Tüdőtranszplantáció magyar betegek számára

When conservative treatment fails, lung transplantation often remains the only therapeutic option for patients with end stage parenchymal or vascular lung diseases. According to the statistics of the International Society for Heart and Lung Transplantation, in 2010 more than 3500 lung transplantations have been performed worldwide. The Department of Thoracic Surgery at the University of Vienna is considered to be one of the world's leading lung transplantation centres; in the last year 115, since 1989 more than 1500 lung transplantation procedures under the supervision of Prof. Dr. Walter Klepetko. Similar to other Central-European countries, lung transplantation procedures of Hungarian patients have also been performed in Vienna whithin the framework of a twinning aggreement. However, many crucial tasks in the process, such indication and patient selection preoperative rehabilitation organ procurement and long term follow-up care have been stepwise taken over by the Hungarian team. Although the surgery itself is still preformed in Vienna, professional experience is already available in Hungary, since the majority of Hungarian recipients have been transplanted by hungarian surgeons who are authors of this article the professional and personal requirements of performing lung transplantations are already available in Hungary. The demand of performing lung transplantation in Hungary has been raising since 1999 and it soon reaches the extent which justifies launching of an individual national program. Providing the technical requirements is a financial an organisational issue. In order to proceed, a health policy decision has to be made

Mechanisms of vascularization in murine models of primary and metastatic tumor growth

Directed capillary ingrowth has long been considered synonymous with tumor vascularization. However, the vasculature of primary tumors and metastases is not necessarily formed by endothelial cell sprouting; instead, malignant tumors can acquire blood vessels via alternative vascularization mechanisms, such as intussusceptive microvascular growth, vessel co-option, and glomeruloid angiogenesis. Importantly, in response to anti-angiogenic therapies, malignant tumors can switch from one vascularization mechanism to another. In this article, we briefly review the biological features of these mechanisms and discuss on their significance in medical oncology

Circulating endothelial cells, bone marrow-derived endothelial progenitor cells and proangiogenic haematopoietic cells in cancer: From biology to therapy

Vascularization, a hallmark of tumorigenesis, is classically thought to occur exclusively through angiogenesis (i.e. endothelial sprouting). However, there is a growing body of evidence that endothelial progenitor cells (EPCs) and proangiogenic hematopoietic cells (HCs) are able to support the vascularization of tumors and may therefore play a synergistic role with angiogenesis. An additional cell type being studied in the field of tumor vascularization is the circulating endothelial cell (CEC), whose presence in elevated numbers reflects vascular injury. Levels of EPCs and CECs are reported to correlate with tumor stage and have been evaluated as biomarkers of the efficacy of anticancer/antiangiogenic treatments. Furthermore, because EPCs and subtypes of proangiogenic HCs are actively participating in capillary growth, these cells are attractive potential vehicles for delivering therapeutic molecules. The current paper provides an update on the biology of CECs, EPCs and proangiogenic HCs, and explores the utility of these cell populations for clinical oncology

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

Erythropoietin receptor expression is a potential prognostic factor in human lung adenocarcinoma

Recombinant human erythropoietins (rHuEPOs) are used to treat cancer-related anemia. Recent preclinical studies and clinical trials, however, have raised concerns about the potential tumor-promoting effects of these drugs. Because the clinical significance of erythropoietin receptor (EPOR) signaling in human non-small cell lung cancer (NSCLC) also remains controversial, our aim was to study whether EPO treatment modifies tumor growth and if EPOR expression has an impact on the clinical behavior of this malignancy. A total of 43 patients with stage III-IV adenocarcinoma (ADC) and complete clinicopathological data were included. EPOR expression in human ADC samples and cell lines was measured by quantitative real-time polymerase chain reaction. Effects of exogenous rHuEPOalpha were studied on human lung ADC cell lines in vitro. In vivo growth of human ADC xenografts treated with rHuEPOalpha with or without chemotherapy was also assessed. In vivo tumor and endothelial cell (EC) proliferation was determined by 5-bromo-2'-deoxy-uridine (BrdU) incorporation and immunofluorescent labeling. Although EPOR mRNA was expressed in all of the three investigated ADC cell lines, rHuEPOalpha treatment (either alone or in combination with gemcitabine) did not alter ADC cell proliferation in vitro. However, rHuEPOalpha significantly decreased tumor cell proliferation and growth of human H1975 lung ADC xenografts. At the same time, rHuEPOalpha treatment of H1975 tumors resulted in accelerated tumor endothelial cell proliferation. Moreover, in patients with advanced stage lung ADC, high intratumoral EPOR mRNA levels were associated with significantly increased overall survival. This study reveals high EPOR level as a potential novel positive prognostic marker in human lung ADC

Apelin promotes lymphangiogenesis and lymph node metastasis

Whereas the role of the G-protein-coupled APJ receptor and its ligand, apelin, in angiogenesis has been well documented, the ability of the apelin/APJ system to induce lymphangiogenesis and lymphatic metastasis has been largely unexplored. To this end, we first show that APJ is expressed in lymphatic endothelial cells (LECs) and, moreover, that it responds to apelin by activating the apelinergic signaling cascade. We find that although apelin treatment does not influence the proliferation of LECs in vitro, it enhances their migration, protects them against UV irradiation-induced apoptosis, increases their spheroid numbers in 3D culture, stimulates their in vitro capillary-like tube formation and, furthermore, promotes the invasive growth of lymphatic microvessels in vivo in the matrigel plug assay. We also demonstrate that apelin overexpression in malignant cells is associated with accelerated in vivo tumor growth and with increased intratumoral lymphangiogenesis and lymph node metastasis. These results indicate that apelin induces lymphangiogenesis and, accordingly, plays an important role in lymphatic tumor progression. Our study does not only reveal apelin as a novel lymphangiogenic factor but might also open the door for the development of novel anticancer therapies targeting lymphangiogenesis

Nem tapintható tüdőgócok drót- és izotópjelölés segítségével történő minimálinvazív műtéti eltávolítása = Minimally invasive resection of nonpalpable pulmonary nodules after wire- and isotope-guided localization

Absztrakt: Bevezetés: Napjainkban egyre kisebb méretű tüdőgócok kerülnek felismerésre, melyek esetén az elsődleges választás azok minimálinvazív műtéti technikával történő eltávolítása diagnosztikus és terápiás céllal. Számos előnye mellett a minimálinvazív technika hátránya a tüdő áttapintásának korlátozottsága, a tüdőgócok felkeresése. Célkitűzés: A probléma megoldására több lehetőség is rendelkezésre áll. Ezek közül kettőt próbáltunk ki párhuzamosan, a drót-, illetve az izotópjelöléssel történő tüdőgóc-lokalizációt. Anyag és módszer: Az Országos Onkológiai Intézet Mellkassebészeti Osztályán öt betegnél távolítottunk el tüdőgócot minimálinvazív technikával kettős, azaz drót- és izotópjelölés mellett. A tüdőgócok mérete 0,5 és 1,2 cm között váltakozott. A betegek életkora 44 és 65 év között volt; minden beteg alacsony műtéti rizikójú csoportba tartozott, súlyos társbetegség nélkül. Eredmények: Minden betegnél sikeresen eltávolításra került a tüdőgóc a kettős jelölés mellett. Jelölés után közvetlenül egy betegnél 2–3 mm-es légmellet észleltünk, mely azonnali beavatkozásra nem szorult, és egy betegnél a drót miatt kiterjedt bevérzés jelent meg a szúrcsatornában. A műtét során, a tüdőkollapszusnál két betegnél a drót kimozdult, egynél pedig az említett kiterjedt bevérzés a mellüregbe került, és diffúz izotópaktivitás jelent meg. Egy betegnél a műtét során drótjelöléses területet reszekálva további izotópaktivitás állt fenn, mert a jelölt tüdőgóc a reszekciós sík alatt volt. Következtetés: Mind az izotóppal, mind a dróttal történő tüdőgócjelölés segítséget nyújt a nem tapintható tüdőgócok minimálinvazív technikával történő eltávolításában. Kezdeti tapasztalataink alapján azonban az izotópos jelölés esetén a tüdőgóc mélységi megítélése pontosabb, és nem kell a drótkimozdulással járó kellemetlenségre számítani. Ugyanakkor az infrastrukturális háttér, illetve a műtéti időpont tervezése az izotópbeadás esetében nagyobb kihívást jelent, szemben a drótjelöléssel. Orv Hetil. 2018; 159(34): 1399–1404. | Abstract: Introduction: Nowadays ever smaller, sub-centimetre lung nodules are screened and diagnosed. For these, minimally invasive resection is strongly recommended both with diagnostic and therapeutic purpose. Aim: Despite many advantages of minimally invasive thoracic surgery, thorough palpation of the lung lobes and thus the localization of lung nodules are still limited. There are several options to solve this problem. From the possibilities we have chosen and tried wire- and isotope-guided lung nodule localization. Materials and methods: In 2017, at the Thoracic Surgery Department of the National Institute of Oncology we performed wire- and isotope-guided minimally invasive pulmonary nodule resection in five patients. The diameter of the lung nodules was between 0.5 and 1.2 cm. The age of the patients was between 44 and 65 years and none of them had severe comorbidities, which meant low risk for complications. Results: We successfully performed the minimally invasive atypical resection in all cases. After the wire and isotope placement we found a 2–3 mm pneumothorax in one patient that did not need urgent drainage. In another patient we found that high amount of intraparenchymal bleeding surrounded the channel of the wire. During the operation, two wires were displaced when the lung collapsed, and in another case the mentioned bleeding got into the thoracic cavity and made it difficult to detect the nodule. In one case we resected the wire-guided lung tissue, but the isotope-guided lung nodule was below the resection line. Conclusion: Both techniques could help to localize the non-palpable lung nodules. Based on our initial experiences, the isotope-guided method provides more details to estimate the exact depth of the nodule from the visceral surface of the pleura and we can avoid the unpleasantness of wire displacement. On the other hand, the production of the isotope requires a more developed infrastructure and the exact timing of the operation after the isotope injection is more strict. Orv Hetil. 2018; 159(34): 1399–1404

Circulating complement component 4d (C4d) correlates with tumor volume, chemotherapeutic response and survival in patients with malignant pleural mesothelioma

Only limited information is available on the role of complement activation in malignant pleural mesothelioma (MPM). Thus, we investigated the circulating and tissue levels of the complement component 4d (C4d) in MPM. Plasma samples from 55 MPM patients, 21 healthy volunteers (HV) and 14 patients with non-malignant pleural diseases (NMPD) were measured by ELISA for C4d levels. Tissue specimens from 32 patients were analyzed by C4d immunohistochemistry. Tumor volumetry was measured in 20 patients. We found no C4d labeling on tumor cells, but on ectopic lymphoid structures within the tumor stroma. Plasma C4d levels did not significantly differ between MPM, HV or NMPD. Late-stage MPM patients had higher plasma C4d levels compared to early-stage (p = 0.079). High circulating C4d was associated with a higher tumor volume (p = 0.047). Plasma C4d levels following induction chemotherapy were significantly higher in patients with stable/progressive disease compared to those with partial/major response (p = 0.005). Strikingly, patients with low C4d levels at diagnosis had a significantly better overall survival, confirmed in a multivariate cox regression model (hazard ratio 0.263, p = 0.01). Our findings suggest that circulating plasma C4d is a promising new prognostic biomarker in patients with MPM and, moreover, helps to select patients for surgery following induction chemotherapy

Innovációs lehetőségek a medicinában: 3D tervezési és 3D nyomtatási lehetőségek a felnőtt szív- és mellkassebészeti betegellátásban. Magyarországi tapasztalatok = Innovation in medicine: opportunities of 3D modeling and printing for perioperative care of cardio and thoracic surgical patients Experiences in Hungary

Absztrakt: A 3D tervezés és 3D nyomtatás nyújtotta lehetőségek folyamatosan bővülnek az orvosi gyakorlatban. A technológia leggyakoribb felhasználási területe a 3D anatómiai modellek nyomtatása sebészi döntéstámogatás céljából. Az így személyre szabott és kinyomtatott modelleknek számos egyéb felhasználási területük van: komplex anatómiai szituációk pontos megjelenítése, az adott beteg sebészi beavatkozásának szimulációja a tényleges beavatkozást megelőzően, betegoktatás és a különböző diszciplínák között az eset megbeszélésének megkönnyítése. A technológia szívsebészeti vonatkozásában kiemelendő a kamrákat és a nagyereket érintő elváltozások 3D anatómiai modellezése és funkcionális elemzése, míg a mellkassebészetben az onkológiai betegek erősen vaszkularizált tumorának eradikálásakor lehet a sebészi terápia felállításában szerepe. A virtuális és 3D nyomtatott modellek új diagnosztikai lehetőséget jelentenek, melyek segítségével egyes sebészi beavatkozások standardizálhatók, így személyre szabott terápiás döntéseket lehet kidolgozni. A 3D projekt a Semmelweis Egyetemen 2018-ban kezdődött a Semmelweis Egyetem Városmajori Szív- és Érgyógyászati Klinikájának és az Országos Onkológiai Intézet Mellkassebészeti Osztályának kooperációja során. A szerzők a technológia ismertetése mellett az eddigi 121 tervezés és 49 személyre szabott 3D nyomtatás során megszerzett tapasztalataikat és a technológia orvosi szempontból való előnyeit ismertetik. Orv Hetil. 2019; 160(50): 1967–1975. | Abstract: Use of 3D planning and 3D printing is expanding in healthcare. One of the common applications is the creation of anatomical models for the surgical procedure from DICOM files. These patient-specific models are used for multiple purposes, including visualization of complex anatomical situations, simulation of surgical procedures, patient education and facilitating communication between the different disciplines during clinical case discussions. Cardiac and thoracic surgical applications of this technology development include the use of patient-specific 3D models for exploration of ventricle and aorta function and surgical procedural planning in oncology. The 3D virtual and printed models provide a new visualization perspective for the surgeons and more efficient communication between the different clinical disciplines. The 3D project was started at the Semmelweis University with the cooperation of the Thoracic Surgery Department of the National Institute of Oncology in 2018. The authors want to share their experiences in 3D designed medical tools. Orv Hetil. 2019; 160(50): 1967–1975

Ki67 index is an independent prognostic factor in epithelioid but not in non-epithelioid malignant pleural mesothelioma: a multicenter study

BACKGROUND: Estimating the prognosis in malignant pleural mesothelioma (MPM) remains challenging. Thus, the prognostic relevance of Ki67 was studied in MPM. METHODS: Ki67 index was determined in a test cohort of 187 cases from three centres. The percentage of Ki67-positive tumour cells was correlated with clinical variables and overall survival (OS). The prognostic power of Ki67 index was compared with other prognostic factors and re-evaluated in an independent cohort (n=98). RESULTS: Patients with Ki67 higher than median (>15%) had significantly (P<0.001) shorter median OS (7.5 months) than those with low Ki67 (19.1 months). After multivariate survival analyses, Ki67 proved to be-beside histology and treatment-an independent prognostic marker in MPM (hazard ratio (HR): 2.1, P<0.001). Interestingly, Ki67 was prognostic exclusively in epithelioid (P<0.001) but not in non-epithelioid subtype. Furthermore, Ki67 index was significantly lower in post-chemotherapy samples when compared with chemo-naive cases. The prognostic power was comparable to other recently published prognostic factors (CRP, fibrinogen, neutrophil-to-leukocyte ratio (NLR) and nuclear grading score) and was recapitulated in the validation cohort (P=0.048). CONCLUSION: This multicentre study demonstrates that Ki67 is an independent and reproducible prognostic factor in epithelioid but not in non-epithelioid MPM and suggests that induction chemotherapy decreases the proliferative capacity of MPM