Decreasing incidence and mortality of lung cancer in Hungary between 2011 and 2021 revealed by robust estimates reconciling multiple data sources.

Objective: Hungary has repeatedly been shown to have the highest cancer-related mortality and incidence in Europe. Despite lung cancer being the most abundant malignant diagnosis in Hungary, numerous concerns have been raised recently regarding the bias inherent to reported incidence estimates. Re-analysis of reimbursement claims has been suggested previously by our group as an alternative approach, offering revised figures of lung cancer incidence between 2011 and 2016. Leveraging on this methodology, we aimed at updating Hungarian lung cancer incidence estimates with an additional 5 years (2017-2021), including years affected by the COVID-19 pandemic. Additionally, we also attempted to improve the robustness of estimates by taking additional characteristics of the patient pathway into account. Methods: Lung cancer patients between 2011 and 2021 were identified based on reimbursement-associated ICD-10 codes, histology codes and time patterns. Multiple query architectures were tested for sensitivity and compared to official estimates of the Hungarian National Cancer Registry (HNCR). Epidemiological trends were estimated by Poisson-regression, corrected for age and sex. Results: A total of 89,948 lung cancer patients diagnosed in Hungary between 2011 and 2021 have been identified by our study. In 2019 alone, 7,887 patients were diagnosed according to our optimized query. ESP2013 standardized rate was estimated between 92.5/100,000 (2011) and 78.4/100,000 (2019). In 2019, standardized incidence was 106.8/100,000 for men and 59.7/100,000 for women. Up until the COVID-19 pandemic, lung cancer incidence was decreasing by 3.18% (2.1%-4.3%) yearly in men, while there was no significant decrease in women. Young age groups (40-49 and 50-59) featured the largest improvement, but women aged 60-79 are at an increasing risk for developing lung cancer. The COVID-19 pandemic resulted in a statistically significant decrease in lung cancer incidence, especially in the 50-59 age group (both sexes). Conclusion: Our results show that using an optimized approach, re-analysis of reimbursement claims yields robust estimates of lung cancer incidence. According to this approach, the incidence rate of male lung cancer is declining in Hungary, in concordance with the trend observed for lung cancer mortality. Among women aged 60-79, the incidence of lung cancer has risen, requiring more attention in the near future.

Significant changes in advanced lung cancer survival during the past decade in Hungary: impact of modern immunotherapy and the COVID-19 pandemic.

Objective: The approval of immunotherapy (I-O) for the treatment of late-stage non-small cell lung cancer (NSCLC) opened new perspectives in improving survival outcomes. However, survival data have not yet been provided from the period of the Covid-19 pandemic. The aims of our study were to assess and compare survival outcomes of patients with advanced LC receiving systemic anticancer treatment (SACT) before and after the approval of immunotherapy in Hungary, and to examine the impact of pandemic on survival outcomes using data from the Hungarian National Health Insurance Fund (NHIF) database. Methods: This retrospective, longitudinal study included patients aged ≥20 years who were diagnosed with advanced stage lung cancer (LC) (ICD-10 C34) between 1 January 2011 and 31 December 2021 and received SACT treatment without LC-related surgery. Survival rates were evaluated by year of diagnosis, sex, age, and LC histology. Results: In total, 35,416 patients were newly diagnosed with advanced LC and received SACT during the study period (mean age at diagnosis: 62.1-66.3 years). In patients with non-squamous cell carcinoma, 3-year survival was significantly higher among those diagnosed in 2019 vs. 2011-2012 (28.7% [95% CI: 26.4%-30.9%] vs. 14.45% [95% CI: 13.21%-15.69%], respectively). In patients with squamous cell carcinoma, 3-year survival rates were 22.3% (95% CI: 19.4%-25.2%) and 13.37% (95% CI: 11.8%-15.0%) in 2019 and 2011-2012, respectively, the change was statistically significant. Compared to 2011-2012, the hazard ratio of survival change for non-squamous cell carcinoma patients was 0.91, 0.82, and 0.62 in 2015-2016, 2017-2018, and 2019, respectively (p<0.001 for all cases). In the squamous cell carcinoma group, corresponding hazard ratios were 0.93, 0.87, and 0.78, respectively (p<0.001 for all cases). Survival improvements remained significant in both patient populations during the Covid-19 pandemic (2020-2021). No significant improvements were found in the survival of patients with small cell carcinoma. Platinum-based chemotherapy was the most common first-line treatment in all diagnostic periods, however, the proportion of patients receiving first- or second-line immunotherapy significantly increased during the study period. Conclusion: 3-year survival rates of NSCLC almost doubled among patients with non-squamous cell carcinoma and significantly improved at squamous cell carcinoma over the past decade in Hungary. Improvements could potentially be attributable by the introduction of immunotherapy and were not offset by the Covid-19 pandemic.

Large-Scale Plasma Proteome Epitome Profiling is an Efficient Tool for the Discovery of Cancer Biomarkers.

Current proteomic technologies focus on the quantification of protein levels, while little effort is dedicated to the development of system approaches to simultaneously monitor proteome variability and abundance. Protein variants may display different immunogenic epitopes detectable by monoclonal antibodies. Epitope variability results from alternative splicing, posttranslational modifications, processing, degradation, and complex formation and possesses dynamically changing availability of interacting surface structures that frequently serve as reachable epitopes and often carry different functions. Thus, it is highly likely that the presence of some of the accessible epitopes correlates with function under physiological and pathological conditions. To enable the exploration of the impact of protein variation on the immunogenic epitome first, here, we present a robust and analytically validated PEP technology for characterizing immunogenic epitopes of the plasma. To this end, we prepared mAb libraries directed against the normalized human plasma proteome as a complex natural immunogen. Antibody producing hybridomas were selected and cloned. Monoclonal antibodies react with single epitopes, thus profiling with the libraries is expected to profile many epitopes which we define by the mimotopes, as we present here. Screening blood plasma samples from control subjects (n = 558) and cancer patients (n = 598) for merely 69 native epitopes displayed by 20 abundant plasma proteins resulted in distinct cancer-specific epitope panels that showed high accuracy (AUC 0.826-0.966) and specificity for lung, breast, and colon cancer. Deeper profiling (≈290 epitopes of approximately 100 proteins) showed unexpected granularity of the epitope-level expression data and detected neutral and lung cancer-associated epitopes of individual proteins. Biomarker epitope panels selected from a pool of 21 epitopes of 12 proteins were validated in independent clinical cohorts. The results demonstrate the value of PEP as a rich and thus far unexplored source of protein biomarkers with diagnostic potential.

Architectural Grade Combined With Spread Through Air Spaces (STAS) Predicts Recurrence and is Suitable for Stratifying Patients Who Might Be Eligible for Lung Sparing Surgery for Stage I Adenocarcinomas.

The spread through air spaces (STAS) has a main role in local recurrence of stage I lung adenocarcinomas (LAs), therefore its presence might question sublobar resection as a therapeutic option. The aim of our study was to evaluate the distribution of STAS in stage I LAs, to stratify patients according to local recurrence and to identify a group of patients who might be suitable for sublobar surgery. Patients resected with LA were included. The presence of STAS was recorded on hematoxylin eosin stained slides and clinicopathological data were obtained from medical charts. Overall survival (OS) and disease-free survival (DFS) were registered. Statistical methods included Kruskal-Wallis tests, Kaplan-Meier analyses, log-rank tests and Cox-regressions. 292 patients were included. STAS was identified in 38.7% and 95.7% of micropapillary carcinomas showed STAS. Significant correlation was found between STAS and high-grade patterns. Significant differences were found between OS and DFS estimates of STAS0 and STAS1 cases (5-y-OS: 80.0% vs. 68.4%; 5-y-DFS: 71.1% vs. 57.1%). The presence of STAS was associated with unfavorable prognosis in low and intermediate architectural grades, but not in high-grade. Multivariate analysis revealed that architectural grade (HR(OS):2.09; HR(DFS):1.52) and STAS (HR(OS):1.51; HR(DFS):1.48) were independent prognostic markers in stage I LA. Architectural grade combined with STAS was superior to other prognostic grades. The combination of architectural grade and STAS proved to be a prognostic factor that is superior to previously introduced grading systems. Patients having low and intermediate grade LAs without STAS might be eligible for sublobar resection.

The efficacy and safety of bevacizumab in addition to platinum-based chemotherapy for the first-line treatment of patients with advanced nonsquamous non-small-cell lung cancer: Final results of AVALANCHE, an observational cohort study.

The previous results of former clinical studies confirmed that first-line bevacizumab (BEV) in combination with chemotherapy improves clinical outcomes in patients with advanced non-squamous non-small cell lung cancer. The AVALANCHE study (ClinicalTrials.gov Identifier NCT03170284) was undertaken to assess the clinical outcomes of first-line BEV combined with standard platinum-based regimens in the Hungarian clinical practice. This observational study was conducted in 28 Hungarian sites, with patients enrolled between July 2008 and April 2011. Patients with untreated locally advanced, metastatic or recurrent lung adenocarcinoma received BEV (7.5 mg/kg, q3w) with any platinum-doublet for up to 6 cycles, and then non-progressors proceeded to receive BEV until disease progression or unacceptable toxicity. The primary endpoint was time-to-progression, and secondary endpoints included overall survival (OS), tumour control rate and safety. Patients were also analysed as two cohorts (non-progressors vs. progressors) based on whether or not they received BEV maintenance therapy following completion of first-line chemotherapy plus BEV. The study enrolled 283 patients (median age: 58.2 (18-78) years; males: 50.5%; stage: III/B: 18.4%, IV: 79.9%; adenocarcinoma/other: 95.8/4.2%; ECOG PS 0/1/2/≥3: 30.8/59.7/2.6/1.4%). Centrally located tumours were reported in 21.6%. Cisplatin/carboplatin-based regimens: 53.8/46.2%. A total of 43% of patients received BEV maintenance therapy. The median number of BEV cycles was 6. Median progression-free survival (PFS) was 7.2 months and OS was 15.2 months for the entire cohort. Longer PFS and OS were observed in patients who received BEV maintenance therapy [median OS, 26.2 vs. 10.2 months (P<0.001); median PFS, 9.2 vs. 5.8 months (P<0.001)]. Contrary to the results of previous OCS no significant difference was recorded in the different age groups or gender. Best tumour response: Complete remission/partial remission/stable disease/progressive disease/not reported were: 1.5/29.9/26.9/9.1/32.6% of all patients. In conclusion, clinical outcomes obtained in this real-life population were consistent with pivotal studies. BEV maintenance treatment was associated with a significantly longer PFS and OS.

[Perioperative factors influencing the tolerability of chemotherapy after lung lobe resection]. / Tüdolebeny-eltávolítást követo kemoterápia tolerabilitását befolyásoló perioperatív tényezok.

INTRODUCTION: Lung cancer is the leading cause of malignancy-related deaths in Hungary, involving complex surgical and oncological treatment. AIM: Factors influencing the tolerability of complete/planned and incomplete postoperative chemotherapy after surgery were analyzed. METHOD: During a 6-year period (January 1, 2011-December 31, 2016), data of 72 patients operated with lung cancer (adenocarcinoma and squamous cell carcinoma), receiving complete (4 cycles) and incomplete (<4 cycles) postoperative chemotherapy were analyzed. The following factors among the two groups [complete: n = 53; incomplete: n = 19] were analyzed: gender, mean age, body mass index, Malnutrition Universal Screening Tool, Charlson Comorbidity Index, second malignant tumor, atrial fibrillation, Forced Expiratory Volume 1 sec, Performance Status, open/Video-Assisted Thoracic Surgery (VATS) lobectomy, duration of surgery, postoperative fever, need for transfusion, prolonged air leak, redo surgery, histology, tumor stage. RESULTS: The rate of complete postoperative cycles obtained from logistic regression analysis, were substantially higher after VATS lobectomies [n = 26 (83.87%)] compared to open procedures [n = 27 (65.85%)]; (p = 0.092; OR = 0.356), without significance. Multivariate analysis (open/VATS lobectomy, upper/middle-lower lobe resection, diabetes, prolonged air leak, postoperative fever) showed significantly increased successful uptake of complete cycles after VATS (p = 0.0495), while upper/middle lobe resections (p = 0.0678) and the lack of diabetes (p = 0.0971) notably increased the number of complete cycles, without significance. CONCLUSION: Twenty-six percent of patients were unable to receive complete planned postoperative chemotherapy. VATS lobectomy patients received significantly higher number of complete cycles of postoperative chemotherapy. Diabetes and lower lobe lobectomies had a negative effect on the tolerability of postoperative chemotherapy. Orv Hetil. 2018; 159(19): 748-755.

The more the micropapillary pattern in stage I lung adenocarcinoma, the worse the prognosis-a retrospective study on digitalized slides.

Although the majority of lung adenocarcinomas show mixed pattern, only the predominant component is taken into account according to the novel classification. We evaluated the proportion of different patterns and their impact on overall survival (OS) and disease-free survival (DFS). Patterns were recorded according to predominance and their proportions were rated and calculated by objective area measuring on digitalized, annotated slides of resected stage I lung adenocarcinomas. Spearman's rank correlation, Kaplan-Meier models and the log rank test were used for statistical evaluation. Two hundred forty-three stage I adenocarcinoma were included. Lepidic pattern is more frequent in tumours without recurrence (20 vs. 8%), and lepidic predominant tumours have favourable prognosis (OS 90.5%, DFS 89.4%), but proportions above 25% are not associated with improving outcome. Solid and micropapillary patterns are more frequent in patients with recurrence (48 vs. 5% and 13 vs. 4%) and predominance of each one is associated with unfavourable prognosis (OS 64.1%, DFS 56.3% and OS 28.1%, DFS 28.1%, respectively). Above 25%, a growing proportion of solid or micropapillary pattern is not associated with worsening prognosis. In contrast, tumours having micropapillary pattern as secondly predominant form a different intermediate group (OS 51.1%, DFS 57.8%). Our study was based on measured area of each growth pattern on all available slides digitalized. This is the most precise way of determining the size of each component from the material available. We propose using predominant and secondly predominant patterns for prognostic purposes, particularly in tumours having solid or micropapillary patterns.

[Changes in the clinicopathological features of surgically treated lung cancer around the millennium]. / A mutétileg kezelt tüdorák klinikopatológiai jellemzoinek változása az ezredfordulónkon.

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.

Pulmonary epithelioid haemangioendothelioma studies in vitro and in vivo: new diagnostic and treatment methods.

BACKGROUND: Pulmonary epithelioid haemangioendothelioma is a rare endothelial tumour without standard treatment. For this reason, our aim is to present contemporary research outlining new therapeutic possibilities; thus in vitro and in vivo methods were combined. PATIENTS AND METHODS: Pulmonary epithelioid haemangioendothelioma was diagnosed in a 49-year-old female patient. A bronchial excision was obtained from a parenchymal lesion, and the excised sample was manipulated with in vitro-standardized experiments to support the diagnostic and therapeutic procedures. RESULTS: according to in vitro examination of tumour pulmonum and metastases from bone, carboplatin, docetaxel and pharmarubicin was the most effecient treatment modality. CONCLUSION: Currently, pulmonary epithelioid haemangioendothelioma does not have any standard treatment; the most efficient therapeutic regimen was gradually developed by combining in vitro and in vivo methods, which proved to be an efficient therapeutic modality hitherto.

[Primary pulmonary epitheloid haemangioendothelioma]. / Primer pulmonalis epitheloid haemangioendothelioma.

A 49-year-old female patient was admitted in July 2009 because of cough, weight loss and effort dyspnoe. Chest X-ray and CT showed multiple bilateral nodules which have been identified earlier and these nodules were unchanged. However, there was a new parenchymal lesion in the right upper lobe, and new right hilar and mediastinal lymphadenomegaly was also found. Sample was taken by bronchoscope and the pathological diagnosis was pulmonary epitheloid haemangioendothelioma. This rare endothelial tumor usually affects middle-aged patients with a female predominance and it presents with chest pain, effort dyspnoe, cough, sputum, or it may remain asymptomatic. Multiple bilateral nodules are usually detected by radiologic examination. The diagnosis of this tumor is often challenging and, because of its rarity, it does not have any standard therapeutic regimen. Treatment can be surgery, chemo-, radio-, hormone- or immunotherapy. In order to find the most effective anticancer treatment, authors performed in vitro studies. On the basis of the results, chemotherapy was initiated which resulted in a partial regression.

Randomized, placebo-controlled phase II study of vandetanib plus docetaxel in previously treated non small-cell lung cancer.

PURPOSE: Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor kinase activity. The activity of vandetanib plus docetaxel was assessed in patients with previously treated non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: This two-part study comprised an open-label run-in phase and a double-blind randomized phase. Eligible patients had locally advanced or metastatic (stage IIIB/IV) NSCLC after failure of first-line platinum-based chemotherapy. The primary objective of the randomized phase was to prolong progression-free survival (PFS) in patients receiving vandetanib (100 or 300 mg/d) plus docetaxel (75 mg/m2 intravenous infusion every 21 days) versus placebo plus docetaxel. The study was designed to have more than 75% power to detect 50% prolongation at a one-sided significance level of P < .20. Secondary objectives included objective response rate, overall survival, safety and tolerability. RESULTS: In the randomized phase (n = 127), median PFS was 18.7 weeks for vandetanib 100 mg plus docetaxel (n = 42; hazard ratio v docetaxel = 0.64; one-sided P = .037); 17.0 weeks for vandetanib 300 mg plus docetaxel (n = 44; hazard ratio v docetaxel = 0.83; one-sided P = .231); and 12 weeks for docetaxel (n = 41). There was no statistically significant difference in overall survival among the three treatment arms. Common adverse events included diarrhea, rash, and asymptomatic prolongation of corrected QT (QTC) interval. CONCLUSION: The primary objective was achieved, with vandetanib 100 mg plus docetaxel demonstrating a significant prolongation of PFS compared with docetaxel in relation to the prespecified significance level. On the basis of these encouraging data, phase III evaluation of vandetanib 100 mg plus docetaxel in second-line NSCLC has been initiated.