Szemelvények a Semmelweis Egyetem, az Országos Onkológiai Intézet és az Országos Korányi Tbc és Pulmonológiai Intézet együttműködésén alapuló tüdőrák-kutatási programból

Lung cancer places a significant socio-economic burden on the Hungarian population. This overview summarizes the findings of collaborative translational lung cancer research efforts of three Hungarian flagship academic institutions, the Semmelweis University, the National Institute of Oncology and the National Koranyi Institute of TB and Pulmonology. With regards to the molecular factors regulating tumor angiogenesis, we identified the prognostic significance of apelin and erythropoietin receptor (EPOR) expression in non-small cell lung cancer (NSCLC). Furthermore, the impact of KRAS mutation subtypes and ERCC1 (excision repair cross-complementation group 1) expression on the response to platinum-based chemotherapy have been studied. We also described the epidemiology and predictive power of rare EGFR (epidermal growth factor receptor) mutations in a large Hungarian patient cohort. Lastly, the expression of molecular factors associated with NSCLC progression was studied specifically in brain metastatic matched cases series. These preclinical and clinical studies provide clinically relevant information that hopefully will contribute to the improvement of lung cancer patient care

A COVID–19-járvány hatása a leggyakoribb légzőszervi megbetegedések lefolyására

Bevezetés: A SARS-CoV-2 által okozott fertőzés az elmúlt három évben meghatározta mindennapi életünket, és nem várt terhet rótt az egészségügyi ellátórendszerre, többek között azáltal, hogy komoly kockázati tényezőt jelenthet a már meglévő, különböző légzőszervi megbetegedésekkel küzdő betegek számára is. Célkitűzés: A COVID–19 és a fertőzéskor már fennálló légzőszervi megbetegedések, elsősorban a krónikus obstruk- tív tüdőbetegség (COPD), valamint az asztma összefüggéseinek feltárása. Módszer: Hazai vizsgálatunkban közel 29 000 beteg adatait dolgoztuk fel retrospektíven. Eredmények: Eredményeink alapján elmondható, hogy a COPD mint társbetegség megléte a nemzetközi megállapí- tással egybehangzóan összefüggést mutat a COVID–19-fertőzés súlyosságával, illetve enyhén növeli az intenzív osz- tályos kezelés és a gépi lélegeztetés szükségességének kockázatát a SARS-CoV-2 okozta megbetegedés során. Asztma esetében mindezt nem sikerült kimutatnunk, vagyis sem a SARS-CoV-2-fertőzés súlyosságát, sem az intenzív osztá- lyos kezelés és a gépi lélegeztetés szükségességét nem befolyásolta jelentősen az asztma mint társbetegség megléte. Megbeszélés: Ahogy nemzetközi tanulmányokban is olvasható, a COPD mint társbetegség megléte nem növeli jelentős mértékben a SARS-CoV-2-fertőzés kockázatát. Ugyanakkor kijelenthető, hogy a COPD növeli a COVID–19-pozitív betegek kórházba kerülésének esélyét, és emeli a megbetegedés súlyosabb lefolyásának valószínűségét. Tekintettel a COPD-betegekben a tüdő károsodása során végbemenő szerkezeti átépülésre és rendellenes regenerálódási folyamatokra, e betegek a vírusfertőzés lezajlása után fokozott odafigyelést, valamint személyre szabott rehabilitációt igényelnek. Következtetés: Összességében elmondható, hogy a jövőben a személyre szabott terápiás megközelítés bevezetéséhez elengedhetetlen a különböző COPD-s fenotípusok (valamint egyéb krónikus tüdőbetegségek) és a SARS-CoV-2-fer- tőzés klinikai megnyilvánulásainak mélyreható vizsgálata

Fibulin-3 levels in malignant pleural mesothelioma are associated with prognosis but not diagnosis

BACKGROUND: Fibulin-3 (FBLN3) was recently presented as a promising novel biomarker for malignant pleural mesothelioma (MPM), warranting independent validation studies. METHODS: ELISA was used to measure cellular and secreted FBLN3 in cell lines, in plasma of xenograft tumour-bearing mice, in plasma from two independent series of MPM and non-MPM patients and in pleural fluid from a third series. Diagnostic and prognostic potential of FBLN3 was assessed by receiver operating characteristics curve analysis and Kaplan-Meier method, respectively. RESULTS: FBLN3 was expressed in all MPM and benign mesothelial cell lines tested, and a correlation was observed between cellular protein expression and secreted levels. Human FBLN3 was detectable in plasma of tumour-bearing mice, suggesting that MPM cells contribute to levels of circulating FBLN3. Plasma FBLN3 was significantly elevated in MPM patients from the Sydney cohort, but not the Vienna cohort, but the diagnostic accuracy was low (63%, (95% CI: 50.1-76.4) and 56% (95% CI: 41.5-71.0), respectively). Although FBLN3 levels in pleural effusions were not significantly different between cases and controls, FBLN3 levels in pleural effusion fluid were found to be independently associated with prognosis (hazard ratio of 9.92 (95% CI: 2.14-45.93)). CONCLUSIONS: These data confirm the potential prognostic value of pleural effusion FBLN3, but question the diagnostic value of this protein in MPM patients

High circulating activin A level is associated with tumor progression and predicts poor prognosis in lung adenocarcinoma

Activin A (ActA)/follistatin (FST) signaling has been shown to be deregulated in different tumor types including lung adenocarcinoma (LADC). Here, we report that serum ActA protein levels are significantly elevated in LADC patients (n=64) as compared to controls (n=46, p=0.015). ActA levels also correlated with more advanced disease stage (p<0.0001) and T (p=0.0035) and N (p=0.0002) factors. M1 patients had significantly higher ActA levels than M0 patients (p<0.001). High serum ActA level was associated with poor overall survival (p<0.0001) and was confirmed as an independent prognostic factor (p=0.004). Serum FST levels were increased only in female LADC patients (vs. female controls, p=0.031). Two out of five LADC cell lines secreted biologically active ActA, while FST was produced in all of them. Transcripts of both type I and II ActA receptors were detected in all five LADC cell lines. In conclusion, our study does not only suggest that measuring blood ActA levels in LADC patients might improve the prediction of prognosis, but also indicates that this parameter might be a novel non-invasive biomarker for identifying LADC patients with organ metastases

Prenylation Inhibition-Induced Cell Death in Melanoma: Reduced Sensitivity in BRAF Mutant/PTEN Wild-Type Melanoma Cells.

While targeted therapy brought a new era in the treatment of BRAF mutant melanoma, therapeutic options for non-BRAF mutant cases are still limited. In order to explore the antitumor activity of prenylation inhibition we investigated the response to zoledronic acid treatment in thirteen human melanoma cell lines with known BRAF, NRAS and PTEN mutational status. Effect of zoledronic acid on proliferation, clonogenic potential, apoptosis and migration of melanoma cells as well as the activation of downstream elements of the RAS/RAF pathway were investigated in vitro with SRB, TUNEL and PARP cleavage assays and videomicroscopy and immunoblot measurements, respectively. Subcutaneous and spleen-to-liver colonization xenograft mouse models were used to evaluate the influence of zoledronic acid treatment on primary and disseminated tumor growth of melanoma cells in vivo. Zoledronic acid more efficiently decreased short-term in vitro viability in NRAS mutant cells when compared to BRAF mutant and BRAF/NRAS wild-type cells. In line with this finding, following treatment decreased activation of ribosomal protein S6 was found in NRAS mutant cells. Zoledronic acid demonstrated no significant synergism in cell viability inhibition or apoptosis induction with cisplatin or DTIC treatment in vitro. Importantly, zoledronic acid could inhibit clonogenic growth in the majority of melanoma cell lines except in the three BRAF mutant but PTEN wild-type melanoma lines. A similar pattern was observed in apoptosis induction experiments. In vivo zoledronic acid did not inhibit the subcutaneous growth or spleen-to-liver colonization of melanoma cells. Altogether our data demonstrates that prenylation inhibition may be a novel therapeutic approach in NRAS mutant melanoma. Nevertheless, we also demonstrated that therapeutic sensitivity might be influenced by the PTEN status of BRAF mutant melanoma cells. However, further investigations are needed to identify drugs that have appropriate pharmacological properties to efficiently target prenylation in melanoma cells

Trabectedin is active against malignant pleural mesothelioma cell and xenograft models and synergizes with chemotherapy and bcl-2 inhibition in vitro

Malignant pleural mesothelioma (MPM) is characterized by widespread resistance to systemic therapy. Trabectedin is an antineoplastic agent targeting both the malignant cells and the tumor microenvironment which has been approved for the treatment of advanced soft tissue sarcoma and ovarian cancer. In this preclinical study we evaluated the antineoplastic potential of trabectedin as a single agent and in drug combination approaches in human MPM. Therefore we utilized an extended panel of MPM cell lines (N=6) and primary cell cultures from surgical MPM specimens (N=13) as well as non-malignant pleural tissues samples (N=2). Trabectedin exerted a dose-dependent cytotoxic effect in all MPM cell cultures in vitro when growing as adherent monolayers or non-adherent spheroids with IC50 values {less than or equal to} 2.6 nM. Non-malignant mesothelial cells were significantly less responsive. The strong anti-mesothelioma activity was based on cell cycle perturbation and apoptosis induction. The activity of trabectedin against MPM cells was synergistically enhanced by co-administration of cisplatin, a drug routinely used for systemic MPM treatment. Comparison of gene expression signatures indicated an inverse correlation between trabectedin response and bcl-2 expression. Accordingly, bcl-2 inhibitors (Obatoclax, ABT-199) markedly synergized with trabectedin paralleled by deregulated expression of the bcl-2 family members bcl-2, bim, bax, Mcl-1 and bcl-xL as a consequence of trabectedin exposure. Additionally, trabectedin exerted significant antitumor activity against an intraperitoneal MPM xenograft model. Together these data suggest that trabectedin exerts strong activity in MPM and synergizes with chemotherapy and experimental bcl-2 inhibitors in vitro. Thus, it represents a promising new therapeutic option for MPM

Encephalitis and GABA_B receptor antibodies:Novel findings in a new case series of 20 patients

OBJECTIVE: To report the clinical features of 20 newly diagnosed patients with GABA(B) receptor (GABA(B)R) antibodies and determine the frequency of associated tumors and concurrent neuronal autoantibodies. METHODS: Clinical data were retrospectively obtained and evaluated. Serum and CSF samples were examined for additional antibodies using methods previously reported. RESULTS: Seventeen patients presented with seizures, memory loss, and confusion, compatible with limbic encephalitis (LE), one patient presented with ataxia, one patient presented with status epilepticus, and one patient presented with opsoclonus-myoclonus syndrome (OMS). Nineteen (95%) patients eventually developed LE during the course of the disease. Small-cell lung cancer (SCLC) was identified in 10 (50%) patients, all with LE. Treatment and outcome was available from 19 patients: 15 showed complete (n = 7) or partial (n = 8) neurologic improvement after steroids, IV immunoglobulins, or plasma exchange and oncologic treatment when indicated; 1 patient died of tumor progression shortly after the first cycle of immunotherapy, and 3 were not treated. Five patients with SCLC had additional onconeuronal antibodies (Ri, amphiphysin, or SOX1), and 2 without tumor had GAD65 and NMDAR antibodies, respectively. GABA(B)R antibodies were not detected in serum of 116 patients with SCLC without neurologic symptoms. CONCLUSION: Our study confirms GABA(B)R as an autoantigen of paraneoplastic and nonparaneoplastic LE and expands the phenotype of GABA(B)R antibodies to ataxia, OMS, and status epilepticus. The long-term prognosis is dictated by the presence of a tumor. Recognition of syndromes associated with GABA(B)R antibodies is important because they usually respond to treatment

Cell migration after zoledronic acid treatment in melanoma cells.

<p>(<b>A-C</b>) Migrated distance as a function of time and (<b>D</b>) average migrated distance after zoledronic acid (ZA) treatment in melanoma cells measured by videomicroscopy. A profound and significant increase in migrated distance was found in all of the BRAF mutant cells. A modest but significant increase in migration was found in VM-47 triple wild-type and VM-15 NRAS mutant cells. Colors blue, red and green indicate BRAF, NRAS mutation and wild-type for these genes, respectively. Data shown as average ± SEM are from at least three independent measurements. Asterisks indicate significant difference of p < 0.05 from the respective control with unpaired two-tailed T test.</p

<i>In vivo</i> effects of zoledronic acid treatment.

<p>Effect of zoledronic acid (ZA) treatment using <i>in vivo</i> subcutaneous xenograft model of human melanoma cells in SCID mice (<b>A, C, E</b>). ZA treatment failed to show effects in the subcutaneous growth of melanoma cells with either mutation. (<b>B, D, F</b>) Effect of ZA treatment using <i>in vivo</i> spleen liver colonization model of human melanoma cells in SCID mice. ZA did not inhibit the primary tumor or metastatic growth of melanoma cells. Data shown as average ± SEM.</p