Neuroimmune Modulation Through Vagus Nerve Stimulation Reduces Inflammatory Activity in Crohn's Disease Patients: A Prospective Open-label Study.

BACKGROUND AND AIMS: Crohn's disease [CD] is a debilitating, inflammatory condition affecting the gastrointestinal tract. There is no cure and sustained clinical and endoscopic remission is achieved by fewer than half of patients with current therapies. The immunoregulatory function of the vagus nerve, the 'inflammatory reflex', has been established in patients with rheumatoid arthritis and biologic-naive CD. The aim of this study was to explore the safety and efficacy of vagus nerve stimulation in patients with treatment-refractory CD, in a 16-week, open-label, multicentre, clinical trial. METHODS: A vagus nerve stimulator was implanted in 17 biologic drug-refractory patients with moderately to severely active CD. One patient exited the study pre-treatment, and 16 patients were treated with vagus nerve stimulation [4/16 receiving concomitant biologics] during 16 weeks of induction and 24 months of maintenance treatment. Endpoints included clinical improvement, patient-reported outcomes, objective measures of inflammation [endoscopic/molecular], and safety. RESULTS: There was a statistically significant and clinically meaningful decrease in CD Activity Index at Week 16 [mean ±â€…SD: -86.2 ±â€…92.8, p = 0.003], a significant decrease in faecal calprotectin [-2923 ±â€…4104, p = 0.015], a decrease in mucosal inflammation in 11/15 patients with paired endoscopies [-2.1 ±â€…1.7, p = 0.23], and a decrease in serum tumour necrosis factor and interferon-γ [46-52%]. Two quality-of-life indices improved in 7/11 patients treated without biologics. There was one study-related severe adverse event: a postoperative infection requiring device explantation. CONCLUSIONS: Neuroimmune modulation via vagus nerve stimulation was generally safe and well tolerated, with a clinically meaningful reduction in clinical disease activity associated with endoscopic improvement, reduced levels of faecal calprotectin and serum cytokines, and improved quality of life.

Clinical Outcomes with Targeted Temperature Management (TTM) in Comatose Out-of-Hospital Cardiac Arrest Patients-A Retrospective Cohort Study.

Purpose: we evaluated the effects of the shift of a targeted temperature management (TTM) strategy from 33 °C to 36 °C in comatose out-of-hospital cardiac arrest (OHCA) patients admitted to the Intensive Care Unit (ICU). Methods: we performed a retrospective study of all comatose (GCS < 8) OHCA patients treated with TTM from 2010 to 2018 (n = 798) from a single-center academic hospital. We analyzed 90-day mortality, and neurological outcome (CPC score) at ICU discharge and ICU length of stay, as primary and secondary outcomes, respectively. Results: we included 798 OHCA patients (583 in the TTM33 group and 215 in the TTM36 group). We found no association between the TTM strategy (TTM33 and TTM36) and 90-day mortality (hazard ratio (HR)] 0.877, 95% CI 0.677−1.135, with TTM36 as reference). Also, no association was found between TTM strategy and favorable neurological outcome at ICU discharge (odds ratio (OR) 1.330, 95% CI 0.941−1.879). Patients in the TTM33 group had on average a longer ICU LOS (beta 1.180, 95% CI 0.222−2.138). Conclusion: no differences in clinical outcomes­both 90-day mortality and favorable neurological outcome at ICU discharge­were found between targeted temperature at 33 °C and 36 °C. These results may help to corroborate previous trial findings and assist in implementation of TTM.

Do Women Have a Higher Mortality Risk Than Men following ICU Admission after Out-of-Hospital Cardiac Arrest? A Retrospective Cohort Analysis.

PURPOSE: previous studies showed that women have a higher mortality risk than men after out-of-hospital cardiac arrest (OHCA). This sex difference may disappear after adjustment for cardiac arrest characteristics. Most studies also included patients who were not admitted to the intensive care unit (ICU). We analyzed whether sex impacts the mortality of ICU-admitted OHCA patients. METHODS: a retrospective cohort analysis of 1240 OHCA patients admitted to the ICU (310 women, 25%, AgeMedian 64.0 (IQR 53.8-73.0)) at an academic hospital in the Netherlands between 1 January 2007 and 31 December 2018. The primary outcome was 90-day mortality; the secondary outcome was a favorable cerebral performance category (CPC) score at ICU discharge and ICU length of stay (ICU LOS). RESULTS: we found no association between sex and 90-day mortality (hazard ratio (HR) 0.867; 95% confidence interval (95% CI) 0.678-1.108) after adjusting for relevant cardiac arrest characteristics. Similarly, we found no difference for favorable CPC score (OR 1.117; 95% CI 0.777-1.608) or ICU LOS between sexes (Beta 0.428; 95% CI -0.442 to 1.298). CONCLUSIONS: after adjusting for cardiac arrest characteristics, we found no difference between women and men with respect to 90-day mortality, ICU LOS, and CPC score.

CT detected indeterminate pulmonary nodules in a chemoprevention trial of fluticasone.

INTRODUCTION: In animal models of lung carcinogenesis, inhaled corticosteroids appear to reduce the number of new lung tumors. In a trial of budesonide in smokers with bronchial dysplasia, the proportion of indeterminate CT detected pulmonary nodules that resolved was larger in the treatment group. We performed a secondary analysis of CT data of subjects at risk of lung cancer enrolled in a chemoprevention trial of fluticasone. METHODS: Subjects with bronchial squamous metaplasia or dysplasia had a baseline chest CT scan. They were randomized to fluticasone or a placebo. After 6 months a repeat CT was performed and the change in number and size of nodules was evaluated. RESULTS: Two hundred and one subjects were screened. Of the 108 volunteers included in the study, 74 were male, mean age was 53 years and mean number of pack years 48. Baseline: 35 subjects had 91 nodules in total, 62% <4mm. In the fluticasone arm more subjects had a decrease and fewer had an increase in number of nodules, however this trend did not reach statistical significance. CONCLUSION: In this preliminary study there was a tendency of nodules to resolve, however, studies with CT detected nodules as inclusion criterion are needed.

Comprehensive CADM1 promoter methylation analysis in NSCLC and normal lung specimens.

Methylation-mediated silencing of the tumour suppressor CADM1 has been functionally linked to lung cancer development. We aimed to determine whether CADM1 promoter methylation is a candidate early detection marker for lung cancer. To this end frozen tissue samples of 36 non-small cell lung cancers, 26 corresponding tumour distant normal tissue samples as well as 6 samples of normal lung from non-lung cancer patients were tested for DNA methylation at three different regions within the CADM1 promoter (M1, M5 and M9) using methylation specific PCR followed by methylation specific reverse line blot analysis. Sixty-four percentage of tumour samples tested positive at the M1 region, 47% at M5 and 74% at the M9 region, compared with 65% (M1), 23% (M5) and 46% (M9) of paired normal tissue samples. Methylation of each of these promoter regions was also detected in the majority of non-lung cancer control samples. Dense methylation, defined as methylation at ≥2 promoter regions, was detected in 66% of tumour samples compared with 38% of paired normal tissues and 67% of non-lung cancer control samples. Within the small subgroup of female patients dense methylation was found in all tumour samples but only 22% of paired normal samples. Neither methylation of individual sites nor dense methylation was correlated with disease free survival. In conclusion, CADM1 promoter methylation is a frequent event in NSCLC as well as normal lung, both of lung cancer and non-lung cancer patients. Hence, CADM1 methylation analysis is unlikely to have diagnostic value for the early detection of lung cancer in an unselected population. However, a diagnostic value for selected subjects, such as females, cannot be excluded.

The finding of premalignant lesions is not associated with smoking cessation in chemoprevention study volunteers.

BACKGROUND AND STUDY AIMS: Screening programs for lung cancer may lead to a heightened awareness of the risks of smoking and enhance quitting. The aim of this study was to evaluate whether the participation on a chemoprevention study for premalignant lesions could influence smoking cessation. METHODS: Two hundred one volunteers, current (n = 188) and former smokers (n = 13) with more than 20 pack years had been screened for the chemoprevention study. One hundred forty-six of the current smokers at time of chemoprevention study screening have been retrospectively interviewed about their smoking behavior > or =1 year after their first contact for the chemoprevention study. Structured questionnaires were used, and interviews were held by telephone. The quitters at the time of these first interviews were contacted again 4 years after the initial interview about their current smoking behavior. RESULTS: Of the 146 smoking volunteers, 83 were diagnosed with premalignant lesions of the bronchial mucosa and participated in the chemoprevention study, and 63 had no premalignant lesions and were not included in that study.The majority of participants were men: 87 (60%). The mean age of the participants was 52 +/- 9 years, and the mean age at which volunteers started smoking was 15 +/- 3. Mean number of pack years was 47 +/- 27. Ten volunteers in the group without premalignant lesions and 19 in the group with premalignant lesions had quit smoking at time of the first interview. The smoking cessation rate of the total study group was 20%.Univariate logistic regression analysis demonstrated that smoking cessation was only significantly associated with male gender. No significant associations were found between smoking cessation and the finding of premalignant lesions, sex, age, level of addiction, educational level, marital condition, history of cancer/pulmonary diseases, age at start smoking, previous attempts to quit smoking, and motivation to quit smoking.Within the group of subjects who had quit smoking at the time of the first interview, 15 of 29 persons who had stopped smoking at the time of the first interview have reported that participation in the bronchoscopy screening and/or the trial has been of major influence on their decision to stop smoking. CONCLUSIONS: A smoking cessation rate of 20% has been found among volunteers for a chemopreventive trial investigating smoking-related premalignant lesions after almost 2 years after initial contact has been found. Volunteers experienced screening and trial participation as having influenced their smoking cessation. Smoking cessation was significantly associated with male gender, whereas the finding of premalignant lesions by bronchoscopy was not.

Prognostic value of hTERT mRNA expression in surgical samples of lung cancer patients: the European Early Lung Cancer Project.

Lung cancer is the most important cause of cancer-related mortality. Resectability and eligibility for treatment with adjuvant chemotherapy is determined by staging according to the TNM classification. Other determinants of tumour behaviour that predict disease outcome, such as molecular markers, may improve decision-making. Activation of the gene encoding human telomerase reverse transcriptase (hTERT) is implicated in the pathogenesis of lung cancer, and consequently detection of hTERT mRNA might have prognostic value for patients with early stage lung cancer. A cohort of patients who underwent a complete resection for early stage lung cancer was recruited as part of the European Early Lung Cancer (EUELC) project. In 166 patients expression of hTERT mRNA was determined in tumour tissue by quantitative real-time RT-PCR and related to that of a house-keeping gene (PBGD). Of a subgroup of 130 patients tumour-distant normal tissue was additionally available for hTERT mRNA analysis. The correlation between hTERT levels of surgical samples and disease-free survival was determined using a Fine and Gray hazard model. Although hTERT mRNA positivity in tumour tissue was significantly associated with clinical stage (Fisher's exact test p=0.016), neither hTERT mRNA detectability nor hTERT mRNA levels in tumour tissue were associated with clinical outcome. Conversely, hTERT positivity in adjacent normal samples was associated with progressive disease, 28% of patients with progressive disease versus 7.5% of disease-free patients had detectable hTERT mRNA in normal tissue [adjusted HR: 3.60 (1.64-7.94), p=0.0015]. hTERT mRNA level in tumour tissue has no prognostic value for patients with early stage lung cancer. However, detection of hTERT mRNA expression in tumour-distant normal lung tissue may indicate an increased risk of progressive disease.

Color fluorescence ratio for detection of bronchial dysplasia and carcinoma in situ.

BACKGROUND: Autofluorescence bronchoscopy is more sensitive than conventional bronchoscopy for detecting early airway mucosal lesions. Decreased specificity can lead to excessive biopsy and increased procedural time. Onco-LIFE, a device that combines fluorescence and reflectance imaging, allows numeric representation by expressing red-to-green ratio (R/G ratio) within the region of interest. The aim of the study was to determine if color fluorescence ratio (R/G ratio) added to autofluorescence bronchoscopy could provide an objective means to guide biopsy. METHODS: Subjects at risk for lung cancer were recruited at two centers: VU University Medical Centre (Amsterdam) and BC Cancer Agency (Canada). R/G ratio for each site appearing normal or abnormal was measured before biopsy. R/G ratios were correlated with pathology, and a receiver operating characteristic curve of R/G ratio for high-grade and moderate dysplasia was done. Following analysis of the training data set obtained from two centers, a prospective validation study was done. RESULTS: Three thousand three hundred sixty-two adequate biopsies from 738 subjects with their corresponding R/G ratios were analyzed. R/G ratio 0.54 conferred 85% sensitivity and 80% specificity for the detection of high-grade and moderate dysplasia, area under the curve was 0.90, and 95% confidence interval was 0.88 to 0.92. In another 70 different sites that were assessed, kappa measurements of agreement of R/G ratios with visual scores and pathology were 0.66 (P < 0.0001) and 0.61 (P < 0.0001), respectively. R/G ratio combined with visual score improved specificity to 88% (95% confidence interval, 0.73-0.96) for high-grade and moderate dysplasia. CONCLUSION: Color fluorescence ratio can objectively guide the bronchoscopist in selecting sites for biopsy with good pathologic correlation.

The influence of fluticasone inhalation on markers of carcinogenesis in bronchial epithelium.

RATIONALE: Bronchial epithelium exposed to cigarette smoke undergoes a series of histologic changes that may ultimately lead to invasive cancer. Inhaled corticosteroids reduce the number of lung tumors developing in rats exposed to cigarette smoke. OBJECTIVES: We studied the effect of inhaled fluticasone on premalignant lesions in smokers and patients curatively treated for head and neck cancer or lung cancer. METHODS: Participants were screened for premalignant lesions by bronchoscopy. Biopsies were taken from three to five locations and classified using WHO criteria. In case of a metaplasia index of > 15%, participants were randomized to receive a powder inhalation device containing either fluticasone 500 microg or a placebo, to be used twice a day. After 6 months, biopsies were obtained from the same locations as previously sampled. Efficacy of treatment was assessed by reversal of metaplasia/dysplasia; secondary endpoints were reversal of increased p53 and KI-67 immunoreactivity and expression of human telomerase reverse transcriptase. MEASUREMENTS AND MAIN RESULTS: Of the 201 subjects that were screened, 108 were included. Mean age was 53 yr (35-71), mean number of pack-years 48 (18-99), mean metaplasia index 48%, and 32% had some degree of dysplasia at baseline. The two treatment arms did not differ with respect to response or change in either metaplasia index or the expression of the markers p53, KI-67, or human telomerase reverse transcriptase. CONCLUSIONS: Inhaled fluticasone in a dose of 500 mug twice a day does not affect the natural course of premalignant lesions in the central airways.