Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): a double-blind, randomised, placebo-controlled phase 3 trial.

BACKGROUND: Maintenance therapy following autologous stem cell transplantation (ASCT) can delay disease progression and prolong survival in patients with multiple myeloma. Ixazomib is ideally suited for maintenance therapy given its convenient once-weekly oral dosing and low toxicity profile. In this study, we aimed to determine the safety and efficacy of ixazomib as maintenance therapy following ASCT. METHODS: The phase 3, double-blind, placebo-controlled TOURMALINE-MM3 study took place in 167 clinical or hospital sites in 30 countries in Europe, the Middle East, Africa, Asia, and North and South America. Eligible participants were adults with a confirmed diagnosis of symptomatic multiple myeloma according to International Myeloma Working Group criteria who had achieved at least a partial response after undergoing standard-of-care induction therapy followed by high-dose melphalan (200 mg/m2) conditioning and single ASCT within 12 months of diagnosis. Patients were randomly assigned in a 3:2 ratio to oral ixazomib or matching placebo on days 1, 8, and 15 in 28-day cycles for 2 years following induction, high-dose therapy, and transplantation. The initial 3 mg dose was increased to 4 mg from cycle 5 if tolerated during cycles 1-4. Randomisation was stratified by induction regimen, pre-induction disease stage, and response post-transplantation. The primary endpoint was progression-free survival (PFS) by intention-to-treat analysis. Safety was assessed in all patients who received at least one dose of ixazomib or placebo, according to treatment actually received. This trial is registered with ClinicalTrials.gov, number NCT02181413, and follow-up is ongoing. FINDINGS: Between July 31, 2014, and March 14, 2016, 656 patients were enrolled and randomly assigned to receive ixazomib maintenance therapy (n=395) or placebo (n=261). With a median follow-up of 31 months (IQR 27·3-35·7), we observed a 28% reduction in the risk of progression or death with ixazomib versus placebo (median PFS 26·5 months [95% CI 23·7-33·8] vs 21·3 months [18·0-24·7]; hazard ratio 0·72, 95% CI 0·58-0·89; p=0·0023). No increase in second malignancies was noted with ixazomib therapy (12 [3%] patients) compared with placebo (eight [3%] patients) at the time of this analysis. 108 (27%) of 394 patients in the ixazomib group and 51 (20%) of 259 patients in the placebo group experienced serious adverse events. During the treatment period, one patient died in the ixazomib group and none died in the placebo group. INTERPRETATION: Ixazomib maintenance prolongs PFS and represents an additional option for post-transplant maintenance therapy in patients with newly diagnosed multiple myeloma. FUNDING: Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company.

Tonotopic organisation of the auditory cortex in sloping sensorineural hearing loss.

Although the tonotopic organisation of the human primary auditory cortex (PAC) has already been studied, the question how its responses are affected in sensorineural hearing loss remains open. Twenty six patients (aged 38.1 ± 9.1 years; 12 men) with symmetrical sloping sensorineural hearing loss (SNHL) and 32 age- and gender-matched controls (NH) participated in an fMRI study using a sparse protocol. The stimuli were binaural 8s complex tones with central frequencies of 400 HzCF, 800 HzCF, 1600 HzCF, 3200 HzCF, or 6400 HzCF, presented at 80 dB(C). In NH responses to all frequency ranges were found in bilateral auditory cortices. The outcomes of a winnermap approach, showing a relative arrangement of active frequency-specific areas, was in line with the existing literature and revealed a V-shape high-frequency gradient surrounding areas that responded to low frequencies in the auditory cortex. In SNHL frequency-specific auditory cortex responses were observed only for sounds from 400 HzCF to 1600 HzCF, due to the severe or profound hearing loss in higher frequency ranges. Using a stringent statistical threshold (p < 0.05; FWE) significant differences between NH and SNHL were only revealed for mid and high-frequency sounds. At a more lenient statistical threshold (p < 0.001, FDRc), however, the size of activation induced by 400 HzCF in PAC was found statistically larger in patients with a prelingual, as compared to a postlingual onset of hearing loss. In addition, this low-frequency range was more extensively represented in the auditory cortex when outcomes obtained in all patients were contrasted with those revealed in normal hearing individuals (although statistically significant only for the secondary auditory cortex). The outcomes of the study suggest preserved patterns of large-scale tonotopic organisation in SNHL which can be further refined following auditory experience, especially when the hearing loss occurs prelingually. SNHL can induce both enlargement and reduction of the extent of responses in the topically organized auditory cortex.

Beneficial Effects of 6-Month Supplementation with Omega-3 Acids on Selected Inflammatory Markers in Patients with Chronic Kidney Disease Stages 1-3.

INTRODUCTION: Chronic kidney disease (CKD) is accompanied by inflammation. The aim of this study was to evaluate the effect of 6-month supplementation with omega-3 acids on selected markers of inflammation in patients with CKD stages 1-3. METHODS: Six-month supplementation with omega-3 acids (2 g/day) was administered to 87 CKD patients and to 27 healthy individuals. At baseline and after follow-up, blood was taken for C-reactive protein (CRP) and monocyte chemotactic protein-1 (MCP-1) concentration and white blood cell (WBC) count. Serum concentration of omega-3 acids-eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and alpha-linolenic acid (ALA)-was determined using gas chromatography. And 24-hour urinary collection was performed to measure MCP-1 excretion. RESULTS: After six-month omega-3 supplementation, ALA concentration increased in CKD patients and in the reference group, while EPA and DHA did not change. At follow-up, a significant decrease in urinary MCP-1 excretion in CKD (p = 0.0012) and in the reference group (p = 0.001) was found. CRP, serum MCP-1, and WBC did not change significantly. The estimated glomerular filtration rate (eGFR) did not change significantly in the CKD group. CONCLUSIONS: The reduction of urinary MCP-1 excretion in the absence of MCP-1 serum concentration may suggest a beneficial effect of omega-3 supplementation on tubular MCP-1 production. TRIAL REGISTRATION: This study was registered in ClinicalTrials.gov (identifier: NCT02147002).

Influence of Acoustic Overstimulation on the Central Auditory System: An Functional Magnetic Resonance Imaging (fMRI) Study.

BACKGROUND The goal of the fMRI experiment was to explore the involvement of central auditory structures in pathomechanisms of a behaviorally manifested auditory temporary threshold shift in humans. MATERIAL AND METHODS The material included 18 healthy volunteers with normal hearing. Subjects in the exposure group were presented with 15 min of binaural acoustic overstimulation of narrowband noise (3 kHz central frequency) at 95 dB(A). The control group was not exposed to noise but instead relaxed in silence. Auditory fMRI was performed in 1 session before and 3 sessions after acoustic overstimulation and involved 3.5-4.5 kHz sweeps. RESULTS The outcomes of the study indicate a possible effect of acoustic overstimulation on central processing, with decreased brain responses to auditory stimulation up to 20 min after exposure to noise. The effect can be seen already in the primary auditory cortex. Decreased BOLD signal change can be due to increased excitation thresholds and/or increased spontaneous activity of auditory neurons throughout the auditory system. CONCLUSIONS The trial shows that fMRI can be a valuable tool in acoustic overstimulation studies but has to be used with caution and considered complimentary to audiological measures. Further methodological improvements are needed to distinguish the effects of TTS and neuronal habituation to repetitive stimulation.