Identification of a highly lethal V3+ TP53+ subset in ALK+ lung adenocarcinoma.

Tyrosine kinase inhibitors (TKI) have improved prognosis in metastatic anaplastic lymphoma kinase (ALK)-driven lung adenocarcinoma, but patient outcomes vary widely. We retrospectively analyzed the clinical course of all cases with assessable baseline TP53 status and/or ALK fusion variant treated at our institutions (n = 102). TP53 mutations were present in 17/87 (20%) and the echinoderm microtubule-associated protein-like 4 (EML4)-ALK variant 3 (V3) in 41/92 (45%) patients. The number of metastatic sites at diagnosis was affected more by the presence of V3 than by TP53 mutations, and highest with both factors (mean 5.3, p < 0.001). Under treatment with ALK TKI, progression-free survival (PFS) was shorter with either TP53 mutations or V3, while double positive cases appeared to have an even higher risk (hazard ratio [HR] = 2.9, p = 0.015). The negative effect of V3 on PFS of TKI-treated patients was strong already in the first line (HR = 2.5, p = 0.037) and decreased subsequently, whereas a trend for PFS impairment under first-line TKI by TP53 mutations became stronger and statistically significant only when considering all treatment lines together. Overall survival was impaired more by TP53 mutations (HR = 4.9, p = 0.003) than by V3 (HR = 2.4, p = 0.018), while patients with TP53 mutated V3-driven tumors carried the highest risk of death (HR = 9.1, p = 0.02). Thus, TP53 mutations and V3 are independently associated with enhanced metastatic spread, shorter TKI responses and inferior overall survival in ALK+ lung adenocarcinoma. Both markers could assist selection of cases for more aggressive management and guide development of novel therapeutic strategies. In combination, they define a patient subset with very poor outcome.

[Joint Statement of the German Radiological Society and the German Respiratory Society on a Quality-Assured Early Detection Program for Lung Cancer with Low-dose CT]. / Positionspapier der Deutschen Röntgengesellschaft und der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin zu einem qualitätsgesicherten Früherkennungsprogramm des Lungenkarzinoms mittels Niedrigdosis-CT.

Substantial new data on early detection of lung cancer with low-dose CT has become available since the last joint statement of the German Roentgenological Society and the German Respiratory Society was published in 2011. The German S3 guideline on lung cancer was revised in 2018 and now contains a weak recommendation towards early detection of lung cancer with low-dose CT in a quality-assured early detection program. These new developments required a repositioning of the involved professional societies. This present joint statement describes main features of a quality-assured program for early detection of lung cancer with low-dose CT in Germany.

[Endoscopic interventions in pulmonology]. / Endoskopische Interventionen in der Pneumologie.

Bronchoscopy plays a significant role in the diagnosis and treatment of pulmonary diseases. Hemoptysis, or central airway obstruction, is a common indication for interventional bronchoscopy. In addition, the treatment of early lung cancer is the domain of bronchoscopy in inoperable patients. In recent years, endoscopic techniques have also been established as new therapeutic options in advanced chronic obstructive pulmonary disease and uncontrolled bronchial asthma.

Novel Endoscopic Approaches to Treating Chronic Obstructive Pulmonary Disease and Emphysema.

Chronic obstructive pulmonary disease (COPD) is a widespread disease associated with high morbidity and mortality. The principal aim of therapy is preventing disease progression. Besides rehabilitation and pharmacological treatment, different endoscopic approaches were developed in the past decade extending the therapeutic spectrum. Various endoscopic lung volume reduction (ELVR) techniques are available that differ in the implementation, mechanism of action, complication spectrum, and reversibility. So far, the data on efficacy and safety are variable and still very limited. The most comprehensive data are available for endoscopic valve therapy. This reversible technique leads to lobar atelectasis and thus significant lobar volume reduction in patients with severe emphysema and low collateral ventilation. Implantation of coils leading to parenchymal compression and bronchoscopic thermal vapor ablation inducing an inflammatory reaction are nonblocking ELVR techniques and thus independent of collateral ventilation. Besides ELVR techniques, targeted lung denervation has evolved as the latest development in the field of endoscopic therapy in COPD. The aim of this endoscopic method is sustainable bronchodilation by minimizing the influence of parasympathetic pulmonary nerves on smooth muscles of the airways. This review summarizes the different endoscopic procedures, their mechanism of action, and the results of the clinical trials including efficacy and safety.

Tumour cell proliferation (Ki-67) in non-small cell lung cancer: a critical reappraisal of its prognostic role.

BACKGROUND: Uncontrolled proliferation is a hallmark of malignant tumour growth. Its prognostic role in non-small cell lung cancer (NSCLC) has been investigated in numerous studies with controversial results. We aimed to resolve these controversies by assessing the Ki-67 proliferation index (PI) in three large, independent NSCLC cohorts. METHODS: Proliferation index was retrospectively analysed by immunohistochemistry in a cohort of 1065 NSCLC and correlated with clinicopathological data including outcome and therapy. RESULTS were validated in two independent cohorts of 233 squamous cell carcinomas (SQCC) and 184 adenocarcinomas (ADC). RESULTS: Proliferation index (overall mean: 40.7%) differed significantly according to histologic subtypes with SQCC showing a mean PI (52.8%) twice as high as ADC (25.8%). In ADC PI was tightly linked to growth patterns. In SQCC and ADC opposing effects of PI on overall (OS), disease-specific and disease-free survival were evident, in ADC high PI (optimised validated cut-off: 25%) was a stage-independent negative prognosticator (hazard ratio, HR OS: 1.56, P=0.004). This prognostic effect was largely attenuated by adjuvant radio-/chemotherapy. In SQCC high PI (optimised validated cut-off: 50%) was associated with better survival (HR OS: 0.65, P=0.007). CONCLUSIONS: Our data demonstrate that PI is a clinically meaningful biomarker in NSCLC with entity-dependent cut-off values that allow reliable estimation of prognosis and may potentially stratify ADC patients for the need of adjuvant therapy.

Role of endobronchial and endoscopic ultrasound in pulmonary medicine.

In the last decade, endobronchial ultrasound (EBUS) has evolved into an important tool for diagnostic bronchoscopy in daily practice. EBUS has established as a standard for the diagnosis of hilar or mediastinal lymphadenopathy, as a guidance technique for peripheral pulmonary lesions and for the evaluation of tumor involvement of the tracheobronchial wall or mediastinum. In the meantime, EBUS has also taken a significant role in mediastinal staging in lung cancer patients. However, EBUS plays not only a role in the diagnosis of malignancies, it is also important for the diagnosis of benign disorders.

[Preoperative pulmonary function analysis and cardiorespiratory risk assessment: the current standard]. / Präoperative Lungenfunktionsanalyse und kardiorespiratorische Risikoabschätzung, aktueller Standard.

The aim of preoperative lung function analysis and diagnostic cardiology is to identify patients with an increased risk of complications and to best inform the patients about treatment options and risks so that an informed treatment decision can be made. The identification of patients at increased peri-interventional risk by preoperative physiological diagnostics also forms the basis for further developments and improvements of interventions and intervention techniques in order to reduce the risk of complications. The acquisition of a detailed medical history, a thorough physical examination, and the diagnosis using ECG and spirometry may provide the first evidence for the presence of relevant comorbidities. In elective surgery a detailed preoperative evaluation of comorbidities must be done. The association of age and operative mortality is not only due to age alone, but also involves the spectrum of comorbidities. The algorithms for Germany are based on the "S3 Guidelines of the German Society of Pneumology of 2010". Both German and international guidelines recommend the discussion of each case before lung resections in an interdisciplinary case discussion with thoracic surgeons, oncologists, radio-oncologists and pulmonologists. Patients of advanced age should always be subjected to an extended preoperative cardiopulmonary investigation.

[Respiratory therapy with Ez-PAP for treatment of dynamic hyperinflation in patients with severe COPD and emphysema]. / Atemtherapie mit Ez-PAP zur Behandlung der dynamischen Überblähung bei Patienten mit schwerer COPD und Lungenemphysem.

BACKGROUND: Non-pharmacological respiratory physiotherapy in treatment of COPD with severe emphysema is achieving increasing importance. Ez-PAP, a compact CPAP- or flow-PEP system, supports inspiration by using the Coanda effect in addition to a PE(E)P-effect during expiration. METHODS AND PATIENTS: 30 patients with severe COPD and emphysema and hypercapnic respiratory failure under non-(NIV) (n = 28) and invasive ventilation (n = 2) were treated in ventilator-free intervals with Ez-PAP and analyzed retrospectively. Clinical courses such as ventilator-dependency, dyspnea by visual CR-10 Borg scale, results of six-minute walk tests (6MWT), lung function tests and recordings of transcutaneous CO2 measurements were evaluated where possible. RESULTS: Analyzed patients showed less ventilator dependancy (n = 9), reported a median decrease of shortness of breath by 3,3 points (n = 10) and improved by 50,4 m in the 6MWT (n = 5). A median increase of vital capacity by 544 ml (n = 5) was shown by spirometry. Combined with manual techniques for reducing air-trapping, treatment success was documented by a median reduction of pCO2 by 7,3 mmHg (n = 6) using transcutaneous pCO2 measurement. CONCLUSION: Ez-PAP is a simple mechanical method to reduce dynamic hyperinflation in severe COPD, thus achieving relief of respiratory muscles and more effective breathing. Prospective studies of this promising method are urgently required.

[Smoking cessation in patients with COPD]. / Tabakentwöhnung bei COPD.

Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide. Cigarette smoking is the main cause of COPD. Quitting smoking is thus the most effective treatment strategy and central in COPD prevention. A number of guidelines on prevention, diagnosis, therapy and rehabilitation of COPD have been published. To help implementing and standardizing smoking cessation in COPD a guideline was published 2008 in Germany focusing on this complex issue. The present guideline is an update of the 2008 guideline and has a high grade of evidence (S3 according to the AWMF; Arbeitsgemeinschaft wissenschaftlicher medizinischer Fachgesellschaften). The guideline gives comprehensive and practical information on how to integrate smoking cessation as an central part of COPD therapy.

Comparison of cryobiopsy and forceps biopsy for the diagnosis of mediastinal lesions: A randomised clinical trial.

INTRODUCTION: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is the standard approach for lung cancer staging. However, its diagnostic utility for other mediastinal diseases might be hampered by the limited tissue retrieved. Recent evidence suggests the novel sampling strategies of forceps biopsy and cryobiopsy as auxiliary techniques to EBUS-TBNA, considering their capacity for larger diagnostic samples. METHODS: This study determined the added value of forceps biopsy and cryobiopsy for the diagnosis of mediastinal diseases. Consecutive patients with mediastinal lesions of 1 cm or more in the short axis were enrolled. Following completion of needle aspiration, three forceps biopsies and one cryobiopsy were performed in a randomised pattern. Primary endpoints included diagnostic yield defined as the percentage of patients for whom mediastinal biopsy led to a definite diagnosis, and procedure-related complications. RESULTS: In total, 155 patients were recruited and randomly assigned. Supplementing EBUS-TBNA with either forceps biopsy or cryobiopsy increased diagnostic yield, with no significant difference between EBUS-TBNA plus forceps biopsy and EBUS-TBNA plus cryobiopsy (85.7 % versus 91.6 %, P = 0.106). Yet, samples obtained by additional cryobiopsies were more qualified for lung cancer molecular testing than those from forceps biopsies (100.0 % versus 89.5 %, P = 0.036). When compared directly, the overall diagnostic yield of cryobiopsy was superior to forceps biopsy (85.7 % versus 70.8 %, P = 0.001). Cryobiopsies produced greater samples in shorter procedural time than forceps biopsies. Two (1.3 %) cases of postprocedural pneumothorax were detected. CONCLUSIONS: Transbronchial mediastinal cryobiopsy might be a promising complementary tool to supplement traditional needle biopsy for increased diagnostic yield and tissue harvesting. TRIAL REGISTRATION: ChiCTR2000030373.

Collateral ventilation.

Although known for more than 80 years, 'collateral ventilation' (CV) became a focus of endoscopic research in the recent decade. Implantation of one-way valves presents an effective treatment option for patients with advanced heterogeneous emphysema optimizing symptoms and quality of life. However, this treatment modality is only successful in case of low interlobar CV. Based on this evidence, attempts to develop different approaches for the quantification of CV have been initiated. In this regard, it is crucial to illuminate the meaning and different aspects of CV.

[Familial pulmonary cysts and papular skin lesions in a 37-year-old woman]. / Familiäre pulmonale Zysten und papulöse Hauteffloreszenzen bei einer 37-jährigen Patientin.

A 37-year-old female patient presented with sudden dyspnea and chest pain. Spontaneous pneumothoraces had been observed several times before in this patient and two members of the patient´s family in the last years. Moreover, she exhibited papular facial skin lesions. Radiomorphologically a pneumothorax apical on the left side and basal accentuated cystic lung destruction on both sides could be seen. Pleurodesis and several wedge resections with insertion of a drainage on the left side were performed therapeutically. Histology disclosed multiple cysts, whereby typical differential diagnoses could be excluded by immunohistochemistry. A molecular genetic investigation detected a heterozygous mutation in the gene coding for follikulin (FLCN). Thereby, Birt-Hogg-Dubé syndrome (BHDS) was diagnosed. BHDS follows autosomal dominant inheritance and is characterized by cystic lung lesions with recurrent pneumothoraces, cutaneous fibrofolliculomas and an increased risk of renal carcinomas. It is based on mutations in the gene coding for the protein FLCN on chromosome 17.

[Diagnostic and predictive analyses of cytological specimens of non-small cell lung cancer: strategies and challenges]. / Diagnose und prädiktive Analysen an zytologischen und bioptischen Tumorproben nicht-kleinzelliger Lungenkarzinome: Aktuelle Strategien und Herausforderungen.

Personalised medicine is becoming the standard care for advanced non-small cell lung cancer. Tumour-specific therapies based on biomarker analyses, e. g., EGFR mutations or translocations of the ALK gene locus, result in a superior patient outcome compared to unselected therapy approaches. However, predictive molecular analyses can be challenging and require significant experience with cell- and tissue-based diagnostic methods. The major challenge relates to the sometimes low amount of available tumour material for both diagnostic and predictive analyses. As yet, there are no standardised or evidence-based recommendations concerning biopsies, specimen processing, and analyses. Respective guidelines require combined interdisciplinary actions to consider both clinical and pathological aspects. In order to establish a basis for high quality procedures, different approaches, methods, and protocols were interdisciplinary discussed with an emphasis on cytological specimens. Detailed evaluation of the parameters and consented recommendations might contribute to optimised strategies in the interdisciplinary, more and more complex care of non-small cell lung cancer patients.

[Chronic cough]. / Chronischer Husten.

Coughing is an important protective reflex of the respiratory tract and primarily serves clearance of the bronchial system. It is also an exceptionally common symptom in outpatient care that can be an expression of a variety of diseases. Coughing duration of longer than 8 weeks is referred to as chronic cough. A structured, often interdisciplinary diagnostic process is essential. The aim here is to identify causal treatment options, avoiding overdiagnosis and simultaneously not overlooking severe illness. This article discusses current diagnostic procedures, important differential diagnoses and possible treatment options.

Endobronchial ultrasound-guided lymph node biopsy with transbronchial needle forceps: a pilot study.

One limitation of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is the size of the available needles, frequently yielding only cells for cytological examination. The aim of this pilot study was to evaluate the efficacy and safety of newly developed needle forceps to obtain tissue for the histological diagnosis of enlarged mediastinal lymph nodes. Patients with enlarged, positron emission tomography (PET)-positive lymph nodes were included. The transbronchial needle forceps (TBNF), a sampling instrument combining the characteristics of a needle (bevelled tip for penetrating through the bronchial wall) with forceps (two serrated jaws for grasping tissue) was used through the working channel of the EBUS-TBNA scope. Efficacy and safety was assessed. 50 patients (36 males and 14 females; mean age 51 yrs) with enlarged or PET-positive lymph nodes were included in this pilot study. In 48 (96%) patients penetration of the bronchial wall was possible and in 45 patients tissue for histological diagnosis was obtained. In three patients TBNF provided inadequate material. For patients in whom the material was adequate for a histological examination, a specific diagnosis was established in 43 (86%) out of 50 patients (nonsmall cell lung cancer: n=24; small cell lung cancer: n=7; sarcoidosis: n=4; Hodgkin's lymphoma: n=4; tuberculosis: n=2; and non-Hodgkin's lymphoma: n=2).No clinically significant procedure-related complications were encountered. This study demonstrated that EBUS-TBNF is a safe procedure and provides diagnostic histological specimens of mediastinal lymph nodes.

Cryobiopsy increases the diagnostic yield of endobronchial biopsy: a multicentre trial.

Forceps, brushes or needles are currently the standard tools used during flexible bronchoscopy when diagnosing endobronchial malignancies. The new biopsy technique of cryobiopsy appears to provide better diagnostic samples. The aim of this study was to evaluate cryobiopsy over conventional endobronchial sampling. A total of 600 patients in eight centres with suspected endobronchial tumours were included in a prospective, randomised, single-blinded multicentre study. Patients were randomised to either sampling using forceps or the cryoprobe. After obtaining biopsy samples, a blinded histological evaluation was performed. According to the definitive clinical diagnosis, the diagnostic yield for malignancy was evaluated by a Chi-squared test. A total of 593 patients were randomised, of whom 563 had a final diagnosis of cancer. 281 patients were randomised to receive endobronchial biopsies using forceps and 282 had biopsies performed using a flexible cryoprobe. A definitive diagnosis was achieved in 85.1% of patients randomised to conventional forceps biopsy and 95.0% of patients who underwent cryobiopsy (p<0.001). Importantly, there was no difference in the incidence of significant bleeding. Endobronchial cryobiopsy is a safe technique with superior diagnostic yield in comparison with conventional forceps biopsy.

Simultaneous computed tomography-guided biopsy and radiofrequency ablation of solitary pulmonary malignancy in high-risk patients.

BACKGROUND: In recent years experience has been accumulated in percutaneous radiofrequency ablation (RFA) of lung malignancies in nonsurgical patients. OBJECTIVES: In this study, we retrospectively evaluated a simultaneous diagnostic and therapeutic approach including CT-guided biopsy followed immediately by RFA of solitary malignant pulmonary lesions. METHODS: CT-guided transthoracic core needle biopsy of solitary pulmonary lesions suspicious for malignancy was performed and histology was proven based on immediate frozen sections. RFA probes were placed into the pulmonary tumors under CT guidance and the ablation was performed subsequently. The procedure-related morbidity was analyzed. Follow-up included a CT scan and pulmonary function parameters. RESULTS: A total of 33 CT-guided biopsies and subsequent RFA within a single procedure were performed. Morbidity of CT-guided biopsy included pulmonary hemorrhage (24%) and a mild pneumothorax (12%) without need for further interventions. The RFA procedure was not aggravated by the previous biopsy. The rate of pneumothorax requiring chest tube following RFA was 21%. Local tumor control was achieved in 77% with a median follow-up of 12 months. The morbidity of the CT-guided biopsy had no statistical impact on the local recurrence rate. CONCLUSIONS: The simultaneous diagnostic and therapeutic approach including CT-guided biopsy followed immediately by RFA of solitary malignant pulmonary lesions is a safe procedure. The potential of this combined approach is to avoid unnecessary therapies and to perform adequate therapies based on histology. Taking the local control rate into account, this approach should only be performed in those patients who are unable to undergo or who refuse surgery.

[Bronchial foreign bodies]. / Fremdkörper im Bronchialsystem.

Coughing, wheezing, dyspnea and recurrent pneumonia can be signs of foreign body aspiration. About 80% of all foreign body aspirations occur in children, especially in infants between 1 and 3 years of age. Although most foreign bodies are found in the bronchi they are especially dangerous in the larynx or trachea. Foreign body aspiration is less common in adults, being confirmed in only about 1-2 of every 1,000 bronchoscopies. The most common foreign bodies are foods particles. Bronchoscopy is the method of choice for foreign body removal.