The residual effects of N-desmethyldiazepam in patients

Sixty anxious in-patients complaining of insomnia were treated with either 20 mg of N-desmethyldiazepam, 10 mg of this drug, 200 mg of amylobarbitone sodium, or placebo, given at night. The hypnotic effects of these treatments were assessed by self-rating, psychiatrists' ratings and night nurses' observations after one night's treatment and after a week of treatment and compared with pretreatment values. The residual effects of the treatments were estimated 12 h after ingestion using a series of cognitive and motor tasks. No significant differences between the treatments were found after one night. After the week of treatment, the benzodiazepine groups were achieving the best quality of self-rated sleep with fewest subjective feelings of hang-over. Some improvement in performance was found over time for all groups. However, on two motor tests, the higher dose of N-desmethyldiazepam was associated with less improvement, i.e., some impairment relative to placebo was detected.     

Prognostic factors in primary central nervous system lymphomas

Efforts to identify survival predictors in primary central nervous system lymphoma (PCNSL) have produced isolated, unconfirmed observations in small retrospective and prospective series. Age and performance status are two unanimously accepted prognostic factors. These and other independent predictors of survival were used by the International Extranodal Lymphoma Study Group (IELSG) to establish a prognostic scoring system able to distinguish risk groups in PCNSL. The IELSG score will improve further with better knowledge of these malignancies, especially with the inclusion of molecular and pharmacogenetic variables able to identify lymphomas with different chemosensitivities or degrees of aggressiveness. In the years ahead, a well-established prognostic score will allow the separation of patients into risk groups, which could result in the application of risk-tailored therapeutic strategies.     

Aberrant methylation profile of human malignant mesotheliomas and its relationship to SV40 infection

Malignant mesothelioma (MM) is associated with asbestos exposure and the presence of SV40 viral sequences. Recently, we reported that SV40 infection of human mesothelial cells (HM) causes aberrant methylation of the tumor suppressor gene (TSG) RASSF1A. We investigated methylation of 12 genes by methylation-specific PCR in 63 MMs, six MM cell lines, and two foci of SV40-infected HM. Methylation percentages of the tested genes ranged from 3 to 65%. The frequencies of HPP1, RASSF1A, Cyclin D2, and RRAD methylation, and the value of the methylation index, were significantly higher in SV40 sequence-positive MMs than in SV40-negative MMs. Methylation of TMS1 and HIC-1 was associated with shortened survival. SV40-infected HM showed progressive aberrant methylation of seven genes (RASSF1A, HPP1, DcR1, TMS1, CRBP1, HIC-1, and RRAD) during serial passage. Our results demonstrate a relationship between SV40 and methylation of multiple genes in MM, indicating that the virus plays a role in the pathogenesis of MM.     

Characteristics of women refusing follow-up for tests or symptoms suggestive of breast cancer

BACKGROUND: Delay in diagnosis of breast cancer can occur at several points on the diagnostic pathway. We examined characteristics of women with breast cancer who before diagnosis actively refused recommended follow-up of tests or symptoms suggestive of breast cancer. METHODS: We identified women aged 50 years or older diagnosed with late-stage (metastatic disease or tumors > or = 3 cm at diagnosis) and a matched sample of women with early-stage (tumors < 3 cm) breast cancer from 1995 to 1999. Using medical records, we investigated clinical characteristics, use of health care, and documentation of care refusal during the 3 years before diagnosis. We used logistic regression models to compare refusers to nonrefusers. RESULTS: Of the 2694 women studied, 7.2% refused provider follow-up advice during the 3 years. These women were more likely to have late-stage breast cancer at diagnosis than were nonrefusers (odds ratio [OR] = 1.9, 95% confidence interval [CI] = 1.4 to 2.6). They were more likely to be aged 75 years or older (OR = 1.9, 95% CI = 1.4 to 2.7 compared with age 50-64) or to have six or more children (OR = 2.3, 95% CI = 1.3 to 4.2 compared to women with one to two children). Clinical factors associated with refusal included low use of mammography, high use of clinical breast exam, and missed appointments. A minority of women who refused had a reason documented in the medical record; the most frequent reasons were avoidance-denial-fatalism, fear of diagnostic tests, and fear of surgery or disfigurement. CONCLUSIONS: Our results suggest that certain demographic and clinical characteristics are associated with women's refusal of diagnostic testing for breast cancer. Further study is needed on refusers' characteristics and on how such refusals affect outcomes. Efforts aimed at identifying and counseling women with abnormal results who refuse follow-up are warranted.     

See-and-treat strategy for diagnosis and management of cervical squamous intraepithelial lesions

In a see-and-treat protocol, patients referred for colposcopy because of an abnormal Pap smear in cervical-cancer screening can be treated by loop excision, without biopsy, during one visit to the clinic. However, overtreatment in the see-and-treat strategy has been reported to be 1.2-83.3% for low-grade squamous intraepithelial lesions (SIL) and to be 13.3-83.3% for high-grade SIL. Range of overtreatment narrowed to 4.0-23.5% for those with normal pathology and to 18.0-29.4% for those with normal or low-grade pathology when calculation of overtreatment was restricted to patients diagnosed with high-grade SIL on colposcopy and referral Pap smear. Most common treatment complications are bleeding and infection. Nonetheless, the strategy has become accepted internationally: low costs, decreased patient anxiety, and increased compliance make it appealing, especially in settings with limited health resources, and for patients at risk of not being treated in a timely manner or of not returning for a second appointment. Mathematical modelling may give information about the appropriateness and usefulness of this treatment while the results of long-term clinical trials are awaited.     

Chemotherapy regimen GOLF induces apoptosis in colon cancer cells through multi-chaperone complex inactivation and increased Raf-1 ubiquitin-dependent degradation

The multi-drug combination of oxaliplatin (OXA), 5-Fluorouracil (5-FU) and leucovorin (LF) is currently considered as the gold standard treatment for metastatic colorectal carcinoma. In previous studies, we have studied a chemotherapy regimen containing gemcitabine (GEM), OXA, LF, and 5-FU (named GOLF regimen) that has shown a good safety profile and highly significant anti-tumor activity. In the present study, we have investigated on the anti-tumour mechanisms of GOLF in human colon cancer HT-29 and WiDr cell lines. We have found that GOLF induced growth inhibition that was largely caused by apoptosis differently from other combinations. Moreover, the different drugs composing GOLF were highly synergistic in inducing growth inhibition. Apoptosis induced by GOLF combination was paralleled by PARP cleavage and caspase 9 and 3 activation that were not recorded in the other combinations. An about 85% decrease of the activity of Erk and Akt was found in GOLF-treated cells. These effects were likely due to decreased expression of the upstream activator Raf-1 and of Akt itself, respectively. The intracellular levels of these signalling components can be post-translationally regulated by ubiquitin-dependent degradation through proteasome. Therefore, we have evaluated the expression of some chaperone components and we have found that GOLF did not affect the expression of both heat shock protein (HSP) 90 and 27 but induced an about 90% increase of HSP70 levels suggesting the inactivation of the multi-chaperone complex. Moreover, an about 4-fold increase of the ubiquitination of Raf-1 was also found and the addition for 12 h of 10 microM proteasome inhibitor lactacystin caused an accumulation of the ubiquitinated isoforms of Raf-1. In conclusions, GOLF was a combination highly synergistic in inducing both growth inhibition and apoptosis of colon cancer cells. These effects likely occurred through the disruption of critical survival pathways and the inactivation of multi-chaperone complex.