Chemotherapy use in end-of-life digestive cancer patients: a retrospective AGEO observational study.

BACKGROUND: The use of chemotherapy (CT) near the end-of-life (EOL) is an important issue in oncology since it could degrade quality of life. CT near EOL is still poorly studied, with no dedicated study in gastrointestinal (GI) cancer patients. AIM: To analyze in GI cancer patients the factors associated with the use of CT within 3- and 1-month before patients' death. METHODS AND PARTICIPANTS: All consecutive patients who died from a GI cancer in 10 French tertiary care hospitals during 2014 were included in this retrospective study. Clinical, demographical and biological data were collected and compared between patients receiving or not CT within 3- and 1-month before death. Variables associated with overall survival (OS) was also determined using of univariate and multivariate analyses with a Cox model. RESULTS: Four hundred and thirty-seven patients with a metastatic GI cancer were included in this study. Among them, 293 pts (67.0%) received CT within 3-months before death, and 121 pts (27.7%) received CT within 1-month before death. Patients receiving CT within 3-months before death were significantly younger (median age: 65.5 vs 72.8 years, p < 0.0001), with a better PS (PS 0 or 1: 53.9 vs 29.3%, p < 0.0001) and a higher albumin level (median: 32.8 vs 31.0 g/L, p = 0.048). Similar results were found for CT within 1 month before death. Palliative care team intervention was less frequent in patients who received CT in their last month of life (39.7% vs 51.3%, p = 0.02). In multivariate analysis, median OS from diagnosis was shorter in the group receiving CT within 1-month before death (HR = 0.59; 95% CI [0.48-0.74]). CONCLUSION: In GI-cancer patients, CT is administered within 3- and 1-month before death, in two and one third of patients, respectively. Patients receiving CT within 1-month before death, had more aggressive disease with poor OS. Palliative care team intervention was associated with less administration of CT in the last month of life. These results highlight the need to better anticipate the time to stop CT treatment in the end-of-life and the importance of an active collaboration between oncology and palliative care teams.

Atogepant Has No Clinically Relevant Effects on the Pharmacokinetics of an Ethinyl Estradiol/Levonorgestrel Oral Contraceptive in Healthy Female Participants.

The incidence of migraine is higher among women than men and peaks during the reproductive years, when contraceptive medication use is common. Atogepant, a potent, selective antagonist of the calcitonin gene-related peptide receptor-in development for migraine prevention-is thus likely to be used by women taking oral contraceptives. This phase 1, open-label, single-center, 2-period, fixed-sequence study examined the effect of multiple-dose atogepant 60 mg once daily on the single-dose pharmacokinetics of a combination oral contraceptive, ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg (EE/LNG), in healthy postmenopausal or oophorectomized women. For participants in period 1, a single dose of EE/LNG was followed by a 7-day washout. In period 2, atogepant was given once daily on days 1-17; an oral dose of EE/LNG was coadministered with atogepant on day 14. Plasma pharmacokinetic parameters for EE and LNG were assessed following administration with and without atogepant. Twenty-six participants aged 45-64 years enrolled; 22 completed the study in accordance with the protocol. The area under the concentration-time curve extrapolated to infinity (AUC0-∞ ) of LNG was increased by 19% when administered with atogepant. Coadministration of atogepant and a single dose of EE/LNG did not substantially alter the pharmacokinetics of EE; the ∼19% increase in plasma AUC0-∞ of LNG is not anticipated to be clinically significant. Overall, atogepant alone and in combination with EE/LNG was generally well tolerated, with no new safety signals identified.

Comparative Bioavailability of Oral Granule Formulations of the HIV Antiretroviral Drugs Doravirine, Lamivudine, and Tenofovir Disoproxil Fumarate.

Doravirine is a non-nucleoside reverse transcriptase inhibitor indicated for the treatment of human immunodeficiency virus-1 infection, available as a single tablet in combination with other antiretroviral agents or as a fixed-dose regimen with lamivudine and tenofovir disoproxil fumarate (TDF). Alternative formulations of these drugs are being developed for individuals who have difficulty swallowing tablets. Two phase 1 trials were conducted, both in 24 healthy adults, to assess the pharmacokinetics of uncoated and coated oral granule formulations of doravirine, lamivudine, and TDF administered alone and with vanilla pudding or apple sauce. The pharmacokinetics for all uncoated granules, and of coated lamivudine and TDF granules, were similar to those of currently marketed tablets (geometric mean ratios [GMRs] 0.92-1.04). Coated doravirine granules had decreased AUC0-∞ (11%) and Cmax (23%) values versus the tablet. The pharmacokinetics were similar for uncoated and coated doravirine granules administered with or without pudding (GMRs 0.96-1.10); administration with apple sauce increased doravirine AUC0-∞ (26-29%), Cmax (56-59%), and C24 (20-21%) versus administration of granules alone. Lamivudine granules administered with pudding or apple sauce decreased AUC0-∞ and Cmax (14-25%) versus granules alone. Tenofovir AUC0-∞, Cmax, and C24 increased for TDF granules administered with pudding or apple sauce versus alone (11-23%). Pharmacokinetic differences when administering doravirine, lamivudine, or TDF as uncoated or coated granules versus tablets, or when granules were administered with (versus without) pudding or apple sauce, are not considered clinically meaningful, supporting further development of these granule formulations.

Magnetic resonance imaging of the hand and wrist in a randomized, double-blind, multicenter, placebo-controlled trial of infliximab for rheumatoid arthritis: Comparison of dynamic contrast enhanced assessments with semi-quantitative scoring.

The objective of this study was to compare the scope and the discriminative power of Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) to those of semi-quantitative MRI scoring for evaluating treatments for rheumatoid arthritis (RA) in multicenter randomized clinical trials (RCTs). Sixty-one patients with active RA participated in a double-blind, parallel group, randomized, multicenter methodology study receiving infliximab or placebo through 14 weeks. The most symptomatic wrist and metacarpophalangeal joints (MCPs) were imaged using MRI. In addition to clinical assessments with DAS28(CRP), the severity of inflammation was measured as synovial leak of gadolinium based contrast agent (GBCA) using DCE-MRI (Ktrans, primary endpoint) at weeks 0, 2, 4, and 14. Two radiologists independently scored synovitis, osteitis and erosion using RA MRI Score (RAMRIS) and cartilage loss using a 9-point MRI scale (CARLOS). Infliximab showed greater decrease from baseline in DAS28(CRP), DCE-MRI Ktrans of wrist and MCP synovium, and RAMRIS synovitis and osteitis at all visits compared with placebo (p<0.001). Treatment effect sizes of infliximab therapy were similar for DAS28(CRP) (1.08; 90% CI (0.63-1.53)) and MRI inflammation endpoints: wrist Ktrans (1.00 (0.55-1.45)), RAMRIS synovitis (0.85 (0.38-1.28)) and RAMRIS osteitis (0.99 (0.52-1.43)). Damage measures of bone erosion (RAMRIS) and cartilage loss (CARLOS) were reduced with infliximab compared to with placebo at 14 weeks (p≤0.025). DCE-MRI and RAMRIS were equally sensitive and responsive to the anti-inflammatory effects of infliximab. RAMRIS and CARLOS showed suppression of erosion and cartilage loss, respectively, at 14 weeks. (ClinicalTrials.gov registration: NCT01313520).

Can measures of cognitive function predict locomotor behaviour in complex environments following a traumatic brain injury?

PRIMARY OBJECTIVE: To determine the relationships between clinical measures of executive function and attention, and laboratory measures of anticipatory locomotor adaptations with dual tasks following a TBI. METHODS AND PROCEDURES: Ten people with moderate or severe TBI were compared to 10 healthy subjects for neuropsychological measures in the clinic, as well as locomotor patterns and reading time in the laboratory for adapted Stroop tasks (Bar and Word) during unobstructed and obstructed walking. MAIN OUTCOMES AND RESULTS: As previously found 1 (Vallee M, McFadyen BJ, Swaine B, Doyon J, Cantin JF, Dumas D. Effects of environmental demands on locomotion after traumatic brain injury. Archives of Physical Medicine Rehabilitation 2006;87:806--813) during the locomotor activities, subjects with TBI walked slower, had higher clearance margins and took longer to read during the Stroop tasks than healthy subjects. In general, subjects with TBI also showed deficits in executive functions and attention. Significant relationships were specifically observed between scores on Trail Making B and clearance margins for subjects with TBI, but not for healthy subjects. Alternatively, significant relationships between clinical scores on Stroop and dual task Stroop reading times were obtained for healthy subjects but not for subjects with TBI. CONCLUSIONS: These results suggest that measures of executive functioning and attention may be associated to locomotor behaviour in complex environments following a moderate to severe TBI.

Effect of the Women's Health Initiative study publication on hormone replacement therapy use among women who have undergone BRCA1/2 testing.

BACKGROUND: Since the publication, in July 2002, of the Women's Health Initiative (WHI) study, use of hormone replacement therapy (HRT) has decreased substantially in the general population. However, little is known about the effect of WHI study results on HRT use among women at high risk of breast cancer. The purpose of this study is to compare HRT use, prepublication versus postpublication of the WHI study, among women tested for BRCA1/2 mutations. METHODS: Participants were >35 years of age and had received their result of genetic testing (delivered within the interdisciplinary research program Interdisciplinary Health Research International Team on Breast Cancer Susceptibility), no later than February 28, 2005. HRT use was reported in self-administered questionnaires, 1 year after result disclosure. Women returning their questionnaire before July 17, 2002 were classified as pre-WHI, whereas those returning it after October 15, 2002 comprised the post-WHI group. RESULTS: Four hundred fifty-seven women (199 and 258 in the pre-WIH and post-WHI groups, respectively) were included in this analysis. Globally, there was no difference in HRT use between prepublication and postpublication of the WHI study (8% and 11%, respectively; prevalence ratio, 0.74; 95% confidence interval, 0.43-1.28). However, noncarriers of the familial mutation were less likely to use HRT after publication of the WHI study results (9%) than before (21%; P = 0.03). CONCLUSIONS: Overall, HRT use among women tested for BRCA1/2 mutations is relatively low and apparently uninfluenced by the WHI study findings. However, the HRT use reduction among noncarriers is similar to that of women in the general population and consistent with the Canadian Cancer Society's recent HRT use recommendations.

Effects of environmental demands on locomotion after traumatic brain injury.

OBJECTIVE: To determine the effects of increasingly demanding environments related to simultaneous visual tasks and physical obstructions on the locomotor ability of people with traumatic brain injury (TBI). DESIGN: Group comparison study. SETTING: Gait analysis laboratory within a postacute rehabilitation facility. PARTICIPANTS: Volunteer sample of 9 people (8 men, 1 woman; age, 39.3+/-13.0y) with moderate to severe TBI and a comparison group of 9 subjects without neurologic problems matched for age and sex (8 men, 1 woman; age, 39.7+/-12.3y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Reading times for the Stroop bar and Stroop word tasks, walking speeds, stride lengths, and obstacle clearance margin. RESULTS: The TBI group was slower than the control group in performing the Stroop bar task during sitting (P=.002), and while avoiding the narrow obstacle (P=.05), and in performing the Stroop word task while avoiding the wide obstacle (P=.019). Despite their relatively normal gait speeds on level ground, subjects with TBI walked more slowly than control subjects for the narrow (P=.024) and the wide (P=.019) obstacle conditions and for the most complex dual task (P=.042). Greater lead-limb clearance margins were observed for the TBI group than for control subjects for all conditions whereas no differences were found for the trail limb except at the far end of the wide obstacle. CONCLUSIONS: Despite their good recovery of locomotor function, with respect to normal level walking speeds and ability to avoid obstacles, subjects with moderate and severe TBI showed residual deficits in relation to greater difficulties in dealing with environments that challenge their locomotor and attentional abilities. The use of such naturally based dual tasks may help identify some of the environmental obstructions to social participation after TBI.