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Contains fulltext : 290747.pdf (Publisher’s version ) (Open Access) INTRODUCTION/AIMS: Although the extent of muscle weakness and organ complications has not been well studied in patients with late-onset myotonic dystrophy type 1 (DM1), adult-onset DM1 is associated with severe muscle involvement and possible life-threatening cardiac and respiratory complications. In this study we aimed to compare the clinical phenotype of adult-onset vs late-onset DM1, focusing on the prevalence of cardiac, respiratory, and muscular involvement. METHODS: Data were prospectively collected in the Dutch DM1 registry. RESULTS: Two hundred seventy-five adult-onset and 66 late-onset DM1 patients were included. Conduction delay on electrocardiogram was present in 123 of 275 (45%) adult-onset patients, compared with 24 of 66 (36%) late-onset patients (P = .218). DM1 subtype did not predict presence of conduction delay (odds ratio [OR] 0.706; confidence interval [CI] 0.405 to 1.230, P = .219). Subtype did predict indication for noninvasive ventilation (NIV) (late onset vs adult onset: OR, 0.254; CI, 0.104 to 0.617; P = .002) and 17% of late-onset patients required NIV compared with 40% of adult-onset patients. Muscular Impairment Rating Scale (MIRS) scores were significantly different between subtypes (MIRS 1 to 3 in 66% of adult onset vs 100% of late onset [P

Introduction: Chronic hypercapnic respiratory failure induces considerable morbidity and mortality in patients with myotonic dystrophy type 1 (DM1). This study systematically reviews the effects of noninvasive home mechanical ventilation (HMV) on gas exchange, quality of life, survival, and compliance in DM1 patients. Methods: A systematic Medline and Embase search was performed (January 1995 to January 2020). Records were screened for eligibility criteria, data were extracted from included studies, and risk of bias was assessed. We present findings mainly using a narrative synthesis. Results: Twenty-eight relevant full-text articles were screened for eligibility criteria. Nine studies were included. Randomized controlled trials were not found. Studies had either an observational (n = 8) or interventional (n = 1) design. In the pooled data analysis, HMV showed to improve mean oxygen saturation with 4.8% and decreased mean carbon dioxide values with 3 mm Hg. Compliance varied widely between studies, from no use to more than 12 h per day. Quality of life was not studied extensively, but some studies reported positive effects of HMV on symptoms of chronic respiratory failure. HMV may improve survival in DM1 patients with chronic hypercapnic respiratory failure. Conclusion: This review shows that HMV can improve gas exchange and relieve symptoms with a possible survival benefit in DM1 patients with chronic hypercapnic respiratory failure. Future studies should focus on developing strategies to optimize the timing of HMV initiation and to promote compliance.

Background and purposeReducing breathing motion in radiotherapy (RT) is an attractive strategy to reduce margins and better spare normal tissues. The objective of this prospective study (NCT03729661) was to investigate the feasibility of irradiation of non-small cell lung cancer (NSCLC) with visually guided moderate deep inspiration breath-hold (IBH) using nasal high-flow therapy (NHFT).Material and methodsLocally advanced NSCLC patients undergoing photon RT were given NHFT with heated humidified air (flow: 40 L/min with 80% oxygen) through a nasal cannula. IBH was monitored by optical surface tracking (OST) with visual feedback. At a training session, patients had to hold their breath as long as possible, without and with NHFT. For the daily cone beam CT (CBCT) and RT treatment in IBH, patients were instructed to keep their BH as long as it felt comfortable. OST was used to analyze stability and reproducibility of the BH, and CBCT to analyze daily tumor position. Subjective tolerance was measured with a questionnaire at 3 time points.ResultsOf 10 included patients, 9 were treated with RT. Seven (78%) completed the treatment with NHFT as planned. At the training session, the mean BH length without NHFT was 39 s (range 15-86 s), and with NHFT 78 s (range 29-223 s) (p = .005). NHFT prolonged the BH duration by a mean factor of 2.1 (range 1.1-3.9s). The mean overall stability and reproducibility were within 1 mm. Subjective tolerance was very good with the majority of patients having no or minor discomfort caused by the devices. The mean inter-fraction tumor position variability was 1.8 mm (-1.1-8.1 mm;SD 2.4 mm).ConclusionNHFT for RT treatment of NSCLC in BH is feasible, well tolerated and significantly increases the breath-hold duration. Visually guided BH with OST is stable and reproducible. We therefore consider this an attractive patient-friendly approach to treat lung cancer patients with RT in BH.

The Respiratory Intensive Care Assembly of the European Respiratory Society organised the first Respiratory Failure and Mechanical Ventilation Conference in Berlin in February 2020. The conference covered acute and chronic respiratory failure in both adults and children. During this 3-day conference, patient selection, diagnostic strategies and treatment options were discussed by international experts. Lectures delivered during the event have been summarised by Early Career Members of the Assembly and take-home messages highlighted., During #RFMV2020, patient selection, diagnostic strategies and treatment options were discussed by international experts. This review summarises the most important take-home messages. https://bit.ly/3murkoa

Introduction: Knowledge about long-term outcome in patients using home mechanical ventilation (HMV) is important to optimize shared decision making and advanced care planning. This study is aimed to assess the 1-year overall mortality and to identify its predictors in patients starting with HMV. Methods: Patients who started HMV in our centre between January 1, 2012–December 31, 2017 were included. Data on demographics, diagnosis, blood gasses and lung function were assessed as well as the Severe Respiratory Insufficiency (SRI) questionnaire and Care Dependency Scale (CDS). Univariate and multivariate logistic regression were used for statistical analysis. Results: The 1-year overall mortality in 812 adults (mean age 63 years [range 53-70]) was 20%. Classified by disease category, the mortality was respectively 48%, 21%, 10%, 8% and 7% in rapidly progressive neuromuscular disease (NMD), end-stage lung diseases/Chronic Obstructive Pulmonary Disease (ELD/COPD), slowly progressive NMD and thoracic deformities, myotonic dystrophy type 1 and sleep disorders. Independent predictors for mortality were: age (odds ratio (OR) 1.033 [confidential interval (CI)] 1.014-1.053), diagnosis category (OR 3.433 [CI] 2.207-5.339), base excess (BE)>4 (OR 0.599 [CI] 0.370-0.970), peak expiratory flow (PEF) (OR 0.998 [CI] 0.996-1.000), CDS (OR 0.968 [CI] 0.945-0.992), SRI total (OR 1.162 [CI] 1.033-1.307), SRI respiratory complaints (RC) (OR 0.951 [CI] 0.915-0.989), SRI mental well-being (WB) (OR 0.955 [CI] 0.922-0.990). Method: The 1-year overall mortality in patients starting HMV is 20% and the highest in rapidly progressive NMD and in ELD/COPD. Survival was strongly related to age, diagnosis, BE>4, PEF, CDS, SRI-total, SRI-RC, SRI-WB.

Background: Initiating home mechanical ventilation (HMV) in patients suffering from chronic respiratory failure is one of the most advanced and complicated types of medical treatment taking place outside a hospital setting. This study was aimed to assess complexity with regard to quality of life, mental health and the need for care of patients starting on HMV. Methods: Patients who started HMV between July, 2014 and January, 2016 were included. Demographic data, diagnosis, severity of respiratory failure, severe respiratory insufficiency questionnaire (SRI), hospital anxiety and depression scale (HADS), care dependency scale (CDS) and care giver strain index (CSI) were assessed. Results: 142 Patients (44% males, age: 60.9±13.4years) were included and classified by disease category: 27%(n:38) End-stage Lung Diseases/Chronic Obstructive Pulmonary Disease (ELD/COPD), 20%(n:28) rapidly progressive neuromuscular disease (rpNMD), 21%(n:30) slowly progressive NMD and thoracic deformities, 15%(n:22) myotonic dystrophy type 1 and 17%(n:24) hypercapnic sleep disorders. Overall, the SRI summary scale (range 0-100) was 48.0±13.4. Respectively 27% and 23% had HADS depression and HADS anxiety scores >11 points. 30% of subjects scored a CDS as fully independent and 49% patients scored the CSI as being overloaded. Patients with ELD/COPD had the worst results followed by rpNMD. Myotonic Dystrophy type 1 and slowly progressive NMD and thoracic deformities scored best. Conclusions: In patients starting with HMV the need of care is advanced and complex, especially in ELD/COPD and in rpNMD group. Integrated assessment before initiating HMV can be helpful in to provide the best care for these patients.

Loss of skeletal muscle oxidative fiber types and mitochondrial capacity is a hallmark of chronic obstructive pulmonary disease and chronic heart failure. Based on in vivo human and animal studies, tissue hypoxia has been hypothesized as determinant, but the direct effect of hypoxia on muscle oxidative phenotype remains to be established. Hence, we determined the effect of hypoxia on in vitro cultured muscle cells, including gene and protein expression levels of mitochondrial components, myosin isoforms (reflecting slow-oxidative versus fast-glycolytic fibers), and the involvement of the regulatory PPAR/PGC-1alpha pathway. We found that hypoxia inhibits the PPAR/PGC-1alpha pathway and the expression of mitochondrial components through HIF-1alpha. However, in contrast to our hypothesis, hypoxia stimulated the expression of slow-oxidative type I myosin via HIF-1alpha. Collectively, this study shows that hypoxia differentially regulates contractile and metabolic components of muscle oxidative phenotype in a HIF-1alpha-dependent manner.

Being well-established in advanced chronic obstructive pulmonary disease (COPD), skeletal muscle dysfunction and its underlying pathology have been scarcely investigated in patients with mild-to-moderate airflow obstruction. We hypothesized that a loss of oxidative phenotype (oxphen) associated with decreased endurance is present in the skeletal muscle of patients with mild-to-moderate COPD. In quadriceps muscle biopsies from 29 patients with COPD (forced expiratory volume in 1 s [FEV1] 58 ± 16%pred, body mass index [BMI] 26 ± 4 kg/m2) and 15 controls (BMI 25 ± 3 kg/m2) we assessed fiber type distribution, fiber cross-sectional areas (CSA), oxidative and glycolytic gene expression, OXPHOS protein levels, metabolic enzyme activity, and levels of oxidative stress markers. Quadriceps function was assessed by isokinetic dynamometry, body composition by dual-energy X-ray absorptiometry, exercise capacity by an incremental load test, and physical activity level by accelerometry. Compared with controls, patients had comparable fat-free mass index, quadriceps strength, and fiber CSA, but quadriceps endurance was decreased by 29% ( P = 0.002). Patients with COPD had a clear loss of muscle oxphen: a fiber type I-to-II shift, decreased levels of OXPHOS complexes IV and V subunits (47% and 31%, respectively; P < 0.05), a decreased ratio of 3-hydroxyacyl-CoA dehydrogenase/phosphofructokinase (PFK) enzyme activities (38%, P < 0.05), and decreased peroxisome proliferator-activated receptor-γ coactivator-1α (40%; P < 0.001) vs. increased PFK (67%; P < 0.001) gene expression levels. Within the patient group, markers of oxphen were significantly positively correlated with quadriceps endurance and inversely with the increase in plasma lactate relative to work rate during the incremental test. Levels of protein carbonylation, tyrosine nitration, and malondialdehyde protein adducts were comparable between patients and controls. However, among patients, oxidative stress levels were significantly inversely correlated with markers of oxphen and quadriceps endurance. Reduced muscle endurance associated with underlying loss of muscle oxphen is already present in patients with mild-to-moderate COPD without muscle wasting.

Hemomediastinum is a rare pathological event. Multiple underlying causes and contributory factors can be identified, such as trauma, malignancy, iatrogenic, bleeding disorder or mediastinal organ hemorrhage. Also, a mediastinal bronchial artery aneurysm may be the source of a hemomediastinum. Hemoptysis is an important directive symptom, however occasionally, patients only present with thoracic pain or symptoms related to extrinsic compression of the airways or esophagus. Using contrast-enhanced computed tomography (CT) of the chest, hemomediastinum can be adequately diagnosed, and the involved vascular structures can be revealed. In case of a (ruptured) bronchial artery aneurysm, transcatheter embolization provides a minimally invasive procedure and is treatment of first choice. In this case report, a 76-year-old female is presented with spontaneous rupture of a mediastinal bronchial artery aneurysm resulting in hemomediastinum causing thoracic pain. Superselective embolization of the left bronchial artery was successfully performed.

The aim of this study was to evaluate specific immunostaining and background staining in formalin-fixed, paraffin-embedded human tissues with the 2 most frequently used immunohistochemical detection systems, Avidin-Biotin-Peroxidase (ABC) and EnVision+. A series of fixed tissues, including breast, colon, kidney, larynx, liver, lung, ovary, pancreas, prostate, stomach, and tonsil, was used in the study. Three monoclonal antibodies, 1 against a nuclear antigen (Ki-67), 1 against a cytoplasmic antigen (cytokeratin), and 1 against a cytoplasmic and membrane-associated antigen and a polyclonal antibody against a nuclear and cytoplasmic antigen (S-100) were selected for these studies. When the ABC system was applied, immunostaining was performed with and without blocking of endogenous avidin-binding activity. The intensity of specific immunostaining and the percentage of stained cells were comparable for the 2 detection systems. The use of ABC caused widespread cytoplasmic and rare nuclear background staining in a variety of normal and tumor cells. A very strong background staining was observed in colon, gastric mucosa, liver, and kidney. Blocking avidin-binding capacity reduced background staining, but complete blocking was difficult to attain. With the EnVision+ system no background staining occurred. Given the efficiency of the detection, equal for both systems or higher with EnVision+, and the significant background problem with ABC, we advocate the routine use of the EnVision+ system.

Objectives Both bone and brain are frequent sites of metastasis in non-small cell lung cancer (NSCLC). Conflicting data exist whether EGFR mutant (+) patients are more prone to develop brain metastases or have a better outcome with brain metastases compared to EGFR/KRAS wildtype (WT) or KRAS+ patients. For bone metastases this has not been studied. Methods In this retrospective case-control study all EGFR+ (exons 19 and 21) patients diagnosed at two pathology departments were selected (2004/2008 to 2012). For every EGFR+ patient a consecutive KRAS+ and WT patient with metastatic NSCLC (mNSCLC) was identified. Patients with another malignancy within 2 years of mNSCLC diagnosis were excluded. Data regarding age, gender, performance score, histology, treatment, bone/brain metastases diagnosis, skeletal related events (SRE) and subsequent survival were collected. Results 189 patients were included: 62 EGFR+, 65 KRAS+, 62 WT. 32%, 35% and 40%, respectively, had brain metastases (p = 0.645). Mean time to brain metastases was 20.8 [±12.0], 10.8 [±9.8], 16.4 [±10.2] months (EGFR+–KRAS+, p = 0.020, EGFR+–WT, p = 0.321). Median post brain metastases survival was 12.1 [5.0–19.1], 7.6 [1.2–14.0], 10.7 [1.5–19.8] months (p = 0.674). 60%, 52% and 50% had metastatic bone disease (p = 0.528). Mean time to development of metastatic bone disease was 13.4 [±10.6], 23.3 [±19.4], 16.4 [±9.6] months (p = 0.201). Median post metastatic bone disease survival was 15.0 [10.6–20.3], 9.0 [5.2–12.9], 3.2 [0.0–6.9] months (p = 0.010). Time to 1st SRE was not significantly different. Conclusions Incidence of brain and bone metastases was not different between EGFR+, KRAS+ and WT patients. Post brain metastases survival, time from mNSCLC diagnosis to metastatic bone disease and 1st SRE did not differ either. Post metastatic bone disease survival was significantly longer in EGFR+ patients. Although prevention of SRE's is important for all patients, the latter finding calls for a separate study for SRE preventing agents in EGFR+ patients.

Background Selection of early stage non-small cell lung cancer patients with a high risk of recurrence is warranted in order to select patients who will benefit from adjuvant treatment strategies. We evaluated the prognostic value of integrin expression profiles in a retrospective study on frozen primary tumors of 68 patients with early stage non-small cell lung cancer. Methods A retrospective study was performed on frozen primary tumors of 68 early stage non-small cell lung cancer patients with a follow up of at least 10 years. From all tumor tissues, RNA was isolated and reverse transcribed into cDNA. qPCR was used to generate mRNA expression profiles including integrins alpha1, 2, 3, 4, 5, 6, 7, 11, and V as well as integrins beta1, 3, 4, 5, 6, and 8. Results The expression levels of integrins alpha5, beta1 and beta3 predicted overall survival and disease free survival in early stage NSCLC patients. There was no association between integrin expression and lymph node metastases. Comparison between the histological subtypes revealed a distinct integrin signature for squamous cell carcinoma while the profiles of adenocarcinoma and large cell carcinoma were largely the same. Conclusion Integrin expression in NSCLC is important for the development and behavior of the tumor and influences the survival of the patient. Determining the integrin expression profile might serve as a tool in predicting the prognosis of individual patients.