News in respiratory medicine.

Pneumology and phthisiology (respiratory medicine) has undergone dynamic development in the last two decades. The main focus of pulmonology in the past was care for patients with tuberculosis and pneumonia. Since then, respiratory medicine evolved and the current focus is on chronic pulmonary diseases, including chronic obstructive pulmonary disease, bronchial asthma, interstitial lung diseases, but also on acute lung conditions (e.g., pneumonia, pleural diseases, respiratory failure), pneumooncology or highly specialized care for rare lung diseases (e.g., cystic fibrosis, rare interstitial diseases). Bronchology, interventional pneumology and pulmonary function testing are also important components of respiratory medicine. The importance of respiratory medicine was apparent during the COVID-19 pandemic. In this article, we provide a brief overview of the most important news to the field of respiratory medicine in the year 2022, addressing the thematic areas of bronchology, cystic fibrosis, chronic obstructive pulmonary disease, asthma, interstitial lung diseases, pleural diseases, pneumooncology, tuberculosis and non-tuberculous mycobacteria.

Pembrolizumab-induced hypothyreosis and subcutaneous bleeding.

Pembrolizumab belongs to so called immune checkpoint inhibitors. Frequent adverse event of this therapy is hypothyroidism. The authors present a case report of patient treated with pembrolizumab for non-small cell lung carcinoma, in whom severe hypothyroidism followed quite rapidly after transient phase of subclinical hyperthyroidism - at this time point new and spontaneous onset of large subcutaneous hematomas was observed. Acquired von Willebrand syndrome, acquired hemophilia A, dysfibrinogenemia, activation of fibrinolysis and thrombocytopathy were all actively ruled out in hematological differential diagnosis. Concomittantly, laboratory markers of secondary autoimmune disease and myositis were excluded. Despite continuous pembrolizumab treatment, there were no other bleeding complications seen after intensification of endocrine substitution therapy with thyroid hormones. Causal relationship between subcutaneous hematomas and severe drug-induced hypothyroidism is established per exclusionem.

Driver and actionable mutations in younger patients with lung cancer - are we searching properly?

AIMS: The authors focused on a group of young lung cancer patients with the aim of better understanding the mechanisms of tumor pathogenesis in these patients and search for potential targetable mutations. METHODS: We collected retrospective data on patients under 40 years diagnosed with lung cancer (NSCLC or small-cell lung cancer) from 2011-2020 at the Department of Respiratory Diseases, University Hospital Brno, Czech Republic. Tumor tissue of these patients was analysed by next-generation sequencing (NGS, a panel of 550 variants in 19 genes). Demographic characteristics, smoking history, histology, molecular-genetic results and clinical stage of the disesase were recorded in all eligible patients from accessible medical databases. RESULTS: Of 17 identified patients in only 8 cases was successful NGS carried out due to lack of sufficient good quality material in the other cases. The most frequently found molecular genetic changes were EGFR, RICTOR and HER2 amplification and MET and FGFR1 amplification. In addition, we found rare pathogenic variants in BRAF and PIK3CA genes. Actionable variants were detected in 75% patients. CONCLUSION: We detected very frequent driver and potentially actionable alterations in young patients with lung cancer. This suggests different mechanisms of carcinogenesis in these patients and indicates that they might benefit more from a specific approach than older lung cancer patients.

Effectiveness of first-line anticancer treatment may predict treatment response in further lines in stage III/IV patients with non-small cell lung cancer.

PURPOSE: The aim of our study was to evaluate if therapeutic success in the first-line of anticancer treatments in patients with NSCLC may predict treatment success in the following lines. METHODS: We analyzed the data of patients with NSCLC stage III/IV from the TULUNG registry separately for chemotherapy, TKIs, ALK inhibitors, and immunotherapy in the first line during the years 2011-2019. "Succesful treatment " was defined as PFS ≥ 6 months, a "good responder " was a patient with ˃50% of "successful treatment " lines. Treatment responses were analyzed separately for each drug group. Descriptive statistics, Fisher exact test, Pearson Chi-Squared test, log-rank test, and univariate/multivariate logistic regression models were used. RESULTS: The first-line TKI therapy was successful in 66.2%, while good responders accounted for 50.7% of the cohort and their rates were similar for all types of TKIs. First-line platinum-based chemotherapy was successful in 43.1% and 48.6% for combinations with pemetrexed and bevacizumab, respectively. Good responders accounted for 29.5% and 25.9%, respectively. In the group of ALK inhibitors, we observed treatment success in 52.3% of cases, while alectinib showed the highest effectiveness (up to 70%). Good responders constituted 50% of the group. In the first-line immunotherapy group, survival benefit was observed in 52.3%, and good responders constituted 52.3% of the cohort. CONCLUSION: We concluded that the treatment success in first-line therapies in patients with NSCLC may predict survival benefits in the subsequent lines, particularly in EGFR- or ALK-positive disease and immunotherapy-treated patients.

Serious Immune-related Adverse Events Are Associated With Greater Efficacy of Nivolumab Therapy Against Non-small Cell Lung Cancer.

BACKGROUND/AIM: The aim of this study was to investigate possible association between adverse events of nivolumab therapy and the effectiveness of treatment in patients with non-small cell lung cancer (NSCLC). Focusing on serious adverse events (i.e., those of grade ≥3), we evaluated overall survival (OS), progression-free survival (PFS), as well as objective response rate (ORR) to treatment. PATIENTS AND METHODS: We retrospectively analyzed a set of patients from the TULUNG database of NSCLC treated with nivolumab in eight oncology centers. We evaluated OS data based upon this set. To reduce possible bias, we further evaluated a subgroup of patients treated at the University Hospital in Pilsen, where the occurrence of adverse events, PFS, and ORR were independently examined by two experienced physicians. Survival statistics were evaluated using the Kaplan-Meier method and Cox analysis. RESULTS: We observed significantly greater OS, PFS, and ORR in the group of patients experiencing adverse events upon nivolumab treatment versus in those patients without such events. Although the univariable model analyzing the data set of all patients demonstrated higher OS in patients with serious adverse events, only a nonsignificant trend was observed in the Cox multivariable model. In a subgroup of patients with PFS and ORR evaluation, we did observe significant, favorable effects for patients having had serious adverse effects. CONCLUSION: Patients experiencing severe adverse events show a tendency toward better OS, PFS, and ORR compared to patients without or having only mild adverse events with nivolumab treatment.

The risk of post-operative pulmonary complications in lung resection candidates with normal forced expiratory volume in 1 s and diffusing capacity of the lung for carbon monoxide: a prospective multicentre study.

Introduction: According to the guidelines for preoperative assessment of lung resection candidates, patients with normal forced expiratory volume in 1 s (FEV1) and diffusing capacity of the lung for carbon monoxide (D LCO) are at low risk for post-operative pulmonary complications (PPC). However, PPC affect hospital length of stay and related healthcare costs. We aimed to assess risk of PPC for lung resection candidates with normal FEV1 and D LCO (>80% predicted) and identify factors associated with PPC. Methods: 398 patients were prospectively studied at two centres between 2017 and 2021. PPC were recorded from the first 30 post-operative days. Subgroups of patients with and without PPC were compared and factors with significant difference were analysed by uni- and multivariate logistic regression. Results: 188 subjects had normal FEV1 and D LCO. Of these, 17 patients (9%) developed PPC. Patients with PPC had significantly lower pressure of end-tidal carbon dioxide (P ETCO2 ) at rest (27.7 versus 29.9; p=0.033) and higher ventilatory efficiency (V'E/V'CO2 ) slope (31.1 versus 28; p=0.016) compared to those without PPC. Multivariate models showed association between resting P ETCO2 (OR 0.872; p=0.035) and V'E/V'CO2 slope (OR 1.116; p=0.03) and PPC. In both models, thoracotomy was strongly associated with PPC (OR 6.419; p=0.005 and OR 5.884; p=0.007, respectively). Peak oxygen consumption failed to predict PPC (p=0.917). Conclusions: Resting P ETCO2 adds incremental information for risk prediction of PPC in patients with normal FEV1 and D LCO. We propose resting P ETCO2 be an additional parameter to FEV1 and D LCO for preoperative risk stratification.

Prediction of Postoperative Complications: Ventilatory Efficiency and Rest End-tidal Carbon Dioxide.

BACKGROUND: Cardiopulmonary exercise testing parameters including ventilatory efficiency (VE/VCO2 slope) are used for risk assessment of lung resection candidates. However, many patients are unable or unwilling to undergo exercise. VE/VCO2 slope is closely related to the partial pressure of end-tidal carbon dioxide (PETCO2). We hypothesized PETCO2 at rest predicts postoperative pulmonary complications. METHODS: Consecutive lung resection candidates were included in this prospective multicenter study. Postoperative respiratory complications were assessed from the first 30 postoperative days or from the hospital stay. Student t test or Mann-Whitney U test was used for comparison. Multivariate stepwise logistic regression analysis was used to analyze association with the development of postoperative pulmonary complications. The De Long test was used to compare area under the curve (AUC). Data are summarized as median (interquartile range). RESULTS: Three hundred fifty-three patients were analyzed, of which 59 (17%) developed postoperative pulmonary complications. PETCO2 at rest was significantly lower (27 [24-30] vs 29 [26-32] mm Hg; P < .01) and VE/VCO2 slope during exercise significantly higher (35 [30-40] vs 29 [25-33]; P < .01) in patients who developed postoperative pulmonary complications. Both rest PETCO2 with odds ratio 0.90 (95% confidence interval [CI] 0.83-0.97); P = .01 and VE/VCO2 slope with odds ratio 1.10 (95% CI 1.05-1.16); P < .01 were independently associated with postoperative pulmonary complications by multivariate stepwise logistic regression analysis. There was no significant difference between AUC of both models (rest PETCO2: AUC = 0.79 (95% CI 0.74-0.85); VE/VCO2 slope: AUC = 0.81 (95% CI 0.75-0.86); P = .48). CONCLUSIONS: PETCO2 at rest has similar prognostic utility as VE/VCO2 slope, suggesting rest PETCO2 may be used for postoperative pulmonary complications prediction in lung resection candidates.

Ventilatory efficiency is superior to peak oxygen uptake for prediction of lung resection cardiovascular complications.

INTRODUCTION: Ventilatory efficiency (VE/VCO2 slope) has been shown superior to peak oxygen consumption (VO2) for prediction of post-operative pulmonary complications in patients undergoing thoracotomy. VE/VCO2 slope is determined by ventilatory drive and ventilation/perfusion mismatch whereas VO2 is related to cardiac output and arteriovenous oxygen difference. We hypothesized pre-operative VO2 predicts post-operative cardiovascular complications in patients undergoing lung resection. METHODS: Lung resection candidates from a published study were evaluated by post-hoc analysis. All of the patients underwent preoperative cardiopulmonary exercise testing. Post-operative cardiovascular complications were assessed during the first 30 post-operative days or hospital stay. One-way analysis of variance or the Kruskal-Wallis test, and multivariate logistic regression were used for statistical analysis and data summarized as median (IQR). RESULTS: Of 353 subjects, 30 (9%) developed pulmonary complications only (excluded from further analysis), while 78 subjects (22%) developed cardiovascular complications and were divided into two groups for analysis: cardiovascular only (n = 49) and cardiovascular with pulmonary complications (n = 29). Compared to patients without complications (n = 245), peak VO2 was significantly lower in the cardiovascular with pulmonary complications group [19.9 ml/kg/min (16.5-25) vs. 16.3 ml/kg/min (15-20.3); P<0.01] but not in the cardiovascular only complications group [19.9 ml/kg/min (16.5-25) vs 19.0 ml/kg/min (16-23.1); P = 0.18]. In contrast, VE/VCO2 slope was significantly higher in both cardiovascular only [29 (25-33) vs. 31 (27-37); P = 0.05] and cardiovascular with pulmonary complication groups [29 (25-33) vs. 37 (34-42); P<0.01)]. Logistic regression analysis showed VE/VCO2 slope [OR = 1.06; 95%CI (1.01-1.11); P = 0.01; AUC = 0.74], but not peak VO2 to be independently associated with post-operative cardiovascular complications. CONCLUSION: VE/VCO2 slope is superior to peak VO2 for prediction of post-operative cardiovascular complications in lung resection candidates.

Lung Cancer Versus "Young Cancer": Is Non-Small Cell Lung Cancer in Young Patients a Different Entity?

Purpose: Aim was to analyze demographic and tumor characteristics, treatment, and survival of patients with lung cancer younger than 40 years of age (U40) compared to older subgroups (41-70 and >70 years). Methods: We analyzed data of young patients diagnosed and treated in 2011-2019 in five pneumo-oncology centers in Czechia. Standard descriptive statistics, chi-squared test, Fisher exact test, and Kaplan-Meier survival analysis were used. p-Values <0.05 were considered significant. These data were compared with two control subgroups (cohort 1: 41-70 years, cohort 2: >70 years). Results: We identified 66 patients U40, 61 with non-small cell lung cancer (NSCLC)-50.8% men, mean age 34.6 years, 54.1% nonsmokers, daily good performance status, and 82% in stage IV. Adenocarcinomas dominated, endothelial growth factor receptor (EGFR) positivity was less common than in older groups contrary to anaplastic lymphoma kinase (ALK) mutations. Median progression-free survival was 3.7 months (vs. 4.9 and 6.2 months; p = 0.006) and overall survival reached 11.7 months (vs. 22.3 and 27.3 months; p < 0.001). Young patients in stage IV and never-smokers had shorter survival than older patients. Conclusion: Patients with NSCLC U40 had significantly worse prognosis than older patients.

Can Previous Chemotherapy Affect the Outcome of Nivolumab Treatment in Non-small Cell Lung Cancer?

AIM: This study compared the results of nivolumab treatment in patients with pulmonary adenocarcinomas based upon previous chemotherapeutic regimens. PATIENTS AND METHODS: The data source for this retrospective study was the Czech VILP registry of patients with nivolumab-treated adenocarcinomas in second and higher lines of treatment. In relation to objective response rate, progression-free interval, and overall survival, three comparisons of patient were made: A: Those treated in first line with cisplatin and pemetrexed versus carboplatin with paclitaxel or vinorelbine; B: treatment with cisplatin and pemetrexed versus carboplatin with paclitaxel/vinorelbine and bevacizumab; and C: treatment in previous lines with pemetrexed (first-line cisplatin and pemetrexed plus those treated in second line with pemetrexed) versus treatment with taxane (first-line carboplatin and paclitaxel only plus those treated with second-line docetaxel). RESULTS: We observed no differences in objective response rate or progression-free survival between patients treated with the stated chemotherapeutic regimens. We observed a trend towards better overall survival for patients treated with carboplatin plus taxanes or vinorelbine with/without bevacizumab. CONCLUSION: From our overall survival data, a chemotherapeutic regimen of carboplatin plus taxanes or vinorelbine with/without bevacizumab might be a better partner for immunotherapy than a cisplatin and pemetrexed-based one.