M Hetzel

Transbronchial Cryobiopsy: A New Tool for Lung Biopsies

Background: Specimens from transbronchial lung biopsies lack sufficient quality due to crush artifact and are generally too small for diagnosis of diffuse lung diseases. Flexible cryoprobes have been shown to be useful in therapeutic bronchoscopy. We introduce a novel technique for obtaining lung biopsies bronchoscopically, using a flexible cryoprobe. Objectives: The purpose of this study was to show the feasibility of using a cryoprobe to obtain lung biopsies during flexible bronchoscopy. Methods: Forty-one patients with radiographic signs of diffuse lung disease were selected for transbronchial biopsy. During flexible bronchoscopy, conventional transbronchial biopsies using forceps were done first. Then a flexible cryoprobe was introduced into the selected bronchus under fluoroscopic guidance. Once brought into position, the probe was cooled and then retracted with the frozen lung tissue being attached on the probe’s tip. The tissue was processed for histology. After establishing a diagnosis, the specimen area was measured using a digital morphometry system. Results: We evaluated the biopsy samples of 41 patients. The mean specimen area was 5.82 mm2 (0.58–20.88 mm2) taken by forceps compared to 15.11 mm2 obtained using the cryoprobe (2.15–54.15 mm2, p < 0.01). Two patients had a pneumothorax which resolved with tube thoracostomy. Biopsy-associated bleeding did not require any intervention. Transbronchial cryobiopsy contributed in a substantial number of cases to a definitive diagnosis. Conclusions: Transbronchial cryobiopsy is a novel technique which allows to obtain large biopsy samples of lung parenchyma that exceed the size and quality of forceps biopsy samples. Prospective trials are needed to compare this technique with surgical lung biopsy for diagnosis of diffuse lung diseases.

Different effects of growth factors on proliferation and matrix production of normal and fibrotic human lung fibroblasts.

Objectives and methods: In idiopathic pulmonary fibrosis (IPF), proliferation of fibroblasts and increased matrix deposition result in pulmonary damage and respiratory insufficiency. We cultured human fibroblasts from lung biopsies of healthy adults and of three patients with IPF (histologically usual interstital pneumonitis, UIP) in order to compare proliferation ([3H]thymidine incorporation, cell count) and matrix protein expression (immune fluorescence, quantification of fibronectin synthesis using time-resolved immune fluorescence) of normal and UIP fibroblasts in response to various growth factors. Findings: The growth factors platelet-derived growth factor-BB (PDGF), epidermal growth factor (EGF), insulin growth factor-1 (IGF-1), insulin-like growth factor-2 (IGF-2), tumor necrosis factor α (TNFα), Transforming growth factor-β (TGFβ1), and fibroblast growth factor-2 (FGF-2) stimulate proliferation of normal lung fibroblasts significantly more than proliferation of UIP fibroblasts. Immunofluorescence reveals extensive expression of collagen I, collagen III, and fibronectin induced by serum, TGFβ1, and TNFα. This expression is more pronounced in UIP fibroblasts than in normal fibroblasts. Quantification of fibronectin synthesis reveals an enhanced fibronectin synthesis by UIP fibroblasts in response to PDGF, EGF, IGF-1, IGF-2, TNFα, TGFβ1, and FGF-2). Conclusions: Fibroblasts from normal and UIP lungs differ in their response to growth factors: Whereas normal fibroblasts show a predominantly proliferative response, UIP fibroblasts show an enhanced synthetic activity. Different fibroblast responses may contribute to progressive pulmonary fibrosis in patients with UIP.

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.

Randomized Phase III Study of Surgery Alone or Surgery Plus Preoperative Cisplatin and Gemcitabine in Stages IB to IIIA Non–Small-Cell Lung Cancer

PURPOSE This study aimed to determine whether three preoperative cycles of gemcitabine plus cisplatin followed by radical surgery provides a reduction in the risk of progression compared with surgery alone in patients with stages IB to IIIA non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients with chemotherapy-naive NSCLC (stages IB, II, or IIIA) were randomly assigned to receive either three cycles of gemcitabine 1,250 mg/m(2) days 1 and 8 every 3 weeks plus cisplatin 75 mg/m(2) day 1 every 3 weeks followed by surgery, or surgery alone. Randomization was stratified by center and disease stage (IB/IIA v IIB/IIIA). The primary end point was progression-free survival (PFS). Results The study was prematurely closed after the random assignment of 270 patients: 129 to chemotherapy plus surgery and 141 to surgery alone. Median age was 61.8 years and 83.3% were male. Slightly more patients in the surgery alone arm had disease stage IB/IIA (55.3% v 48.8%). The chemotherapy response rate was 35.4%. The hazard ratios for PFS and overall survival were 0.70 (95% CI, 0.50 to 0.97; P = .003) and 0.63 (95% CI, 0.43 to 0.92; P = .02), respectively, both in favor of chemotherapy plus surgery. A statistically significant impact of preoperative chemotherapy on outcomes was observed in the stage IIB/IIIA subgroup (3-year PFS rate: 36.1% v 55.4%; P = .002). The most common grade 3 or 4 chemotherapy-related adverse events were neutropenia and thrombocytopenia. No treatment-by-histology interaction effect was apparent. CONCLUSION Although the study was terminated early, preoperative gemcitabine plus cisplatin followed by radical surgery improved survival in patients with clinical stage IIB/IIIA NSCLC.

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.

Endobronchial tumor debulking with a flexible cryoprobe for immediate treatment of malignant stenosis

OBJECTIVE In addition to use of a laser, argon plasma coagulation, electrocautery, or coring with a rigid bronchoscope, tumor debulking with a flexible cryoprobe is used for therapeutic bronchoscopy with an immediate effect for endobronchial pathologies. We performed this analysis to determine the usefulness, efficacy, and safety of the flexible cryorecanalization in a large population under routine conditions. METHODS We identified 225 bronchoscopic interventions that were done as cryorecanalization with a flexible cryoprobe. All patients had symptomatic airway stenosis. We determined the endoscopic success rate and safety (bleeding and perforation) of the procedure. RESULTS Successful cryorecanalization was achieved in 205 (91.1%) of 225 patients. The flexible cryoprobe was used with all patients, in most patients in combination with flexible bronchoscopy and only in a minority (n = 31, 13.8%) in combination with a rigid bronchoscope. Additional interventional techniques used were endobronchial stents (n = 11, 4.9%) and argon plasma coagulation (n = 37, 16.4%). Mild bleeding (if ice-cold NaCl or epinephrine solution was necessary) occurred in 9 (4.0%) patients, moderate bleeding (if argon plasma coagulation or a bronchus blocker was required) occurred in 18 (8.0%) patients, and severe bleeding (events with hemodynamic instability) never occurred. CONCLUSIONS Cryorecanalization with the flexible cryoprobe for treatment of symptomatic endobronchial tumor stenosis is a safe technique with a high success rate and immediate treatment effect.

Old Meets Modern: The Use of Traditional Cryoprobes in the Age of Molecular Biology

Background: Endobronchial forceps biopsies are often small and are associated with a relevant extent of artifacts. To overcome these limitations is an important task. Especially when considering predictive factors for pharmacological therapies of lung cancer (ERCC1, RRM1) a development of biopsy techniques seems to be essential. This is the first report on a new endobronchial biopsy technique called cryobiopsy. Objectives: In this study the feasibility and the potential advantages of applying cryoprobes for harvesting samples for histological examination in flexible bronchoscopies will be focused on. Methods: In 12 patients suffering from exophytic endobronchial malignancies, a modified flexible cryoprobe was used for immediate recanalization. The extracted tissue was examined histologically regarding sample quality and sample size. Results: Tissue samples obtained using the cryoprobe showed an extraordinary good quality in terms of size (median diameter of 6.7 mm, range 4.2–13 mm) and artifact-free sample area (75% of the samples showed an artifact-free sample area of more than 75%). Additionally molecular markers were shown to be well preserved. Conclusions: The new technique termed cryobiopsy might widen the chest physician’s range of tools for diagnostic bronchoscopies.

Prospective controlled animal study on biopsy sampling with new flexible cryoprobes versus forceps: evaluation of biopsy size, histological quality and bleeding risk.

Background: Cryoextraction is a procedure used for the recanalization of obstructed airways caused by visible exophytic endobronchial tumor. Biopsy samples obtained by this technique have been shown to be useful for histological assessment. Objectives: The aim of the present animal study was to systematically evaluate biopsy size, histological quality and bleeding risk after cryobiopsy with new, flexible cryoprobes in comparison with forceps biopsy, serving as the gold standard. Methods: Biopsies were obtained from anesthetized pigs with the flexible bronchoscopy technique, and evaluated histologically with respect to their size and quality. Bleeding frequency, bleeding duration and histological changes in the biopsy bed were also recorded. Results: Cryobiopsies were significantly larger than forceps biopsies. The size of cryobiopsies was dependent on the freezing time. The histological quality of the cryobiopsy specimenswas not impaired by the freezing process, whereas forceps biopsies showed typical crush artifacts. Despite the larger defects left in the tracheobronchial system after cryobiopsy, bleeding frequency and duration were not higher compared to forceps biopsy. Conclusions: Since cryobiopsy sampling is not associated with a higher bleeding risk compared with forceps biopsy, this new biopsy technique offers – in addition to a good specimen quality – a safe and valuable tool with the potential of improving the outcome of diagnostic endoscopy.

An unusual case of Hughes-Stovin syndrome

In 1959 HUGHES and STOVIN described a syndrome consisting of multiple pulmonary aneurysms and peripheral venous thrombosis. Since that time several cases of the Hughes-Stovin syndrome have been published. We present the case of a 25 yr old man who, in addition to the classical symptoms, had multiple aneurysms of the bronchial arteries, which were the cause of severe haemoptysis. An aneurysm of the left hepatic artery was also detected. To our knowledge this is the first description of aneurysms of the bronchial arteries in Hughes-Stovin syndrome. Bleeding was successfully treated by double embolization of bronchial arteries via transfemoral catheter.

Reliability of symptoms to determine use of bone scans to identify bone metastases in lung cancer: prospective study

Based on the hypotheses that most skeletal metastases in lung cancer are clinically symptomatic, that the incidence of bony metastases in early stages is low, and that bone scintigraphy has a sensitivity of nearly 100%, leading professional societies recommend diagnostic skeletal imaging depending on clinical symptoms.1 2 No study has assessed the significance of skeletal symptoms as a criterion for skeletal imaging in patients with lung cancer since 1991.3 But in the intervening period gamma camera technology has been considerably refined and more sensitive methods such as magnetic resonance imaging have become available for skeletal imaging. We redetermine the role of symptoms and serum concentrations in detecting bony metastases in lung cancer and reassess the accuracy of bone scans for screening. From September 1999 to September 2001 we recruited 153 consecutive patients at University Hospital Ulm. We included patients based on cytological or histological evidence of lung cancer returned no more than …