Biochemical failure as a determinant of distant metastasis and death in prostate cancer treated with radiotherapy

PURPOSE: Biochemical failure (BF), defined by a rising prostate-specific antigen (PSA) profile, is an early surrogate of treatment failure. However, little evidence is available to show that BF is associated with death for patents with prostate cancer treated with radiotherapy. We examined the relationship between BF and death from prostate cancer. METHODS AND MATERIALS: A total of 942 patients were treated between 1987 and 1998 with external beam radiotherapy who had sufficient PSA determinations in follow-up for the analyses described. The median radiation dose was 72 Gy, median PSA was 9.9 ng/mL, and median follow-up was 73 months. The American Society for Therapeutic Radiology and Oncology consensus definition was used to define BF. Kaplan-Meier calculations were from the start of radiotherapy. Cox proportional hazards regression multivariate analyses were used to investigate the association of BF (time-dependent variable) and other factors to distant metastasis (DM), cause-specific death (CSD), and overall death (OD). The year of treatment was included in some of the multivariate analyses to correct for potential unknown factors that may have occurred during the years of the study, such as stage migration. RESULTS: BF was observed in 316 patients (34%), and 66 (7%) experienced DM, 32 (3%) died of prostate cancer, and 230 (24%) died overall during the study period. The Kaplan-Meier 5-year rate estimates from the start of treatment for BF, DM, CSD, and OD were 38%, 6%, 3%, and 13%, respectively. All patients with DM had BF. In multivariate analyses, BF was associated with DM and CSD, but not OD. The inclusion of the year of treatment did not alter these relationships. CONCLUSION: BF, as a time-dependent covariate, was the strongest determinant of DM and was also very significantly related to CSD. The inclusion of the year of treatment had little effect on these associations. Longer follow-up is needed to determine conclusively the relationship of BF to OD.     

Effects of dietary folate and alcohol intake on promoter methylation in sporadic colorectal cancer: the Netherlands cohort study on diet and cancer

Sporadic colorectal cancer (CRC) is characterized by genetic and epigenetic changes such as regional DNA hypermethylation and global DNA hypomethylation. Epidemiological and animal studies suggest that aberrant DNA methylation is associated with low dietary folate intake, which is aggravated by high alcohol intake. The relationship between promoter methylation of genes involved in CRC carcinogenesis and folate and alcohol intake was investigated. Methylation of the APC-1A, p14(ARF), p16(INK4A), hMLH1, O(6)-MGMT, and RASSF1A promoters was studied using methylation-specific PCR in 122 sporadic CRCs, derived from patients with folate and alcohol intake at either the lower or the higher quintiles of the distribution. Overall, promoter hypermethylation frequencies observed were: 39% for APC; 33% for p14(ARF); 31% for p16(INK4A); 29% for hMLH1; 41% for O(6)-MGMT; and 20% for RASSF1A. For each of the tested genes, the prevalence of promoter hypermethylation was higher in CRCs derived from patients with low folate/high alcohol intake (n = 61) when compared with CRCs from patients with high folate/low alcohol intake (n = 61), but the differences were not statistically significant. The number of CRCs with at least one gene methylated was higher (84%) in the low folate intake/high alcohol intake group when compared with the high folate intake/low alcohol intake group (70%; P = 0.085). Despite the size limitations of this study, these data suggest that folate and alcohol intake may be associated with changes in promoter hypermethylation in CRC.     

Routine mammography is associated with earlier stage disease and greater eligibility for breast conservation in breast carcinoma patients age 40 years and older

BACKGROUND: Reduction in breast carcinoma mortality is a major benefit of screening mammography and has been demonstrated in multiple randomized clinical trials and service screening programs. Another benefit from screening is that it allows the patient a wider choice of treatment options, particularly the possibility of conservation surgery. The current study analyzed the impact of mammography in the staging and treatment of breast carcinoma. METHODS: A total of 1591 women aged > or = 40 years were treated for breast carcinoma between July 1995 and October 2001. Three subgroups were defined and compared. Group 1 had 192 patients with no previous mammography, Group 2 was comprised of 695 patients who underwent mammography on average less often than once yearly, and Group 3 was comprised of 704 patients who on average underwent mammography once yearly or more often. RESULTS: The difference in tumor stage was found to be statistically significant between the groups (P < 0.0001). In Group 1, 15% of the patients had ductal carcinoma in situ (DCIS) compared with 21% of patients in Group 2 and 26% of patients in Group 3. In addition, 32% of patients in Group 1 had T1 tumors, whereas 50% of patients in Group 2 and 56% of patients in Group 3 had T1 tumors. The tumor size was < or = 1 cm in 8% of the patients in Group 1 compared with 20-23% of patients in Groups 2 and 3 (P = 0.0092). Breast conservation was an option for 41% of the patients in Group 1 but mastectomy was recommended in another 41% of patients. However, in Groups 2 and 3, 61% of patients were offered breast conservation and mastectomy was recommended to 28% (P < 0.0001). CONCLUSIONS: In the current study, women age > or = 40 years with breast carcinoma who underwent mammography at least once yearly were diagnosed with DCIS more often compared with patients who underwent mammography less frequently or those who had no prior mammography. Women who underwent mammographic screening were found to have smaller tumors, which resulted in a majority of these patients being able to consider breast conservation as an alternative to mastectomy.     

The proto-oncoprotein c-Fos negatively regulates hepatocellular tumorigenesis

Hepatocytes adopt an invasive and metastatic phenotype caused by the cooperation of transforming growth factor (TGF)-beta and oncogenic Ha-Ras. In the initial phase of this process, c-Fos is rapidly induced by TGF-beta, but then decreases to undetectable levels. Here, we investigated the functional implications of c-Fos activation and its contribution to hepatocellular tumorigenesis. By employing conditional c-Fos expression, we observed that continuous activation of c-Fos and consequently AP-1 activity leads to depolarization of differentiated murine epithelial hepatocytes. Most remarkably, this change in morphology was associated with inhibition of proliferation and induction of cell death. Coexpression of antiapoptotic Bcl-XL or scavenging of reactive oxygen species was sufficient to prevent the c-Fos-mediated phenotype. In contrast, the cooperation of c-Fos with oncogenic Ha-Ras or a Ras mutant selectively activating the MAPK pathway even enhanced c-Fos-induced effects. Showing the negative role in hepatocellular tumorigenesis, c-Fos repressed oncogenic Ras-driven anchorage-independent growth in vitro and strongly suppressed tumour formation in vivo. Taken together, we demonstrate that c-Fos modulates plasticity of epithelial hepatocytes and acts tumour suppressive in neoplastic hepatocytes by stimulating cell cycle inhibition and cell death.     

Adherence to HIV medications in a cohort of men who have sex with men: Impact of September 11th

Adherence to highly active antiretroviral therapy (HAART) regimens remains a challenge for people living with human immunodeficiency virus (HIV). Severe traumas like that of September 11, 2001, can exacerbate the difficulties already associated with adherence. A community-based sample of 68 HIV-seropositive men who have sex with men (MSM) living in New York City who were on protease inhibitor HAART regimens completed quantitative assessments to examine adherence in the aftermath of September 11th. Data were drawn from a larger study of drug use and HIV medication adherence. Assessments conducted from September 24, 2001 to October 24, 2001 were compared to assessments taken 2–4 months prior to September 11th. Repeated measures analyses of variance were used to analyze the number of missed and suboptimal doses (doses taken outside the prescribed time by ±4 hours) reported in the 2 weeks prior to each respective assessment. The results indicated a significant increase in the number of missed doses and the number of suboptimal doses immediately after the events of September 11th. Differences in adherence were not influenced, however, by sociodemographic characteristics. These results suggest that the events of September 11th had an impact on adherence to HIV medications among MSM in New York City and provide further support for the notion that the events of September 11th may have adversely impacted the lives of seropositive individuals. Attention should be paid by clinicians working with HIV-positive individuals on how this event has been incorporated into lives of individuals already burdened by a chronic and demanding disease.     

The mechanisms of cell death in focal cerebral ischemia highlight neuroprotective perspectives by anti-caspase therapy

A number of studies have validated the importance of caspase activation in ischemia-induced brain damage. Caspases participate in both the initiation and execution phases of apoptosis, and play a central role in neuronal death after global cerebral ischemia. In focal ischemia, apoptosis occurs in the penumbra during the secondary phase of expansion of the lesion. However, ultrastructural and biochemical analysis have also shown signs of apoptosis in the initial lesion, or infarct core, which is traditionally considered necrotic. Specific caspase pathways are activated in the core and in the penumbra, and participate in both cytoplasmic and nuclear apoptotic events, notwithstanding their initial classification as activator or initiator caspases. This confirms previous suggestions that caspase inhibition holds tremendous neuroprotective potential in stroke and other apoptosis-related degenerative diseases. Consequently, two new approaches, aimed at treating stroke-induced brain damage by anti-apoptotic molecules, are being developed in academic and industrial laboratories. These are based, respectively, on the use of small peptide sequences corresponding to the preferred cleavage site of a caspase, and on genomic constructions derived from the fusion of endogenous anti-caspase molecules with a protein transduction domain from the human immunodeficiency virus-1. Fusion proteins containing endogenous caspases inhibitors efficiently counteract apoptosis in vitro. In in vivo models of focal cerebral ischemia, fusion proteins successfully cross the blood brain barrier and protect cells from ischemic death. This new approach by protein therapy could prove to be an interesting alternative for the reduction of the dramatic consequences of stroke, provided that the long-term efficiency of this protection in terms of functional recovery is demonstrated.