Peter W.A. Kunst

Ventilation and perfusion imaging by electrical impedance tomography: a comparison with radionuclide scanning

Electrical impedance tomography (EIT) is a technique that makes it possible to measure ventilation and pulmonary perfusion in a volume that approximates to a 2D plane. The possibility of using EIT for measuring the left-right division of ventilation and perfusion was compared with that of radionuclide imaging. Following routine ventilation (81mKr) and perfusion scanning (99mTc-MAA), EIT measurements were performed at the third and the sixth intercostal level in 14 patients with lung cancer. A correlation (r = 0.98, p < 0.005) between the left-right division for the ventilation measured with EIT and that with 81mKr was found. For the left-right division of pulmonary perfusion a correlation of 0.95 (p < 0.005) was found between the two methods. The reliability coefficient (RC) was calculated for estimating the left-right division with EIT. The RC for the ventilation measurements was 94% and 96% for the perfusion measurements. The correlation analysis for reproducibility of the EIT measurements was 0.95 (p < 0.001) for the ventilation and 0.93 (p < 0.001) for the perfusion measurements. In conclusion, EIT can be regarded as a promising technique to estimate the left-right division of pulmonary perfusion and ventilation.

Phase I study of aerosolized SLIT cisplatin in the treatment of patients with carcinoma of the lung.

Purpose: To investigate the safety and pharmacokinetics of aerosolized Sustained Release Lipid Inhalation Targeting (SLIT) Cisplatin in patients with lung carcinoma. Experimental Design: Phase I, dose-escalating study of SLIT Cisplatin given in two sessions daily. Safety data, including laboratory variables, adverse events, pulmonary function tests, and radiographic imaging, were collected and analyzed for all patients to determine toxicity. Pharmacokinetic monitoring was done during the first course. Results: Seventeen patients and one tracheostomy patient on compassionate use received treatment. Aerosolized cisplatin was well tolerated. No dose-limiting toxicity was observed at the maximum delivered dose. Safety data showed no hematologic toxicity, nephrotoxicity, ototoxicity, or neurotoxicity. Most common adverse events were nausea (64.7%), vomiting (47.1%), dyspnea (64.7%), fatigue (64.7%), and hoarseness (47.1%). Pharmacokinetic data showed very low plasma platinum levels only with the longest repeated inhalations. Common Toxicity Criteria grade 2 decrease in forced expiratory volume in one second and diffusing lung capacity for carbon monoxide after one course occurred both in two patients and grade one decrease in forced expiratory volume in one second and diffusing lung capacity for carbon monoxide in six and five patients, respectively. Direct airway deposition via the tracheostomy resulted in clinical deterioration after two cycles best described as bronchitis, completely reversible within days. Overall response: stable disease in 12 patients and progressive disease in 4 patients (one patient received one cycle). Conclusions: Aerosolized liposomal cisplatin was found to be feasible and safe.

Regional pressure volume curves by electrical impedance tomography in a model of acute lung injury.

Objective: A new noninvasive method, electrical impedance tomography (EIT), was used to make pressure‐impedance (PI) curves in a lung lavage model of acute lung injury in pigs. The lower inflection point (LIP) and the upper deflection point (UDP) were determined from these curves and from the traditional pressure‐volume (PV) curves to determine whether the PI curves resemble the traditional PV curves. Furthermore, regional differences in the mentioned determinants were investigated. Design: Prospective, experimental study. Setting: Animal research laboratory. Interventions: In nine anesthetized pigs, repeated lung lavage was performed until a PaO2 <80 torr was reached. Thereafter, an inspiratory PV curve was made using a constant flow of oxygen. During the intervention, EIT measurements were performed. Measurements and Main Results: In this study, the LIPEIT was within 2 cm H2O of the LIPPV. Furthermore, it was possible to visualize regional PI curves by EIT. No significant difference was found between the LIPPV (21.3 ± 3.0 cm H2O) and the LIPEIT of the total lung (21.5 ± 3.0 cm H2O) or the anterior parts of the lung (21.5 ± 2.9 cm H2O). A significantly higher LIP (29.5 ± 4.9 cm H2O) was found in the posterior parts of the lung. A UDPPV could be found in three animals only, whereas in all animals a UDPEIT could be determined from the anterior part of the lung. Conclusions: Using EIT, determination of LIP and UDP from the regional PI curves is possible. The obtained information from the regional PI curves may help in understanding alveolar recruitment. The use of this new bedside technique for clinical decision making remains to be examined.

Monitoring of recruitment and derecruitment by electrical impedance tomography in a model of acute lung injury

ObjectiveTo evaluate a noninvasive system for obtaining information about alveolar recruitment and derecruitment in a model of acute lung injury. DesignProspective experimental study. SettingAnimal research laboratory. SubjectsNine anesthetized pigs. InterventionsElectrical impedance tomography measurements were performed. Electrical impedance tomography is an imaging technique that can register the ventilation-induced impedance changes in different parts of the lung. In nine anesthetized pigs, repeated lung lavages were performed until a Pao2 of <80 mm Hg was reached. Thereafter, the lungs were recruited according to two different recruitment protocols: the open lung approach and the open lung concept. Five time points for measurements were chosen: healthy (reference), lavage (atelectasis), recruitment, derecruitment, and maintain recruited (final). Measurements and Main ResultsAfter lavage, there was a significant increase in the impedance ratio, defined as the ventilation-induced impedance changes of the anterior part of the lung divided by that of the posterior part (from 1.75 ± 0.63 to 4.51 ± 2.22;p < .05). The impedance ratio decreased significantly after performing the recruitment protocol (from 4.51 ± 2.22 to 1.18 ± 0.51). During both recruitment procedures, a steep increase in baseline impedance change was seen. Furthermore, during derecruitment, a decrease in the slope in baseline impedance change was seen in the posterior part of the lung, whereas the anterior part showed no change. ConclusionElectrical impedance tomography is a technique that can show impedance changes resembling recruitment and derecruitment of alveoli in the anterior and posterior parts of the lung. Therefore, electrical impedance tomography may help in determining the optimal mechanical ventilation in a patient with acute lung injury.

PULMONARY PERFUSION MEASURED BY MEANS OF ELECTRICAL IMPEDANCE TOMOGRAPHY

Electrical impedance tomography (EIT) is a recent imaging technique based on electrical impedance, offering the possibility of measuring pulmonary perfusion. In the present study the influence of several pulmonary haemodynamical parameters on the EIT signal were investigated. First, the influence on the systolic wave of the EIT signal (delta Zsys) of stroke volume, large pulmonary artery distensibility (both assessed by means of MRI) and the extent of the pulmonary peripheral vascular bed in 11 emphysematous patients (reduced peripheral vascular bed) and 9 controls (normal peripheral vascular bed) was investigated. Second, the influence of hypoxic pulmonary vasoconstriction on delta Zsys was examined in 14 healthy subjects. Finally, the origin of the diastolic wave was examined in three patients with atrioventricular dissociation. Multiple regression analysis showed that delta Zsys was only dependent on the variable emphysema (p < 0.02), but not dependent on stroke volume (p < 0.3) or pulmonary artery distensibility (p > 0.9). The mean value of delta Zsys for emphysematous patients (131 +/- 32 arbitrary units (AU)) was significantly lower (p < 0.001) than in the control group (200 +/- 39). In the group of healthy subjects delta Zsys decreased significantly (p < 0.001) during hypoxia (193 +/- 38 AU) compared with rest measurements (260 +/- 62 AU). The absence of the diastolic wave in the cardiological patients suggests the influence of reverse venous blood flow on the EIT signal. It is concluded that volume changes in the small pulmonary vessels contribute significantly to the EIT signal. Moreover, the hypoxia induced decrease in delta Zsys indicates the potential of EIT for measuring pulmonary vascular responses to external stimuli.

A Phase II Study of Sorafenib in Patients with Platinum-Pretreated, Advanced (Stage IIIb or IV) Non–Small Cell Lung Cancer with a KRAS Mutation

Purpose: Sorafenib inhibits the Ras/Raf pathway, which is overactive in cancer patients with a KRAS mutation. We hypothesized that patients with non–small cell lung cancer (NSCLC) with KRAS mutation will benefit from treatment with sorafenib. Experimental Design: In this phase II study, patients with KRAS-mutated, stage IIIb or IV NSCLC that progressed after at least one platinum-containing regimen were treated with sorafenib. Treatment consisted of sorafenib 400 mg twice daily until disease progression or unacceptable toxicity. Pretreatment serum from each patient was obtained to predict outcome using a proteomic assay (VeriStrat). Primary endpoint was disease control rate (DCR) at 6 weeks. Results: Fifty-nine patients were entered between May 2010 and February 2011. Fifty-seven patients started sorafenib. Mean age was 58.5 (SD = ±8.1) years, 16 male/41 female, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0/1/2 24/30/3. At 6 weeks, 5 partial response, 25 stable disease, and 27 progressive disease were observed; DCR was 52.6%. Median duration of treatment was 9 weeks. The median progression-free survival (PFS) was 2.3 months and median overall survival (OS) was 5.3 months. Patients with a prediction of good prognosis according to VeriStrat serum proteomics assay showed a significantly superior PFS [HR, 1.4; 95% confidence interval (CI), 1.0–1.9] but not OS (HR, 1.3; 95% CI, 0.9–1.7). Sorafenib-related grade III/IV toxicity was reported in 10 patients (17.5%); all but one patient experienced grade III skin toxicity (14.0%) or grade III gastrointestinal toxicity (8.8%). Conclusion: Treatment with sorafenib has relevant clinical activity in patients with NSCLC harboring KRAS mutations. Further randomized study with this agent is warranted as single-agent or combination therapy. Clin Cancer Res; 19(3); 743–51. ©2012 AACR.

Transcriptome sequencing (RNA-Seq) of human endobronchial biopsies: asthma versus controls

The cellular and molecular pathways in asthma are highly complex. Increased understanding can be obtained by unbiased transcriptomic analysis (RNA-Seq). We hypothesised that the transcriptomic profile of whole human endobronchial biopsies differs between asthma patients and controls. First, we investigated the feasibility of obtaining RNA from whole endobronchial biopsies suitable for RNA-Seq. Secondly, we examined the difference in transcriptomic profiles between asthma and controls. This cross-sectional study compared four steroid-free atopic asthma patients and five healthy nonatopic controls. Total RNA from four biopsies per subject was prepared for RNA-Seq. Comparison of the numbers of reads per gene in asthma and controls was based on the Poisson distribution. 46 genes were differentially expressed between asthma and controls, including pendrin, periostin and BCL2. 10 gene networks were found to be involved in cellular morphology, movement and development. RNA isolated from whole human endobronchial biopsies is suitable for RNA-Seq, showing different transcriptomic profiles between asthma and controls. Novel and confirmative genes were found to be linked to asthma. These results indicate that biological processes in the airways of asthma patients are regulated differently when compared to controls, which may be relevant for the pathogenesis and treatment of the disease. Transcriptome sequencing shows processes in the airways of asthmatics are differently regulated at transcriptomic level http://ow.ly/kDnln

Glucocorticoid-induced Changes in Gene Expression of Airway Smooth Muscle in Patients with Asthma

RATIONALE Glucocorticoids are the mainstay of asthma therapy. However, it is unclear whether the benefits of glucocorticoids in asthma are merely based on antiinflammatory properties. Glucocorticoids may also alter gene expression of airway smooth muscle (ASM). We hypothesized that the gene expression profile of the ASM layer in endobronchial biopsies of patients with asthma is altered by oral glucocorticoid therapy as compared with placebo. OBJECTIVES First, we investigated the change in ASM transcriptomic profile in endobronchial biopsies after 14 days of oral glucocorticoid therapy. Second, we investigated the association between changes in ASM transcriptomic profile and lung function. METHODS Twelve steroid-free patients with atopic asthma were included in this double-blind intervention study. Endobronchial biopsies were taken before and after 14 days of oral prednisolone (n = 6) or placebo (n = 6). RNA of laser-dissected ASM was sequenced (RNA-Seq) using GS FLX+ (454/Roche). Gene networks were identified by Ingenuity Pathway Analysis. RNA-Seq reads were assumed to follow a negative binomial distribution. At the current sample size the estimated false discovery rate was approximately 3%. MEASUREMENTS AND MAIN RESULTS Fifteen genes were significantly changed by 14 days of oral prednisolone. Two of these genes (FAM129A, SYNPO2) were associated with airway hyperresponsiveness (provocative concentration of methacholine causing a 20% drop in FEV1: r = -0.740, P < 0.01; r = -0.746, P < 0.01). Pathway analysis revealed three gene networks that were associated with cellular functions including cellular growth, proliferation, and development. CONCLUSIONS Oral prednisolone changes the transcriptomic profile of the ASM layer in asthma. This indicates that in parallel to antiinflammatory properties, glucocorticoids also exert effects on gene expression of ASM, which is correlated with improved airway function.

Pleural drainage and pleurodesis: implementation of guidelines in four hospitals

The aim of the present study was to evaluate the implementation of the 2003 Dutch guideline on the diagnosis and treatment of malignant pleural effusions, and the potential effect of the implementation on the clinical outcome of pleurodesis. All patients with malignant pleural effusion who had a pleural drain placed with the intention of performing pleurodesis were registered prospectively in four centres. Details of the procedure and fluid recurrence and survival data were noted. Patients with a proven malignancy (n = 100) were entered into the registration database. Diagnostic guideline recommendations were followed in 60–70% of the patients. Surprisingly, pleurodesis was performed in only 75% of the patients, mainly due to the presence of a trapped lung. All pleurodeses were performed using talc, according to the guideline. Follow-up revealed fluid recurrence in 27 (36%) patients after a mean follow-up of 17 days (range 2–285 days); 14 patients with successful pleurodesis died with a median survival of 61 days (range 13–174 days). Systemic treatment following pleurodesis and good apposition of the pleural surfaces during drainage were good prognostic factors. Despite reasonable-to-good adherence to the guideline, the number of successful pleurodeses was low. Better predictors of a good pleurodesis outcome are needed.

Restaging of Mediastinal Nodes with Transbronchial Needle Aspiration after Induction Chemoradiation for Locally Advanced Non-small Cell Lung Cancer

Introduction: Selecting the appropriate treatment strategy for patients with locally advanced non-small cell carcinoma (NSCLC) is of utmost importance to determine patient outcome. Previous studies have shown that nodal down-staging after induction therapy and definitive local irradiation in these patients better predict survival when combined with surgery. However, nodal restaging can be technically difficult. We investigated the role of transbronchial needle aspiration (TBNA) in mediastinal restaging of patients who had completed induction cytotoxic therapy. Methods: A total of 14 patients with proven stage IIIa-N2 NSCLC who received chemotherapy or chemo-radiotherapy as induction regimen between 2005 and 2006 were studied. Outpatient flexible bronchoscopy with TBNA was performed in all patients under local anesthesia, and 17 TBNA procedures were performed. TBNA results were matched against the histopathology of surgical specimens. Results: Seventeen lymph nodes in 14 patients who had undergone induction therapy were sampled. Positron emission tomography (PET) scan results of 11 patients were also available for comparison. All positive TBNA procedures had positive PET scans. However, for five patients with lymph nodes measuring 9 to 17 mm, the PET scans were falsely positive, as mediastinoscopy and subsequent surgically resected lymph nodes revealed no tumor. TBNA achieved a correct diagnosis in 71% of patients who underwent mediastinal restaging and obviated further need for invasive procedures in 35%. Conclusion: For patients presenting with locally advanced NSCLC who are surgical candidates after induction chemo- and/or radiotherapy, TBNA should be considered as the initial procedure of choice for restaging of the mediastinum.