Measuring what matters MOST: Validation of the Measure of Ovarian Symptoms and Treatment, a patient-reported outcome measure of symptom burden and impact of chemotherapy in recurrent ovarian cancer (ROC)

Purpose: Gynecologic Cancer Intergroup Symptom Benefit Study (GCIG-SBS) Stage 2 aimed to review, revise, and validate a patient-reported outcome measure (PROM), the Measure of Ovarian Symptoms and Treatment concerns (MOST), developed in GCIG-SBS Stage 1 (MOSTv1, 35 items), and document recurrent ovarian cancer (ROC) symptom burden and benefit. Methods: GCIG-SBS Stage 2 recruited patients with platinum-resistant/refractory ROC (PRR-ROC) or potentially platinum-sensitive ROC with ≥ 3 lines of prior chemotherapy (PPS-ROC ≥ 3). Patients completed MOSTv1, QLQ-C30, QLQ-OV28, and FACT-O/FOSI at baseline and before cycle 3 of chemotherapy (pre-C3), and global assessments of change (MOST-Change) pre-C3. Clinicians rated patients’ cancer-related symptoms, performance status, and adverse events. Convergent and divergent validity (Spearman’s correlations), discriminative validity (effect sizes between groups classified by clinician-rated characteristics), and responsiveness (paired t tests in patients expected to experience clinically meaningful change) were assessed. Results: Of 948 recruits, 903 completed PROMs at baseline and 685 pre-C3. Baseline symptom burden was substantial for PRR-ROC and PPS-ROC ≥ 3. MOSTv2 has 24 items and five multi-item scales: abdominal symptoms (MOST-Abdo), disease or treatment-related symptoms (MOST-DorT), chemotherapy-related symptoms (MOST-Chemo), psychological symptoms (MOST-Psych), and MOST-Well-being. Correlations confirmed concurrent and divergent validity. Discriminative validity was confirmed by effect sizes that conformed with a priori hypotheses. MOST-Abdo was responsive to improvements in abdominal symptoms and MOST-Chemo detected the adverse effects of chemotherapy. Conclusions: The MOSTv2 validly quantifies patient-reported symptom burden, adverse effects, and symptom benefit in ROC, and as such is fit-for-purpose for clinical trials of palliative chemotherapy in ROC. Further research is required to assess test–retest reliability

Design of MKC-442 (emivirine) analogues with improved activity against drug-resistant HIV mutants.

Two analogues of the nonnucleoside inhibitor of HIV-1 RT, MKC-442 (emivirine), containing different C6 substituents have been designed to be less susceptible to the commonly found drug-resistance mutation of Tyr181Cys. Compound TNK-6123 had a C6 thiocyclohexyl group designed to have more flexibility in adapting to the mutated drug-binding site. GCA-186 had additional 3',5'-dimethyl substituents aimed at forming close contacts with the conserved residue Trp229. Both compounds showed approximately 30-fold greater inhibitory effect than MKC-442 to the Tyr181Cys mutant virus as well as to the clinically important Lys103Asn virus. X-ray crystallographic structure determination of complexes with HIV-1 RT confirmed the predicted binding modes. These strategies might be used to improve the resilience of other NNRTI series against common drug-resistance mutations

Testing IWC retrieval methods using radar and ancillary measurements with in situ data

Vertical profiles of ice water content (IWC) can now be derived globally from spaceborne cloud satellite radar (CloudSat) data. Integrating these data with Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observation (CALIPSO) data may further increase accuracy. Evaluations of the accuracy of IWC retrieved from radar alone and together with other measurements are now essential. A forward model employing aircraft Lagrangian spiral descents through mid-and low-latitude ice clouds is used to estimate profiles of what a lidar and conventional and Doppler radar would sense. Radar reflectivity Z e and Doppler fall speed at multiple wavelengths and extinction in visible wavelengths were derived from particle size distributions and shape data, constrained by IWC that were measured directly in most instances. These data were provided to eight teams that together cover 10 retrieval methods. Almost 3400 vertically distributed points from 19 clouds were used. Approximate cloud optical depths ranged from below 1 to more than 50. The teams returned retrieval IWC profiles that were evaluated in seven different ways to identify the amount and sources of errors. The mean (median) ratio of the retrieved-to-measured IWC was 1.15 (1.03) Ϯ 0.66 for all teams, 1.08 (1.00) Ϯ 0.60 for those employing a lidar-radar approach, and 1.27 (1.12) Ϯ 0.78 for the standard CloudSat radar-visible optical depth algorithm for Z e Ͼ Ϫ28 dBZ e. The ratios for the groups employing the lidar-radar approach and the radar-visible optical depth algorithm may be lower by as much as 25% because of uncertainties in the extinction in small ice particles provided to the groups. Retrievals from future spaceborne radar using reflectivity-Doppler fall speeds show considerable promise. A lidar-radar approach, as applied to measurements from CALIPSO and CloudSat, is useful only in a narrow range of ice water paths (IWP) (40 Ͻ IWP Ͻ 100 g m Ϫ2). Because of the use of the Rayleigh approximation at high reflectivities in some of the algorithms and differences in the way nonspherical particles and Mie effects are considered, IWC retrievals in regions of radar reflectivity at 94 GHz exceeding about 5 dBZ e are subject to uncertainties of Ϯ50%