Martin Kohlhäufl

Double tracer gas single-breath washout: reproducibility in healthy subjects and COPD

The applicability and interpretation of inert tracer gas washout tests is hampered by the lack of feasible protocols and reproducibility data. We assessed feasibility, variability and reproducibility of a new easy to perform double tracer gas (DTG) single-breath washout (SBW) test and compared this with conventional nitrogen washouts. In 40 healthy nonsmokers and 20 patients with stable chronic obstructive pulmonary disease (COPD), we performed three N2 vital capacity SBWs, three N2 multiple-breath washouts and three tidal DTG-SBW tests. Follow-up was after 1 week, 1 month and 6 months. Main outcomes were the lung clearance index (LCI) (N2 multiple-breath washout), slope of phase III (dN2) (N2 vital capacity SBW) and slope of phase III (SIIIDTG) (DTG-SBW). In healthy subjects, mean±sd LCI at baseline was 6.94±0.61, dN2 0.99±0.42% N2 per litre and SIIIDTG −0.206±0.108 g·mol−1·L−1. In COPD, LCI and dN2 were significantly higher (LCI 12.23±2.67, dN2 7.43±5.38% N2 per litre; p<0.001) and SIIIDTG significantly steeper (−0.653±0.428 g·mol−1·L−1, p<0.001). Reproducibility was high for main outcome parameters: the intraclass correlation coefficient over 6 months was 0.77 (0.86 in COPD) for LCI, 0.82 (0.89) for dN2 and 0.83 (0.93) for SIIIDTG. The tidal DTG-SBW is a reproducible test in healthy and COPD subjects that seems attractive for use in routine clinical settings. DTG-SBW may play a role in detection and monitoring of small airway diseases or as an outcome in drug trials http://ow.ly/x15bw

A Novel, Highly Sensitive ALK Antibody 1A4 Facilitates Effective Screening for ALK Rearrangements in Lung Adenocarcinomas by Standard Immunohistochemistry

Introduction: Successful treatment of lung cancer patients with crizotinib depends on the accurate diagnosis of anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangements. The approved fluorescence in-situ hybridization test is complex and difficult to use in daily diagnostic practice. Immunohistochemical assays—rapid and perfectly adapted for routine pathology practice—have been proposed as alternatives. We evaluated the novel high affinity ALK 1A4 antibody for routine diagnostics in formalin fixed, paraffin-embedded tumor specimens. Methods: Detection of ALK protein expression was investigated by comparing the new 1A4 antibody and the established D5F3 antibody/Ventana system in 218 lung cancer specimens with known ALK status preanalyzed by quantitative reverse transcription-polymerase chain reaction and fluorescence in-situ hybridization (20 ALK-positive cases, 198 ALK-negative cases). Results: The accuracy of both immunohistochemical assays for the detection of ALK rearrangements was high. Using a conventional staining procedure without signal enhancement, the 1A4 antibody assay identified all 20 ALK-rearranged tumors (100% sensitivity) and correctly characterized 196 of 198 negative cases (99.1% specificity). The D5F3/Ventana assay detected 19 ALK-rearranged tumors and typed 217 of 218 tumors correctly (95% sensitivity, 99.5 % specificity). Conclusions: The novel 1A4 antibody represents a promising candidate for screening lung tumors for the presence of ALK rearrangements.

Detection of Rearrangements and Transcriptional Up-Regulation of ALK in FFPE Lung Cancer Specimens Using a Novel, Sensitive, Quantitative Reverse Transcription Polymerase Chain Reaction Assay

Introduction: The approved dual-color fluorescence in situ hybridization (FISH) test for the detection of anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangements in non-small-cell lung cancer (NSCLC) is complex and represents a low-throughput assay difficult to use in daily diagnostic practice. We devised a sensitive and robust routine diagnostic test for the detection of rearrangements and transcriptional up-regulation of ALK. Methods: We developed a quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay adapted to RNA isolated from routine formalin-fixed, paraffin-embedded material and applied it to 652 NSCLC specimens. The reliability of this technique to detect ALK dysregulation was shown by comparison with FISH and immunohistochemistry. Results: qRT-PCR analysis detected unbalanced ALK expression indicative of a gene rearrangement in 24 (4.6%) and full-length ALK transcript expression in six (1.1%) of 523 interpretable tumors. Among 182 tumors simultaneously analyzed by FISH and qRT-PCR, the latter accurately typed 97% of 19 rearranged and 158 nonrearranged tumors and identified ALK deregulation in two cases with insufficient FISH. Six tumors expressing full-length ALK transcripts did not show rearrangements of the gene. Immunohistochemistry detected ALK protein overexpression in tumors with gene fusions and transcriptional up-regulation, but did not distinguish between the two. One case with full-length ALK expression carried a heterozygous point mutation (S1220Y) within the kinase domain potentially interfering with kinase activity and/or inhibitor binding. Conclusions: Our qRT-PCR assay reliably identifies and distinguishes ALK rearrangements and full-length transcript expression in formalin-fixed, paraffin-embedded material. It is an easy-to-perform, cost-effective, and high-throughput tool for the diagnosis of ALK activation. The expression of full-length ALK transcripts may be relevant for ALK inhibitor therapy in NSCLC.

The Severe Respiratory Insufficiency Questionnaire for Subjects With COPD With Long-Term Oxygen Therapy

BACKGROUND: Respiratory insufficiency in COPD may present as hypoxic and/or hypercapnic respiratory failure treated with long-term oxygen therapy (LTOT) and/or noninvasive ventilation (NIV) with LTOT. The Severe Respiratory Insufficiency Questionnaire (SRI) is a tool for the assessment of health-related quality of life (HRQOL) in subjects receiving NIV. However, it remains unclear whether the SRI is also capable of assessing and discriminating HRQOL in subjects receiving LTOT. METHODS: Stable subjects with COPD receiving LTOT or NIV + LTOT (NIV) were prospectively recruited and completed the SRI, lung function tests, and blood gases. Confirmatory factor analysis for construct validity and internal consistency reliability were calculated. RESULTS: One hundred fifty-five subjects were included (113 LTOT, 42 NIV). The Cronbach α coefficient of the 7 subscales ranged between 0.69 and 0.89 (LTOT) and between 0.79 and 0.93 (NIV), respectively. In both groups, confirmatory factor analysis revealed a one-factor model for the SRI summary scale; in 5 subscales, one- or 2-factor models could be established. Group differences in the SRI subsets were all P <.05 (except for physical functioning) with higher scores in subjects receiving NIV. CONCLUSIONS: The SRI showed high reliability and validity in subjects with COPD receiving LTOT. Subjects receiving LTOT had lower SRI scores, indicating a poorer HRQOL compared with subjects with established NIV and LTOT.

Telemedizin bei Patienten mit COPD – gibt es eine Evidenz?

ZusammenfassungDie enorme sozioökonomische Bedeutung der Volkskrankheit COPD ist international und national unbestritten. Telemonitoring kann potentiell die Versorgung gerade älterer COPD-Patienten – unabhängig vom Aufenthaltsort – in wichtigen Bereichen wie Behandlungsqualität und Qualitätsmanagement, Therapietreue und Selbstverantwortung sowie Lebensqualität und Sicherheit im Alltag verbessern. Auf der Basis aktueller, evidenzbasierter Analysen gibt die Arbeit einen Überblick zum therapeutischen Nutzen der Telemedizin bei COPD in Bezug auf wichtige Zielvariablen wie Zahl der Exazerbationen, Lebensqualität, Notwendigkeit stationärer Behandlungen und Mortalität.AbstractThe enormous socioeconomic significance of chronic obstructive pulmonary disease (COPD) is nationally and internationally undisputed. Telemonitoring can potentially improve the routine treatment in important areas of treatment quality and quality management, patient compliance, self-responsibility, quality of life and safety, especially for older patients and independent of the location. On the basis of current evidence-based analyses this article gives an overview of the therapeutic benefits of telemedicine for COPD with respect to important target variables, such as the number of exacerbations, quality of life, necessity for inpatient treatment and mortality.

Pulmonale Manifestationen rheumatologischer Erkrankungen

Kollagenosen konnen diverse pulmonale und thorakale Manifestationen aufweisen. Hierbei sind kollagenoseassoziierte interstitielle Lungenerkrankungen (CTD-ILD) eine der wichtigsten Differenzialdiagnosen interstitieller Lungenerkrankung. Zumeist findet sich ein NSIP-Muster, allerdings konnen alle Muster bis hin zur alveolaren Hamorrhagie auftreten. Zudem ist die Abgrenzung zu infektiosen Komplikationen oder zur medikamentenassoziierten ILDs zum Teil komplex. Eine Indikation zur immunsuppressiven Therapie bei CTDILDs ist fur progrediente und/oder klinisch signifikante Erkrankungen reserviert und sollte in enger Absprache mit dem betreuenden Rheumatologen erfolgen. Eine weitere wichtige Organmanifestation ist die kollagenoseassoziierte pulmonale Hypertonie. Daneben kann es auch zu Bronchiektasen/Bronchiolitiden, zu pleuralen Affektionen oder auch zu einer Mitbeteiligung der Atemmuskulatur kommen.

Prolonged paradoxical reaction to antituberculous treatment after discontinuation of TNF-alpha- blocker therapy with adalimumab. Rare clinical documentation

Abstract In the past decades, tumor necrosis factor alpha (TNF-a) antagonist has been a milestone in the treatment of many chronic inflammatory diseases. TNF antagonist can increase patients´ susceptibility to many different kinds of infections especially those requiring granuloma formations despite regular performance of Screening for latent tuberculosis infection (LTBI). We report 2 cases of patients who developed tuberculosis under treatment with adalimumab, which was discontinued after the diagnosis of tuberculosis. During the tuberculosis therapy they unexpectedly developed a prolonged paradoxical reaction. In both cases we were only able to manage the progress of the paradoxical reaction through high steroid doses. Patients undergoing therapy with TNF- alphablocker are prone to develop tuberculosis infection, which could in turn lead to severe prolonged paradoxical reaction during anti-tuberculous treatment. An increased steroid dose may be required and is sometimes necessary

Pulmonary leiomyosarcoma mimicking glomus tumor at first biopsy and surgically treated with isolated left main bronchus resection: rare clinical documentation

Soft tissue tumors originating within the endobronchial tree are extremely rare and most of them correspond to lipomas or leiomyomas. We here report a rare clinical presentation of leiomyosarcoma mimicking glomus tumor at initial biopsy arising from the left main bronchial trunk leading to left lower lobe atelectasis. Primary leiomyosarcoma of the lung is an unusual malignancy. Among this entity, the endobronchial form is very rare and the preoperative diagnosis is extremely difficult. We documented two different presentations and outcomes of primary endobronchial leiomyosarcoma of the lung. In this clinical presentation, histological study and immunohistochemical stain of the surgical resection provided the final diagnosis. Through the following we present the diagnostic and therapeutic difficulties encountered with endobronchial leiomyosarcoma.

Late onset of pulmonary cement embolism after a regular vertebroplasy. A clinical documentation

Vertebroplasty is a new minimal-invasive procedure for the treatment of painful vertebral fractures. The risk of a pulmonary embolism ranges from 3.5 to 23% for osteoporotic fractures. However, data about the incidence and treatment strategies of pulmonary cement embolisms (PCE) are limited. We report a case of a patient with symptomatic pulmonary cement embolism after the vertebroplasty. The diagnosis was confirmed by means of CT- scan. In cases of asymptomatic patients with peripheral PCE we recommend no treatment besides clinical follow-up. In our case of symptomatic embolisms, we recommend to proceed according to the guidelines regarding the treatment of thrombotic pulmonary embolisms, which includes initial heparinization and a following 6-month coumarin therapy.

Lung emphysema treated successfully using volume reduction with lung sealant (AeriSeal

Emphysema is a progressive and irreversible disease for which there is no cure to date. Endoscopic lung volume reduction with valve implantation or using lung sealant is a treatment option for patients with severe emphysema. A 60-year-old ex-smoker (80 pack years) referred to our center because of severe lung emphysema with progressive worsening of the obstructive ventilator pattern and clinical condition. By our patient we detected collateral channels by using the Chartis system®, which allow airflow into the target lobe and prevent atelectasis and significant lung volume reduction. Thus, we decided to treat the advanced emphysema of our patient with endoscopic volume reduction using lung sealant (AeriSeal®). The foam of lung sealant AeriSeal® is instilled into the peripheral airways and alveoli where it polymerizes and functions as tissue glue, forming a film of material on the lung surface that seals the target region to cause durable absorption atelectasis. Over a period of 16 weeks, the air within the sealed region was absorbed. The follow- up evaluation of this patient showed improved lung function (increased FEV 1, and a reduction of TLC and RV) with improved quality of life. Correlation between changes in primary and secondary outcome measures in the lung function parameters and 6- minute-walking test before and after the application of AeriSealant revealed significant reduction of hyperinflation and improvement both in the flow rates and physical capacity of our patient.