To evaluate the influence of treatment on health-related quality of life (HRQoL) in 919 women with recurrent ovarian cancer enrolled in the TRINOVA-1 study, a randomized, placebo-controlled phase 3 study that demonstrated that trebananib 15 mg/kg QW plus weekly paclitaxel significantly improved PFS compared with placebo plus weekly paclitaxel (7.2 versus 5.4 months; hazard ratio, 0.66; 95% CI, 0.57-0.77; P<0.001).
HRQoL was assessed with the Functional Assessment of Cancer Therapy-Ovary (FACT-O; comprising FACT-G and the ovarian cancer-specific subscale [OCS]) and EuroQOL EQ-5D instruments before treatment on day 1 of weeks 1, 5, 9, 13, 17, and every 8 weeks thereafter and at the safety follow-up visit. A pattern-mixture model was used to evaluate influence of patient dropout on FACT-O and OCS scores over time.
834 of 919 randomized patients (91%) had a baseline and ≥1 post-baseline HRQoL assessment. At baseline, scores for all instruments were similar for both arms. At 25 weeks mean±SD changes from baseline were negligible, with mean±SD changes typically <1 unit from baseline: -2.4±16.6 in the trebananib arm and -1.6±15.2 in the placebo arm for FACT-O, -0.71±5.5 in the trebananib arm and -0.86±4.9 in the placebo arm for OCS, and -0.02±0.22 in the trebananib arm and 0.02±0.19 in the placebo arm for EQ-5D. Distribution of scores was similar between treatment arms at baseline and over the course of the study. In pattern-mixture models, there was no evidence that patient dropout affected differences in mean FACT-O or OCS scores. Edema had limited effect on either FACT-O or OCS scores in patients with grade ≥2 edema or those with grade 1 or no edema.
Our results demonstrate that the improvement in PFS among patients in the trebananib arm in the TRINOVA-1 study was achieved without compromising HRQoL.
© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].

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This study aimed to validate a predefined algorithm for osteonecrosis of the jaw (ONJ) among cancer patients in the Danish National Registry of Patients and to assess the nature of clinical information recorded in medical charts of ONJ patients.
We identified potential ONJ cases recorded in 2005-2010 among cancer patients at the hospital Departments of Oral and Maxillofacial Surgery (DOMS) in three Danish regions, using a set of codes from the International Classification of Diseases, 10th revision (ICD-10). We abstracted DOMS charts of the potential cases, had the ONJ status adjudicated by an expert ONJ adjudication committee (ONJAC), and computed positive predictive values. For patients with ONJAC-confirmed ONJ, we abstracted the charts for information on ONJ clinical course. Sensitivity of the algorithm was computed using a separate sample of 101 known ONJ cases accrued in 2005-2011.
We identified 212 potential ONJ cases, of which 197 (93%) had charts available for abstraction. Eighty-three potential cases were confirmed by ONJAC, with a positive predictive value of 42% (95% confidence interval [CI] 35%-49%). DOMS charts of these 83 cases contained complete information on ONJ clinical course. Information about antiresorptive treatment was recorded for 84% of the patients. Among the 101 known ONJ cases, 74 had at least one prespecified ICD-10 code recorded in the Danish National Registry of Patients within ±90 days of the ONJ diagnosis (sensitivity 73%; 95%CI [64%-81%]).
The predefined algorithm is not adequate for monitoring ONJ in pharmacovigilance studies. Additional case-finding approaches, coupled with adjudication, are necessary to estimate ONJ incidence accurately.
Copyright © 2015 John Wiley & Sons, Ltd.

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The widespread presence of pepsin-like enzymes in eukaryotes together with their relevance in the control of multiple biological processes is reflected in the large number of studies published so far for this family of enzymes. By contrast, pepsin homologs from bacteria have only recently started to be characterized. The work with recombinant shewasin A from Shewanella amazonensis provided the first documentation of this activity in prokaryotes. Here we extend our studies to shewasin D, the pepsin homolog from Shewanella denitrificans, to gain further insight into this group of bacterial peptidases that likely represent ancestral versions of modern eukaryotic pepsin-like enzymes. We demonstrate that the enzymatic properties of recombinant shewasin D are strongly reminiscent of eukaryotic pepsin homologues. We determined the specificity preferences of both shewasin D and shewasin A using proteome-derived peptide libraries and observed remarkable similarities between both shewasins and eukaryotic pepsins, in particular with BACE-1, thereby confirming their phylogenetic proximity. Moreover, we provide first evidence of expression of active shewasin D in S. denitrificans cells, confirming its activity at acidic pH and inhibition by pepstatin. Finally, our results revealed an unprecedented localization for a family A1 member by demonstrating that native shewasin D accumulates preferentially in the cytoplasm.

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Venetoclax is a selective, first-in-class, Bcl-2 inhibitor that has demonstrated clinical efficacy in several hematological malignancies. Two studies evaluated the relative bioavailability of venetoclax in healthy subjects: 1) a bioequivalence study to compare the bioavailability of the film-coated tablet to that of an earlier uncoated tablet and 2) a food effect study to evaluate the effect of food on venetoclax pharmacokinetics. Both studies were open-label, single-dose, crossover studies. In the bioequivalence study, 15 subjects received a single dose of venetoclax 50 mg under nonfasting conditions in each of two periods; one period used the uncoated tablet and the other used the film-coated tablet. In the food effect study, 24 subjects received a single dose of venetoclax film-coated 100 mg tablet under fasting conditions, after a low-fat breakfast, or after a high-fat breakfast in different periods. The venetoclax film-coated tablet was bioequivalent to the uncoated tablet which indicates that the film coating does not impact the bioavailability. Median Tmax of venetoclax was delayed by about 2 hours when administered with food. Compared to fasting conditions, Cmax and AUC increased by approximately 3.4-fold following a low-fat breakfast. High-fat meals increased Cmax and AUC by approximately 50% relative to low fat meals. The mean terminal half-life was comparable between the high-fat meal and fasting conditions (19.1 hours versus 16.1 hours). Based on these results and the venetoclax exposure-response profile, venetoclax should be administered with food, and without specific recommendations for fat content, to ensure adequate and consistent bioavailability. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.

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In the early stages of human papillomavirus (HPV) infection, the viral proteins elicit specific immune responses that can participate to regression of ano-genital lesions. HPV E6 protein for instance can reduce type I interferon (IFN) including IFN-κ that is involved in immune evasion and HPV persistence. To evaluate the role of E2 protein in innate immunity in HPV16-associated cervical lesions, genome-wide expression profiling of human primary keratinocytes (HPK) transduced by HPV16 E2 was investigated using microarrays and innate immunity associated genes were specifically analyzed. The analyses showed that the expression of 779 genes was modulated by HPV16E2 and 92 of them were genes associated with innate immunity. Notably IFN-κ and STING were suppressed in HPK expressing the E2 proteins of HPV16 or HPV18 and the trans-activation amino-terminal domain of E2 was involved in the suppressive effect. The relationship between STING, IFN-κ and interferon stimulated genes (ISGs) in HPK was confirmed by gene silencing and real time PCR. The expression of STING and IFN-κ were further determined in clinical specimens by real time PCR. STING and IFN-κ were down-modulated in HPV positive low grade squamous intraepithelial lesions compared with HPV negative controls. This study demonstrates that E2 proteins of high risk HPV reduce STING and IFN-κ transcription and its downstream target genes that might be an immune evasion mechanism involved in HPV persistence and cervical cancer development.

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