Christian Witt

[Prevention, diagnosis, therapy, and follow-up of lung cancer].

Authors G. Goeckenjan1, H. Sitter2, M. Thomas3, D. Branscheid4, M. Flentje5, F. Griesinger6, N. Niederle7, M. Stuschke8, T. Blum9, K.-M. Deppermann10, J. H. Ficker11, L. Freitag12, A. S. Lübbe13, T. Reinhold14, E. Späth-Schwalbe15, D. Ukena16, M. Wickert17, M. Wolf18, S. Andreas19, T. Auberger20, R. P. Baum21, B. Baysal22, J. Beuth23, H. Bickeböller24, A. Böcking25, R. M. Bohle26, I. Brüske27, O. Burghuber28, N. Dickgreber29, S. Diederich30, H. Dienemann31, W. Eberhardt32, S. Eggeling33, T. Fink34, B. Fischer35, M. Franke36, G. Friedel37, T. Gauler38, S. Gütz39, H. Hautmann40, A. Hellmann41, D. Hellwig42, F. Herth43, C. P. Heußel44, W. Hilbe45, F. Hoffmeyer46, M. Horneber47, R. M. Huber48, J. Hübner49, H.-U. Kauczor50, K. Kirchbacher51, D. Kirsten52, T. Kraus53, S. M. Lang54, U. Martens55, A. Mohn-Staudner56, K.-M. Müller57, J. Müller-Nordhorn58, D. Nowak59, U. Ochmann59, B. Passlick60, I. Petersen61, R. Pirker62, B. Pokrajac63, M. Reck64, S. Riha65, C. Rübe66, A. Schmittel67, N. Schönfeld68, W. Schütte69, M. Serke70, G. Stamatis71, M. Steingräber72, M. Steins73, E. Stoelben74, L. Swoboda75, H. Teschler76, H. W.Tessen77, M. Weber78, A. Werner79, H.-E. Wichmann80, E. Irlinger Wimmer81, C. Witt82, H. Worth83

Bronchoscopic thermal vapour ablation therapy in the management of heterogeneous emphysema

The need for a less invasive procedure than surgical lung volume reduction that can produce consistent improvements with reduced morbidity remains a medical goal in patients with emphysema. We sought to determine the effect of bronchoscopic thermal vapour ablation (BTVA) on lung volumes and outcomes in patients with emphysema. 44 patients with upper lobe-predominant emphysema were treated unilaterally with BTVA. Entry criteria included: age 40–75 yrs, forced expiratory volume in 1 s (FEV1) 15–45% predicted, previous pulmonary rehabilitation and a heterogeneity index (tissue/air ratio of lower lobe/upper lobe) from high-resolution computed tomography (HRCT) ≥1.2. Changes in FEV1, St Georges Respiratory Questionnaire (SGRQ), 6-min walk distance (6MWD), modified Medical Research Council (mMRC) dyspnoea score, and hyperinflation were measured at baseline, and 3 and 6 months post-BTVA. At 6 months, mean±se FEV1 improved by 141±26 mL (p<0.001) and residual volume was reduced by 406±113 mL (p<0.0001). SGRQ total score improved by 14.0±2.4 points (p<0.001), with 73% improving by ≥4 points. Improvements were observed in 6MWD (46.5±10.6 m) and mMRC dyspnoea score (0.9±0.2) (p<0.001 for both). Lower respiratory events (n=11) were the most common adverse event and occurred most often during the initial 30 days. BTVA therapy results in clinically relevant improvements in lung function, quality of life and exercise tolerance in upper lobe predominant emphysema.

SHOX2 DNA Methylation is a Biomarker for the diagnosis of lung cancer based on bronchial aspirates

BackgroundThis study aimed to show that SHOX2 DNA methylation is a tumor marker in patients with suspected lung cancer by using bronchial fluid aspirated during bronchoscopy. Such a biomarker would be clinically valuable, especially when, following the first bronchoscopy, a final diagnosis cannot be established by histology or cytology. A test with a low false positive rate can reduce the need for further invasive and costly procedures and ensure early treatment.MethodsMarker discovery was carried out by differential methylation hybridization (DMH) and real-time PCR. The real-time PCR based HeavyMethyl technology was used for quantitative analysis of DNA methylation of SHOX2 using bronchial aspirates from two clinical centres in a case-control study. Fresh-frozen and Saccomanno-fixed samples were used to show the tumor marker performance in different sample types of clinical relevance.ResultsValid measurements were obtained from a total of 523 patient samples (242 controls, 281 cases). DNA methylation of SHOX2 allowed to distinguish between malignant and benign lung disease, i.e. abscesses, infections, obstructive lung diseases, sarcoidosis, scleroderma, stenoses, at high specificity (68% sensitivity [95% CI 62-73%], 95% specificity [95% CI 91-97%]).ConclusionsHypermethylation of SHOX2 in bronchial aspirates appears to be a clinically useful tumor marker for identifying subjects with lung carcinoma, especially if histological and cytological findings after bronchoscopy are ambiguous.

Lung volume reduction coil treatment for patients with severe emphysema: a European multicentre trial

Background The lung volume reduction (LVR) coil is a minimally invasive bronchoscopic nitinol device designed to reduce hyperinflation and improve elastic recoil in severe emphysema. We investigated the feasibility, safety and efficacy of LVR coil treatment in a prospective multicentre cohort trial in patients with severe emphysema. Methods Patients were treated in 11 centres. Safety was evaluated by recording all adverse events, efficacy by the St Georges Respiratory Questionnaire (SGRQ) as primary endpoint, and pulmonary function testing, modified Medical Research Council dyspnoea score (mMRC) and 6-min walk distance (6MWD) up to 12 months after the final treatment. Results Sixty patients (60.9 ± 7.5 years, forced expiratory volume in 1 s (FEV1) 30.2 ± 6.3% pred) were bronchoscopically treated with coils (55 bilateral, 5 unilateral), with a median of 10 (range 5–15) coils per lobe. Within 30 days post-treatment, seven chronic obstructive pulmonary disease exacerbations (6.1%), six pneumonias (5.2%), four pneumothoraces (3.5%) and one haemoptysis (0.9%) occurred as serious adverse events. At 6 and 12 months, respectively, ΔSGRQ was −12.1±12.9 and −11.1±13.3 points, Δ6MWD was +29.7±74.1 m and +51.4±76 m, ΔFEV1 was +0.11±0.20 L and +0.11±0.30 L, and ΔRV (residual volume) was −0.65±0.90 L and −0.71±0.81 L (all p<0.01). Post hoc analyses showed significant responses for SGRQ, 6MWD and RV in patients with both heterogeneous and homogeneous emphysema. Conclusions LVR coil treatment results in significant clinical improvements in patients with severe emphysema, with a good safety profile and sustained results for up to 1 year. Trial registration number: NCT01328899.

Bronchoalveoloar lavage fluid cytokines and chemokines as markers and predictors for the outcome of interstitial lung disease in systemic sclerosis patients

IntroductionInterstitial lung disease (ILD) is a frequent manifestation of systemic sclerosis (SSc), and cytokines can contribute to the disease pathology. The aim of the current study was to identify specific changes in cytokine levels that may serve as disease markers and possible targets for therapy.MethodsCytokines were measured with bioplex analysis in 38 bronchoalveolar fluids (BALFs) from 32 SSc patients (27 with alveolitis and 11 without alveolitis) and 26 control patients. In the case of SSc patients, cytokines were correlated with the respective bronchoalveolar lavage (BAL) cell differentiation, lung function, and thoracic HR-CT score. For 35 BALF samples derived from 29 SSc patients, follow-up investigations of clinical data, lung-function parameter, or thoracic HR-CT scans were available to evaluate the predictive capacity of BALF cytokines and chemokines.ResultsHigh IL-7 levels were characteristic of SSc-associated interstitial lung disease (ILD) and, in addition, when compared with ILD-negative SSc patients, ILD-positive SSc patients revealed higher IL-4, IL-6, IL-8, and CCL2 (MCP-1) BALF levels. High CCL2 and IL-8 BALF concentrations were associated with neutrophilic and mixed alveolitis. Cytokine levels of IL-4, IL-8, and CCL2 correlated negatively with lung-function parameters; CCL2 concentrations also correlated with HR-CT scores. High concentrations of several cytokines were associated with the progress of ILD and end-stage ILD. Univariate analyses revealed high IL-2 and tumor necrosis factor-alpha (TNF-α) levels as the best predictors for progressive disease, together with lung-function parameters, young age, and neutrophilic alveolitis. Multivariate analyses partially confirmed these results but did not sufficiently converge because of the limited number of patients.ConclusionsThe association of BALF cytokines with lung fibrosis and its progress suggests that cytokines contribute to the pathogenesis of ILD and hence could be regarded as potential therapeutic targets.

Acute Right-Sided Heart Failure Due to Hemorrhage Into a Pericardial Cyst

This is a description of a rare complication of a pericardial cyst with spontaneous internal hemorrhage and following tamponade. The noninvasive diagnosis was done by transesophageal echocardiography and computed thoracic tomography. The cyst was thoracoscopically removed and pathologically examined. This case demonstrates a rare but important and life-threatening complication of mostly asymptomatic pericardial cysts.

Substance P expression in TRPV1 and trkA-positive dorsal root ganglion neurons innervating the mouse lung.

In the present study, the co-localisation of substance P (SP) with the vanilloid receptor TRPV1 and the neurotrophin receptor tyrosine kinase trkA was analysed in airway-specific murine dorsal root ganglion (DRG) neurons. DRG neurons labelled with Fast Blue were predominantly found at the segmental levels T2-T5. Immunoreactivity for the receptor TRPV1 was localized to 12% of Fast Blue labelled DRG neurons. Double-labelling immunohistochemistry revealed that a substantial number of them also co-express SP (7.6 +/- 1.1% (mean +/- S.E.M.)), whereas neurons with immunoreactivity for TRPV1 only were found in 4.4 +/- 1.3% of the retrogradely labelled neuronal population. Further analysis of retrogradely labelled neurons showed that their majority expressed trkA (62.8 +/- 1.4%), neurofilament protein 68-kDa (64.8 +/- 1.5%) or glutamate alone (19.5 +/- 1.9%). SP was always expressed in trkA-positive neurons. Based on the extent of co-localization of SP with the receptors TRPV1 and trkA in DRG airway neurons, the present study indicates that the DRG pathway may have effects on the magnitude of neurogenic inflammation in airway diseases such as asthma.

Experimental models of tracheobronchial stenoses: a useful tool for evaluating airway stents.

BACKGROUND Stent implantation is a conservative alternative to open operation for treating benign tracheobronchial strictures. Most of the presently available stents were primarily designed for endovascular use. Their respiratory use entails a risk of iatrogenic complications. From a scientific and from an ethical point of view these risks justify preclinical evaluation of new respiratory stents in experimental models of central airway stenoses. Therefore, an attempt was made to develop such models in piglets and adult minipigs. METHODS Tracheal stenoses were obtained by creating first a segmental tracheomalacia through extramucosal resection of cartilaginous arches. The fibrous component of the stenoses was then obtained through bronchoscopic application of a caustic agent causing progressive deep mucosal and submucosal injury. Stenoses of the main bronchi were created by topical application of the caustic agent only. RESULTS These models demonstrated the typical features of benign fibromalacic tracheobronchial stenoses with constant recurrence after mechanical dilation. Preliminary experiments showed that short-term problems of tolerance of stent prototypes are easily demonstrable in these models. CONCLUSIONS These experimental models, which simulate quite realistically human diseases, offer the opportunity to perfect new tracheobronchial stents specifically designed for respiratory use and to evaluate their long-term tolerance before their use in humans.

Pulmonary hypertension due to chronic lung disease: Updated Recommendations of the Cologne Consensus Conference 2011

The 2009 European Guidelines on Pulmonary Hypertension did not cover only pulmonary arterial hypertension (PAH) but also some aspects of pulmonary hypertension (PH) in chronic lung disease. These guidelines point out that the drugs currently used to treat patients with PAH (prostanoids, endothelin receptor antagonists and phosphodiesterase type-5 inhibitors) have not been sufficiently investigated in other forms of PH. Therefore, the use of these drugs in patients with chronic lung disease and PH is not recommended. This recommendation, however, is not always in agreement with medical needs as physicians feel sometimes inclined to also treat other forms of pulmonary hypertension which may affect the quality of life and survival of these patients in a similar manner as in PAH. In June 2010, a consensus conference was held in Cologne, Germany, to discuss open and controversial issues surrounding the practical implementation of the European Guidelines. The conference was sponsored by the German Society of Cardiology, the German Society of Respiratory Medicine and the German Society of Pediatric Cardiology (DGK, DGP and DGPK). To this end, a number of working groups were initiated, one of which was specifically dedicated to the diagnosis and treatment of PH due to chronic lung disease. This manuscript describes in detail the results and recommendations of this working group which were last updated in October 2011.

Efficacy of Bronchoscopic Thermal Vapor Ablation and Lobar Fissure Completeness in Patients with Heterogeneous Emphysema

Background: Bronchoscopic thermal vapor ablation (BTVA) ablates emphysematous tissue through a localized inflammatory response followed by contractive fibrosis and tissue shrinkage leading to lung volume reduction that should not be influenced by collateral ventilation. Objectives: To determine the correlation of clinical data from a trial of BTVA with fissure integrity visually assessed by computed tomography (CT). Methods: We conducted a single-arm study of patients with upper lobe-predominant emphysema (n = 44). Patients received BTVA either to the right upper lobe or left upper lobe, excluding the lingula. Primary efficacy outcomes were forced expiratory volume in 1 s (FEV1) and St. George’s Respiratory Questionnaire (SGRQ) at 6 months. Lobar volume reduction from CT was another efficacy outcome measurement. The fissure of the treated lobe was analyzed visually on preinterventional CT. Incompleteness of the small fissure, the upper half of the right large fissure and the whole left large fissure were estimated visually in 5% increments, and the relative amount of fissure incompleteness was calculated. Pearson correlation coefficients were calculated for the association between fissure incompleteness and change in efficacy outcomes (baseline to 6 months) of BTVA. Results: A total of 38 out of 44 patients (86%) had incompleteness in the relevant fissure. Calculated relevant fissure incompleteness was a mean of 13% of fissure integrity (range 0–63). Correlation coefficients for the association of incompleteness with outcomes were as follows: FEV1 = 0.17; lung volume reduction = –0.27; SGRQ score = –0.10; 6-min walk distance = 0.0; residual volume (RV) = –0.18, and RV/total lung capacity = –0.14. Conclusions: Lobar fissure integrity has no or minimal influence on BTVA-induced lung volume reduction and improvements in clinical outcomes.