A suitable protocol for measuring alveolar nitric oxide in asthma with differing severity to assess peripheral airways inflammation.

OBJECTIVE: Extended nitric oxide (NO) analysis offers the partitioned monitoring of inflammation in central and peripheral airways. Different mathematical models are used to estimate pulmonary NO dynamics in asthma with variable results and limitations. We aimed to establish a protocol for extended NO analysis in patients with differing asthma severity. METHODS: Forty patients with stable asthma and 25 matched control subjects were recruited. Exhaled NO was measured at constant flow rates between 10 and 300 mL/s. Twelve controls performed NO measurements weekly for 4 weeks. RESULTS: The proportions of patients with technically acceptable measurements at 10-30-50-100-150-200-250-300 mL/s exhalation flow rates were 8-58-100-98-98-95-90-80%, respectively. Alveolar NO (CANO) and total flux of NO in the conducting airways (JawNO) were calculated with the linear method from NO values measured at 100-150-200-250 mL/s exhalation flows. The mean intrasubject bias for JawNO and CANO in controls was 0.16 nL/s and 0.85 ppb, respectively. Both JawNO (1.31/0.83-2.97/vs. 0.70/0.54-0.87/nL/s, p < 0.001) and CANO (4.08/2.63-7.16/vs. 2.42/1.83-2.89/ppb, p < 0.001) were increased in patients with asthma compared to controls. In patients, CANO correlated with RV/TLC (r = 0.58, p < 0.001), FEF25-75% (p = 0.02, r = -0.36) and DL,CO (r = -0.46, p = 0.004). JawNO was not related to lung function parameters. CONCLUSIONS: Calculation of alveolar NO concentration with the linear method from values obtained at medium flow rates (100-250 mL/s) is feasible even in asthmatic patients with severe airflow limitation and may provide information on small airways dysfunction in asthma.

[Role of pembrolizumab in the treatment of non-small cell lung cancer (NSCLC)]. / A pembrolizumab szerepe a nem kissejtes tüdõrák (NSCLC) kezelésében.

Lung cancer is the leading cause of cancer-related death, not only in our country but also worldwide. It is particularly the incidence and mortality regarding females that have increased significantly in recent years. For many years chemotherapeutic treatments of lung cancer were the only way forward in the treatment of patients. In 2015 immunotherapy proved to be a great breakthrough in the treatment of non-small cell lung cancer (NSCLC), resulting from a new treatment strategy, described as immune checkpoint inhibition. Recent studies have shown the best efficacy of immunotherapy, especially in squamous cell lung cancer and the smoking-related non-squamous cell lung cancer which is explained by research regarding the high occurrence of increased mutation rate caused by smoking. The introduction of immunotherapy carries a great challenge for clinicians regarding the best therapeutic efficacy, longer survival, better quality of life as well as the management of the different profile of side effects. Pembrolizumab was the first PD-1 inhibitor, which was registered for first-line, second-line or greater treatment of non-small cell lung cancer.

[Gefitinib treatment in lung cancer -- rebiopsy, retreatment, remission]. / Rebiopszia és ismételt gefitinibkezeléssel elért remisszió tüdorákban.

The authors present a case of a 81-year-old non-smoker woman who was diagnosed with extended, bilateral bronchial adenocarcinoma in 2008. Two years later the tumor showed marked progression. EGFR sensitizing mutation (exon 19 deletion) was detected and gefitinib treatment was started in March 2010. After 12 months of spectacular and complete remission and 8 months of slow progression docetaxel therapy was applied and yielded partial remission. When progression redeveloped rebiopsy was performed and revealed EGFR exon 19 deletion again. Gefitinib retreatment was introduced in February 2013 and resulted in partial remission with excellent clinical status. In March, 2014 the patient is still on gefitinib treatment without any signs or symptoms of lung cancer but with very slow radiological progression. The authors overview the most important theoretical and practical questions regarding rebiopsy and retreatment in lung cancer with EGFR-TKI therapy.

Targeted therapeutic options in early and metastatic NSCLC-overview.

The complex therapeutic strategy of non-small cell lung cancer (NSCLC) has changed significantly in recent years. Disease-free survival increased significantly with immunotherapy and chemotherapy registered in perioperative treatments, as well as adjuvant registered immunotherapy and targeted therapy (osimertinib) in case of EGFR mutation. In oncogenic-addictive metastatic NSCLC, primarily in adenocarcinoma, the range of targeted therapies is expanding, with which the expected overall survival increases significantly, measured in years. By 2021, the FDA and EMA have approved targeted agents to inhibit EGFR activating mutations, T790 M resistance mutation, BRAF V600E mutation, ALK, ROS1, NTRK and RET fusion. In 2022, the range of authorized target therapies was expanded. With therapies that inhibit KRASG12C, EGFR exon 20, HER2 and MET. Until now, there was no registered targeted therapy for the KRAS mutations, which affect 30% of adenocarcinomas. Thus, the greatest expectation surrounded the inhibition of the KRAS G12C mutation, which occurs in ∼15% of NSCLC, mainly in smokers and is characterized by a poor prognosis. Sotorasib and adagrasib are approved as second-line agents after at least one prior course of chemotherapy and/or immunotherapy. Adagrasib in first-line combination with pembrolizumab immunotherapy proved more beneficial, especially in patients with high expression of PD-L1. In EGFR exon 20 insertion mutation of lung adenocarcinoma, amivantanab was registered for progression after platinum-based chemotherapy. Lung adenocarcinoma carries an EGFR exon 20, HER2 insertion mutation in 2%, for which the first targeted therapy is trastuzumab deruxtecan, in patients already treated with platinum-based chemotherapy. Two orally administered selective c-MET inhibitors, capmatinib and tepotinib, were also approved after chemotherapy in adenocarcinoma carrying MET exon 14 skipping mutations of about 3%. Incorporating reflex testing with next-generation sequencing (NGS) expands personalized therapies by identifying guideline-recommended molecular alterations.

[Examination of ERCC1 expression in lung cancer patients treated with platinum-based chemotherapy]. / ERCC1-expresszió vizsgálata platinabázisú kezelésben részesülõ tüdõrákos betegekben.

Platinum-based chemotherapies are widely used in the treatment of lung cancer. However, little is known about their effect in the expression of certain tissue biomarkers. We have studied the ERCC1 (excision repair cross-complementation group 1) expression in tissue samples of patients treated with neoadjuvant chemotherapy. Fifty lung cancer tissue blocks of 25 patients (15 males, 10 females) were studied. They included 25 bronchoscopic biopsies (14 squamous cell carcinomas and 11 adenocarcinomas) together with their corresponding surgical biopsies after neoadjuvant chemotherapy. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded tissues to study the expression of ERCC1. Staining scores (0-300) were calculated by multiplying the percentage of positive tumor cells (0-100) by the staining intensity (0-3). All but one bronchosopic squamous cell carcinoma tissues (13/14) expressed ERCC1. Four of these cases became negative after neoadjuvant therapy, and in 8 cases the level of expression decreased. In the adenocarcinoma group all but one bronchosopic tissues (10/11) expressed ERCC1. Six of these cases became negative after neoadjuvant therapy, and in 4 cases the level of expression decreased. Comparison of staining scores before and after chemotherapy revealed more pronounced decrease in adenocarcinomas and in female patients. There was no newly expressed ERCC1-positive case in the surgical biopsy group. The results of the present study suggest that platinum-based chemotherapy affects the expression of tissue biomarker (ERCC1) which may have predictive value, and probably induces a selection of tumor cells with more aggressive phenotype. This knowledge might be of importance when designing treatment protocols for non-small cell lung cancer patients.

Circulating Survivin Protein Levels in Lung Cancer Patients Treated With Platinum-Based Chemotherapy.

The survivin protein contributes to the development and progression of tumors. Protein expression and mRNA levels correlate with clinicopathological parameters and survival of cancer patients. Our purpose was to evaluate whether circulating survivin levels have any diagnostic or predictive value in lung cancer. 118 patients with advanced stage lung cancer participated in our study. 53 suffered from adenocarcinoma (ADC), 33 from squamous cell carcinoma (SqCC), and 32 from small cell lung cancer (SCLC). We also enrolled 21 control subjects. Blood samples were collected before and after two cycles of chemotherapy. We measured survivin concentrations with ELISA. Non-parametric tests were used for analysis. We did not find significant difference in survivin levels between patients and control subjects (17.19/0-829.74/vs. 49.13/0-165.92/pg/ml; p = 0.07). We found lower survivin concentrations in patients with SqCC (0/0-171.24/pg/ml) than in those with ADC (24.94/0-626.46 pg/ml) and SCLC (45.51/0-829.74/pg/ml) (ADC vs. SqCC p < 0.0001, ADC vs. SCLC p = 0.0405, SqCC vs. SCLC p < 0.0001). Survivin levels were higher in stage IV patients than in patients without distant metastases (p = 0.0061), and concentrations were progressively higher with increasing number of metastatic organ sites (p = 0.04). We observed a decrease in survivin levels in ADC patients after platinum plus pemetrexed chemotherapy (26.22/0-626.46/pg/ml before vs. 0/0-114.36/pg/ml after; p = 0.01). Neither progression-free nor overall survival correlated with survivin levels at baseline. Our data imply that survivin may be involved in the development of metastases and it might be used as a biomarker of disease progression. However, circulating survivin concentrations do not predict survival of patients with lung cancer.

Assessment of the circulating klotho protein in lung cancer patients.

The anti-aging factor, klotho has been identified as a tumor suppressor in various human cancers, including lung cancer. In vitro studies provided evidence that klotho expression influences the characteristics of lung cancer cells, however, in vivo results are lacking. The aim of our study was to evaluate whether circulating klotho protein might serve as a potential biomarker of lung cancer. Blood samples were taken from 45 newly diagnosed lung cancer patients (31 NSCLC, 14 SCLC) and 43 control subjects. Plasma klotho concentration was measured using ELISA. No difference in plasma klotho values was detected between patients and control subjects (366.3 (257.9-486.8) vs. 383.5 (304.6-489.7) pg/ml respectively (median (IQR)); p > 0.05). Plasma klotho levels in patients with distant metastasis did not differ from less advanced stage disease (354.2 (306.9-433.3 vs. 328.5 (242.5-419.7) pg/ml, p > 0.05). In contrast, analyzed with one-way ANOVA, significant difference (p = 0.04) was found between the examined histological types of lung cancer: adenocarcinoma (353 (329.4-438.5) pg/ml), squamous cell carcinoma (308 (209.6-348.1) pg/ml) and small cell lung cancer (388.8 (289.9-495.4) pg/ml). However, Tukey's post hoc test did not reveal significant difference between any pairs of histological groups. There was no difference between any histological subtype and health either. Our results suggest that circulating klotho protein cannot be considered as a biomarker for lung cancer. Further studies are warranted in order to examine the relationship between klotho expression in lung tissue and circulating levels of the protein, and to explore its mechanism of action in lung cancer.

Renal Impairment Hampers Bisphosphonate Treatment in a Quarter of Lung Cancer Patients with Bone Metastasis.

Renal function impairment in lung cancer patients with bone metastases was investigated, as this can limit the application of bisphosphonates representing the gold standard in the management of such cases. Clinicopathological data of 570 lung cancer patients were retrospectively analysed for changes in renal function parameters. Comorbidities included hypertension (50%), COPD (33%) and diabetes mellitus (15%). Statistical analysis was performed with Fisher's exact tests and a Cox proportional hazards model. In patients suffering from hypertension, both median serum creatinine and blood urea nitrogen (BUN) were higher (81.9 versus 75.8 µmol/L, p < 0.001 and 6.0 versus 5.7 mmol/L, p = 0.005, respectively). Such a difference could not be observed in patients with diabetes. In patients with COPD, only serum creatinine was higher (81.1 versus 77.3 µmol/L, p = 0.004). In the whole cohort, we found that while at the time of lung cancer diagnosis the ratio of patients in the pathological range (PRR) was 8.67% for serum creatinine (median: 75 µmol/L) and 14.16% for BUN (median: 5.4 mmol/L), at the time of bone metastasis the PRR for serum creatinine increased to 16.11% (median: 77.0 µmol/L) and for BUN to 24.07% (median: 6.0 mmol/L), which is a significant increase for both parameters (p < 0.001). For the whole cohort, the last laboratory results showed a 26.37% PRR for serum creatinine and 45.66% PRR for BUN (significant increase for both, p < 0.001). Multivariate analysis revealed that patients with hypertension had a higher chance for switching to the pathological range sooner (p = 0.033, HR: 1.372, CI: 1.025-1.835). Also, the appearance of the bone metastasis correlated with an acceleration of the onset of such a switch (p < 0.001, HR: 2.655, CI: 1.581-4.456). Our results suggest that renal function is impaired in a significant proportion of patients with lung cancer and highlight the importance of non-nephrotoxic drug in the management of bone metastases.

Renal Impairment Hampers Bisphosphonate Treatment in a Quarter of Lung Cancer Patients with Bone Metastasis.

Renal function impairment in lung cancer patients with bone metastases was investigated, as this can limit the application of bisphosphonates representing the gold standard in the management of such cases. Clinicopathological data of 570 lung cancer patients were retrospectively analysed for changes in renal function parameters. Co-morbidities included hypertension (50%), COPD (33%) and diabetes mellitus (15%). Statistical analysis was performed with Fisher's exact tests and a Cox proportional hazards model. In patients suffering from hypertension, both median serum creatinine and blood urea nitrogen (BUN) were higher (81.9 versus 75.8 µmol/l, p<0.001 and 6.0 versus 5.7 mmol/l, p=0.005, respectively). Such a difference could not be observed in patients with diabetes. In COPD patients, only serum creatinine was higher (81.1 versus 77.3 µmol/l, p=0.004). In the whole cohort, we found that while at the time of lung cancer diagnosis the ratio of patients in the pathological range (PRR) was 8.67% for serum creatinine (median: 75 µmol/l) and 14.16% for BUN (median: 5.4 mmol/l), at the time of bone metastasis the PRR for serum creatinine increased to 16.11% (median: 77.0 µmol/l) and for BUN to 24.07% (median: 6.0 mmol/l), which is a significant increase for both parameters (p<0.001). For the whole cohort, the last laboratory results showed a 26.37% PRR for serum creatinine and 45.66% PRR for BUN (significant increase for both, p<0.001). Multivariate analysis revealed that patients with hypertension had a higher chance for switching to the pathological range sooner (p=0.033, HR: 1.372, CI: 1.025-1.835). Also, the appearance of the bone metastasis correlated with an acceleration of the onset of such a switch (p<0.001, HR: 2.655, CI: 1.581-4.456). Our results suggest that renal function is impaired in a significant proportion of lung cancer patients and highlight the importance of non-nephrotoxic drug in the management of bone metastases. This article is protected by copyright. All rights reserved.

Decreased ERCC1 Expression After Platinum-Based Neoadjuvant Chemotherapy in non-Small Cell Lung Cancer.

We have already demonstrated in a small cohort of 17 non-small cell lung cancer patients that ERCC1 (excision repair cross-complementation group 1) protein expression decreased after platinum-based treatment, however, certain clinicopathological parameters, such as histologic subtypes, ERCC1 expression scores, chemotherapeutic combinations, response rate, gender and smoking history were not analyzed. The aim of our present study was to extend the studied cohort and analyze those parameters. ERCC1 protein expression was examined in 46 patients treated with neoadjuvant chemotherapy. 46 bronchoscopic biopsy samples (27 squamous cell carcinomas /SCC/ and 19 adenocarcinomas /ADC/) together with their corresponding surgical biopsies were studied. ERCC1 immunohistochemistry was performed on formalin-fixed, paraffin-embedded tissues. Staining scores were calculated by multiplying the percentage of positive tumor cells (0-100) by the staining intensity (0-3). 24/27 bronchoscopic SCC tissues expressed ERCC1. Thirteen of these cases became negative after neoadjuvant therapy and the expression differences between pre- and postchemotherapy samples were highly significant (p < 0.001). 11/19 bronchoscopic ADC tissues expressed ERCC1. Six of these cases became negative after neoadjuvant therapy and the expression differences were significant (p < 0.010). There was no newly expressed ERCC1 postoperatively. Comparison of staining score changes revealed more pronounced decrease in SCC (p = 0.032). We observed no correlation between initial ERCC1 level or ERCC1 decrease and overall survival, but we demonstrated correlations between decrease in ERCC1 expression and histologic subtypes of tumors and gender. We could confirm our previous data in a larger cohort that platinum-based chemotherapy affects the ERCC1 expression probably referring to an induction of tumor cell selection.