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Introduction: The effect of platinum-based chemotherapy (Chem.) and second- or multiple- line immune checkpoint PD-1 blocking therapy by Nivolumab or Pembrolizumab (ICI) was assayed in the peripheral blood of non-small cell lung cancer (NSCLC) patients., Methods: Flow cytometry was used to detect NSCLC-related antigen binding IgG antibodies. The Luminex MagPix multiplex bead-based cytokine/chemokine detecting system was used to quantitatively measure 17 soluble markers in the plasma samples. Single-cell mass cytometry was applied for the immunophenotyping of peripheral leukocytes., Results: The incubation of patient derived plasma with human NSCLC tumor cell lines, such as A549, H1975, and H1650, detected NSCLC-specific antibodies reaching a maximum of up to 32% reactive IgG-positive NSCLC cells. The following markers were detected in significantly higher concentration in the plasma of Chem. group versus healthy non-smoker and smoker controls: BTLA, CD27, CD28, CD40, CD80, CD86, GITRL, ICOS, LAG-3, PD-1, PD-L1, and TLR-2. The following markers were detected in significantly higher concentration in the plasma of ICI group versus healthy non-smoker and smoker controls: CD27, CD28, CD40, GITRL, LAG-3, PD-1, PD-L1, and TLR-2. We showed the induction of CD69 and IL-2R on CD4+ CD25+ T-cells upon chemotherapy; the exhaustion of one CD8+ T-cell population was detected by the loss of CD127 and a decrease in CD27. CD19+CD20+, CD79B+, or activated B-cell subtypes showed CD69 increase and downregulation of BTLA, CD27, and IL-2R in NSCLC patients following chemotherapy or ICI., Discussion: Peripheral immunophenotype caused by chemotherapy or PD-1 blocking was shown in the context of advanced NSCLC., Competing Interests: LP is the CEO of Avidin Ltd. and GS an employee of CS-Smartlab-Devices Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Neuperger, Szalontai, Gémes, Balog, Tiszlavicz, Furák, Lázár, Puskás and Szebeni.)

The prognostic markers of lung squamous cell carcinoma (LSCC) are less investigated. The aim of our study was to evaluate tumour budding (TB), minimal cell nest size, nuclear diameter (ND), and spread through air spaces (STAS) among patients with resected LSCC, semi-quantitatively. Furthermore, we aimed to identify a grading system for the best prognostic stratification of LSCC. Patients who underwent surgical resection at the Department of Surgery, University of Szeged between 2010 and 2016 were included. Follow-up data were collected from medical charts. Morphological characteristics were recorded from histologic revision of slides. Kaplan-Meier analysis, log rank test and Cox proportional-hazards model, ROC curve analysis, and intraclass correlation were utilised. Altogether 220 patients were included. In univariate analysis, higher degree of TB, infiltrative tumour border, larger ND, the presence of single cell invasion (SCI) and STAS were associated with adverse prognosis. Based on our results, we proposed an easily applicable grading scheme focusing on TB, ND, and SCI. In multivariate analysis, the proposed grading system (p OS  < 0.001, p RFS  < 0.001) and STAS (p OS  = 0.008, p RFS  < 0.001) were independent prognosticators. Compared to the previously introduced grading systems, ROC curve analysis revealed that the proposed grade had the highest AUC values (AUC OS : 0.83, AUC RFS : 0.78). Each category of the proposed grading system has good (ICC: 0.79-0.88) reproducibility. We validated the prognostic impact of TB, SCI, ND, and STAS in LSCC. We recommend a reproducible grading system combining TB, SCI, and ND for proper prognostic stratification of LSCC patients. Further research is required for validation of this grading scheme., (© 2023. The Author(s).)

Introduction: Lung cancer is the most common malignant tumor in Europe and Hungary. In 2010, 10 557 new cases were registered in Hungary; 80-85% of these cases were associated with smoking., Aim: In our work we analyzed the data of lung cancer patients of the last 15 years retrospectively., Method: We examined the demographic characteristics, the histological type, the stage of the lung cancer, the type of the surgical procedure used, other supplemental treatment and survival retrospectively., Results: Lung cancer has occurred 50 per cent more often among females in the last decade. This growth is due to the increase of adenocarcinoma cases. Thanks to the improving diagnostic modalities and the routine follow-up of oncological patients, the number of I/A cases has been doubled recently and the preoperative staging and physical condition check-up have become more accurate. Neoadjuvant treatment has been introduced, the proportion of sublobar resections has risen, the ratio of pneumonectomy and sleeve lobectomy has become equal, so many previously unresectable cases turned to be resectable and the tolerance of adjuvant therapy has also improved. Videothoracoscopic lobectomy has become an everyday practice, leading to a decrease in the operative stress on patients., Conclusion: In spite of this development, the five-year survival has not changed significantly, staying around 50%. Orv Hetil. 2018; 159(10): 391-396.

The aim of the study was to investigate the correlation between claudin (CLDN) protein expression and clinicopathological parameters as well as survival in histological subtypes of non-small cell lung cancer. Archived surgical resection specimens of 137 pathologic stage I primary bronchial cancers including 49 adenocarcinomas of non-lepidic variants (ADC), 46 adenocarcinomas of lepidic variants (L-ADC), and 42 squamous cell carcinomas (SCC) were examined. Immunohistochemistry (IHC) using antibodies against CLDN1,-2,-3,-4,-7 proteins as well as semiquantitative estimation (IHC scores 0-5) were performed. Claudin IHC scores of L-ADC differed significantly from ADC (CLDN1: p = 0.009, CLDN2: p = 0.005, CLDN3: p = 0.004, CLDN4: p = 0.001, CLDN7: p < 0.001, respectively) and SCC (CLDN1: p < 0.001, CLDN3: p < 0.001, CLDN7: p < 0.001, respectively). Highly significant CLDN3-CLDN4 parallel expression could be demonstrated in ADC and L-ADC (p < 0.001 in both), which was not observed in SCC (p = 0.131). ADC and SCC showed no correlation with smoking, whereas in case of L-ADC heavier smoking correlated with higher CLDN3 expression (p = 0.020). Regarding claudin expression and survival, in SCC significant correlation could be demonstrated between CLDN1 IHC positivity and better survival (p = 0.038). In NSCLC as a whole, high CLDN2 expression proved to be a better prognostic factor when compared with cases where CLDN2 IHC score was 0-1 vs. 2-5 (p = 0.009), however, when analyzed separately, none of the histological subgroups showed correlation between CLDN2 expression and overall survival. The claudin expression pattern was significantly different not only between the SCC-ADC and SCC-L-ADC but also between the L-ADC and ADC histological subgroups, which strongly underlines that L-ADC represents a distinct entity within the ADC group. CLDN1 overexpression is a good prognostic factor in NSCLC, but only in the SCC subgroup.

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.

Background: Dosimetric data and acute oesophageal toxicity (AET) during chemoradiotherapy (CRT) were evaluated in patients with non-small cell lung cancer (NSCLC)., Patients and Methods: Fifty patients were treated with paclitaxel-based conformal CRT with a mean ± SD dose of 60.7 ± 9.8 Gy. The oesophageal toxicity was prospectively registered and evaluated in relation to the maximal dose (Dmax), mean dose (D(mean)), length and volume of oesophagus irradiated with 35-60 Gy (V(35-60Gy)), and according to the seriousness of AET., Results: Dmax and D(mean) to the oesophagus were 57.0 ± 10.8 Gy and 24.9 ± 9.0 Gy, respectively. AET of grade 1, 2 and 3 developed in 16 (32%), 14 (28%) and three (6%) cases, respectively. The Dmax, D(mean), length and the V(35-60Gy) were all related to dysphagia (p<0.001). V(45Gy) was the most reliable predictor of AET of grade 2 or more., Conclusion: Our results indicate that keeping oesophageal V(45Gy) below 32.5% can prevent severe AET during CRT of NSCLC.

Background: Solid tumours have worse prognosis when associated with thrombocytosis. Our study assessed the prognostic value of thrombocytosis, and its relation with smoking habits in lung cancer., Patients and Methods: A total of 398 patients were operated on then divided into two groups, those with normal platelet counts (n=312), and those with thrombocytosis (n=86); 348 out of 398 patients had data for smoking habits (99 non-smokers, 249 smokers)., Results: The frequency of thrombocytosis was 18.6%, 19.3%, 27.5 and 28.6% in patients with tumor stages I to IV, respectively. Thrombocytosis appeared most frequently in patients with squamous cell lung cancer, and among smokers. The overall 5-year survival was worse in patients with thrombocytosis (p<0.001). By uni- and multivariate analyses, platelet count, and T and N status were found to be independent prognostic factors., Conclusion: Our study indicates that the presence of perioperative thrombocytosis in patients undergoing surgery should be considered as an independent prognostic factor of poor survival, and should be taken into account in regard to therapy.

Background: The associations between B-cell lymphoma 2 (BCL-2) and multi-drug resistance associated P-glycoprotein (MDR1) expressions and chemoradiotherapy outcome of patients with non-small cell lung cancer (NSCLC) were analysed., Patients and Methods: Thirty-two NSCLC patients were treated with paclitaxel-based chemoradiotherapy. The tumour expressions of BCL-2 and MDR1 were analysed by means of immunohistochemistry with regard to the clinical response and survival data., Results: Partial remission and stable disease were achieved in 19 (59%) and 10 (31%) cases, respectively. Significant differences in progression-free survival were observed between responders and non-responders (13.7 vs. 6.0 months, p=0.028), and between patients with or without a gross tumour volume (GTV) shrinkage (GTV(>50) 13.7 vs. 6.0 months, p=0.009). Overexpression of BCL-2 and of MDR1 was observed in 6 (21.4%) cases each. Overexpression of both markers together was associated with poor response (GTV reduction: p=0.005; RECIST: p=0.023) and lower progression-free survival (overexpression of both, low expression of both, mixed: 3.1, 13.4, 4.1 months, respectively, p<0.001)., Conclusion: BCL-2 and MDR1 overexpression may predict the inefficacy of paclitaxel-based chemoradiotherapy.

Objective: To investigate the role of growth/adhesion-regulatory lectins in the prognosis of the stage II non-small cell lung carcinomas (NSCLCs) via quantitative lectinhistochemical examinations and measurement of microvascularization of the tumour., Methods: In 94 radically operated lung cancer patients, stage II NSCLC was confirmed histologically (T1N1: 6, T2N1: 66, T3N0: 22). Immunohistochemical methods were applied to investigate the galectin-1, galectin-3, CL-16 and hyaluronic-acid-binding capacities of the tumours, and also the expression of galectin-1, -3 and heparin binding lectin. Sections were examined with the aid of qualitative (stained/not-stained) and syntactic structure analysis. The microvessels were detected by staining with anti-factor VIII antibodies. The findings were compared with the survival data., Results: In the univariate survival examinations, the prognosis was poorer for the galectin-1 and -3-expressing tumours (p=0.014 and p=0.003) and in multivariate analysis for the galectin-3-expressing tumours (p=0.046, RR: 2.026). Correlations could be demonstrated between the survival and the distance between the tumour cell for the tumours binding galectin-3 (p=0.039, RR: 5.944) and expressing galectin-3 (p=0.041, RR: 3.335). An elevation of the volume fraction of microvessels was a sign of a poor prognosis (p=0.017, RR: 2.334), however the increase of surface fraction improves the survival (p=0.01, RR: 0.956)., Conclusions: In stage II NSCLC, galectin-3 expression is indicative of a poor prognosis. In tumour expressing and binding galectin-3, the distance between the tumour cells is of prognostic significance. An increase in the microvessel volume fraction points to a poorer survival rate.

Lung cancer is the leading cause of mortality worldwide. The median survival of advanced disease is in the range of 8 to 10 months. Intrinsic or acquired drug resistance pose major challenges to the success of chemotherapy. The HER2 gene, also known as c-erbB-2 or neu, is a proto-oncogene that encodes a membrane-bound receptor tyrosine kinase of the epithelial growth factor receptor (EGFR) family. It has a possible role in tumor cell proliferation, tumor invasion, tumor metastasis and drug resistance. We retrospectively investigated 88 samples of non-small cell lung cancer (NSCLC) and assessed the correlation between HER2 expression and tumor histology. The expression of HER2 protein was analyzed by immunohistochemical staining (IHC) and HER2 DNA amplification was detected by using fluorescence in situ hybridization (FISH). HER2 overexpression (2+, 3+) was detected in 5 (5.7%) out of 88 specimens. All of the HER2-overexpressing tumors histologically proved to be squamous cell carcinoma (SCC). Cases with 2+ HER2 immunoreactivity showed either no amplification (3.875 and 2.525), or borderline amplification (4.75). Cases with 3+ HER2 immunoreactivity showed moderate amplification (7.35) and strong amplification (15-20 - cluster), respectively. The HER2 expression in NSCLC was relatively low in the selected Hungarian population; consequently, there is no indication for introduction of trastuzumab for the treatment of lung cancer.

Objective: Measurement of microvascularization and determination of its prognostic significance in cases of lung cancer., Methods: Section prepared from histological material from 432 radically operated non-small cell lung cancer patients were stained with antibodies against factor VIII-associated antigen. During computer imaging, the absolute and relative parameters of the vascularization were determined, as was the density of tumour cells situated in the vicinity of the vessels. The results were compared with the TNM status, the cell type and the survival., Results: Each parameter demonstrated an enhanced vascularization in classifications T2 and T4, but only the surface fraction, the mean vascular circumference and the mean vascular area displayed a significant change. The microvascularization parameters did not differ significantly between with different N status, however, the cell density progressively increased in the areas close to the vessels in advanced pN classifications. Elevation of the tumour cell density within 20 microm distance of the vessels was accompanied by a significantly poorer survival rate. The density of tumour cells within 20 microm region was the second strongest prognostic factor after the N status., Conclusions: More advanced tumour classifications grow with enhanced vascularization. A clear-cut connection cannot be demonstrated between the vascularization and appearance of lymph node metastases. The density of tumour cells measured in the direct vicinity of vessels is an important prognostic factor.

Background: We assessed the survival rates regarding different stages of operable lung cancers causing operable brain metastasis in patients with or without cancer-related symptoms. The correlation between survival rates and the disease-free interval between lung surgery and metastasectomy was studied., Methods: Sixty-five patients were operated on for lung cancer and brain metastases. The disease-free interval was divided into 5 subgroups: 0-2 months, 3-5 months, 6-11 months, 12-23 months, and 24 months and beyond. The study group comprised of patients with lung cancer in the following stages: 17 patients in stage I (1 patient in stage IA, 16 patients in stage IB), 16 patients in stage II (2 patients in stage IIA, 14 patients in stage IIB), 9 patients in stage IIIA, 4 patients in stage IIIB, and 19 patients in stage IV. Forty-four patients were symptom-free for lung cancer and 21 patients manifested lung cancer related symptoms., Results: The 5-year survival rates were as follows: stage I = 22%, stage II = 20%, stage IIIA = 22%, stage IIIB = 0%, and stage IV = 23% after lung resections. There were no significant differences in the 5-year survival rates regarding the disease-free interval subgroups after brain metastasectomies (p = 0.19): disease-free interval 0-2 months = 22% and disease-free interval 24 months and beyond = 23%. The 5-year survival rate after metastasectomy was significantly greater (26% vs 5%) in patients without lung cancer related symptoms (p = 0.05)., Conclusions: The 5-year survival rate in stage I, II, IIIA, and IV lung cancer with operable hematogenous brain metastases corresponds to that in the customary stage IIIA (23%). The disease-free interval exhibited no significant impact on the survival rate. The complaint-free status exhibits a significantly greater impact on the survival rate in hematogenic metastasis.

Objective: To determine the expression of endogenous adhesion/growth-regulatory lectins and their binding sites using labeled tissue lectins as well as the binding profile of hyaluronic acid as an approach to define new prognostic markers., Methods: Sections of paraffin-embedded histological material of 481 lungs from lung tumor patients following radical lung excision processed by a routine immunohistochemical method (avidin-biotin labeling, DAB chromogen). Specific antibodies against galectins-1 and -3 and the heparin-binding lectin were tested. Staining by labeled galectins and hyaluronic acid was similarly visualized by a routine protocol. After semiquantitative assessment of staining, the results were compared with the pT and pN stages and the histological type. Survival was calculated by univariate and multivariate methods., Results: Binding of galectin-1 and its expression tended to increase, whereas the parameters for galectin-3 decreased in advanced pT and pN stages at a statistically significant level. The number of positive cases was considerably smaller among the cases with small cell lung cancer than in the group with non-small-cell lung cancer, among which adenocarcinomas figured prominently with the exception of galectin-1 expression. Kaplan-Meier computations revealed that the survival rate of patients with galectin-3-binding or galectin-1-expressing tumors was significantly poorer than that of the negative cases. In the multivariate calculations of survival lymph node metastases (p < 0.0001), histological type (p = 0.003), galectin-3-binding capacity (p = 0.01), galectin-3 expression (p = 0.03) and pT status (p = 0.003) proved to be independent prognostic factors, not correlated with the pN stage., Conclusion: The expression and the capacity to bind the adhesion/growth regulatory galectin-3 is defined as an unfavorable prognostic factor not correlated with the pTN stage.