Characteristics of suicide attempts of patients with major depressive episode and borderline personality disorder: a comparative study

OBJECTIVE: Suicidal behavior is highly prevalent in borderline personality disorder and major depressive episode, although the characteristics of suicide attempts in the two disorders are believed to differ. Comorbidity of borderline personality disorder and major depressive episode may obscure characteristics of suicide attempts that are uniquely related to the psychopathology of each disorder. We compared suicidal behavior in patients with borderline personality disorder, major depressive episode, and borderline personality disorder plus major depressive episode to determine whether characteristics of suicide attempts differed between groups and if aspects of core psychopathology predicted specific attempt characteristics. METHOD: Eighty-one inpatients with borderline personality disorder, including 49 patients with borderline personality disorder plus major depressive episode, were compared to 77 inpatients with major depressive episode alone on measures of depressed mood, hopelessness, impulsive aggression, and suicidal behavior, including lifetime number of attempts, degree of lethal intent, objective planning, medical damage, and degree of violence of suicide methods. RESULTS: No significant differences were found in the characteristics of suicide attempts between patients with borderline personality disorder and those with major depressive episode. However, patients with both disorders had the greatest number of suicide attempts and the highest level of objective planning. An increase in either impulsive aggression or hopelessness or a diagnosis of borderline personality disorder predicted a greater number of attempts. Hopelessness predicted lethal intent in all three groups and predicted objective planning in the group with both disorders. Medical damage resulting from the most serious lifetime suicide attempt was predicted by number of attempts. CONCLUSIONS: Comorbidity of borderline personality disorder with major depressive episode increases the number and seriousness of suicide attempts. Hopelessness and impulsive aggression independently increase the risk of suicidal behavior in patients with borderline personality disorder and in patients with major depressive episode.     

Phase I clinical trial of the farnesyltransferase inhibitor BMS-214662 given as a 1-hour intravenous infusion in patients with advanced solid tumors.

PURPOSE: BMS-214662 is a nonsedating benzodiazepine derivative that exhibits broad spectrum cytotoxicity against human solid tumor cell lines and potently inhibits farnesylation of the H-ras and K-ras oncogenic proteins. This report describes the initial Phase I clinical trial of the compound. The main objective of the study was to determine the dose-limiting toxicities and the maximum tolerated dose of BMS-214662 when administered as a single dose i.v. over 1 h every 21 days to patients with advanced solid tumors. EXPERIMENTAL DESIGN: Patients with advanced solid tumors and adequate organ function were eligible for the study. The dose was escalated according to a modified Fibonacci schedule after evaluating groups of at least three patients for toxicity during the first cycle of therapy at each dose level. Pharmacokinetic and pharmacodynamic studies were performed after administration of the two initial doses. RESULTS: The dose of BMS-214662 was escalated from 36 to 225 mg/m(2) through 5 intermediate dose levels in a total of 44 patients. Dose-limiting toxicities occurred in 3 of the 13 (23%) patients during the first cycle of treatment with 225 mg/m(2), consisting of grade 3 nausea/vomiting in 2 patients and grade 3 diarrhea in another patient. In addition, four of these patients experienced reversible grade 3 transaminitis, which was not considered to be dose-limiting. At the recommended dose for Phase II studies, 200 mg/m(2), the most common side effects were reversible transaminitis, nausea, and vomiting. Although there were no objective responses, one patient with pancreatic cancer continues to receive treatment more than 3.5 years after entering the study. BMS-214662 exhibited linear pharmacokinetics and had a mean biological half-life of 1.55 +/- 0.27 h and a total body clearance of 21.8 +/- 10.8 liters/h/m(2), with a low apparent volume of distribution at steady state (31.5 +/- 12.9 liters/m(2)). In patients treated with the recommended Phase II dose, the mean maximum plasma concentration of the drug was 6.57 +/- 2.94 microg/ml, and farnesyltransferase activity in peripheral blood mononuclear cells decreased to a nadir of 10.5 +/- 6.4% of baseline at the end of the infusion but fully recovered within 24 h. CONCLUSIONS: BMS-214662 can be delivered safely as a single 1-h i.v. infusion at a dose that results in pronounced inhibition of farnesyltransferase activity in peripheral blood mononuclear cells. However, the duration of enzyme inhibition was transient, recovering in parallel with the decline in plasma concentrations of this rapidly eliminated drug. Because indications of anticancer activity were observed in several patients, further optimization of the administration schedule for this promising new compound is warranted.     

Population variations in the initial treatment of non-small-cell lung cancer.

PURPOSE: Dissemination of recommended therapies for non-small-cell lung cancer (NSCLC) have not been described comprehensively. We report the patterns of initial therapy focusing on the investigation of differences in receipt of recommended therapies according to multiple clinical and nonclinical patient characteristics. METHODS: A population-based random sample of newly diagnosed NSCLC patients diagnosed in 10 separate geographic areas was collected in 1996 (n = 898). Data were obtained from medical records. Multiple logistic regression was used to assess the use of recommended therapies. RESULTS: Overall, 52% of NSCLC patients received recommended therapy. Approximately 69%, 48%, and 41% of patients with stages I and II, III, or IV NSCLC received recommended therapy, respectively. For all stages combined, the use of recommended therapy was significantly inversely associated with age and stage at diagnosis. Recommended therapy also was more common in white versus black patients, and in married versus single patients. Stage-specific analyses revealed a significant decline in the use of recommended surgery with increasing age at diagnosis for early-stage NSCLC only, and a significantly lower use of recommended therapy (primarily chemoradiotherapy) for stage III black and Hispanic patients compared with white patients. CONCLUSION: The overall use of recommended therapies for NSCLC is low. Large variations exist in the use of such therapies according to age, race or ethnicity, and marital status. Research combining medical record reviews with other sources of data is needed to better understand the contributions of both patient preferences and physician judgment to these treatment variations.     

The phase III trial in the era of targeted therapy: unraveling the "go or no go" decision.

PURPOSE: To review characteristics of contemporary phase III oncology trials and create an explicit framework to help clinical researchers prioritize novel therapies for phase III testing. METHODS: We searched the MEDLINE and EMBASE databases for all reviews of phase III trials; cataloged all phase III trials in two national clinical trial databases; and reviewed approval criteria of recently approved oncology drugs from public data provided by the US Food and Drug Administration. Industry data not available elsewhere in the medical literature were obtained from a sourcebook published by a large contract research organization. RESULTS: Phase III oncology trials are the most expensive and time-consuming aspect of the drug development process. The results of these trials continue to exert the greatest influence on the treatment decision of oncologists and remain pivotal to the granting of drug approval. Making optimal decisions about which agents to advance to phase III testing may decrease the overall cost of cancer drug development and limit the number of patients exposed to ineffective drugs. A conceptual decision model for prioritizing novel therapies for phase III testing is presented. CONCLUSION: Cancer drug development has become more complex and expensive, whereas overall clinical progress remains slow. The transition from phase II to phase III requires a strategic decision that is based on new considerations. A greater investment in phase I and II drug trials may be required to provide the information necessary for phase III planning.     

CT findings in 14 patients with Mycobacterium chelonae pulmonary infection

OBJECTIVE: The purpose of this report is to describe helical and high-resolution CT findings in 14 patients with pulmonary infection caused by Mycobacterium chelonae, a nontuberculous mycobacterial species that has become increasingly recognized as a rare but significant cause of chronic lung infection in immunocompetent patients. CONCLUSION: Bronchiectasis, nodules, and consolidation are the most common CT features of M. chelonae pulmonary infection. Cavities are less common. These CT findings resemble those reported for Mycobacterium avium complex. In this study, M. chelonae pulmonary infection occurred exclusively in middle-aged and older women.     

Quantitative results

Detailed analysis of information obtained is still under way, but initial trends appear to show stable enrollment, maintenance of minimum service levels, and lower hospital utilization.     

An evaluation of chemical photoreactivity and the relationship to phototoxicity

The existing regulatory guidance for photosafety testing of new drug products states that studies are warranted for those chemicals that both absorb light in the range of 290–700 nm, and that are either applied locally/topically, or “reach” (EMEA)/“significantly partition” (FDA) to the skin or eyes. The initial in vitro study recommended for the assessment of phototoxic potential is the 3T3 Neutral Red Uptake (NRU) Assay. The current study was undertaken to establish superior triggers for the initiation of biological photosafety testing. In this study, photophysical and photochemical parameters for 40 drug or drug-like molecules were studied. Principal Component Analysis (PCA), Partial Least Squares-Discriminant Analysis (PLS-DA), and a fivefold cross-validation PLS algorithm were used to evaluate the relationship between subsets of photophysical and photochemical parameters with the 3T3 NRU PIF/MPE (Photo Irritation Factor/Mean Photo Effect) results. The parameters most indicative of a 3T3 NRU positive PIF or MPE score were the extent of degradation in solution, the quantum yield of formation of singlet oxygen and the relative formation of superoxide anion. The results demonstrate that while absorption of light is critical to the induction of a light-induced process, it is the resultant events that may be used to predict the 3T3 NRU assay result. It is therefore proposed that the trigger for photosafety testing be revised to include a molecular basis for photoreactivity. From this limited investigation, estimated thresholds leading to 3T3 NRU positive results due to photodegradation, formation of singlet oxygen quantum yield or a relative superoxide anion formation value are proposed.     

Expression of HLA class I and II antigens on cells of the human trabecular meshwork

Human corneoscleral tissue containing trabecular meshwork and cultured human trabecular cells were examined for HLA-ABC (class I) and HLA-DR (class II) antigens of the major histocompatibility complex using an indirect immunofluorescence assay. Class I antigens were detected in the trabecular meshwork on frozen sections and on cultured trabecular cells. Class II antigens were constitutively expressed on some, but not all, cells within the trabecular meshwork. Many more cells could be induced to express class II antigens by pre-incubation in human gamma interferon. Cultured trabecular cells did not express class II antigens constitutively, but expression could be induced by gamma interferon. This study suggests that, in addition to Langerhans' cells at the limbus, other cell types within the anterior segment express major histocompatibility complex-encoded class II antigens either constitutively or inducibly. These cells may be important for the initiation and regulation of ocular immunity.