Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor.

BACKGROUND: Expression of the colony-stimulating factor 1 (CSF1) gene is elevated in most tenosynovial giant-cell tumors. This observation has led to the discovery and clinical development of therapy targeting the CSF1 receptor (CSF1R). METHODS: Using x-ray co-crystallography to guide our drug-discovery research, we generated a potent, selective CSF1R inhibitor, PLX3397, that traps the kinase in the autoinhibited conformation. We then conducted a multicenter, phase 1 trial in two parts to analyze this compound. In the first part, we evaluated escalations in the dose of PLX3397 that was administered orally in patients with solid tumors (dose-escalation study). In the second part, we evaluated PLX3397 at the chosen phase 2 dose in an extension cohort of patients with tenosynovial giant-cell tumors (extension study). Pharmacokinetic and tumor responses in the enrolled patients were assessed, and CSF1 in situ hybridization was performed to confirm the mechanism of action of PLX3397 and that the pattern of CSF1 expression was consistent with the pathological features of tenosynovial giant-cell tumor. RESULTS: A total of 41 patients were enrolled in the dose-escalation study, and an additional 23 patients were enrolled in the extension study. The chosen phase 2 dose of PLX3397 was 1000 mg per day. In the extension study, 12 patients with tenosynovial giant-cell tumors had a partial response and 7 patients had stable disease. Responses usually occurred within the first 4 months of treatment, and the median duration of response exceeded 8 months. The most common adverse events included fatigue, change in hair color, nausea, dysgeusia, and periorbital edema; adverse events rarely led to discontinuation of treatment. CONCLUSIONS: Treatment of tenosynovial giant-cell tumors with PLX3397 resulted in a prolonged regression in tumor volume in most patients. (Funded by Plexxikon; ClinicalTrials.gov number, NCT01004861.).

Health-related quality of life of children and adolescents prior to hematopoietic progenitor cell transplantation: diagnosis and age effects.

BACKGROUND: The health-related quality of life (HRQOL) may vary among children before undergoing hematopoietic progenitor cell transplantation (HPCT). This study examined the HRQOL of children scheduled for HPCT, the effects of diagnosis and age on HRQOL, and the convergent validity of one generic and two disease-specific measures of HRQOL. PROCEDURE: The sample consisted of 111 children (mean age = 10.4 years) diagnosed with acute lymphoblastic leukemia (ALL; 22%), other leukemias (26%), neuroblastoma (19%), other solid tumors (18%), and hematologic disorders (15%). Convergence validity was tested with 67 children (mean age = 10.3 years) who had an equivalent distribution of diagnoses except for neuroblastoma (12%). The Child Health Questionnaire (CHQ), a generic measure, and the Pediatric Oncology Quality of Life Scale (POQOL) and the Play Performance Scale (PPS), disease-specific measures, were completed by one parent prior to HPCT. RESULTS: Compared to the norms for healthy children, the CHQ Physical summary scores for every diagnostic subgroup and the CHQ Psychosocial summary scores for ALL were poorer. Compared to the cancer norms for Total POQOL and PPS scores, scores for ALL and neuroblastoma were the poorest. These measures also revealed that adolescents' HRQOL was perceived to be worse than children's. Total POQOL scores showed strong convergent validity with CHQ Physical and Psychosocial scores and moderate convergent validity with the PPS scores. CONCLUSIONS: Based on parental reports, children treated for ALL and neuroblastoma appear to be at the greatest risk for poor HRQOL before undergoing HPCT, and adolescents seem to be more compromised than younger children, based on parental reports. The POQOL measure seems to be the best predictor of HRQOL. These results have clinical implications for the care of children undergoing HPCT.

Lack of increased HIV risk behavior among injection drug users participating in the AIDSVAX B/E HIV vaccine trial in Bangkok, Thailand.

OBJECTIVE: To determine whether HIV vaccine trial participation leads to increased risk behavior through beliefs about vaccine protection against infection. METHODS: Changes in risk behavior were evaluated among 2545 injection drug users participating in the AIDSVAX B/E vaccine trial in Bangkok, enrolled from March 1999 to August 2000. Demographic characteristics, beliefs and risk behavior were assessed at baseline and every 6 months thereafter. Risk-reduction counseling was provided at every study visit. Generalized estimation-equation logistic regression analysis was used to study trends in risk behavior and associated factors. RESULTS: Participants were 93.4% male, their median age was 26 years, and 67.2% had at least secondary education. At baseline, 61.3% were receiving methadone detoxification and 20.9% were receiving methadone maintenance. From baseline to the 12-month follow-up visit, injection drug use decreased from 93.8% to 66.5% (P < 0.001) and needle sharing from 33.0% to 17.5% (P < 0.001). Multivariate analyses showed earlier follow-up time (at baseline and 6 months) and believing the vaccine to be efficacious associated with more-frequent injecting; younger age and lower education associated with less-frequent injecting. Earlier follow-up time (at baseline), younger age, and injection of methamphetamine and midazolam were associated with more-frequent needle sharing; methadone treatment and injecting less than weekly were associated with less-frequent needle sharing. CONCLUSIONS: Injection drug use and needle sharing decreased during the first 12 months of the trial. No increases in risk behavior in relation to beliefs about vaccine protection against HIV infection could be identified.