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Ovarian cancer, the leading cause of death from gynecologic cancer in the United States, is one of the few solid tumors in which the five-year survival rate for patients has improved in recent years. 1 , 2 Nevertheless, most women with advanced ovarian cancer die of the disease. Even those with stage III cancer and minimal residual intraperitoneal masses (<2 cm in the greatest dimension) have a median survival of only about 40 months. 3 , 4 Standard chemotherapy for advanced ovarian cancer includes a platinum analogue (either cisplatin or carboplatin). In an attempt to maximize its activity against ovarian cancer, cisplatin has been . . .

The most common human cancers are malignant neoplasms of the skin 1 , 2 . Incidence of cutaneous melanoma is rising especially steeply, with minimal progress in non-surgical treatment of advanced disease 3 , 4 . Despite significant effort to identify independent predictors of melanoma outcome, no accepted histopathological, molecular or immunohistochemical marker defines subsets of this neoplasm 2 , 3 . Accordingly, though melanoma is thought to present with different ‘taxonomic’ forms, these are considered part of a continuous spectrum rather than discrete entities 2 . Here we report the discovery of a subset of melanomas identified by mathematical analysis of gene expression in a series of samples. Remarkably, many genes underlying the classification of this subset are differentially regulated in invasive melanomas that form primitive tubular networks in vitro , a feature of some highly aggressive metastatic melanomas 5 . Global transcript analysis can identify unrecognized subtypes of cutaneous melanoma and predict experimentally verifiable phenotypic characteristics that may be of importance to disease progression.

Solar ultraviolet (UV) light is a major etiological factor in skin carcinogenesis, with solar UV-stimulated signal transduction inducing pathological changes and skin damage. The primary sensor of solar UV-induced cellular signaling has not been identified. We use an experimental system of solar simulated light (SSL) to mimic solar UV and we demonstrate that Fyn is a primary redox sensor involved in SSL-induced signal transduction. Reactive oxygen species (ROS) generated by SSL exposure directly oxidize Cys488 of Fyn, resulting in increased Fyn kinase activity. Fyn oxidation was increased in mouse skin after SSL exposure and Fyn-knockout mice formed larger and more tumors compared with Fyn wild-type mice when exposed to SSL for an extended period of time. Murine embryonic fibroblasts (MEFs) lacking Fyn and cells in which Fyn expression was knocked down were resistant to SSL-induced apoptosis. Furthermore, cells expressing mutant Fyn (C448A) were resistant to SSL-induced apoptosis. These findings suggest that Fyn acts as a regulatory nexus between solar UV, ROS and signal transduction during skin carcinogenesis.

Purpose: Non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with lower risk of certain cancers, but data on the effect on skin cancer risk have been limited and contradictory. We prospectively examined whether use of NSAIDS or acetaminophen was associated with a lower risk of skin cancer in women. Methods: The 92,125 Caucasian women in the Nurses' Health Study provided information on aspirin use in 1980. Other NSAIDs and acetaminophen were added in 1990. Medication use, frequency, and quantity were reassessed on biennial questionnaires. Through 2008, we confirmed 658 melanoma cases, 1,337 squamous cell carcinoma (SCC) cases, and had 15,079 self-reports of basal cell carcinoma (BCC). We used COX proportional hazards models to compute relative risks (RR) adjusted for known skin cancer risk factors. Results: Neither aspirin nor non-aspirin NSAID use was associated with a lower risk of melanoma, SCC, or BCC, even for women with high quantity, frequency, or duration of use. Instead, we observed an increased risk of melanoma among current aspirin users (RR = 1.32, 95 % CI 1.03—1.70), though an increase of similar magnitude among past users and lack of a dose—response effect did not support a pharmacologic mechanism. We observed a mild reduction in SCC risk in current acetaminophen users (RR = 0.88, 95 % CI 0.75—1.02), with a linear decrease in risk with greater frequency of use (p = 0.04). Conclusions: Aspirin and other NSAIDs were not associated with a lower risk of melanoma, SCC, or BCC in women. Our large, prospective study does not support a chemoprotective effect of NSAIDs against skin cancers.

The risks of colorectal cancer and adenoma, the precursor lesion, are believed to be influenced by diet. 1 Burkitt's proposal that a high-fiber diet protects against colon cancer was based on the low rates of colorectal cancer in Africa. 2 Insoluble fibers, such as wheat-bran fiber, are thought to protect against colon cancer by absorbing carcinogens in the gastrointestinal tract. 3 Indeed, wheat-bran fiber has been shown to dilute fecal concentrations of bile acids 4 , 5 and to bind bile acids, thereby increasing their fecal excretion. 6 , 7 Although an inverse correlation was observed between mortality rates from colon cancer and per capita cereal consumption, . . .

Ovarian cancer is the fourth leading cause of cancer death among women in the United States. First-line chemotherapy offered to patients with ovarian cancer generally consists of an intravenous (IV) platinum plus taxane regimen and has remained virtually unchanged for the past 10 years. A number of recently completed phase III randomized trials in the United States have reported improved progression-free survival (PFS) and/or overall survival (OS) with the intraperitoneal (IP) administration of cisplatin. The purpose of this study was to pool the published data to perform a meta-analysis of randomized trials of IP cisplatin in the initial chemotherapy treatment of ovarian cancer patients. This study was initiated to obtain a more valid estimate of the therapeutic impact of IP treatment for these patients. A search strategy was initiated that searched published findings of randomized trials of IP cisplatin therapy from multiple sources from January 1990 through January 2006. Six randomized trials of 1716 ovarian cancer patients were identified and included in this analysis. The pooled hazard ratio (HR) for PFS of IP cisplatin as compared to IV treatment regimens is 0.792 (95% CI: 0.688–0.912, P = 0.001), and the pooled HR for OS is 0.799 (95% CI: 0.702–0.910, P = 0.0007). These findings strongly support the incorporation of an IP cisplatin regimen to improve survival in the front-line treatment of stage III, optimally debulked ovarian cancer.

BACKGROUND : Excess adiposity has been shown to be associated with increased risk for breast cancer recurrence, and a plant-based eating pattern has been hypothesized to be protective. Whether a plant-based diet without specific energy goals will result in weight loss or changes in body composition in women who have been diagnosed with breast cancer has not been fully explored. AIM OF THE STUDY : This study was conducted to identify changes in body weight, anthropometric measures, and body composition over a four year period in a sub-sample of breast cancer survivors participating in a dietary intervention targeting increased intake of vegetables, fruit and fiber and decreased dietary fat intake. METHODS : This randomized, controlled dietary intervention study compared longitudinal changes in intakes, body weight, waist:hip ratio (WHR), body mass index (BMI) and body composition by treatment group among fiftytwo women previously treated for Stage I, II, or IIIA breast cancer from the Arizona site of the Women’s Healthy Eating and Living Study. The dietary intervention aimed for eight servings of fruit and vegetables, 30 g fiber, ≤ 20% total energy from fat per day, as well as daily intake of vegetable juice. The comparison group was advised to follow general dietary guidelines for cancer prevention. RESULTS : The dietary intervention resulted in a significant and sustained increase in fiber, fruit, vegetable, and vegetable juice consumption (p < 0.05) among intervention group subjects as compared to comparison group subjects. The first 6 months resulted in a reduction in body weight and body fat among the intervention group subjects while the comparison group subjects remained stable. Subsequent measurements, at 12, 24 or 36, and 48 months, showed no significant differences in mean body weight, BMI, WHR, or body composition by study group. Also, no significant changes in these measures were demonstrated for either study group between baseline and 48 months. CONCLUSIONS : The dietary intervention efforts resulted in significant changes in diet toward an increase in plant foods and a decrease in dietary fat. Changes in weight, WHR, BMI, and body composition were not different over time or by study group assignment. Interventions that promote a plantbased diet without specific energy restriction do not appear to promote changes in body weight or body composition in women who have been diagnosed with breast cancer. To adequately examine the role of energy restriction in reducing obesity-associated breast cancer recurrence, future interventions should include prescribed energy imbalance either through reduced intake and/or increased expenditure.

Most sporadic colon adenomas acquire mutations in the adenomatous polyposis coli gene (APC) and show defects in APC-dependent signaling. APC influences the expression of several genes, including the c-myc oncogene and its antagonist Mad1. Ornithine decarboxylase (ODC), the first enzyme in polyamine synthesis, is a transcriptional target of c-myc and a modifier of APC-dependent tumorigenesis. A single-nucleotide polymorphism exists in intron 1 of the human ODC gene, which lies between two myc-binding domains. This region is known to affect ODC transcription, but no data exist on the relationship of this polymorphism to risk of colorectal neoplasia in humans. We show that individuals homozygous for the minor ODC A-allele who reported using aspirin are ≈0.10 times as likely to have an adenoma recurrence as non-aspirin users homozygous for the major G-allele. Mad1 selectively suppressed the activity of the ODC promoter containing the A-allele, but not the G-allele, in a human colon cancer-derived cell line (HT29). Aspirin (≥10 µM) did not affect ODC allele-specific promoter activity but did activate polyamine catabolism and lower polyamine content in HT29 cells. We propose that the ODC polymorphism and aspirin act independently to reduce the risk of adenoma recurrence by suppressing synthesis and activating catabolism, respectively, of colonic mucosal polyamines. These findings confirm the hypothesis that the ODC polymorphism is a genetic marker for colon cancer risk, and support the use of ODC inhibitors and aspirin, or other nonsteroidal antiinflammatory drugs (NSAIDs), in combination as a strategy for colon cancer prevention.

Platinum-resistant ovarian cancer continues to be a difficult therapeutic problem. Clearly, molecularly targeted agents should be evaluated in this patient population. Patients were eligible for this phase II study with stage III or IV ovarian cancer, whose tumor expressed Kit (CD117) or platelet-derived growth factor receptor (PDGFR) and with relapse of measurable disease within 6 months of completing frontline, platinum- and taxane-based chemotherapy. Patients were treated daily with 400 mg of imatinib mesylate orally. It was assumed that the agent would be of no further interest if the population response rate was less than 10%. A two-stage design was used for patient accrual. A total of 34 patients were registered to the study. Of these, 15 were found to be ineligible or not evaluable (8 because their tumor samples were negative for both DC117 and PDGFR). Of 19 evaluable patients, 2 (11%) tested positively for c-Kit and 17 (89%) tested positively for PDGFR. There were no objective responders. Thirteen patients (68%) had increasing disease or symptomatic deterioration, and six (32%) went off protocol during the first month due to adverse events. Median progression-free survival was 2 months (95% CI 1–3 months) and median overall survival was 10 months (95% CI 6–18 months). Eleven percent of patients experienced grade 4 hematologic/metabolic toxicity and 37% experienced grade 3 nonhematologic toxicity. We conclude that imatinib mesylate as a single agent does not appear to have useful clinical activity in c-Kit and/or PDGFR positive, recurrent ovarian cancer in heavily pretreated patients with ovarian cancer