Phase I study of high-dose cytosine arabinoside and etoposide in patients with advanced malignancies

Summary Cytosine arabinsodie (ara-C) and etoposide (VP-16) display synergy in the laboratory. Twenty-six patients participated in a phase I study of high-dose ara-C in combination with VP-16. The dose of VP-16 was held constant at 50 mg/m² as an intermittent infusion over 33 h; escalating doses of ara-C were given as infusions during hours 9–12 and 21–24. Myelosuppression was the dose-limiting toxicity and occurred with doses considerably less than those expected from studies of the two drugs as single agents. The suggested initial doses for phase II trials with this schedule are 750 mg/m²×2 doses of ara-C and 50 mg/m² of VP-16. Nonhematologic toxicity was minimal; therefore, further dose escalation is feasible in patients in whom myelosuppression is acceptable.Supported in part by grants from the National Cancer Institute (CA-12197 and CA-09422) and the American Cancer Society CF-85-182     

Human papillomavirus genotype distribution in low-grade cervical lesions: comparison by geographic region and with cervical cancer.

Low-grade squamous intraepithelial lesions (LSIL) associated with certain human papillomavirus (HPV) genotypes may preferentially progress to cervical cancer. HPV genotyping may thus have the potential to improve the effectiveness of screening programs and to reduce overtreatment. LSIL cases (n = 8,308) from 55 published studies were included in a meta-analysis. HPV genotype distribution was assessed by geographic region and in comparison with published data on cervical squamous cell carcinoma (SCC). HPV detection in LSIL was 80% in North America but less than 70% in other regions, most likely reflecting regional differences in LSIL diagnosis. Among 5,910 HPV-positive LSILs, HPV16 was the most common genotype (26.3%) followed by HPV31 (11.5%), HPV51 (10.6%), and HPV53 (10.2%). HPV-positive LSILs from Africa were 2-fold less likely to be infected with HPV16 than those in Europe, and HPV-positive LSILs from North America were more likely to be infected with HPV18 than those from Europe or South/Central America. Interpretation for rarer genotypes was hampered by variation in HPV testing methodology. SCC/LSIL prevalence ratios indicated that HPV16 was 2-fold and HPV18 was 1.5-fold more common in SCC than in HPV-positive LSIL, thus appearing more likely to progress than other high-risk genotypes (SCC/LSIL prevalence ratios between 0.05 and 0.85). HPV53 and HPV66 showed SCC/LSIL ratios of 0.02 and 0.01, respectively. HPV genotype distribution in LSIL differs from that in cervical cancer, highlighting the importance of HPV genotype in the risk of progression from LSIL to malignancy. Some regional differences in the relative importance of HPV genotypes in LSIL were noted.     

Hemodynamic responses to alfentanil in halothane-anesthetized dogs

Alfentanil is an opioid that has been used both as a sole anesthetic and in conjunction with other inhalation anesthetics. However, its effects on myocardial performance and regional blood flow are not clearly known. Using sonomicrometry and radioactive microsphere techniques, we examined the hemodynamic responses to alfentanil when given as a loading dose (45 micrograms/kg) followed by continuous infusion (3 micrograms X kg-1 X min-1) in dogs anesthetized with halothane. Similar plasma levels of alfentanil were observed after the loading and infusion doses, and both techniques of administration produced a significant reduction in arterial pressure without change in global or regional function of the left ventricle. Although cardiac output and left ventricular end-diastolic pressure remained unchanged, heart rate and systemic vascular resistance decreased significantly after the loading dose and recovered slightly when alfentanil was infused continuously. Despite the systemic hypotension, alfentanil did not alter perfusion to the heart, brain, muscle, and skin; however, blood flow to the renal cortex and the arterial supply to the liver decreased by 25 and 60%, respectively. Reduction in blood flow to the kidneys and the liver suggests that alfentanil should be used with caution when normal function of these organs is in question.     

Contribution of genetic factors for melanoma susceptibility in sporadic US melanoma patients

Abstract:  The risks of developing malignant melanoma (MM) include ultraviolet irradiation and genetic factors. To examine the contribution of rare and common variation within known MM genes in sporadic US MM patients, coding regions of known MM susceptibility genes [cyclin-dependent kinase inhibitor 2A ( CDKN2A ), cyclin-dependent kinase 4, melanocortin 1 receptor ( MC1R ) and tyrosinase ( TYR )] were resequenced in 109–135 MM cases. The significance of variants was examined by comparing their frequencies in 390 cancer-free controls. Potential deleterious mutations in CDKN2A were found in two patients and two others had variants of unknown significance. Cases were more likely than controls to harbour the MC1R 'R' variants known or predicted to alter its function ( P  = 0.002), particularly the R160W variant ( P  = 0.0035). The associated TYR R402Q variant (rs1126809*A) was found in 29% of cases, similar to what has been described previously. One MM patient with a family history of MM, who had developed other skin cancers, was homozygous for a novel TYR variant (P406L) of unknown significance. Hence, rare variants in TYR may be important risk factors for skin cancer.     

Remission and Recovery in the Treatment for Adolescents With Depression Study (TADS): Acute and Long-Term Outcomes

ObjectiveWe examine remission rate probabilities, recovery rates, and residual symptoms across 36 weeks in the Treatment for Adolescents with Depression Study (TADS).MethodThe TADS, a multisite clinical trial, randomized 439 adolescents with major depressive disorder to 12 weeks of treatment with fluoxetine, cognitive–behavioral therapy, their combination, or pill placebo. The pill placebo group, treated openly after week 12, was not included in the subsequent analyses. Treatment differences in remission rates and probabilities of remission over time are compared. Recovery rates in remitters at weeks 12 (acute phase remitters) and 18 (continuation phase remitters) are summarized. We also examined whether residual symptoms at the end of 12 weeks of acute treatment predicted later remission.ResultsAt week 36, the estimated remission rates for intention-to-treat cases were as follows: combination, 60%; fluoxetine, 55%; cognitive–behavioral therapy, 64%; and overall, 60%. Paired comparisons reveal that, at week 24, all active treatments converge on remission outcomes. The recovery rate at week 36 was 65% for acute phase remitters and 71% for continuation phase remitters, with no significant between-treatment differences in recovery rates. Residual symptoms at the end of acute treatment predicted failure to achieve remission at weeks 18 and 36.ConclusionsMost depressed adolescents in all three treatment modalities achieved remission at the end of 9 months of treatment.     

Shyness and face scanning in children

Contrary to popular beliefs, a recent empirical study using eye tracking has shown that a non-clinical sample of socially anxious adults did not avoid the eyes during face scanning. Using eye-tracking measures, we sought to extend these findings by examining the relation between stable shyness and face scanning patterns in a non-clinical sample of 11-year-old children. We found that shyness was associated with longer dwell time to the eye region than the mouth, suggesting that some shy children were not avoiding the eyes. Shyness was also correlated with fewer first fixations to the nose, which is thought to reflect the typical global strategy of face processing. Present results replicate and extend recent work on social anxiety and face scanning in adults to shyness in children. These preliminary findings also provide support for the notion that some shy children may be hypersensitive to detecting social cues and intentions in others conveyed by the eyes. Theoretical and practical implications for understanding the social cognitive correlates and treatment of shyness are discussed.