IL-23 is pro-proliferative, epigenetically regulated and modulated by chemotherapy in non-small cell lung cancer

Background IL-23 is a member of the IL-6 super-family and plays key roles in cancer. Very little is currently known about the role of IL-23 in non-small cell lung cancer (NSCLC). Methods RT-PCR and chromatin immunopreciptiation (ChIP) were used to examine the levels, epigenetic regulation and effects of various drugs (DNA methyltransferase inhibitors, Histone Deacetylase inhibitors and Gemcitabine) on IL-23 expression in NSCLC cells and macrophages. The effects of recombinant IL-23 protein on cellular proliferation were examined by MTT assay. Statistical analysis consisted of Student's t-test or one way analysis of variance (ANOVA) where groups in the experiment were three or more. Results In a cohort of primary non-small cell lung cancer (NSCLC) tumours, IL-23A expression was significantly elevated in patient tumour samples (p<0.05). IL-23A expression is epigenetically regulated through histone post-translational modifications and DNA CpG methylation. Gemcitabine, a chemotherapy drug indicated for first-line treatment of NSCLC also induced IL-23A expression. Recombinant IL-23 significantly increased cellular proliferation in NSCLC cell lines. Conclusions These results may therefore have important implications for treating NSCLC patients with either epigenetic targeted therapies or Gemcitabine. © 2012 Elsevier Ireland Ltd

Interventions for the treatment of persistent post-viral olfactory dysfunction

Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows:. To assess the effects (benefits and harms) of interventions that have been used to treat post-viral olfactory dysfunction

Interventions for the treatment of persistent post‐COVID‐19 olfactory dysfunction

Background: Olfactory dysfunction is an early and sensitive marker of COVID-19 infection. Although self-limiting in the majority of cases, when hyposmia or anosmia persists it can have a profound effect on quality of life. Little guidance exists on the treatment of post-COVID-19 olfactory dysfunction, however several strategies have been proposed from the evidence relating to the treatment of post-viral anosmia (such as medication or olfactory training). Objectives: To assess the effects (benefits and harms) of interventions that have been used, or proposed, to treat persisting olfactory dysfunction due to COVID-19 infection. A secondary objective is to keep the evidence up-to-date, using a living systematic review approach. Search methods: The Cochrane ENT Information Specialist searched the Cochrane COVID-19 Study Register; Cochrane ENT Register; CENTRAL; Ovid MEDLINE; Ovid Embase; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished studies. The date of the search was 16 December 2020. Selection criteria: Randomised controlled trials including participants who had symptoms of olfactory disturbance following COVID-19 infection. Only individuals who had symptoms for at least four weeks were included in this review. Studies compared any intervention with no treatment or placebo. Data collection and analysis: We used standard Cochrane methodological procedures. Primary outcomes were the recovery of sense of smell, disease-related quality of life and serious adverse effects. Secondary outcomes were the change in sense of smell, general quality of life, prevalence of parosmia and other adverse effects (including nosebleeds/bloody discharge). We used GRADE to assess the certainty of the evidence for each outcome. Main results: We included one study with 18 participants, which compared the use of a 15-day course of oral steroids combined with nasal irrigation (consisting of an intranasal steroid/mucolytic/decongestant solution) with no intervention. Psychophysical testing was used to assess olfactory function at baseline, 20 and 40 days. Systemic corticosteroids plus intranasal steroid/mucolytic/decongestant compared to no intervention. Recovery of sense of smell was assessed after 40 days (25 days after cessation of treatment) using the Connecticut Chemosensory Clinical Research Center (CCCRC) score. This tool has a range of 0 to 100, and a score of ≥ 90 represents normal olfactory function. The evidence is very uncertain about the effect of this intervention on recovery of the sense of smell at one to three months (5/9 participants in the intervention group scored ≥ 90 compared to 0/9 in the control group; risk ratio (RR) 11.00, 95% confidence interval (CI) 0.70 to 173.66; 1 study; 18 participants; very low-certainty evidence). Change in sense of smell was assessed using the CCCRC score at 40 days. This study reported an improvement in sense of smell in the intervention group from baseline (median improvement in CCCRC score 60, interquartile range (IQR) 40) compared to the control group (median improvement in CCCRC score 30, IQR 25) (1 study; 18 participants; very low-certainty evidence). Serious adverse events andother adverse events were not identified in any participants of this study; however, it is unclear how these outcomes were assessed and recorded (1 study; 18 participants; very low-certainty evidence). Authors' conclusions: There is very limited evidence available on the efficacy and harms of treatments for persistent olfactory dysfunction following COVID-19 infection. However, we have identified other ongoing trials in this area. As this is a living systematic review we will update the data regularly, as new results become available. For this (first) version of the living review we identified only one study with a small sample size, which assessed systemic steroids and nasal irrigation (intranasal steroid/mucolytic/decongestant). However, the evidence regarding the benefits and harms from this intervention to treat persistent post-COVID-19 olfactory dysfunction is very uncertain

Interventions for the prevention of persistent post‐COVID‐19 olfactory dysfunction

Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows:. To assess the effects (benefits and harms) of interventions that have been used, or proposed, to prevent persisting olfactory dysfunction due to COVID-19 infection. A secondary objective is to maintain the currency of the evidence, using a living systematic review approach

Smoking, attitudes to smoking and provision of smoking cessation advice in two teaching hospitals in Ireland: do smoke-free policies matter?

Brief cessation advice from health-care professionals in the hospital setting significantly increases the likelihood of patients quitting smoking, yet patients are not routinely provided with this advice. Smoke-free hospital policies aim to protect individuals from the adverse effects of smoking; however, it is unclear if such policies encourage systematic delivery of cessation advice by health-care professionals. The study’s aim was to determine the prevalence of smoking and cessation advice received by in-patients in two teaching hospitals in Ireland which have implemented smoke-free hospital policies, and to examine patient attitudes towards smoking cessation. Change in smoking prevalence and delivery of smoking cessation advice prior to and post-policy implementation was also examined in one hospital. This study surveyed 466 in-patients across 2 hospital sites, over a 3-week and 5- week period, respectively. Data were also compared to a survey completed prior to the implementation of the smoke-free policy in one of the hospital sites. Smoking prevalence was 17% in Beaumont Hospital and 28% in Connolly Hospital. Overall, nicotine dependence was low (Mean Fagerström Test for Nicotine Dependence = 4.21, ±2.9). Overall, 62% of smokers did not receive smoking cessation advice from a health professional, although 55% indicated a willingness to engage with this type of service. The before-and-after analysis of Beaumont Hospital showed a reduction in smoking prevalence (17% vs 21%) amongst hospital in-patients, and a 6% increase in reported cessation advice provided following the introduction of the hospital smoke-free policy. Smoke-free hospital policies play a role in decreasing the prevalence of in-patient smokers, but further intervention is needed to increase rates of cessation advice provided. Positive attitudes to smoking cessation, coupled with low average nicotine dependence, suggest that lowintensity interventions would be beneficial for most smokers. A systematic focus on provision of brief smoking cessation advice is needed in hospitals

Minimizing Sample Failure Rates for Challenging Clinical Tumor Samples

Identification of somatic variants in cancer by high-throughput sequencing has become common clinical practice, largely because many of these variants may be predictive biomarkers for targeted therapies. However, there can be high sample quality control (QC) failure rates for some tests that prevent the return of results. Stem-loop inhibition mediated amplification (SLIMamp) is a patented technology that has been incorporated into commercially available cancer next-generation sequencing testing kits. The claimed advantage is that these kits can interrogate challenging formalin-fixed, paraffin-embedded tissue samples with low tumor purity, poor-quality DNA, and/or low-input DNA, resulting in a high sample QC pass rate. The study aimed to substantiate that claim using Pillar Biosciences oncoReveal Solid Tumor Panel. Forty-eight samples that had failed one or more preanalytical QC sample parameters for whole-exome sequencing from the Australian Translational Genomics Centre's ISO15189-accredited diagnostic genomics laboratory were acquired. XING Genomic Services performed an exploratory data analysis to characterize the samples and then tested the samples in their ISO15189-accredited laboratory. Clinical reports could be generated for 37 (77%) samples, of which 29 (60%) contained clinically actionable or significant variants that would not otherwise have been identified. Eleven samples were deemed unreportable, and the sequencing data were likely dominated by artifacts. A novel postsequencing QC metric was developed that can discriminate between clinically reportable and unreportable samples.</p

DuRvalumab with chEmotherapy as first line treAtment in advanced pleural Mesothelioma: A phase 3 randomised trial. The DREAM3R trial

Objective: Until recently, standard first-line treatment for advanced mesothelioma was platinum chemotherapy with pemetrexed. Two recent, single-arm, phase 2 trials (DREAM and PrE0505) combining durvalumab with platinum-pemetrexed chemotherapy exceeded pre-specified criteria. DREAM3R aims to determine the effectiveness of adding durvalumab to platinum chemotherapy in advanced mesothelioma. Methods: Treatment naïve patients with advanced mesothelioma will be randomised (2:1) to either (A) durvalumab 1500 mg 3-weekly, with chemotherapy (Cisplatin 75 mg/m2 or Carboplatin AUC5, and pemetrexed 500 mg/m2) 3-weekly for four to six cycles, followed by durvalumab 1500 mg 4-weekly until disease progression, unacceptable toxicity or patient withdrawal; or (B) chemotherapy alone for four to six cycles, followed by observation. Stratification: Age (18-70 years vs. > 70), gender, histology (epithelioid vs. non-epithelioid), platinum drugs (cisplatin vs carboplatin) and region (ANZ vs USA vs others). An amendment is undergoing to add upfront carboplatin AUC 5 as a platinum choice and as a stratification factor. Key inclusion criteria: MPM of all histologies, measurable disease per modified RECIST 1.1 (mRECIST 1.1) without prior radiotherapy to these sites, ECOG 0-1 and adequate bone marrow, kidney and liver function tests. The primary endpoint is overall survival. Secondary endpoints include progression-free survival; objective tumour response (by mRECIST 1.1 and iRECIST); adverse events; health-related quality of life; and healthcare resource use. Tertiary endpoints: Potential prognostic and/or predictive biomarkers: PD-L1 expression, tumour mutation burden and nuanced genomic characteristics, and HLA type in tissue and serial blood samples; validation of radiological measures of response and studies of possible radiomic biomarkers in mesothelioma. The target sample size is 480 patients recruited over 27 months, with follow up for another 24 months. This provides over 85% power if the true hazard ratio for overall survival was 0.70, with two-sided alpha of 0.05, and assuming a median survival of 15 months in the control group. ClinicalTrials.gov Identifier: NCT04334759 and ACTRN 12620001199909.</p