CRM197 enhances antitumor effect of paclitaxel in ovarian cancer

CRM197, an inhibitor of heparin-binding EGF-like factor (HB-EGF), is synergistic with paclitaxel against ovarian cancer, according to a report in the March 15th issue of the International Journal of Cancer.HB-EGF appears to play a critical role in ovarian cancer cell growth and tumor progression, the authors explain. CRM197 binds to HB-EGF and blocks its mitogenic activity by preventing it from binding to EGFR. Dr. Shingo Miyamoto from Fukuoka University, Japan, and colleagues investigated the antitumor effects of paclitaxel and CRM197 in ovarian cancer cell culture and in nude mice injected subcutaneously with ovarian cancer cells. Paclitaxel induced transient ERK activation and sustained activation of JNK and p38 MAPK, effects that were reduced by overexpression of HB-EGF, the authors report. CRM197 effectively suppressed the paclitaxel-induced anti-apoptotic signals mediated by ERK and Akt, and enhanced the pro-apoptotic signals JNK and p38 MAPK. In nude mice with ovarian cancer xenografts, the researchers note, paclitaxel and CRM197 synergistically inhibited tumor formation, completely blocking tumor formation at doses of 10 mg/kg paclitaxel and 5 mg/kg CRM197. "In this study," the authors conclude, "the enhancement of HB-EGF expression abrogates the antitumor effect of paclitaxel by altering the balance of anti-apoptotic and pro-apoptotic signals induced by paclitaxel. The treatment of CRM197 in conjunction with paclitaxel results in a marked synergistic antitumor effect in ovarian cancer cells in vivo, suggesting a novel combination therapy for ovarian cancer patients including those showing chemo-resistance." "Phase 1 study of the use of CRM197 has already started for patients with advanced ovarian cancer in Fukuoka University under the approval of the ethical committee," the investigators add.

CRM197 enhances antitumor effect of paclitaxel in ovarian cancer

CRM197, an inhibitor of heparin-binding EGF-like factor (HB-EGF), is synergistic with paclitaxel against ovarian cancer, according to a report in the March 15th issue of the International Journal of Cancer.HB-EGF appears to play a critical role in ovarian cancer cell growth and tumor progression, the authors explain. CRM197 binds to HB-EGF and blocks its mitogenic activity by preventing it from binding to EGFR. Dr. Shingo Miyamoto from Fukuoka University, Japan, and colleagues investigated the antitumor effects of paclitaxel and CRM197 in ovarian cancer cell culture and in nude mice injected subcutaneously with ovarian cancer cells. Paclitaxel induced transient ERK activation and sustained activation of JNK and p38 MAPK, effects that were reduced by overexpression of HB-EGF, the authors report. CRM197 effectively suppressed the paclitaxel-induced anti-apoptotic signals mediated by ERK and Akt, and enhanced the pro-apoptotic signals JNK and p38 MAPK. In nude mice with ovarian cancer xenografts, the researchers note, paclitaxel and CRM197 synergistically inhibited tumor formation, completely blocking tumor formation at doses of 10 mg/kg paclitaxel and 5 mg/kg CRM197. "In this study," the authors conclude, "the enhancement of HB-EGF expression abrogates the antitumor effect of paclitaxel by altering the balance of anti-apoptotic and pro-apoptotic signals induced by paclitaxel. The treatment of CRM197 in conjunction with paclitaxel results in a marked synergistic antitumor effect in ovarian cancer cells in vivo, suggesting a novel combination therapy for ovarian cancer patients including those showing chemo-resistance." "Phase 1 study of the use of CRM197 has already started for patients with advanced ovarian cancer in Fukuoka University under the approval of the ethical committee," the investigators add.

Triple-negative breast cancer more common in blacks, regardless of age, weight

Black women have a threefold greater risk of developing triple-negative breast cancer (negative for estrogen receptor, progesterone receptor, and HER-2) compared to non-black women, regardless of age or body weight, Boston-based researchers report. "The higher prevalence of triple-negative breast tumors in black women in all age and weight categories likely contributes to black women's unfavorable breast cancer prognosis," Dr. Carol Rosenberg from Boston University School of Medicine noted in comments to Reuters Health. "The reasons explaining this finding are not certain, but it is possible that black women may be at intrinsically greater risk of these more aggressive tumors," she added. Dr. Rosenberg and colleagues looked at the clinical and pathologic features of breast cancers in a diverse group of 415 women. Thirty-six percent of the women were white, 43% were black, 10% Hispanic and 11% of "other" races. Forty-seven percent of the women were obese. Most of the breast tumors (72%) were estrogen receptor-positive and/or progesterone receptor-positive; 20% were triple-negative and 13% were HER2-positive. The investigators focused on triple-negative tumors, which are associated with poor prognosis, and found that the odds ratio for having this tumour type was 3.0 for black women compared with white women. Triple-negative tumors made up equal fractions -- roughly 30% -- of breast cancers in younger and older black women and in obese and non-obese black women, according to the team's report published online March 25 in the journal Breast Cancer Research. "It was known previously," Dr. Rosenberg commented, "that premenopausal black women had more triple-negative tumors. However, there were no previous data about weight. What we found that was new was that these tumors were just as common in black women diagnosed before or after age 50, and in those who were or were not obese." The investigators conclude, "Other factors must determine tumor subtype."

Gemcitabine-cisplatin could be clinically useful in metastatic breast cancer

The combination of gemcitabine and cisplatin is active against metastatic breast cancer, whether prior treatment has been minimal or aggressive, according to two phase 2 studies published online on March 23 by the Journal of Clinical Oncology. The parallel studies, designed by the California Cancer Consortium and Loyola University Chicago and led by Dr. Helen K. Chew at the University of California Davis, Sacramento, enrolled 136 patients with histologically confirmed metastatic or locally recurrent breast cancer. Their median age was 46 years. One of the two study populations comprised 74 women who had been heavily pretreated, with at least two chemotherapy regimens for metastatic disease or disease progression after bone marrow or hematopoietic cell transplantation. In addition, all had received anthracycline or taxane therapy. The 62 women in the minimally treated population had received no more than one prior regimen, without either cisplatin or gemcitabine. Treatment during the study was a 21-day cycle with cisplatin 25 mg/m² daily on days 1 through 4 and gemcitabine 1,000 mg/m² on days 2 and 8. Participants in the heavily pretreated group received a median of three cycles of protocol therapy, while those in the minimally pretreated group received a median of four. The overall response rate was 26% in both groups. The duration of response was 5.3 months in the heavily pretreated group and 5.9 months in the minimally pretreated. Median overall survival was 10.8 months in the heavily pretreated group and 13.1 months in the minimally pretreated. In a subset of 55 patients, the study also analyzed polymorphisms in 10 genes relevant to gemcitabine and cisplatin, including those involved in DNA repair, drug metabolism and cell-cycle control. The XPD-751 polymorphism was associated with significantly increased overall survival, among participants who carried the Lys allele rather than the Gln allele. The XRCC3 polymorphism was associated with significantly better response rate and progression-free survival among patients who carried the Thr/Thr genotype instead of the heterozygous Met/Thr genotype."Our findings," the researchers write, "implicate the potential importance of DNA repair enzymes and drug metabolism enzymes in the prediction of clinical outcome to chemotherapy in metastatic breast cancer."

Fecal occult blood screening may help reduce colorectal cancer mortality

Pilot studies indicate that a population-based approach to guaiac fecal occult blood testing (FOBT) appears likely to reduce colorectal cancer mortality, Scottish researchers report in the April issue of Gut."This study," lead investigator Dr. Robert J. C. Steele told Reuters Health, "clearly demonstrates that a national screening program for bowel cancer using fecal occult blood testing has the potential to reduce death rates from this disease by between 15% and 20%.""As a result of this study," he added, "the Scottish Government Health Department has committed to rolling out a national screening program, which should be complete by the end of 2009. A similar activity is taking place in the rest of the United Kingdom."Dr. Steele of Ninewells Hospital & Medical School, Dundee and colleagues conducted the screenings in the Grampian, Tayside and Fife areas of the country. More than 300,000 subjects participated. Overall, the uptake -- the proportion of those invited who actually attended -- was about 55%.In the first round, the positivity rate was 2.07% and the cancer detection rate was 2.1 per 1000. For the second round, corresponding values were 1.9% and 1.2 per 1000. In the third and final round, they were 1.16% and 0.7 per 1000.Over the 3 rounds, positive predictive values for cancer were 12%, 7% and 7.5%, and for adenoma, they were 36.5%, 30.3% and 29.1%. The corresponding percentages detected at Duke's stage A were 49.2, 40.1 and 36.3.Despite the apparent promise of the approach, concluded Dr. Steele, "it has to be emphasized that success of these programs is crucially dependent on uptake, and future efforts must focus on engaging the British population in this activity."

Steroids pose low risk of adrenal insufficiency after infantile hemangioma therapy

The prevalence of adrenal insufficiency following systemic glucocorticoid therapy does not appear to be at significantly increased risk in infants with hemangiomas, Ohio-based researchers report in the March issue of the Archives of Dermatology.Lead investigator Dr. Jefferson P. Lomenick told Reuters Health that the approach "is commonly used to treat large or disfiguring hemangiomas in young infants. While this therapy is usually successful, steroids are notorious for their side effects, one of which is preventing the body from being able to produce its own steroids naturally -- adrenal suppression or adrenal insufficiency. This can be life-threatening in certain situations."To investigate how prevalent this outcome might be, Dr. Lomenick and colleagues at Cincinnati Children's Hospital Medical Center prospectively studied 16 infants who received prompt adrenal axis evaluation after finishing glucocorticoid therapy. Ten healthy infants acted as controls. The mean duration of treatment was 7.2 months."We found," continued Dr. Lomenick, "that only 1 of 16 infants had adrenal insufficiency following completion of therapy, and this infant had resolution of his adrenal suppression when retested 3 months later. We found similar results in a previous retrospective study."Thus, concluded Dr. Lomenick, "persistent adrenal suppression following completion of glucocorticoid therapy -- as used in our Hemangioma Center -- does not appear to be a problem, and concern for this risk should not dissuade physicians from appropriate use of glucocorticoids for this condition."

Antibiotic strategy can reduce burden of trachoma through herd protection

Frequent mass antibiotic treatment of children can significantly reduce the prevalence of trachoma infection in the overall community, according to a study carried out in rural Ethiopia by U.S. and Ethiopian researchers and published in the March 28 issue of The Lancet. The report indicates that treating children four times a year with a single dose of azithromycin lowers the prevalence of the disease even in untreated individuals, a process analogous to that of herd immunity. There is currently no effective vaccine for trachoma. The study's antibiotic strategy appears to be at least as effective as the approach recommended by the World Health Organization (WHO), which is to treat an entire population annually. The researchers, led by Dr. Thomas Lietman of the University of California, San Francisco, conclude that "this approach could provide a realistic long-term strategy for trachoma programmes." Trachoma is caused by Chlamydia trachomatis infection of the eye. The infection causes severe conjunctival inflammation in young children, which in adulthood can lead to trichiasis (inturned eyelashes), causing painful blindness. In trachoma-hyperendemic areas such as parts of Ethiopia, "more than half of children are affected, almost every adult has scarring, and 10-20% of older people have trichiasis," writes Dr. Hugh R. Taylor of the University of Melbourne, Australia, in an accompanying editorial. Dr. Taylor notes that repeated reinfections appear to be necessary for the severe inflammation that leads to ocular scarring. The cluster-randomized trial took place in 12 communities, where each child aged 1-10 years received four single doses per year of oral azithromycin (approximately 20 mg/kg). Children under 1 year were offered a 6-week course of topical 1% tetracycline. Individuals aged 11 years and older did not receive treatment. In a control group of 12 different communities, no treatment for trachoma was given until after the study ended at 12 months. In a third group of 12 communities, all individuals 1 year and older were offered treatment per WHO guidelines: oral azithromycin or, for children younger than 1 and pregnant women, topical tetracycline. The decline in prevalence of ocular chlamydia infection from baseline to 12 months in the children-treated group was 48.4% to 3.6% in the children 10 and under. Importantly, the mean prevalence of infection in those 11 and older, who had not been treated, also fell significantly, from 15.5% to 8.2%. In the mass-treatment group, the mean prevalence of infection in children aged 10 years and under also declined, from 41.9% to 14.6% over 12 months. However, the latter figure was still significantly higher (p = 0.001) than that for such children in the children-treated group. The prevalence at 12 months in those 11 and older was not significantly different from that in the children-treated group. The researchers suggest that frequent treatment of children could eventually eliminate trachoma infection from the entire community.