Transesophageal ultrasound-guided fine-needle aspiration for the mediastinal restaging of non-small cell lung cancer

Selected patients with stage III (N2/N3) non-small cell lung cancer (NSCLC) who are downstaged to N0 by chemoradiation therapy might benefit from subsequent surgical resection of the tumor. How mediastinal lymph nodes can be best reevaluated is subject of debate. Transesophageal ultrasound-guided fine-needle aspiration (EUS-FNA) is a minimally invasive technique to sample mediastinal nodes. We assessed sensitivity and false-negative rate of EUS-FNA for the mediastinal restaging of patients with stage III NSCLC. Fifty-eight consecutive patients with stage III NSCLC and tissue-proven lymph node metastases N2/N3) who underwent EUS-FNA for restaging purposes after chemoradiation therapy were retrospectively analyzed. Surgical-pathological staging was used as the reference standard for nodal metastases. EUS-FNA found persistent nodal metastases (N2/N3) in 15 patients (26%). Of the 43 patients without persistent mediastinal metastases at EUS, 33 patients subsequently underwent surgical verification of the mediastinal nodes in whom persistent metastases (yN2/N3) were found in 19 patients (58%), and loco-regional downstaging (yN0) was achieved in the other 14 (42%). The prevalence of persistent nodal metastases in the 48 patients who could be analyzed was 71%. Sensitivity and the false-negative rate of EUS-FNA for mediastinal restaging were 44 and 58%, respectively. For mediastinal restaging of stage III NSCLC, EUS-FNA is a minimally invasive and safe method to confirm persistent nodal metastases, but this technique has a low negative predictive value and is therefore not useful for the exclusion of mediastinal metastases. Surgical restaging is indicated in the absence of mediastinal metastases at EUS-FN

Small airways dysfunction and neutrophilic inflammation in bronchial biopsies and BAL in COPD

Background: The single-breath N-2 test (sbN(2)-test) is closely related to small airways pathology in resected lung specimens of smokers. We investigated whether uneven ventilation and airway closure are associated with specific markers of airway inflammation as obtained by bronchial biopsies, BAIL, and induced sputum in patients with manifest COPD. Methods: Fifty-one patients with stable COPD not receiving corticosteroids were examined in a cross-sectional study (43 men; mean [SD] age, 63 +/- 8 years; exsmokers and smokers; median pack-years, 41 [interquartile range, 31 to 51 pack-years]). Postbronchodilator spirometry (FEV1, 63 +/- 8% of predicted) and sbN(2)-test (slope of phase III [Delta N-2], closing capacity [CC]/total lung capacity [TLC] percentage of predicted) were performed. Inflammatory cell counts were assessed in bronchial biopsies, BAL (only in the first half of patients), and induced sputum. Neutrophil elastase (NE), secretoij, leukocyte proteinase inhibitor (SLPI), and interleukin-8 levels were determined in BAL fluid. Results: Delta N-2 increased with subepithelial neutrophil numbers in bronchial biopsies (rs = 0.337, p = 0.017) and with NE levels (rs = 0.443, p = 0.039), NE/neutrophil ratio (rs = 0.575, p = 0.005) and SLPI levels (rs = 0.484, p = 0.022) in BAL. CC/TLC was associated with BAL neutrophil numbers (rs = 0.448, p = 0.048). The sbN(2)-test was not associated with am, other inflammatory cell type in BAL or biopsies, nor with inflammatory cell counts in sputum. Of importance, the correlations between Delta N-2 and BAL NE/neutrophil ratio, and between CC/TLC and BAL neutrophil numbers remained significant when adjusting for FEV1 percentage of predicted. Conclusions: The results of the sbN(2)-test are associated with neutrophilic inflammation in bronchial biopsies and BAL in patients with COPD. Our findings support a role of neutrophilic inflammation in the pathogenesis of small airways dysfunction in COPD

Endoscopic ultrasound added to mediastinoscopy for preoperative staging of patients with lung cancer

Up to 40% of thoracotomies performed for non-small cell lung cancer are unnecessary, predominantly due to inaccurate preoperative detection of lymph node metastases and mediastinal tumor invasion (T4). Mediastinoscopy and the novel, minimally invasive technique of transesophageal ultrasound-guided fine-needle aspiration (EUS-FNA) target different mediastinal lymph node stations. In addition, EUS can identify tumor invasion in neighboring organs if tumors are located adjacent to the esophagus. To investigate the additional value of EUS-FNA to mediastinoscopy in the preoperative staging of patients with non-small cell lung cancer. Prospective, nonrandomized multicenter trial performed in 1 referral and 5 general hospitals in the Netherlands. During a 3-year period (2000-2003), 107 consecutive patients with potential resectable non-small cell lung cancer underwent preoperative staging by both EUS-FNA and mediastinoscopy. Patients underwent thoracotomy with tumor resection if mediastinoscopy was negative. Surgical-pathological staging was compared with preoperative findings and the added benefit of the combined strategy was assessed. The EUS-FNA examination was performed as an additional staging test to mediastinoscopy in all patients. Detection of mediastinal tumor invasion (T4) and lymph node metastases (N2/N3) comparing the combined staging by both EUS-FNA and mediastinoscopy with staging by mediastinoscopy alone. The combination of EUS-FNA and mediastinoscopy identified more patients with tumor invasion or lymph node metastases (36%; 95% confidence interval [CI], 27%-46%) compared with either mediastinoscopy alone (20%; 95% CI, 13%-29%) or EUS-FNA (28%; 95% CI, 19%-38%) alone. This indicated that 16% of thoracotomies could have been avoided by using EUS-FNA in addition to mediastinoscopy. However, 2% of the EUS-FNA findings were false-positive. These preliminary findings suggest that EUS-FNA, when added to mediastinoscopy, improves the preoperative staging of lung cancer due to the complementary reach of EUS-FNA in detecting mediastinal lymph node metastases and the ability to assess mediastinal tumor invasio

Bronchial CD8 cell infiltrate and lung function decline in asthma

RATIONALE: Patients with asthma have an accelerated decline in lung function, which can lead to irreversible airway obstruction. It is generally assumed that this is related to specific aspects of airway inflammation and/or remodeling. OBJECTIVE: We investigated the prognostic significance of bronchial eosinophil and CD8+ cell counts and subepithelial reticular layer thickness for the subsequent decline in lung function in patients with asthma after 7.5 years of follow-up. METHODS: In a prospective study, pre- and post-bronchodilator lung function (FEV1) was measured at baseline, and after 2 years and 7.5 years in 32 patients with asthma. Annual decline in lung function after 7.5 years of follow-up was related to type and severity of airway inflammation and remodeling in bronchial biopsies, which were taken at baseline and at Year 2. RESULTS: Annual decline in post-bronchodilator FEV1 (mean [SD], 46.6 [53.4] ml/year) was significantly larger than the decline in prebronchodilator FEV1 (mean [SD], 27.5 [62.5] ml/year), indicating loss in reversibility. Although annual fall in post-bronchodilator FEV1 was not related to thickness of the reticular layer or to eosinophil counts in bronchial biopsies, there was a significant correlation with CD8+ T cells (r=-0.39, p=0.032). Analyzing the biopsies taken at Year 2, the significant association between annual fall in post-bronchodilator FEV1 and CD8 cells could independently be confirmed (r=-0.39, p=0.036). CONCLUSION: The outcome of asthma, as determined by the annual decline in FEV1, can be predicted by the bronchial CD8+ cell infiltrate. This suggests that the inflammatory phenotype in asthma has prognostic relevance, which may require phenotype-specific therapeutic strategie

Phase III study of cyclophosphamide, doxorubicin, and etoposide compared with carboplatin and paclitaxel in patients with extensive disease small-cell lung cancer 5,55

The progression-free survival (PFS) of cyclophosphamide/doxorubicin/etoposide (CDE) and carboplatin/paclitaxel (CP) was compared in chemonaive patients with extensive disease small-cell lung cancer (ED-SCLC). A total of 203 patients were randomised to three-weekly CDE (n = 102) or CP (n = 101) for five cycles. Tumour response rates in CDE and CP were 60% and 61%. PFS of CP was 5.2 months, PFS of CDE 4.9 months (p = 0.60). The major difference in toxicity between CDE and CP was grade 4 leukocytopaenia in 64% and 9% of the patients (p < 0.0001), leading to febrile neutropaenia in 30% and 4% of the patients (p < 0.0001), respectively. This was the reason for differences in the total number of hospital admissions (63 for CDE and 40 for CP, p = 0.0025). This study failed to demonstrate any benefit in PFS with CP compared with CDE. CP was associated with significantly less haematological toxicity, leading to 37% less hospital admissions for febrile neutropaenia

Phase III study of cyclophosphamide, doxorubicin, and etoposide compared with carboplatin and paclitaxel in patients with extensive disease small-cell lung cancer

The progression-free survival (PFS) of cyclophosphamide/doxorubicin/etoposide (CDE) and carboplatin/paclitaxel (CP) was compared in chemonaive patients with extensive disease small-cell lung cancer (ED-SCLC). A total of 203 patients were randomised to three-weekly CDE (n=102) or CP (n=101) for five cycles. Tumour response rates in CDE and CP were 60% and 61%. PFS of CP was 5.2 months, PFS of CDE 4.9 months (p=0.60). The major difference in toxicity between CDE and CP was grade 4 leukocytopaenia in 64% and 9% of the patients (p <0.0001), leading to febrile neutropaenia in 30% and 4% of the patients (p <0.0001), respectively This was the reason for differences in the total number of hospital admissions (63 for CDE and 40 for CP, p=0.0025). This study failed to demonstrate any benefit in PFS with CP compared with CDE. CP was associated with significantly less haematological toxicity, leading to 37% less hospital admissions for febrile neutropaenia. (c) 2007 Elsevier Ltd. All rights reserved

Adherence to preventive measures after SARS-CoV-2 vaccination and after awareness of antibody response in kidney transplant recipients in the Netherlands: a nationwide questionnaire studyResearch in context

Summary: Background: Kidney transplant recipients (KTRs) were advised to tightly adhere to government recommendations to curb the spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) because of a high risk of morbidity and mortality and decreased immunogenicity after vaccination. The aim of this study was to analyse the change in adherence to preventive measures after vaccination and awareness of antibody response, and to evaluate its effectiveness. Methods: In this large-scale, national questionnaire study, questionnaires were sent to 3531 KTRs enrolled in the Dutch RECOVAC studies, retrospectively asking for adherence to nine preventive measures on a 5-point Likert scale before and after SARS-CoV-2 vaccination and after awareness of antibody response. Blood samples were collected 28 days after the second vaccination. Antibody response was categorised as non-responder (≤50 BAU/mL), low-responder (>50 ≤ 300 BAU/mL) or high-responder (>300 BAU/mL), and shared with participants as a correlate of protection. Participants of whom demographics on sex and age, blood samples and completed questionnaires were available, were included. Our study took place between February 2021 and January 2022. The primary outcome of adherence before and after vaccination was assessed between August and October 2021 and compared via the Wilcoxon signed rank sum test. Logistic regression analysis was performed to estimate the association between antibody response and non-adherence, and adherence on acquiring SARS-CoV-2 infection. This study is registered at ClinicalTrials.gov (NCT04841785). Findings: In 2939 KTRs (83%) who completed the first questionnaire on adherence to preventive measures, adherence was higher before than after vaccination (4.56, IQR 4.11–4.78 and 4.22, IQR 3.67–4.67, p < 0.001). Adherence after awareness of antibody response was analysed in 2399 KTRs (82%) of whom also blood samples were available, containing 949 non-responders, 500 low-responders and 950 high-responders. Compared to non-responders, low- and high-responders reported higher non-adherence. Higher adherence was associated with lower infection rates before and after vaccination (OR 0.67 [0.51–0.91], p = 0.008 and OR 0.48 [0.28–0.86], p = 0.010). Interpretation: Adherence decreased after SARS-CoV-2 vaccination and in KTRs who were aware of a subsequent antibody response compared with those without. Preventive measures in this vulnerable group seem to be effective, regardless of vaccination status. This study starts a debate on sharing antibody results with the patient and future studies should elucidate whether decreased adherence in antibody responders is justified, also in view of future pandemics. Funding: The Netherlands Organization for Health Research and Development and the Dutch Kidney Foundation