Erik H.F.M. van der Heijden

Endosonography vs Conventional Bronchoscopy for the Diagnosis of Sarcoidosis: The GRANULOMA Randomized Clinical Trial

IMPORTANCE Tissue verification of noncaseating granulomas is recommended for the diagnosis of sarcoidosis. Bronchoscopy with transbronchial lung biopsies, the current diagnostic standard, has moderate sensitivity in assessing granulomas. Endosonography with intrathoracic nodal aspiration appears to be a promising diagnostic technique. OBJECTIVE To evaluate the diagnostic yield of bronchoscopy vs endosonography in the diagnosis of stage I/II sarcoidosis. DESIGN, SETTING, AND PATIENTS Randomized clinical multicenter trial (14 centers in 6 countries) between March 2009 and November 2011 of 304 consecutive patients with suspected pulmonary sarcoidosis (stage I/II) in whom tissue confirmation of noncaseating granulomas was indicated. INTERVENTIONS Either bronchoscopy with transbronchial and endobronchial lung biopsies or endosonography (esophageal or endobronchial ultrasonography) with aspiration of intrathoracic lymph nodes. All patients also underwent bronchoalveolar lavage. MAIN OUTCOMES AND MEASURES The primary outcome was the diagnostic yield for detecting noncaseating granulomas in patients with a final diagnosis of sarcoidosis. The diagnosis was based on final clinical judgment by the treating physician, according to all available information (including findings from initial bronchoscopy or endosonography). Secondary outcomes were the complication rate in both groups and sensitivity and specificity of bronchoalveolar lavage in the diagnosis of sarcoidosis. RESULTS A total of 149 patients were randomized to bronchoscopy and 155 to endosonography. Significantly more granulomas were detected at endosonography vs bronchoscopy (114 vs 72 patients; 74% vs 48%; P < .001). Diagnostic yield to detect granulomas for endosonography was 80% (95% CI, 73%-86%); for bronchoscopy, 53% (95% CI, 45%-61%) (P < .001). Two serious adverse events occurred in the bronchoscopy group and 1 in the endosonography group; all patients recovered completely. Sensitivity of the bronchoalveolar lavage for sarcoidosis based on CD4/CD8 ratio was 54% (95% CI, 46%-62%) for flow cytometry and 24% (95% CI, 16%-34%) for cytospin analysis. CONCLUSION AND RELEVANCE Among patients with suspected stage I/II pulmonary sarcoidosis undergoing tissue confirmation, the use of endosonographic nodal aspiration compared with bronchoscopic biopsy resulted in greater diagnostic yield. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00872612.

Obesity, metabolic factors and risk of different histological types of lung cancer: A Mendelian randomization study.

Background Assessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer. Methods and findings We identified genetic instruments for potential metabolic risk factors and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls. The MR risk analysis suggested a causal effect of body mass index (BMI) on lung cancer risk for two of the three major histological subtypes, with evidence of a risk increase for squamous cell carcinoma (odds ratio (OR) [95% confidence interval (CI)] = 1.20 [1.01–1.43] and for small cell lung cancer (OR [95%CI] = 1.52 [1.15–2.00]) for each standard deviation (SD) increase in BMI [4.6 kg/m2]), but not for adenocarcinoma (OR [95%CI] = 0.93 [0.79–1.08]) (Pheterogeneity = 4.3x10-3). Additional analysis using a genetic instrument for BMI showed that each SD increase in BMI increased cigarette consumption by 1.27 cigarettes per day (P = 2.1x10-3), providing novel evidence that a genetic susceptibility to obesity influences smoking patterns. There was also evidence that low-density lipoprotein cholesterol was inversely associated with lung cancer overall risk (OR [95%CI] = 0.90 [0.84–0.97] per SD of 38 mg/dl), while fasting insulin was positively associated (OR [95%CI] = 1.63 [1.25–2.13] per SD of 44.4 pmol/l). Sensitivity analyses including a weighted-median approach and MR-Egger test did not detect other pleiotropic effects biasing the main results. Conclusions Our results are consistent with a causal role of fasting insulin and low-density lipoprotein cholesterol in lung cancer etiology, as well as for BMI in squamous cell and small cell carcinoma. The latter relation may be mediated by a previously unrecognized effect of obesity on smoking behavior.

18F-FDG PET Early Response Evaluation of Locally Advanced Non–Small Cell Lung Cancer Treated with Concomitant Chemoradiotherapy

The potential of 18F-FDG PET changes was evaluated for prediction of response to concomitant chemoradiotherapy in patients with locally advanced non–small cell lung cancer (NSCLC). Methods: For 28 patients, 18F-FDG PET was performed before treatment, at the end of the second week of treatment, and at 2 wk and 3 mo after the completion of treatment. Standardized uptake value (SUV), maximum SUV, metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were obtained. Early metabolic changes were defined as fractional change (ΔTLG) when 18F-FDG PET at the end of the second week was compared with pretreatment 18F-FDG PET. In-treatment metabolic changes, as measured by serial 18F-FDG PET, were correlated with standard criteria of response evaluation of solid tumors by means of CT imaging (Response Evaluation Criteria In Solid Tumors 1.1). Parameters were analyzed for stratification in progression-free survival (PFS). Results: When compared with early metabolic nonresponders, a ΔTLG decrease of 38% or more was associated with a significantly longer PFS (1-y PFS 80% vs. 36%, P = 0.02). Pretreatment TLG was found to be a prognostic factor for PFS. Conclusion: The degree of change in TLG was predictive for response to concomitant chemoradiotherapy as early as the end of the second week into treatment for patients with locally advanced NSCLC. Pretreatment TLG was prognostic for PFS.

Guideline for the acquisition and preparation of conventional and endobronchial ultrasound-guided transbronchial needle aspiration specimens for the diagnosis and molecular testing of patients with known or suspected lung cancer

Rationale: Conventional transbronchial needle aspiration (TBNA) and endobronchial ultrasound (EBUS)-TBNA are widely accepted tools for the diagnosis and staging of lung cancer and the initial procedure of choice for staging. Obtaining adequate specimens is key to provide a specific histologic and molecular diagnosis of lung cancer. Objectives: To develop practice guidelines on the acquisition and preparation of conventional TBNA and EBUS-TBNA specimens for the diagnosis and molecular testing of (suspected) lung cancer. We hope to improve the global unification of procedure standards, maximize the yield and identify areas for research. Methods: Systematic electronic database searches were conducted to identify relevant studies for inclusion in the guideline [PubMed and the Cochrane Library (including the Cochrane Database of Systematic Reviews)]. Main Results: The number of needle aspirations with both conventional TBNA and EBUS-TBNA was found to impact the diagnostic yield, with at least 3 passes needed for optimal performance. Neither needle gauge nor the use of miniforceps, the use of suction or the type of sedation/anesthesia has been found to improve the diagnostic yield for lung cancer. The use of rapid on-site cytology examination does not increase the diagnostic yield. Molecular analysis (i.e. EGFR, KRAS and ALK) can be routinely performed on the majority of cytological samples obtained by EBUS-TBNA and conventional TBNA. There does not appear to be a superior method for specimen preparation (i.e. slide staining, cell blocks or core tissue). It is likely that optimal specimen preparation may vary between institutions depending on the expertise of pathology colleagues.

Glucose Metabolism in NSCLC Is Histology-Specific and Diverges the Prognostic Potential of 18FDG-PET for Adenocarcinoma and Squamous Cell Carcinoma

Introduction: Biological features of non–small-cell lung carcinomas (NSCLCs) are important determinants for prognosis. In this study, differences in glucose metabolism between adeno- and squamous cell NSCLCs were quantified using the hypoxia and glycolysis-related markers glucose transporter 1 (GLUT1), carbonic anhydrase IX (CAIX), monocarboxylate transporter 1 (MCT1) and 4 (MCT4) vasculature, and 18-fluoro-2-deoxyglucose (18FDG)-uptake. Relevance of these markers for disease-free survival (DFS) was analyzed. Methods: Patients with curatively resected stage I to II and resectable stage IIIA, cN0-1 adeno- or squamous cell NSCLC, of whom fresh-frozen lung resection biopsies and pretreatment 18FDG-positron emission tomography (PET) scans were available, were included in this study (n = 108). 18FDG-uptake was quantified by calculating total lesion glycolysis (TLG). Metabolic marker expression was measured by immunofluorescent staining (protein) and quantitative polymerase chain reaction (messenger ribonucleic acid [mRNA]). Patients were retrospectively evaluated for DFS. Results: mRNA and protein expression of metabolic markers, with the exception of MCT4, and TLG were higher in squamous cell carcinomas than in adenocarcinomas, whereas adenocarcinomas were better vascularized. Adenocarcinomas had a worse DFS compared with squamous cell carcinomas (p = 0.016) based on the potential to metastasize. High TLG was associated with a worse DFS only in adenocarcinomas. Conclusion: Our findings suggest that the adenocarcinomas exhibit glycolysis under normoxic conditions, whereas squamous cell carcinomas are exposed to diffusion-limited hypoxia resulting in a very high anaerobic glycolytic rate. Although squamous cell carcinomas have a higher 18FDG-uptake, in general regarded as a poor prognostic factor, adenocarcinomas have a higher metastatic potential and a worse DFS. These findings show that 18FDG-PET should be interpreted in relation to histology. This may improve the prognostic potential of 18FDG-PET and may aid in exploiting 18FDG-PET in treatment strategies allied to histology.

Multivariable normal-tissue complication modeling of acute esophageal toxicity in advanced stage non-small cell lung cancer patients treated with intensity-modulated (chemo-)radiotherapy

BACKGROUND AND PURPOSE The majority of normal-tissue complication probability (NTCP) models for acute esophageal toxicity (AET) in advanced stage non-small cell lung cancer (AS-NSCLC) patients treated with (chemo-)radiotherapy are based on three-dimensional conformal radiotherapy (3D-CRT). Due to distinct dosimetric characteristics of intensity-modulated radiation therapy (IMRT), 3D-CRT based models need revision. We established a multivariable NTCP model for AET in 149 AS-NSCLC patients undergoing IMRT. MATERIALS AND METHODS An established model selection procedure was used to develop an NTCP model for Grade ⩾2 AET (53 patients) including clinical and esophageal dose-volume histogram parameters. RESULTS The NTCP model predicted an increased risk of Grade ⩾2 AET in case of: concurrent chemoradiotherapy (CCR) [adjusted odds ratio (OR) 14.08, 95% confidence interval (CI) 4.70-42.19; p<0.001], increasing mean esophageal dose [Dmean; OR 1.12 per Gy increase, 95% CI 1.06-1.19; p<0.001], female patients (OR 3.33, 95% CI 1.36-8.17; p=0.008), and ⩾cT3 (OR 2.7, 95% CI 1.12-6.50; p=0.026). The AUC was 0.82 and the model showed good calibration. CONCLUSIONS A multivariable NTCP model including CCR, Dmean, clinical tumor stage and gender predicts Grade ⩾2 AET after IMRT for AS-NSCLC. Prior to clinical introduction, the model needs validation in an independent patient cohort.

Distress in suspected lung cancer patients following rapid and standard diagnostic programs: a prospective observational study

Timeliness may influence emotional distress during the diagnostic phase of suspected lung cancer patients. We performed a prospective observational study to compare distress and quality of life (QoL) in two medical centres with a Rapid Outpatient Diagnostic Program (RODP) and two using conventional Stepwise Diagnostic Approach (SDA) on the basis of trained nurse‐led care.

The Prevalence of Pulmonary Embolism in Acute Exacerbations of COPD

With great interest we read the systematic review by Rizkallah et al1 in CHEST reporting a high prevalence of pulmonary embolism (PE) during an acute exacerbation of COPD (AECOPD). The authors suggest that one of four COPD patients who require hospitalization for an acute exacerbation may have a PE. In our opinion however, the results of their study are skewed due to inadequate study sampling and a potential selection bias. For their review, Rizkallah et al1 selected five studies.2–6 Two studies2,3 did not estimate the prevalence of PE during an AECOPD, but rather calculated the coexistence of COPD in patients with a PE. Assuming that every patient with a PE presents with a AECOPD is in our opinion not justified. The three other studies selected4–6 display a high heterogeneity in PE prevalence. Rizkallah and colleagues1 argue that the higher prevalence is seen exclusively in hospitalized patients. However, all three studies also included patients from the emergency department. In our opinion, the discrepancy is due to a selection bias. In two studies,5,6 patients with an obvious infective cause of their AECOPD were excluded. Moreover, one of these studies6 only included patients with a d-dimer level 500 ng/mL. The only study4 not excluding these patient categories showed a low PE prevalence of 3%. We therefore argue that it may be both the exclusion of certain patient categories as well as the erroneous selection of studies that has artificially augmented the result presented by Rizkallah and colleagues.1 The prevalence of PE in AECOPD remains open to debate.

Mediastinal abscess formation after EUS-guided FNA: are patients with sarcoidosis at increased risk?

Sarcoidosis is a disease of unknown etiology mostly affecting young adults and presenting with mediastinal or hilar lymphadenopathy in 85% of patients. Endoscopic US-guided FNA (EUS-FNA) and endobronchial US-guided transbronchial needle aspiration (EBUS-TBNA) of intrathoracic lymph nodes is increasingly used for the diagnosis of pulmonary sarcoidosis. Complications are rare-severe procedure-related infections have been reported in only 2 patients. One patient developed mediastinitis and another a mediastinal abscess after EUS-FNA.(1,2) This case series describes 5 patients with suspected sarcoidosis who developed mediastinal abscesses after EUS-PNA, necessitating surgical treatment in 4 patients

The impact of respiratory gated positron emission tomography on clinical staging and management of patients with lung cancer

OBJECTIVES Respiratory motion artefacts during positron emission tomography (PET) deteriorate image quality, potentially introducing diagnostic uncertainties. The objective of this study was to determine the impact of optimal respiratory gating on clinical staging and management of patients with primary lung cancer. MATERIALS AND METHODS From our fast-track outpatient diagnostic program, 55 patients with primary lung cancer, who underwent whole body [(18)F]-fluorodeoxyglucose (FDG) PET, were included. Respiratory gating was performed on bed positions covering the thorax and abdomen. Independent reading was conducted by two nuclear medicine physicians. The observers scored the number and anatomical location of the lesions, lymph node basins and the presence of distant metastasis in non-gated and gated images. A tumor (T), lymph node (N), and metastasis (M) stage was assigned to each patient according to the 7th revision of the TNM classification. Staging accuracy was determined using histopathological data and follow-up CT imaging. In addition, a management plan was created for each patient based on non-gated and gated images by an experienced pulmonologist. RESULTS For nuclear medicine physician 1 and 2, respiratory gating resulted in detection of more lesions in five and eight patients (9% and 15%) respectively. However, this did not result in any migration in T or M-stage. Migration in N-stage was observed in four and seven patients (7% and 13%) for nuclear medicine physician 1 and 2 respectively. Staging accuracy was slightly improved when respiratory gating was performed. Furthermore, there was substantial agreement in patient management between non-gated and gated images. CONCLUSIONS Respiratory gating improved staging accuracy, mainly in assessment of lymph node involvement. However, the effect on patient management was limited due to the presence of already advanced disease stage in many patients. These findings suggest that the expected impact of respiratory gating will be solely on management of patients with early disease.