Systematic reanalysis of genomic data improves quality of variant interpretation.

As genomic sequencing expands, so does our knowledge of the link between genetic variation and disease. Deeper catalogs of variant frequencies improve identification of benign variants, while sequencing affected individuals reveals disease-associated variation. Accumulation of human genetic data thus makes reanalysis a means to maximize the benefits of clinical sequencing. We implemented pipelines to systematically reassess sequencing data from 494 individuals with developmental disability. Reanalysis yielded pathogenic or likely pathogenic (P/LP) variants that were not initially reported in 23 individuals, 6 described here, comprising a 16% increase in P/LP yield. We also downgraded 3 LP and 6 variants of uncertain significance (VUS) due to updated population frequency data. The likelihood of identifying a new P/LP variant increased over time, as ~22% of individuals who did not receive a P/LP variant at their original analysis subsequently did after 3 years. We show here that reanalysis and data sharing increase the diagnostic yield and accuracy of clinical sequencing.

Bioavailability of penclomedine and systemic exposure to 4-O-demethylpenclomedine in patients receiving oral and intravenous penclomedine.

PURPOSE: Oral administration of penclomedine was investigated based on preclinical studies indicating that an oral schedule of penclomedine treatment may prevent the neurotoxicity observed in phase I studies of an intravenous (i.v.) formulation, possibly by reducing maximum plasma concentrations (Cmax) of the neurotoxic parent species. METHODS: Penclomedine was administered i.v. (200 mg/m2) and orally (250 mg/m2) in alternate sequences to patients with solid tumor malignancies. Plasma concentrations of parent drug and the principal metabolite, 4-O-demethylpenclomedine, were determined by a reversed-phase HPLC assay. RESULTS: Penclomedine was detectable in the plasma of all patients within 1 h of oral penclomedine treatment and Cmax was reached within 1 to 4 h. Consistent with the hypothesis that an oral schedule of administration may circumvent neurotoxicity, a paired data analysis demonstrated a significant reduction in Cmax values following oral administration (P=0.017). However the magnitude of this reduction was highly variable. Similarly an extensive range in the relative exposure to both parent drug and metabolite were observed. The bioavailability of penclomedine ranged from 28% to 98% (median 73%). CONCLUSIONS: Oral penclomedine does produce systemic exposure, but substantial interpatient variability in absorption and systemic exposure is present which may limit the clinical role of the oral route of administration.

Phase I study of paclitaxel on a 3-hour schedule followed by carboplatin in untreated patients with stage IV non-small cell lung cancer.

This study sought to determine the principal toxicities and feasibility of administering paclitaxel as a 3-hour infusion followed by carboplatin without and with granulocyte colony-stimulating factor (G-CSF) in chemotherapy-naive patients with stage IV non-small cell lung carcinoma (NSCLC), and to recommend doses for subsequent clinical trials. Twenty-three patients were treated with paclitaxel at doses ranging from 175 to 225 mg/m2 followed by carboplatin targeting area under the concentration-time curve (AUC) 7 or 9 mg/mL.min every 3 weeks. AUCs were targeted using the Calvert formula with estimated creatinine clearance as a surrogate for the glomerular filtration rate. A high rate of intolerable, mutually exclusive toxicities, consisting primarily of thrombocytopenia, as well as neutropenia, nausea and vomiting, and mucositis, precluded escalation of carboplatin above a targeted AUC of 7 mg/mL.min with paclitaxel 225 mg/m2, which approaches the maximum tolerated dose (MTD) of paclitaxel given as a single agent on a 3-hour schedule. Moderate to severe peripheral neurotoxicity occurred in several patients after multiple courses. Due to the heterogeneous nature of the principal toxicities and the ability to administer clinically-relevant doses of both agents in combination without G-CSF, further dose escalation using G-CSF was not performed. Nine of 23 (39%) total patients and 43% of 21 assessable patients had partial responses (PR). The recommended doses for subsequent clinical trials are paclitaxel 225 mg/m2 as a 3-hour infusion followed by carboplatin at a targeted AUC of 7 mg/mL.min. The ability to administer clinically-relevant single agent doses of paclitaxel and carboplatin in combination, as well as the significant antitumor activity noted in this phase I trial, indicate that further evaluations of this regimen in both advanced and early stage NSCLC are warranted.