Background: TH-302 is a 2-nitroimidazole prodrug of the DNA alkylator bromo-isophosphoramide mustard that is selectively activated under hypoxic conditions. TH-302 has demonstrated anti-myeloma ...activity in preclinical models both in vitro and in vivo, as well as synergistic cytotoxic activity with bortezomib (Bor) in vitro. An ongoing Phase 1/2 study (NCT01522872) investigates TH-302 with dexamethasone (dex) without Bor or with Bor (TBorD) in patients (pts) with relapsed/refractory multiple myeloma (RR MM). The maximum-tolerated dose (MTD) of TH-302 plus dex was previously established at 340 mg/m2. We report preliminary results from pts treated at the MTD of TH-302 plus dex; enrollment in the TBorD arm is ongoing.
Methods: The Phase 1/2 open-label multicenter study investigates IV TH-302 (240-480 mg/m²) plus PO dex (40 mg) with or without Bor (1.3 mg/m2) on Days 1, 4, 8 and 11 of a 21-day cycle. At the MTDs, Simon two-stage designs are implemented to pursue a regimen of TH-302 plus dex if ≥25% response rate or discontinue if ≤5% (90% power, 10% alpha), and pursue TBorD if ≥50% response rate or discontinue if ≤25% (85% power, 10% alpha). Treatment at the MTD of TH-302 plus dex, and establishment of the MTD of TH-302 in TBorD, is ongoing.
Results: 24 pts (19 male, 5 female) with median age 65 years (range: 53 – 86) were enrolled at the 340 mg/m2 MTD of the TH-302 plus dex biweekly regimen. Ten pts had 18 severe adverse events (SAEs), of which 9 were related to TH-302, including 3 pts with cellulitis and 2 pts with pneumonia. Of 17 pts assessable for response at the time of abstract submission, 3 pts achieved a partial response (PR) and 2 pts achieved a minimal response (MR) for an overall response rate of 18% (PR) and a clinical benefit rate of 29% (PR+MR). Nine pts achieved stable disease and 3 pts had progressive disease. Eight pts are undergoing treatment; 16 pts discontinued: progressive disease (10), subject decision (4), AE (1) and alternative therapy (1). The initial dose escalation with TBorD has been completed at 240 mg/m2 TH-302, with enrollment ongoing at 340 mg/m2 TH-302.
Conclusions: TH-302 can be administered at 340 mg/m2 biweekly with dex. Preliminary clinical activity has been noted in pts with heavily pre-treated RR MM. Data from the complete cohort of pts treated with dex and initial patients treated with TBorD will be updated and presented at the meeting.
Laubach:Onyx: Research Funding; Novartis: Research Funding; Millenium: Research Funding; Celgene: Research Funding. Raje:Acetylon: Research Funding; Eli Lilly: Research Funding; Millenium: Consultancy; Celgene: Consultancy; Onyx: Consultancy; Novartis: Consultancy; Amgen: Consultancy. Schlossman:Millennium: Consultancy. Matous:Celgene: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Onyx: Speakers Bureau; Millenium: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Speakers Bureau. Reynolds:Threshold: Honoraria. Shain:Onyx/Amgen: Research Funding; Celgene: Research Funding; Envision/Celgene: Speakers Bureau; L&M Healthcare/Onyx/Amgen: Speakers Bureau. Zackon:Millenium: Speakers Bureau. Mar:Threshold: Employment. Handisides:Threshold: Employment, Equity Ownership. Kroll:Threshold: Employment, Equity Ownership. Anderson:Celgene: Consultancy; Millenium: Consultancy; Onyx: Consultancy; Gilead: Consultancy; Sanofi Aventis: Consultancy; BMS: Consultancy; Oncopep/Acetylon: Equity Ownership. Richardson:Millenium: Membership on an entity’s Board of Directors or advisory committees; JNJ: Membership on an entity’s Board of Directors or advisory committees. Ghobrial:Millennium/Takeda: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees; BMS: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity’s Board of Directors or advisory committees.
Dominant optic atrophy (DOA)
1
,
2
and axonal peripheral neuropathy (Charcot-Marie-Tooth Type 2 or CMT2)
3
are hereditary neurodegenerative disorders most commonly caused by mutations in the ...canonical mitochondrial fusion genes
OPA1
and
MFN2
, respectively
4
. In yeast, homologs of OPA1(Mgm1) and MFN2(Fzo1) work in concert with Ugo1
5
,
6
, which has no human equivalent to date
7
. By whole exome sequencing patients with optic atrophy and CMT2, we identified four families with recessive mutations in
SLC25A46
. We demonstrate that SLC25A46, like Ugo1, is a modified carrier protein that has been recruited to the outer mitochondrial membrane and interacts with the inner membrane remodeling protein, mitofilin(Fcj1). Loss-of-function in cultured cells and in zebrafish unexpectedly leads to increased mitochondrial connectivity, while severely affecting the development and maintenance of neurons in the fish. The discovery of
SLC25A46
strengthens the genetic overlap between optic atrophy and CMT2, while exemplifying a novel class of modified solute transporters linked to mitochondrial dynamics.
IntroductionColorectal cancer is the fourth most common cancer in the UK and an important cause of cancer-related death. In 20% of patients, there is metastasis to the liver or beyond at the time of ...diagnosis. The management of synchronous disease is complex. Conventional surgery removes the colorectal primary first, followed by chemotherapy, with resection of liver metastases as a final step. Advances in the availability and safety of liver surgery, anaesthesia and critical care have made two alternative options feasible. The first is synchronous resection of the primary and liver metastases. The second is resection of the metastatic disease as the first step, termed the reverse or liver-first approach. Currently, evidence is inadequate to inform the selection of care pathway for patients with colorectal cancer and synchronous liver-limited metastases. Specifically, optimal pathways are not defined and there is a dearth of prospectively recorded cohort-defining factors influencing treatment selection or outcome.Methods and analysisColorectal cancer with Synchronous liver-limited Metastases: an Inception Cohort (CoSMIC) is an inception cohort study of patients with a new diagnosis of colorectal cancer with synchronous liver-limited metastases. The sequence of treatment received, and factors influencing treatment decisions, will be evaluated against European Society of Medical Oncology guidelines. Clinical data will be collected, and quality of life, morbidity, mortality and long-term outcome compared for different treatment sequences adjusted for prognostic factors. Disease-free survival or progression will be measured at 1, 2 and 5 years. A nested qualitative study will ascertain patient experiences and clinician perspectives on delivery of care.Ethics and disseminationThe full study protocol was independently peer reviewed by Professor Kees de Jong (University of Maastricht, Holland). CoSMIC has ethical approval from the National Health Service Research Ethics Committee (14/NW/1397). Results will be disseminated to healthcare professionals and patient groups, and may be used to design a definitive trial addressing areas of equipoise in treatment pathways, as well as optimising current pathways to improve outcomes and experiences.Trial registration numberNCT02456285, pre-results.
By combining all the data available from the Genetic Analysis of Multiple sclerosis in EuropeanS (GAMES) project, we have been able to identify 17 microsatellite markers showing consistent evidence ...for apparent association. As might be expected five of these markers map within the Major Histocompatibility Complex (MHC) and are in LD with
HLA-DRB1. Individual genotyping of the 12 non-MHC markers confirmed association for three of them — D11S1986, D19S552 and D20S894. Association mapping across the candidate genes implicated by these markers in 937 UK trio families revealed modestly associated haplotypes in
JAG1 (
p
=
0.019) on chromosome 20p12.2 and
POU2AF1 (
p
=
0.003) on chromosome 11q23.1.
The μ-opioid receptor antagonist effects of naloxonazine on levorphanol-induced thermal antinociception and respiratory depression were examined in rhesus monkeys. Levorphanol (0.032–3.2 mg/kg) ...produced dose-dependent increases in tail-withdrawal latencies from 50°C water in a warm-water tail-withdrawal assay and dose-dependent decreases in ventilation in both air and 5% CO
2 mixed in air. Naloxonazine (0.1–3.0 mg/kg) antagonized both the antinociceptive and ventilatory effects of levorphanol to a similar degree, and the antagonist effects of naloxonazine were greater after 1 h than after 24 h. Under all conditions, the antagonist effects of naloxonazine were fully surmountable. Schild analysis of the antagonist effects of naloxonazine after 1 h pretreatment in the antinociception assay yielded a pA
2 value of 7.6 and a slope of −0.50; by comparison, quadazocine yielded a pA
2 value of 7.5 and a slope of −1.05. These results suggest that naloxonazine acts as a potent and fully reversible μ-opioid receptor antagonist with a moderately long duration of action in rhesus monkeys. In addition, these results suggest that the antinociceptive and ventilatory effects of μ-opioid receptor agonists in rhesus monkeys are mediated by pharmacologically similar populations of μ opioid receptors.
The purpose of the present study was to evaluate the effect of sodium selenite on skeletal and cardiac muscular function in patients with severe Se deficiency.
Skeletal and cardiac muscular function ...was investigated in 10 selenium depleted patients on long-term home parenteral nutrition because of short bowel syndrome. The following examinations were applied: Skeletal muscle biopsy, muscular force test (Kin-Com dynamometer test), electromyography (EMG) and radionuclide ventriculography. The patients were blindly randomized to intravenous supplementation with selenium 200 micrograms 5 to 7 times per week or placebo for 4 months. Hereafter the examinations were repeated. The patients randomized to placebo received selenium in an open study for a further 4 months and hereafter their skeletal and cardiac function was reevaluated.
Plasma selenium increased to normal levels from median .21 mumol/l (range 0-.69) to 1.25 mumol/l (range .9-2.27) following selenium repletion. The muscle biopsies showed only minor abnormalities. The only change after selenium supplementation was a small but statistically significant increase of the mean diameter of fiber type 1. The muscle strength of the quadriceps muscle was unchanged after selenium substitution. EMG did not reveal signs of myopathy. The cardiac function was normal and remained unchanged.
Despite severe selenium depletion ten patients on long term home parenteral nutrition had normal cardiac function, and no clinically significant signs of skeletal myopathy. The only change after selenium supplementation was a small but statistically significant increase of the mean diameter of muscle fiber type 1.
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