Is characteristic frequency limiting real-time electrocochleography during cochlear implantation?

Objectives: Electrocochleography (ECochG) recordings during cochlear implantation have shown promise in estimating the impact on residual hearing. The purpose of the study was (1) to determine whether a 250-Hz stimulus is superior to 500-Hz in detecting residual hearing decrement and if so; (2) to evaluate whether crossing the 500-Hz tonotopic, characteristic frequency (CF) place partly explains the problems experienced using 500-Hz. Design: Multifrequency ECochG comprising an alternating, interleaved acoustic complex of 250- and 500-Hz stimuli was used to elicit cochlear microphonics (CMs) during insertion. The largest ECochG drops (≥30% reduction in CM) were identified. After insertion, ECochG responses were measured using the individual electrodes along the array for both 250- and 500-Hz stimuli. Univariate regression was used to predict whether 250- or 500-Hz CM drops explained low-frequency pure tone average (LFPTA; 125-, 250-, and 500-Hz) shift at 1-month post-activation. Postoperative CT scans were performed to evaluate cochlear size and angular insertion depth. Results: For perimodiolar insertions ( Conclusion: Using 250-Hz stimulus for ECochG feedback during implantation is more predictive of hearing preservation than 500-Hz. This is due to the electrode passing the 500-Hz CF during insertion which may be misidentified as intracochlear trauma; this is particularly important in subjects with smaller cochlear diameters and deeper insertions. Multifrequency ECochG can be used to differentiate between trauma and advancement of the apical electrode beyond the CF

Objective response rate targets for recurrent glioblastoma clinical trials based on the historic association between objective response rate and median overall survival

Durable objective response rate (ORR) remains a meaningful endpoint in recurrent cancer; however, the target ORR for single-arm recurrent glioblastoma trials has not been based on historic information or tied to patient outcomes. The current study reviewed 68 treatment arms comprising 4793 patients in past trials in recurrent glioblastoma in order to judiciously define target ORRs for use in recurrent glioblastoma trials. ORR was estimated at 6.1% [95% CI 4.23; 8.76%] for cytotoxic chemothera + pies (ORR = 7.59% for lomustine, 7.57% for temozolomide, 0.64% for irinotecan, and 5.32% for other agents), 3.37% for biologic agents, 7.97% for (select) immunotherapies, and 26.8% for anti-angiogenic agents. ORRs were significantly correlated with median overall survival (mOS) across chemotherapy (R2= 0.4078, P &lt; .0001), biologics (R2= 0.4003, P = .0003), and immunotherapy trials (R2= 0.8994, P &lt; .0001), but not anti-angiogenic agents (R2= 0, P = .8937). Pooling data from chemotherapy, biologics, and immunotherapy trials, a meta-analysis indicated a strong correlation between ORR and mOS (R2= 0.3900, P &lt; .0001; mOS [weeks] = 1.4xORR + 24.8). Assuming an ineffective cytotoxic (control) therapy has ORR = 7.6%, the average ORR for lomustine and temozolomide trials, a sample size of ≥40 patients with target ORR&gt;25% is needed to demonstrate statistical significance compared to control with a high level of confidence (P &lt; .01) and adequate power (&gt;80%). Given this historic data and potential biases in patient selection, we recommend that well-controlled, single-arm phase II studies in recurrent glioblastoma should have a target ORR &gt;25% (which translates to a median OS of approximately 15 months) and a sample size of ≥40 patients, in order to convincingly demonstrate antitumor activity. Crucially, this response needs to have sufficient durability, which was not addressed in the current study.</p

Objective response rate targets for recurrent glioblastoma clinical trials based on the historic association between objective response rate and median overall survival

Durable objective response rate (ORR) remains a meaningful endpoint in recurrent cancer; however, the target ORR for single-arm recurrent glioblastoma trials has not been based on historic information or tied to patient outcomes. The current study reviewed 68 treatment arms comprising 4793 patients in past trials in recurrent glioblastoma in order to judiciously define target ORRs for use in recurrent glioblastoma trials. ORR was estimated at 6.1% [95% CI 4.23; 8.76%] for cytotoxic chemothera + pies (ORR = 7.59% for lomustine, 7.57% for temozolomide, 0.64% for irinotecan, and 5.32% for other agents), 3.37% for biologic agents, 7.97% for (select) immunotherapies, and 26.8% for anti-angiogenic agents. ORRs were significantly correlated with median overall survival (mOS) across chemotherapy (R$^2$= 0.4078, P 25% is needed to demonstrate statistical significance compared to control with a high level of confidence (P 80%). Given this historic data and potential biases in patient selection, we recommend that well-controlled, single-arm phase II studies in recurrent glioblastoma should have a target ORR > 25% (which translates to a median OS of approximately 15 months) and a sample size of ≥ 40 patients, in order to convincingly demonstrate antitumor activity. Crucially, this response needs to have sufficient durability, which was not addressed in the current study

Consensus recommendations for a standardized Brain Tumor Imaging Protocol in clinical trials

A recent joint meeting was held on January 30, 2014, with the US Food and Drug Administration (FDA), National Cancer Institute (NCI), clinical scientists, imaging experts, pharmaceutical and biotech companies, clinical trials cooperative groups, and patient advocate groups to discuss imaging endpoints for clinical trials in glioblastoma. This workshop developed a set of priorities and action items including the creation of a standardized MRI protocol for multicenter studies. The current document outlines consensus recommendations for a standardized Brain Tumor Imaging Protocol (BTIP), along with the scientific and practical justifications for these recommendations, resulting from a series of discussions between various experts involved in aspects of neuro-oncology neuroimaging for clinical trials. The minimum recommended sequences include: (i) parameter-matched precontrast and postcontrast inversion recovery-prepared, isotropic 3D T1-weighted gradient-recalled echo; (ii) axial 2D T2-weighted turbo spin-echo acquired after contrast injection and before postcontrast 3D T1-weighted images to control timing of images after contrast administration; (iii) precontrast, axial 2D T2-weighted fluid-attenuated inversion recovery; and (iv) precontrast, axial 2D, 3-directional diffusion-weighted images. Recommended ranges of sequence parameters are provided for both 1.5 T and 3 T MR system

Effect of Neutralizing Monoclonal Antibody Treatment on Early Trajectories of Virologic and Immunologic Biomarkers in Patients Hospitalized With COVID-19

BACKGROUND: Neutralizing monoclonal antibodies (nmAbs) failed to show clear benefit for hospitalized patients with coronavirus disease 2019 (COVID-19). Dynamics of virologic and immunologic biomarkers remain poorly understood. METHODS: Participants enrolled in the Therapeutics for Inpatients with COVID-19 trials were randomized to nmAb versus placebo. Longitudinal differences between treatment and placebo groups in levels of plasma nucleocapsid antigen (N-Ag), anti-nucleocapsid antibody, C-reactive protein, interleukin-6, and D-dimer at enrollment, day 1, 3, and 5 were estimated using linear mixed models. A 7-point pulmonary ordinal scale assessed at day 5 was compared using proportional odds models. RESULTS: Analysis included 2149 participants enrolled between August 2020 and September 2021. Treatment resulted in 20% lower levels of plasma N-Ag compared with placebo (95% confidence interval, 12%-27%; P \u3c .001), and a steeper rate of decline through the first 5 days (P \u3c .001). The treatment difference did not vary between subgroups, and no difference was observed in trajectories of other biomarkers or the day 5 pulmonary ordinal scale. CONCLUSIONS: Our study suggests that nmAb has an antiviral effect assessed by plasma N-Ag among hospitalized patients with COVID-19, with no blunting of the endogenous anti-nucleocapsid antibody response. No effect on systemic inflammation or day 5 clinical status was observed. CLINICAL TRIALS REGISTRATION: NCT04501978

Activation of PPARγ in Myeloid Cells Promotes Lung Cancer Progression and Metastasis

Activation of peroxisome proliferator-activated receptor-γ (PPARγ) inhibits growth of cancer cells including non-small cell lung cancer (NSCLC). Clinically, use of thiazolidinediones, which are pharmacological activators of PPARγ is associated with a lower risk of developing lung cancer. However, the role of this pathway in lung cancer metastasis has not been examined well. The systemic effect of pioglitazone was examined in two models of lung cancer metastasis in immune-competent mice. In an orthotopic model, murine lung cancer cells implanted into the lungs of syngeneic mice metastasized to the liver and brain. As a second model, cancer cells injected subcutaneously metastasized to the lung. In both models systemic administration of pioglitazone increased the rate of metastasis. Examination of tissues from the orthotopic model demonstrated increased numbers of arginase I-positive macrophages in tumors from pioglitazone-treated animals. In co-culture experiments of cancer cells with bone marrow-derived macrophages, pioglitazone promoted arginase I expression in macrophages and this was dependent on the expression of PPARγ in the macrophages. To assess the contribution of PPARγ in macrophages to cancer progression, experiments were performed in bone marrow-transplanted animals receiving bone marrow from Lys-M-Cre+/PPARγflox/flox mice, in which PPARγ is deleted specifically in myeloid cells (PPARγ-Macneg), or control PPARγflox/flox mice. In both models, mice receiving PPARγ-Macneg bone marrow had a marked decrease in secondary tumors which was not significantly altered by treatment with pioglitazone. This was associated with decreased numbers of arginase I-positive cells in the lung. These data support a model in which activation of PPARγ may have opposing effects on tumor progression, with anti-tumorigenic effects on cancer cells, but pro-tumorigenic effects on cells of the microenvironment, specifically myeloid cells

Phospho-ERK and AKT status, but not KRAS mutation status, are associated with outcomes in rectal cancer treated with chemoradiotherapy

<p>Abstract</p> <p>Background</p> <p><it>KRAS </it>mutations may predict poor response to radiotherapy. Downstream events from <it>KRAS</it>, such as activation of <it>BRAF</it>, AKT and ERK, may also confer prognostic information but have not been tested in rectal cancer (RC). Our objective was to explore the relationships of <it>KRAS </it>and <it>BRAF </it>mutation status with p-AKT and p-ERK and outcomes in RC.</p> <p>Methods</p> <p>Pre-radiotherapy RC tumor biopsies were evaluated. <it>KRAS </it>and <it>BRAF </it>mutations were assessed by pyrosequencing; p-AKT and p-ERK expression by immunohistochemistry.</p> <p>Results</p> <p>Of 70 patients, mean age was 58; 36% stage II, 56% stage III, and 9% stage IV. Responses to neoadjuvant chemoradiotherapy: 64% limited, 19% major, and 17% pathologic complete response. 64% were <it>KRAS </it>WT, 95% were <it>BRAF </it>WT. High p-ERK levels were associated with improved OS but not for p-AKT. High levels of p-AKT and p-ERK expression were associated with better responses. <it>KRAS </it>WT correlated with lower p-AKT expression but not p-ERK expression. No differences in OS, residual disease, or tumor downstaging were detected by <it>KRAS </it>status.</p> <p>Conclusions</p> <p><it>KRAS </it>mutation was not associated with lesser response to chemoradiotherapy or worse OS. High p-ERK expression was associated with better OS and response. Higher p-AKT expression was correlated with better response but not OS.</p

Differences in inflammation and acute phase response but similar genotoxicity in mice following pulmonary exposure to graphene oxide and reduced graphene oxide

We investigated toxicity of 2-3 layered >1 μm sized graphene oxide (GO) and reduced graphene oxide (rGO) in mice following single intratracheal exposure with respect to pulmonary inflammation, acute phase response (biomarker for risk of cardiovascular disease) and genotoxicity. In addition, we assessed exposure levels of particulate matter emitted during production of graphene in a clean room and in a normal industrial environment using chemical vapour deposition. Toxicity was evaluated at day 1, 3, 28 and 90 days (18, 54 and 162 μg/mouse), except for GO exposed mice at day 28 and 90 where only the lowest dose was evaluated. GO induced a strong acute inflammatory response together with a pulmonary (Serum-Amyloid A, Saa3) and hepatic (Saa1) acute phase response. rGO induced less acute, but a constant and prolonged inflammation up to day 90. Lung histopathology showed particle agglomerates at day 90 without signs of fibrosis. In addition, DNA damage in BAL cells was observed across time points and doses for both GO and rGO. In conclusion, pulmonary exposure to GO and rGO induced inflammation, acute phase response and genotoxicity but no fibrosis

Impaired Carbohydrate Digestion and Transport and Mucosal Dysbiosis in the Intestines of Children with Autism and Gastrointestinal Disturbances

Gastrointestinal disturbances are commonly reported in children with autism, complicate clinical management, and may contribute to behavioral impairment. Reports of deficiencies in disaccharidase enzymatic activity and of beneficial responses to probiotic and dietary therapies led us to survey gene expression and the mucoepithelial microbiota in intestinal biopsies from children with autism and gastrointestinal disease and children with gastrointestinal disease alone. Ileal transcripts encoding disaccharidases and hexose transporters were deficient in children with autism, indicating impairment of the primary pathway for carbohydrate digestion and transport in enterocytes. Deficient expression of these enzymes and transporters was associated with expression of the intestinal transcription factor, CDX2. Metagenomic analysis of intestinal bacteria revealed compositional dysbiosis manifest as decreases in Bacteroidetes, increases in the ratio of Firmicutes to Bacteroidetes, and increases in Betaproteobacteria. Expression levels of disaccharidases and transporters were associated with the abundance of affected bacterial phylotypes. These results indicate a relationship between human intestinal gene expression and bacterial community structure and may provide insights into the pathophysiology of gastrointestinal disturbances in children with autism