Phase I dose-escalation trial of the oral AKT inhibitor uprosertib in combination with the oral MEK1/MEK2 inhibitor trametinib in patients with solid tumors

This study aimed to determine the safety, tolerability, and recommended phase II doses of trametinib plus uprosertib (GSK2141795) in patients with solid tumors likely to be sensitive to MEK and/or AKT inhibition. This was a phase I, open-label, dose-escalation, and dose-expansion study in patients with triple-negative breast cancer or BRAF-wild type advanced melanoma. The primary outcome of the expansion study was investigator-assessed response. Among 126 enrolled patients, 63 received continuous oral daily dosing of trametinib and uprosertib, 29 received various alternative dosing schedules, and 34 were enrolled into expansion cohorts. Doses tested in the expansion cohort were trametinib 1.5 mg once daily (QD) + uprosertib 50 mg QD. Adverse events (AEs) were consistent with those reported in monotherapy studies but occurred at lower doses and with greater severity. Diarrhea was the most common dose-limiting toxicity; diarrhea and rash were particularly difficult to tolerate. Overall, 59% and 6% of patients reported AEs with a maximum severity of grade 3 and 4, respectively. Poor tolerability prevented adequate delivery of uprosertib with trametinib at a concentration predicted to have clinical activity. The study was terminated early based on futility in the continuous-dosing expansion cohorts and a lack of pharmacological or therapeutic advantage with intermittent dosing. The objective response rate was < 5% (1 complete response, 5 partial responses). Continuous and intermittent dosing of trametinib in combination with uprosertib was not tolerated, and minimal clinical activity was observed in all schedules tested.     

Selective β-adrenergic Receptor Expression on Human Memory CD8+ T Lymphocyte Subsets Regulates Mobilization and INF-y Production

Introduction: CD8⁺ T lymphocytes (CD8TLs) express β-adrenergic receptors (βAR), which bind the neurotransmitter norepinephrine and stress hormone epinephrine released during inflammation, trauma, and psychological stress. Little is known about the functions of this βAR expression on CD8TLs. Methods: Volunteers were exposed to a psychological stressor (N=24). Flow cytometry identified CD8TL subsets by CCR7, CD27, CD28 and CD45RA expression. Adrenergic receptor subtype expression was determined by micro-array. The effects of βPAR stimulation on IFN-γ production in activated CD8TLs was tested in vitro using PMA/Ionomycin. Results: Stress caused selective migration of effector-memory (CCR7⁻CD27⁻CD28⁻) CD8TLs into the blood (+148%, p<.001). An 8-fold up-regulation of the β₂AR was demonstrated in effector-memory cells as compared to naïve CD8TLs. Stimulation of the β₂AR subtype completely inhibited IFN-γ production. Conclusion: These results show that β₂AR stimulation enhances peripheral immune surveillance in a highly selective manner, and might protect against excessive cytokine release during inflammation and stress.

     

A Cluster Randomized Clinical Trial Comparing Functional Capacity Evaluation and Functional Interviewing as Components of Occupational Rehabilitation Programs

Purpose Functional capacity evaluations (FCE) are used to identify work abilities and are commonly integrated into rehabilitation programs. We studied whether integrating FCE into rehabilitation leads to better outcomes for injured workers. Methods A cluster randomised controlled trial was conducted at a workers’ compensation rehabilitation facility (registration ISRCTN61284905). Clinicians were randomised into 2 groups: 1 group used FCE while another conducted semi-structured functional interviews. Outcomes included recommendations following assessment, rehabilitation program outcomes including functional work levels and pain intensity, as well as compensation outcomes at 1, 3, and 6 months after assessment. Analysis included Mann–Whitney U, Chi square and t tests. Results Subjects included 225 claimants of whom 105 were tested with FCE. Subjects were predominantly employed (84 %) males (63 %) with sub-acute musculoskeletal conditions (median duration 67 days). Claimants undergoing FCE had ~15 % higher average functional work levels recommended at time of assessment (Mann–Whitney U = 4,391.0, p < 0.001) but differences at other follow-up times were smaller (0–8 %), in favour of functional interviewing, and not statistically significant. Clinically important improvement during rehabilitation in functional work level (0.9/4, SRM = 0.94), pain intensity (2.0/10, SRM = 0.88) and self-reported disability (21.8/100, SRM = 1.45) were only observed in those undergoing the functional interview. Conclusions Performance-based FCE integrated into occupational rehabilitation appears to lead to higher baseline functional work levels compared to a semi-structured functional interview, but not improved RTW rates or functional work levels at follow-up. Functional interviewing has potential for efficiency gains and higher likelihood of clinically important improvement following rehabilitation, however further research is needed.     

Autochthonous hepatitis E in Southwest England: natural history, complications and seasonal variation, and hepatitis E virus IgG seroprevalence in blood donors, the elderly and patients with chronic liver disease

AIMS: To report the natural history of autochthonous hepatitis E and hepatitis E virus (HEV) IgG seroprevalence in Southwest England. METHODS: Patients with unexplained hepatitis were tested for hepatitis E and cases followed until recovery or death. Five hundred blood donors, 336 individuals over the age of 60 years and 126 patients with chronic liver disease were tested for HEV IgG. RESULTS: Forty cases of autochthonous hepatitis E (genotype 3) were identified. Hepatitis E was anicteric in 25% of cases and usually caused a self-limiting hepatitis predominantly in elderly Caucasian males. Six of 40 had a significant complication and three patients died, two of who had previously undiagnosed cirrhosis. Hepatitis E shows a seasonal variation with peaks in the spring and summer and no cases in November and December. HEV IgG prevalence increases with age, is more common in men and is 16% in blood donors, 13% in patients with chronic liver disease and 25% in individuals over 60 years. CONCLUSION: Autochthonous hepatitis E is more common than previously recognized, and should be considered in the differential diagnosis in patients with hepatitis, whatever their age or travel history. It carries a significant morbidity and when seen in the context of chronic liver disease carries an adverse prognosis.     

Endocardial cushion defect associated with cor triatriatum sinistrum or supravalve mitral ring

Clinical and angiographic or autopsy data, or both, on three children with a subdivided left atrium (cor triatriatum) and an associated endocardial cushion defect are reviewed. (One child had ostium primum defect, and two had complete atrioventricular [A-V] canal.) A fourth patient demonstrates the difficulties in differentiating subdivided left atrium from supravalve mitral stenosis in the presence of an endocardial cushion defect. The clinical findings are greatly influenced by the endocardial cushion defect. A pressure gradient between the pulmonary wedge and (left or right) ventricular end-diastolic pressures in patients with an endocardial cushion defect indicates pulmonary venous obstruction and should alert one to the possibility of these combined lesions. The exact diagnosis is made with injections of angiographic contrast medium into the proximal and distal left atrial chambers, to document the respective relations of the pulmonary veins, left atrial appendage and A-V valves to these atrial chambers. All three patients with an endocardial cushion defect and a subdivided left atrium had an associated patent ductus arteriosus. The common association of subdivided left atrium with intracardiac, pulmonary venous and aortic anomalies is again demonstrated.     

Anal incontinence in women with recurrent obstetric anal sphincter rupture: a case control study

Objectives: To determine the risk of recurrent anal sphincter rupture (ASR), and compare the risk of anal incontinence (AI) after recurrent ASR, with that seen in women with previous ASR who deliver by caesarean section or vaginally without sustaining a recurrent ASR.

Methods: Women with recurrent ASR between January 2000 and June 2011 were identified at two delivery wards in Copenhagen. The women answered a questionnaire with a validated scoring system for AI (St. Mark`s score), and the results were compared with those obtained in two control groups: women with subsequent uncomplicated vaginal delivery or caesarean section.

Results: There were 93?437 vaginal deliveries. ASR occurred in 5.5% (n?=?2851) of the nulliparous and 1.5% (n?=?608) of the multiparous women. Recurrent ASR occurred in 8% (n?=?49) of whom 50% reported symptoms of AI. We found no difference in the occurrence of AI between women with recurrent ASR, and those who delivered vaginally without repeat ASR (p?=?0.37; OR?=?2.0) or by caesarean section (p?=?0.77; OR?=?1.3).

Conclusion: Women with a past history of ASR have an 8% risk of recurrence. AI affects half of the women with recurrent ASR. Larger studies are required to confirm our findings.     

Targeting of heat shock protein 32 (Hsp32)/heme oxygenase-1 (HO-1) in leukemic cells in chronic myeloid leukemia: a novel approach to overcome resistance against imatinib

Resistance toward imatinib and other BCR/ABL tyrosine kinase inhibitors remains an increasing clinical problem in the treatment of advanced stages of chronic myeloid leukemia (CML). We recently have identified the heat shock protein 32 (Hsp32)/heme oxygenase-1 (HO-1) as a BCR/ABL-dependent survival molecule in CML cells. We here show that silencing Hsp32/HO-1 in CML cells by an siRNA approach results in induction of apoptosis. Moreover, targeting Hsp32/HO-1 by either pegylated zinc protoporphyrine (PEG-ZnPP) or styrene maleic acid-micelle-encapsulated ZnPP (SMA-ZnPP) resulted in growth inhibition of BCR/ABL-transformed cells. The effects of PEG-ZnPP and SMA-ZnPP were demonstrable in Ba/F3 cells carrying various imatinib-resistant mutants of BCR/ABL, including the T315I mutant, which exhibits resistance against all clinically available BCR/ABL tyrosine kinase inhibitors. Growth-inhibitory effects of PEG-ZnPP and SMA-ZnPP also were observed in the CML-derived human cell lines K562 and KU812 as well as in primary leukemic cells obtained from patients with freshly diagnosed CML or imatinib-resistant CML. Finally, Hsp32/HO-1-targeting compounds were found to synergize with either imatinib or nilotinib in producing growth inhibition in imatinib-resistant K562 cells and in Ba/F3 cells harboring the T315I mutant of BCR/ABL. In summary, these data show that HO-1 is a promising novel target in imatinib-resistant CML.