Deficiency of innate-like T lymphocytes in chronic obstructive pulmonary disease.

BACKGROUND: Based on the phenotypic and functional characteristics unconventional T-lymphocytes such as invariant natural killer T (iNKT) cells and mucosal-associated invariant T (MAIT) cells link the innate and adaptive immune responses. Up to now data are scarce about their involvement in pulmonary disorders including chronic obstructive pulmonary disease (COPD). This study explores simultaneously the frequencies of iNKT and MAIT cells in the peripheral blood and sputum of stable and exacerbating COPD patients. METHODS: By means of multicolor flow cytometry frequencies of total iNKT and MAIT cells and their subsets were enumerated in peripheral blood and sputum samples of healthy controls, and COPD patients. In addition, gene expression of TCR for iNKT, MAIT cells, and CD1d, MR1 were assessed by qPCR in the study cohorts. RESULTS: Percentages of total iNKT and MAIT cells were dramatically dropped in blood, and reduced numbers of iNKT cells were observed in the sputum of COPD patients. Furthermore decreased DN and increased CD4+ iNKT subsets, while increased DN and decreased CD8+ MAIT subpopulations were measured in the blood of COPD patients. Reduced invariant TCR mRNA levels in COPD patients had confirmed these previous findings. The mRNA expression of CD1d and MR1 were increased in stable and exacerbating COPD patients; however both molecules were decreased upon antibiotic and systemic steroid treatments. CONCLUSIONS: Our results support the notion that both invariant T-cell populations are affected in COPD. Further detailed analysis of invariant T cells could shed more light into the complex interactions of these lymphocyte groups in COPD pathogenesis.

The Frequency of EGFR Mutation in Lung Adenocarcinoma and the Efficacy of Tyrosine Kinase Inhibitor Therapy in a Hungarian Cohort of Patients.

In the last decades new therapeutic drugs have been developed for the treatment of non-small cell lung cancer (NSCLC) patients. Tyrosine kinase inhibitors (TKIs) significantly increase the progression free survival (PFS) of patients with NSCLC carrying epidermal growth factor receptor (EGFR) mutations. This type of lung cancer occurs mainly among non-smoking women and Asian origin. However, the new ESMO guideline recommends EGFR mutation analysis in every patient with NSCLC, because in patients with activating EGFR mutation, TKIs should be considered as first line therapy. In our recent work, we analyzed data of patients with EGFR-mutant adenocarcinoma from January 2009. The number of patients investigated was 446, among them 44 cases were positive for EGFR mutation. The ratio of positive cases was 9.86 % that is lower than the average mutation rate in Europe and much lower than that found in Asia. The exon 19 deletion was detected in 61.4 % of the patients, while L858R point mutation in exon 21 was observed in 34.1 % of them. In one subject, both exon 19 and 21 mutations were present simultaneously. A rare mutation located in exon 21 was found in another patient. TKI therapy was conducted in 38 patients. The disease control rate by TKI therapy was 85.7 %; primary resistance was documented in five subjects. Non-smoking patients with EGFR mutant adenocarcinoma had the highest benefit from TKI treatment. Our data support the recommendation that EGFR mutation status should be defined in all cases of locally advanced or metastatic lung adenocarcinoma.

Bone Metastases and the EGFR and KRAS Mutation Status in Lung Adenocarcinoma--The Results of Three Year Retrospective Analysis.

Lung cancer is a heterogeneous group of disease and mutational profiling of lung adenocarcinomas is a routine practice in thoracic oncology. Kirsten-RAS (KRAS) and EGFR mutations play an important role in the carcinogenesis of a subset of lung adenocarcinomas. Our aim was to investigate the correlation between bone metastases and EGFR and KRAS mutation status in lung adenocarcinoma patients. Retrospectively we analysed 224 patients with recurrent or metastatic lung adenocarcinomas. Patients were treated with standard chemotherapy as first line therapy and with EGFR-TK inhibitors as a second or third line therapy. 72 of 224 patients (32 %) had verified bone metastases. Bone metastases and Skeletal Related Events (SRE) were more frequent in men, heavy smokers and without treatment of EGFR TK inhibitors. We have found that EGFR and KRAS mutation status are both predictive factors for the treatment efficacy and prognostic factors for the disease progression. However there were no significant correlation between mutation status and the presence of bone metastases (P = 0, 59). In our study the presence of bone metastases proved to be an independent prognostic factor related to poor performance status and worse Quality of Life (QL).

[Efficacy of first-line afatinib versus chemotherapy in EGFR mutation positive pulmonary adenocarcinoma]. / Az elso vonalban alkalmazott afatinib versus kemoterápia hatásossága EGFR-mutáció-pozitív tüdo-adenokarcinómában.

Therapy of patients with advanced NSCLC has lately changed due to the algorithm based on the presence or absence of oncogenic mutations. There is an agreement nowadays that in the presence of activating EGFR mutations, the administration of EGFR TKI (gefitinib, erlotinib, afatinib) is the most efficacious initial treatment. Unlike the first-generation TKIs, afatinib is a new, irreversible ErbB blocker, selectively and effectively blocking signals from the ErbB family receptors. Afatinib's marketing authorization is based on a large, randomized, phase III clinical trial, LUX-Lung 3, where patients in the control arm were treated with the best available chemotherapy (pemetrexed/cisplatin combination). Primary endpoint was progression-free survival (PFS). Patients with common EGFR mutations showed a PFS of 13.6 months when treated with afatinib, while treatment in the control arm resulted in a PFS of 6.9 months. Overall survival (OS) was 31.6 and 28.2 months, respectively. LUX-Lung 3 has been followed by the LUX-Lung 6 trial, comparing afatinib treatment to traditional chemotherapy (gemcitabine/cisplatin) in Asian patients with NSCLC harboring EGFR mutations. This clinical trial has also proved benefit of afatinib: PFS was 11.0 months in the afatinib arm and 5.6 months in the control arm by independent reviewer, while OS was 23.6 months and 23.5 months, respectively. Similarity of the OS values in both trials is explained by the cross-over treatment. When further analyzing OS data, a statistically significant difference between the afatinib and the control arm was seen in the EGFR exon 19 del subgroup (LUX-Lung 3: 33.3 vs. 21.1 months, LUX-Lung 6: 31.4 vs. 18.4 months, respectively).

PET-CT imaging and reality.

The spectrum of human diseases caused by members of the Aspergillus genus is extensive. It ranges from allergic reactions to colonization of preexisting pulmonary cavities to invasion and destruction of lung parenchyma with pyemic spread to brain, skin, and other organs, causing rapid death. The immune status of the host is a crucial factor in determining the phenotype and severity of the disease. In this case report Chronic Necrotizing Pulmonary Aspergillosis (CNPA), a rare, locally- or semi-invasive variant of pulmonary Aspergillosis, mimicking lung metastasis is presented. The 60-year-old male patient had earlier received multiple cycles of systemic chemotherapy due to colorectal carcinoma. Our case report focuses on the benefits and the possible disadvantages of PET-CT imaging in CNPA.

Erlotinib in advanced non-small cell lung cancer: efficacy and safety findings of the global phase IV Tarceva Lung Cancer Survival Treatment study.

INTRODUCTION: Erlotinib is a small molecule inhibitor of epidermal growth factor receptor tyrosine-kinase activity that has been shown to significantly increase survival for patients with previously treated advanced non-small cell lung cancer. Here, we report safety and efficacy data from a large, global, open-label, phase IV trial of erlotinib (Tarceva Lung Cancer Survival Treatment). METHODS: Patients who had previously failed on chemotherapy or radiotherapy and were unsuitable for these treatments were treated with oral erlotinib (150 mg/d) until disease progression or unacceptable toxicity. RESULTS: The disease control rate was 69% in 5394 patients for whom best response data were available. Survival data were available for 6580 patients. Median progression-free and overall survival times were 3.25 months and 7.9 months, respectively. The 1-year survival rate was 37.7%. Among the 6580 patients included in the safety analysis, 799 (12%) experienced one or more erlotinib-related adverse events (AEs, other than prespecified AEs defined in the protocol), and only 4% experienced an erlotinib-related serious AE. Of the 6580 patients for whom data were available, dose reductions were reported in 1096 (17%), the majority (95%) due to an erlotinib-related AE (most commonly rash 65% or diarrhea 10%). Treatment was discontinued for 337 patients (5%) because of erlotinib-related AEs. Incidence of erlotinib-related rash was investigated as a separate end point. Seventy-one percent of patients for whom data were available experienced erlotinib-related rash; of these, the majority of cases were grade 1/2 (59%). CONCLUSIONS: These data confirm the favorable efficacy and safety profile of erlotinib in a large heterogeneous non-small cell lung cancer population.

Survival after surgery following chemotherapy for non-small-cell lung cancer.

A retrospective study was carried out on 74 patients with advanced non-small-cell lung cancer (52 in stage IIIA, 22 in stage IIIB) who received platinum-based induction chemotherapy in doublets and triplets, followed by tumor resection. Thirty-day postoperative mortality was 5.4% (4 patients); 5 patients in stage IIIB and 17 in stage IIIA did not respond, but the other 47 (63.5%) were downstaged to < IIIA (26 were downstaged to stage I, 20 to stage II, and 1 had complete remission). There was no change in T factor in 22 (30%) patients, nor in N factor in 21 (28%). The actuarial 5-year survival rate for patients in postoperative stages IIIA and IIIB was 0.496; survival was significantly longer in patients who responded to therapy. Parallel improvement in both T and N status predicted worse survival than a multistage regression in any single factor. N status was found to be a stronger survival indicator than T status. Cell type did not influence the response rate or outcome. Induction chemotherapy significantly improved survival in patients who responded, despite a poor prognosis.

[Role of surgery for lung cancer in elderly patients]. / A mûtét szerepe az idôskori tüdôrák kezelésében.

Lung cancer is a leading cause of death in the civilised world. Surgical resection, which play a crucial role in the complex oncological treatment, has to be offered in older ages than it was done before, due to an ageing population. Results of surgical treatment of patients older than 75 years are investigated retrospectively in the present paper. A retrospectively analysis was carried out of 54 from a total of 884 lung resections for primary lung cancer performed for patients older than 75 years between 1995-2005. Twelve of these patients were above 80 years. Kaplan-Meier analysis was performed to calculate survival and multifactor analysis for the risk factors. Average age was 77.5 years (75-85). Two pneumonectomies, two bilobectomies, 41 lobectomies, seven sublobar resections and two lobectomies with chest wall resections were performed. The average hospital stay was 11.4 days (8-36). Mortality: 7.4% (n = 4), morbidity: 52% (n = 28) including: sputum retention: 43%, arrhythmia 33%, atelectasia: 15%. There were two bronchial stump insufficiencies (4%) and three reoperations were performed (5%). The average follow up was: 32 months and the five year survival 33.7% (median 43 months). Multifactorial analysis show that extended resection, male gender, age above 80 years are risk factors for adverse outcome. Female gender, stage Ia and lobectomy are considered as predictive factors for long survival. We conclude, that with proper patient selection (below ASA3, early stage) and with carefully conducted postoperative care (physiotherapy, monitoring) surgical resection should be offered to elderly lung cancer patients as well.

[Erlotinib in second/third line treatment for non-small cell lung cancer (NSCLC)]. / Erlotinib a nem kissejtes tüdorák második-harmadik vonalbeli kezelésében.

In advanced cases of non-small cell lung cancer, cytostatic treatment has small but assessable effect on patient survival as opposed to only symptomatic therapy. Cytostatic drugs, however, are known to have numerous side effects including neurotoxicity, nephrotoxicity, and myelosuppression. Better knowledge of tumor biology has led to the discovery of several key molecular pathways. Due to their beneficial effect and side effect profile, epidermal growth factor receptor tyrosine kinase inhibitors (gefitinib, erlotinib) have now been included in clinical practice in the treatment of non-small cell lung cancer. The predictive characteristics for the indication of these drugs have not yet been cleared up and require further clinical studies. Under the Expanded Access Program it has become possible to give patients with advanced non-small cell lung cancer (stages III/B and IV) epidermal growth factor receptor tyrosine kinase inhibitor erlotinib. Authors present here two cases to illustrate the beneficial effect of the drug when used as second or third line therapy. A more detailed study of the histological specimen (epidermal growth factor receptor expression as well as epidermal growth factor receptor gene mutation) will provide further information as to the anticipated efficacy for erlotinib.

[The role of neoadjuvant therapy in the treatment of locally advanced, stage III non-small-cell lung cancer]. / A neoadjuváns terápia szerepe a lokálisan elôrehaladott, III. stádiumú nem kissejtes tüdôrákos betegek kezelésében.

OBJECTIVE: to review the progress achieved in the neoadjuvant treatment of patients with locally advanced NSCLC by evaluating the articles published during the last 10 years. METHOD: altogether 51 articles (including prospective and retrospective studies, and reviews) were analysed with the intention to evaluate the efficacy of the different neoadjuvant modalities. RESULTS: different types of neoadjuvant treatments were reported. The articles were heterogeneous not only in the aspect of the patient populations but also in regard to the treatment modalities and schedules, the mode and timing of combination of chemotherapy with radiotherapy. Most studies support the advantage of chemoradiotherapy. The chemotherapy should be platinum based, and combination with modern drugs as gemcitabine is recommended. Surgery provides the best local control of the disease. Lobectomy, and in special circumstances sleeve resection, are preferred. The best prognostic factors are the R0 resection and the downstaging of the mediastinal lymph nodes. The cause of death is usually progressive disease, often brain metastases. Because of frequent occurrence of brain metastases, preventive cranial irradiation is recommended by many authors. CONCLUSION: to be able to compare different treatment modalities with consistent patient groups, patients should be classified into well-defined subgroups. T4 tumours (except pleuritis carcinomatosa) behave as locoregional disease, N2/N3 tumours, however, resemble more to systemic diseases. With two- or three-modality treatment, 3-7% improvement can be achieved in the 5-year survival time of patients. Evaluating the results, the heterogeneity of stage III NSCLC should always be kept in mind. It is still unknown to which patients should surgery be offered after neoadjuvant therapy, and who will benefit more from chemoradiotherapy alone. Considering the downstaging effect of the therapy, the tumour and nodal state should be evaluated separately. To answer these questions, it is time to start large randomised studies.