagues conducted a large multicenter study to investigate the impact of germline BRCA1 andBRCA2 mutations on ovarian cancer survival.
The cohort consisted of 3531 women with invasive epithelial ovarian cancer, of whom 1178 were BRCA1 carriers, 367 were BRCA2carriers, and 1986 were noncarriers. The team analyzed survival-time data obtained from 24 studies conducted in the United States, Europe, Israel, and Asia. The main analysis excluded patients who had not or who were likely to have not received platinum-based therapy.
BRCA1 and BRCA2 carriers were more likely than noncarriers to present with advanced-stage disease, high-grade tumors, and serous disease. The authors also observed that BRCA1 carriers tended to be younger than noncarriers at diagnosis (P = 2 × 10–9), and that BRCA2 carriers were slightly older at diagnosis (P = .002).
In terms of tumor stage, grade, and histology, there was no difference between BRCA1 and BRCA2 carriers, but there was a difference in age at diagnosis (P = 2 × 10–14). In an unadjusted analysis, neither BRCA1 nor BRCA2 carriers differed from noncarriers in overall survival (BRCA1 HR, 1.02; P = .77; BRCA2 HR, 0.89; P = .36). However, after adjustment for baseline characteristics, differences in the 3 groups emerged. For noncarriers, 5-year survival was 36%, for BRCA1 carriers it was 46%, and for BRCA2 carriers it was 61%.
The survival differences that were observed between BRCA1 and BRCA2 carriers could be related to differences in tumor biology or chemosensitivity, the authors note.
Welding And Parkinson's, Can Fumes Lead To The Disease?
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Fumes produced by welding contain manganese. Manganese is a chemical element that, even at low levels, has been linked to neurologic problems, including Parkinson's disease-like symptoms. New research suggests that workers exposed to welding fumes may be at risk for developing brain damage in an area of the brain also affected inParkinson's disease.
Brad A. Racette, MD, with Washington University School of Medicine in St. Louis and a Fellow with the American Academy of Neurology stated:
Almost everyone is exposed to small amounts of manganese, a naturally occurring substance in our air, soil, water and food, daily. If kept in check, the body is able to control manganese levels by expelling extra amounts, but if the intake becomes too great, it can become overwhelming and cause a variety of health problems, including permanent nervous system damage.
What makes manganese so dangerous is that the current safety levels may not be adequate, so people may be taking in dangerous levels of this compound that almost no one is aware of.
The study involved 20 welders with no symptoms of Parkinson's disease, 20 people with Parkinson's disease who were not welders and 20 people who were not welders and did not have Parkinson's.
The welders were recruited from two Midwest shipyards and one metal fabrication company. All participants were given brain PET and MRI scans, motor skills tests and examined by a neurologist who specializes in movement disorders. The welders had an average of 30,000 hours of lifetime welding exposure. Their average manganese levels were found to be two times the upper limits of normal.
Scientists found that welders had an average 11.7% reduction in a marker of dopamine in one area of the brain on PET scans as compared to people who did not weld. Dopamine is a chemical messenger that helps nerve cells communicate and is decreased in specific brain regions in people with Parkinson's disease. The welders' motor skills test scores also showed mild movement difficulties that were about half of that found in the early Parkinson's disease patients.
Racette continues:
Perhaps most concerning is that permanent damage to the nervous system may occur after exposure to manganese levels that the Environmental Protection Agency (EPA) has noted as safe.
W. R. Wayne Martin, MD from University of Alberta in Edmonton, Alberta, Canada and also a member of the American Academy of Neurology adds:
Brad A. Racette, MD, with Washington University School of Medicine in St. Louis and a Fellow with the American Academy of Neurology stated:
"There are over one million workers who perform welding as part of their job functions in the United States. If a link between neurotoxic effects and these fumes were proven, it would have a substantial public health impact for the U.S. workforce and economy."
Almost everyone is exposed to small amounts of manganese, a naturally occurring substance in our air, soil, water and food, daily. If kept in check, the body is able to control manganese levels by expelling extra amounts, but if the intake becomes too great, it can become overwhelming and cause a variety of health problems, including permanent nervous system damage.
What makes manganese so dangerous is that the current safety levels may not be adequate, so people may be taking in dangerous levels of this compound that almost no one is aware of.
The study involved 20 welders with no symptoms of Parkinson's disease, 20 people with Parkinson's disease who were not welders and 20 people who were not welders and did not have Parkinson's.
The welders were recruited from two Midwest shipyards and one metal fabrication company. All participants were given brain PET and MRI scans, motor skills tests and examined by a neurologist who specializes in movement disorders. The welders had an average of 30,000 hours of lifetime welding exposure. Their average manganese levels were found to be two times the upper limits of normal.
Scientists found that welders had an average 11.7% reduction in a marker of dopamine in one area of the brain on PET scans as compared to people who did not weld. Dopamine is a chemical messenger that helps nerve cells communicate and is decreased in specific brain regions in people with Parkinson's disease. The welders' motor skills test scores also showed mild movement difficulties that were about half of that found in the early Parkinson's disease patients.
Racette continues:
"While these changes in the brain and dopamine dysfunction may be an early marker of neuron death related to welding exposure, the damage appeared to be different from those of people with full-fledged Parkinson's disease. MRI scans also revealed brain changes in welders that were consistent with manganese deposits in the brain."
Perhaps most concerning is that permanent damage to the nervous system may occur after exposure to manganese levels that the Environmental Protection Agency (EPA) has noted as safe.
W. R. Wayne Martin, MD from University of Alberta in Edmonton, Alberta, Canada and also a member of the American Academy of Neurology adds:
"Although this study shows that these workers had dopamine dysfunction in the brain, the study authors could not determine whether this was specifically related to manganese. Will these individuals develop full-fledged Parkinson's disease? We can't answer that question based on the study but more research should be done to explore this possibility."
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