Cross-calibration of dual-energy X-ray densitometers for a large, multi-center genetic study of osteoporosis

Osteoporosis is a common disease with a strong genetic component characterized by reduced bone mass and an increased risk of fragility fractures. Bone mineral density (BMD) is the most important determinant of osteoporotic fracture risk, but the genes responsible for BMD regulation and fracture are incompletely defined. To enable multi-center studies to examine the genetic influences on BMD there is a requirement to standardize measurements across different manufacturers of bone densitometers, different versions of machines and different normative ranges. This paper describes a method developed to allow near-identical subjects with low age-adjusted BMD (based on Z-scores) to be recruited in 17 centers using 27 different densitometers. Cross-calibration was based on measurements using a European spine phantom circulated to all centers and measured ten times on each individual machine. From theses values an individual exponential curve, based on nominal versus observed BMD, was derived for each machine. As expected, there were large and significant variations in nominal BMD values, not only between scanners from different manufacturers but also between different versions of scanners from the same manufacturer. Hologic scanners tended to underestimate the nominal BMD, while Lunar scanners overestimated the value. Norland scanners gave mixed values over estimating BMD at the lower nominal value (0.5 g/cm²) while underestimating the value at the higher value (1.5 g/cm²). The validity of the exponential equations was tested using hip and spine measurements on 991 non-proband women from a familial osteoporosis study (FAMOS). After cross-calibration there was a considerable reduction in variation between machines. This observation, coupled with the absence of a similar reduction in variation attributable to a linear regression on age, demonstrated the validity of the cross-calibration approach. Use of the cross-calibration curves along with a standard normative range (in the case of this study, the Hologic normative range) allowed age-specific Z-scores to be used as an inclusion criterion in this genetic study, a method that will be useful for other trials where age-specific BMD inclusion criteria are required.     

Phase III study of second-line chemotherapy for advanced non-small-cell lung cancer with weekly compared with 3-weekly docetaxel.

PURPOSE: A phase III study to determine whether a weekly docetaxel schedule improves the therapeutic index compared with the classic 3-weekly schedule. PATIENTS AND METHODS: Patients with stage IIIB-IV non-small-cell lung cancer (NSCLC) were randomly assigned to docetaxel 75 mg/m2 on day 1 every 3 weeks (3-weekly) and 35 mg/m2 on days 1, 8, and 15 (weekly) for < or = eight cycles. End points included survival (primary), toxicity, and response. RESULTS: Of 215 patients enrolled, 208 (103 in the 3-weekly arm and 105 in the weekly arm) were assessable for response. At baseline, 24.5% of patients (51 out of 208) had received prior paclitaxel therapy and 43.3% of patients (90 out of 208) had been progression-free for more than 3 months after first-line therapy. After 12 months' follow-up, median survival was 6.3 months (95% CI, 4.68 to 7.84 months) with 3-weekly docetaxel and 9.2 months (95% CI, 5.83 to 12.59 months) with weekly docetaxel (P = .07) after a median of four (range, one to eight) and two (range, one to eight) treatment cycles, respectively. Overall, response rates were 12.6% v 10.5% with 3-weekly versus weekly docetaxel. Significantly fewer patients reported grade 3 to 4 toxicities with weekly docetaxel versus 3-weekly docetaxel (P < or = .05). There were significantly lower rates of grade 3 to 4 anemia (P < or = .05), leucopenia (P < .0001), and neutropenia (P < or = .001) with weekly versus 3-weekly treatment. No grade 3 to 4 thrombocytopenia or mucositis was reported. CONCLUSION: Weekly docetaxel 35 mg/m2 demonstrated similar efficacy and better tolerability than standard 3-weekly docetaxel 75 mg/m2 and can be recommended as a feasible alternative second-line treatment option for patients with advanced NSCLC.     

Measurement of Ejection Fraction in Man by Videodensitometry

This report describes a new method based on roentgen videodensitometry for the measurement of left ventricular ejection fraction in man. The net forward ejection fraction (NFEF) is calculated directly from the formula NFEF = 1-exp (?.693/N), where N is the number of cardiac cycles necessary for half of the injected contrast material to be washed out of the left ventricle. The derivation of this formula is presented, and the technique is validated by comparison with washout curves from a Lucite model of the heart and with simultaneous angiographically determined left ventricular ejection fractions in man. The videodensitometry technique offers the following advantages over the conventional volume technique: (1) only a small amount of contrast material is required; (2) ectopic beats are uncommon during the washout phase when measurements are made; (3) the ejection fraction measured is an average of several cardiac cycles; and (4) dependence upon operator interpretation is minimized. Furthermore, given adequate mixing within the chamber, NFEF should be independent of ventricular geometry. Thus, NFEF of the unusually shaped left ventricle can be readily determined.     

Comparing methods for clinical investigator site inspection selection: a comparison of site selection methods of investigators in clinical trials

ABSTRACT

Background During the past two decades, the number and complexity of clinical trials have risen dramatically increasing the difficulty of choosing sites for inspection. FDA’s resources are limited and so sites should be chosen with care.

Purpose To determine if data mining techniques and/or unsupervised statistical monitoring can assist with the process of identifying potential clinical sites for inspection.

Methods Five summary-level clinical site datasets from four new drug applications (NDA) and one biologics license application (BLA), where the FDA had performed or had planned site inspections, were used. The number of sites inspected and the results of the inspections were blinded to the researchers. Five supervised learning models from the previous two years (2016–2017) of an on-going research project were used to predict site inspections results, i.e., No Action Indicated (NAI), Voluntary Action Indicated (VAI), or Official Action Indicated (OAI). Statistical Monitoring Applied to Research Trials (SMART^TM) software for unsupervised statistical monitoring software developed by CluePoints (Mont-Saint-Guibert, Belgium) was utilized to identify atypical centers (via a p-value approach) within a study.Finally, Clinical Investigator Site Selection Tool (CISST), developed by the Center for Drug Evaluation and Research (CDER), was used to calculate the total risk of each site thereby providing a framework for site selection. The agreement between the predictions of these methods was compared. The overall accuracy and sensitivity of the methods were graphically compared.

Results Spearman’s rank order correlation was used to examine the agreement between the SMART^TM analysis (CluePoints’ software) and the CISST analysis. The average aggregated correlation between the p-values (SMART^TM) and total risk scores (CISST) for all five studies was 0.21, and range from ?0.41 to 0.50. The Random Forest models for 2016 and 2017 showed the highest aggregated mean agreement (65.1%) amongst outcomes (NAI, VAI, OAI) for the three available studies. While there does not appear to be a single most accurate approach, the performance of methods under certain circumstances is discussed later in this paper.

Limitations Classifier models based on data mining techniques require historical data (i.e., training data) to develop the model. There is a possibility that sites in the five-summary level datasets were included in the training datasets for the models from the previous year’s research which could result in spurious confirmation of predictive ability. Additionally, the CISST was utilized in three of the five site selection processes, possibly biasing the data.

Conclusion The agreement between methods was lower than expected and no single method emerged as the most accurate.     

Responses of small- and large-field bipolar cells to GABA and glycine

Morphologically distinct subtypes of retinal bipolar cells transmit information along parallel pathways to convey different aspects of the visual scene, but the synaptic mechanisms that regulate signal transmission are largely unknown. The all-rod retina of skate provides a comparatively simple system in which to correlate bipolar cell morphology with responses to the inhibitory neurotransmitters GABA and glycine. Two subtypes of bipolar cells can be identified when isolated in culture: large-field bipolar cells with extensive dendritic arbors, and small-field bipolar cells with one or two dendritic branches. Under voltage-clamp, glycine elicited significant current responses from small-field cells, but not from large-field bipolar cells. Although all bipolar cells displayed GABA-activated chloride currents mediated by both GABA(A) and GABA(C) receptors, the small-field bipolar cells showed a significantly greater contribution from GABA(A) receptors. The results of the present study reveal for the first time that the relative expression of the two classes of GABA receptor on each bipolar cell type correlates with cell morphology and the presence of the glycine receptor.     

Phase II trial of gemcitabine/irinotecan in refractory or relapsed small-cell lung cancer

BACKGROUND: Gemcitabine and irinotecan have shown a broad range of activity in solid tumors, including small-cell lung cancer (SCLC), with a synergistic effect on SCLC cell lines. The objective of this phase II trial was to evaluate the activity of gemcitabine/irinotecan in patients with relapsed SCLC. PATIENTS AND METHODS: Thirty-five patients (15 with refractory disease and 20 with sensitive disease) who had experienced treatment failure with 1 previous chemotherapy regimen were recruited. Treatment consisted of gemcitabine 1,000 mg/m(2) and irinotecan 100 mg/m(2) on days 1 and 8 of a 21-day cycle for a maximum of 6 cycles. Eligibility criteria included an Eastern Cooperative Oncology Group performance status of 0-2, adequate organ function, and signed informed consent. RESULTS: All 35 patients were assessable for response, survival, and toxicity. Best objective responses exhibited were as follows: complete response in 2 patients (6%), partial response in 4 (11%; 95% confidence interval [CI], 21%-61%), stable disease in 7 (20%; 95% CI, 9%-45%), and progressive disease in 22 (63%; 95% CI, 17%-57%). Median time to disease progression was 3.4 months and median survival was 5.8 months. The 1-year survival rate was 34%. Toxicity was mainly hematologic. Grade 3/4 nausea and vomiting occurred in 9% of patients, neuropathy occurred in 2.8%, and diarrhea occurred in 14.3%. Survival was not significantly different for patients with refractory versus sensitive disease. CONCLUSION: The combination of gemcitabine/irinotecan was shown to be active as second-line chemotherapy, especially in patients with refractory disease.     

The effect of diets high in fat and/or fiber on colonic absorption of DMH in the rat

The possibility that long-term feeding of diets high in fat or fiber could alter the colonic mucosa and subsequent colonic absorption of 1,2-dimethylhydrazine (DMH) in situ was examined in the rat model. Male Sprague-Dawley rats were fed one of four experimental diets for six weeks prior to studies of DMH absorption and bile acid excretion; dietary treatments consisted of two levels of fat (12 and 47% of calories from corn oil) fed at each of two levels of fiber (plus or minus 15% wheat bran). Two sets of DMH absorption studies (Studies 1 and 2) were performed; the first used a 10- and the second a 20-minute test period. In Study 1, DMH absorption was greater in those animals that had been fed the high level of corn oil when additional fiber was not present in the diet. When a longer absorption period was used (Study 2), this effect of diet on DMH absorption was not apparent. The level of fiber, not the fat intake, altered bile acid excretion. Bile acid concentration (mg/g dry wt) decreased with added fiber, whereas total bile acid excretion (mg/day) increased. These results indicate that high levels of dietary fat may result in small increases in DMH absorption which are unrelated to changes in bile acid concentration.