Clinical insights into small cell lung cancer: Tumor heterogeneity, diagnosis, therapy, and future directions.

Small cell lung cancer (SCLC) is characterized by rapid growth and high metastatic capacity. It has strong epidemiologic and biologic links to tobacco carcinogens. Although the majority of SCLCs exhibit neuroendocrine features, an important subset of tumors lacks these properties. Genomic profiling of SCLC reveals genetic instability, almost universal inactivation of the tumor suppressor genes TP53 and RB1, and a high mutation burden. Because of early metastasis, only a small fraction of patients are amenable to curative-intent lung resection, and these individuals require adjuvant platinum-etoposide chemotherapy. Therefore, the vast majority of patients are currently being treated with chemoradiation with or without immunotherapy. In patients with disease confined to the chest, standard therapy includes thoracic radiotherapy and concurrent platinum-etoposide chemotherapy. Patients with metastatic (extensive-stage) disease are treated with a combination of platinum-etoposide chemotherapy plus immunotherapy with an anti-programmed death-ligand 1 monoclonal antibody. Although SCLC is initially very responsive to platinum-based chemotherapy, these responses are transient because of the development of drug resistance. In recent years, the authors have witnessed an accelerating pace of biologic insights into the disease, leading to the redefinition of the SCLC classification scheme. This emerging knowledge of SCLC molecular subtypes has the potential to define unique therapeutic vulnerabilities. Synthesizing these new discoveries with the current knowledge of SCLC biology and clinical management may lead to unprecedented advances in SCLC patient care. Here, the authors present an overview of multimodal clinical approaches in SCLC, with a special focus on illuminating how recent advancements in SCLC research could accelerate clinical development.

Expression patterns of novel immunotherapy targets in intermediate- and high-grade lung neuroendocrine neoplasms.

BACKGROUND: Advancements in immunotherapeutic approaches only had a modest impact on the therapy of lung neuroendocrine neoplasms (LNENs). Our multicenter study aimed to investigate the expression patterns of novel immunotherapy targets in intermediate- and high-grade LNENs. METHODS: The expressions of V-domain Ig suppressor of T cell activation (VISTA), OX40L, Glucocorticoid-induced TNF receptor (GITR), and T cell immunoglobulin and mucin domain 3 (TIM3) proteins were measured by immunohistochemistry in surgically resected tumor samples of 26 atypical carcinoid (AC), 49 large cell neuroendocrine lung cancer (LCNEC), and 66 small cell lung cancer (SCLC) patients. Tumor and immune cells were separately scored. RESULTS: Tumor cell TIM3 expression was the highest in ACs (p < 0.001), whereas elevated tumor cell GITR levels were characteristic for both ACs and SCLCs (p < 0.001 and p = 0.011, respectively). OX40L expression of tumor cells was considerably lower in ACs (vs. SCLCs; p < 0.001). Tumor cell VISTA expression was consistently low in LNENs, with no significant differences across histological subtypes. ACs were the least immunogenic tumors concerning immune cell abundance (p < 0.001). Immune cell VISTA and GITR expressions were also significantly lower in these intermediate-grade malignancies than in SCLCs or in LCNECs. Immune cell TIM3 and GITR expressions were associated with borderline prognostic significance in our multivariate model (p = 0.057 and p = 0.071, respectively). CONCLUSIONS: LNEN subtypes have characteristic and widely divergent VISTA, OX40L, GITR, and TIM3 protein expressions. By shedding light on the different expression patterns of these immunotherapy targets, the current multicenter study provides support for the future implementation of novel immunotherapeutic approaches.

Pseudomonas aeruginosa infection correlates with high MFI donor-specific antibody development following lung transplantation with consequential graft loss and shortened CLAD-free survival.

BACKGROUND: Donor-specific antibodies (DSAs) are common following lung transplantation (LuTx), yet their role in graft damage is inconclusive. Mean fluorescent intensity (MFI) is the main read-out of DSA diagnostics; however its value is often disregarded when analyzing unwanted post-transplant outcomes such as graft loss or chronic lung allograft dysfunction (CLAD). Here we aim to evaluate an MFI stratification method in these outcomes. METHODS: A cohort of 87 LuTx recipients has been analyzed, in which a cutoff of 8000 MFI has been determined for high MFI based on clinically relevant data. Accordingly, recipients were divided into DSA-negative, DSA-low and DSA-high subgroups. Both graft survival and CLAD-free survival were evaluated. Among factors that may contribute to DSA development we analyzed Pseudomonas aeruginosa (P. aeruginosa) infection in bronchoalveolar lavage (BAL) specimens. RESULTS: High MFI DSAs contributed to clinical antibody-mediated rejection (AMR) and were associated with significantly worse graft (HR: 5.77, p < 0.0001) and CLAD-free survival (HR: 6.47, p = 0.019) compared to low or negative MFI DSA levels. Analysis of BAL specimens revealed a strong correlation between DSA status, P. aeruginosa infection and BAL neutrophilia. DSA-high status and clinical AMR were both independent prognosticators for decreased graft and CLAD-free survival in our multivariate Cox-regression models, whereas BAL neutrophilia was associated with worse graft survival. CONCLUSIONS: P. aeruginosa infection rates are elevated in recipients with a strong DSA response. Our results indicate that the simultaneous interpretation of MFI values and BAL neutrophilia is a feasible approach for risk evaluation and may help clinicians when to initiate DSA desensitization therapy, as early intervention could improve prognosis.

C-Myc protein expression indicates unfavorable clinical outcome in surgically resected small cell lung cancer.

BACKGROUND: By being highly involved in the tumor evolution and disease progression of small cell lung cancer (SCLC), Myc family members (C-Myc, L-Myc, and N-Myc) might represent promising targetable molecules. Our aim was to investigate the expression pattern and prognostic relevance of these oncogenic proteins in an international cohort of surgically resected SCLC tumors. METHODS: Clinicopathological data and surgically resected tissue specimens from 104 SCLC patients were collected from two collaborating European institutes. Tissue sections were stained by immunohistochemistry (IHC) for all three Myc family members and the recently introduced SCLC molecular subtype-markers (ASCL1, NEUROD1, POU2F3, and YAP1). RESULTS: IHC analysis showed C-Myc, L-Myc, and N-Myc positivity in 48%, 63%, and 9% of the specimens, respectively. N-Myc positivity significantly correlated with the POU2F3-defined molecular subtype (r = 0.6913, p = 0.0056). SCLC patients with C-Myc positive tumors exhibited significantly worse overall survival (OS) (20 vs. 44 months compared to those with C-Myc negative tumors, p = 0.0176). Ultimately, in a multivariate risk model adjusted for clinicopathological and treatment confounders, positive C-Myc expression was confirmed as an independent prognosticator of impaired OS (HR 1.811, CI 95% 1.054-3.113, p = 0.032). CONCLUSIONS: Our study provides insights into the clinical aspects of Myc family members in surgically resected SCLC tumors. Notably, besides showing that positivity of Myc family members varies across the patients, we also reveal that C-Myc protein expression independently correlates with worse survival outcomes. Further studies are warranted to investigate the role of Myc family members as potential prognostic and predictive markers in this hard-to-treat disease.

Dual targeting of BCL-2 and MCL-1 in the presence of BAX breaks venetoclax resistance in human small cell lung cancer.

BACKGROUND: No targeted drugs are currently available against small cell lung cancer (SCLC). BCL-2 family members are involved in apoptosis regulation and represent therapeutic targets in many malignancies. METHODS: Expression of BCL-2 family members in 27 SCLC cell lines representing all known four SCLC molecular subtypes was assessed by qPCR, Western blot and mass spectrometry-based proteomics. BCL-2 and MCL-1 inhibition (venetoclax and S63845, respectively) was assessed by MTT assay and flow cytometry and in mice bearing human SCLC tumours. Drug interactions were calculated using the Combenefit software. Ectopic BAX overexpression was achieved by expression plasmids. RESULTS: The highest BCL-2 expression levels were detected in ASCL1- and POU2F3-driven SCLC cells. Although sensitivity to venetoclax was reflected by BCL-2 levels, not all cell lines responded consistently despite their high BCL-2 expression. MCL-1 overexpression and low BAX levels were both characteristic for venetoclax resistance in SCLC, whereas the expression of other BCL-2 family members did not affect therapeutic efficacy. Combination of venetoclax and S63845 resulted in significant, synergistic in vitro and in vivo anti-tumour activity and apoptosis induction in double-resistant cells; however, this was seen only in a subset with detectable BAX. In non-responding cells, ectopic BAX overexpression sensitised to venetoclax and S63845 and, furthermore, induced synergistic drug interaction. CONCLUSIONS: The current study reveals the subtype specificity of BCL-2 expression and sheds light on the mechanism of venetoclax resistance in SCLC. Additionally, we provide preclinical evidence that combined BCL-2 and MCL-1 targeting is an effective approach to overcome venetoclax resistance in high BCL-2-expressing SCLCs with intact BAX.

Expression patterns and prognostic relevance of subtype-specific transcription factors in surgically resected small-cell lung cancer: an international multicenter study.

The tissue distribution and prognostic relevance of subtype-specific proteins (ASCL1, NEUROD1, POU2F3, YAP1) present an evolving area of research in small-cell lung cancer (SCLC). The expression of subtype-specific transcription factors and P53 and RB1 proteins were measured by immunohistochemistry (IHC) in 386 surgically resected SCLC samples. Correlations between subtype-specific proteins and in vitro efficacy of various therapeutic agents were investigated by proteomics and cell viability assays in 26 human SCLC cell lines. Besides SCLC-A (ASCL1-dominant), SCLC-AN (combined ASCL1/NEUROD1), SCLC-N (NEUROD1-dominant), and SCLC-P (POU2F3-dominant), IHC and cluster analyses identified a quadruple-negative SCLC subtype (SCLC-QN). No unique YAP1-subtype was found. The highest overall survival rates were associated with non-neuroendocrine subtypes (SCLC-P and SCLC-QN) and the lowest with neuroendocrine subtypes (SCLC-A, SCLC-N, SCLC-AN). In univariate analyses, high ASCL1 expression was associated with poor prognosis and high POU2F3 expression with good prognosis. Notably, high ASCL1 expression influenced survival outcomes independently of other variables in a multivariate model. High POU2F3 and YAP1 protein abundances correlated with sensitivity and resistance to standard-of-care chemotherapeutics, respectively. Specific correlation patterns were also found between the efficacy of targeted agents and subtype-specific protein abundances. In conclusion, we investigated the clinicopathological relevance of SCLC molecular subtypes in a large cohort of surgically resected specimens. Differential IHC expression of ASCL1, NEUROD1, and POU2F3 defines SCLC subtypes. No YAP1-subtype can be distinguished by IHC. High POU2F3 expression is associated with improved survival in a univariate analysis, whereas elevated ASCL1 expression is an independent negative prognosticator. Proteomic and cell viability assays of human SCLC cell lines revealed distinct vulnerability profiles defined by transcription regulators. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Nationwide lung cancer screening with low-dose computed tomography: implementation and first results of the HUNCHEST screening program.

OBJECTIVES: Lung cancer (LC) kills more people than any other cancer in Hungary. Hence, there is a clear rationale for considering a national screening program. The HUNCHEST pilot program primarily aimed to investigate the feasibility of a population-based LC screening in Hungary, and determine the incidence and LC probability of solitary pulmonary nodules. METHODS: A total of 1890 participants were assigned to undergo low-dose CT (LDCT) screening, with intervals of 1 year between procedures. Depending on the volume, growth, and volume doubling time (VDT), screenings were defined as negative, indeterminate, or positive. Non-calcified lung nodules with a volume > 500 mm3 and/or a VDT < 400 days were considered positive. LC diagnosis was based on histology. RESULTS: At baseline, the percentage of negative, indeterminate, and positive tests was 81.2%, 15.1%, and 3.7%, respectively. The frequency of positive and indeterminate LDCT results was significantly higher in current smokers (vs. non-smokers or former smokers; p < 0.0001) and in individuals with COPD (vs. those without COPD, p < 0.001). In the first screening round, 1.2% (n = 23) of the participants had a malignant lesion, whereas altogether 1.5% (n = 29) of the individuals were diagnosed with LC. The overall positive predictive value of the positive tests was 31.6%. Most lung malignancies were diagnosed at an early stage (86.2% of all cases). CONCLUSIONS: In terms of key characteristics, our prospective cohort study appears consistent to that of comparable studies. Altogether, the results of the HUNCHEST pilot program suggest that LDCT screening may facilitate early diagnosis and thus curative-intent treatment in LC. KEY POINTS: • The HUNCHEST pilot study is the first nationwide low-dose CT screening program in Hungary. • In the first screening round, 1.2% of the participants had a malignant lesion, whereas altogether 1.5% of the individuals were diagnosed with lung cancer. • The overall positive predictive value of the positive tests in the HUNCHEST screening program was 31.6%.

Current therapy of KRAS-mutant lung cancer.

KRAS mutations are the most frequent gain-of-function alterations in patients with lung adenocarcinoma (LADC) in the Western world. Although they have been identified decades ago, prior efforts to target KRAS signaling with single-agent therapeutic approaches such as farnesyl transferase inhibitors, prenylation inhibition, impairment of KRAS downstream signaling, and synthetic lethality screens have been unsuccessful. Moreover, the role of KRAS oncogene in LADC is still not fully understood, and its prognostic and predictive impact with regards to the standard of care therapy remains controversial. Of note, KRAS-related studies that included general non-small cell lung cancer (NSCLC) population instead of LADC patients should be very carefully evaluated. Recently, however, comprehensive genomic profiling and wide-spectrum analysis of other co-occurring genetic alterations have identified unique therapeutic vulnerabilities. Novel targeted agents such as the covalent KRAS G12C inhibitors or the recently proposed combinatory approaches are some examples which may allow a tailored treatment for LADC patients harboring KRAS mutations. This review summarizes the current knowledge about the therapeutic approaches of KRAS-mutated LADC and provides an update on the most recent advances in KRAS-targeted anti-cancer strategies, with a focus on potential clinical implications.

The evidence for and against different modes of tumour cell extravasation in the lung: diapedesis, capillary destruction, necroptosis, and endothelialization.

The development of lung metastasis is a significant negative prognostic factor for cancer patients. The extravasation phase of lung metastasis involves interactions of tumour cells with the pulmonary endothelium. These interactions may have broad biological and medical significance, with potential clinical implications ranging from the discovery of lung metastasis biomarkers to the identification of targets for intervention in preventing lung metastases. Because of the potential significance, the mechanisms of tumour cell extravasation require cautious, systematic studies. Here, we discuss the literature pertaining to the proposed mechanisms of extravasation and critically compare a recently proposed mechanism (tumour cell-induced endothelial necroptosis) with the already described extravasation mechanisms in the lung. We also provide novel data that may help to explain the underlying physiological basis for endothelialization as a mechanism of tumour cell extravasation in the lung. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Vessel co-option is common in human lung metastases and mediates resistance to anti-angiogenic therapy in preclinical lung metastasis models.

Anti-angiogenic therapies have shown limited efficacy in the clinical management of metastatic disease, including lung metastases. Moreover, the mechanisms via which tumours resist anti-angiogenic therapies are poorly understood. Importantly, rather than utilizing angiogenesis, some metastases may instead incorporate pre-existing vessels from surrounding tissue (vessel co-option). As anti-angiogenic therapies were designed to target only new blood vessel growth, vessel co-option has been proposed as a mechanism that could drive resistance to anti-angiogenic therapy. However, vessel co-option has not been extensively studied in lung metastases, and its potential to mediate resistance to anti-angiogenic therapy in lung metastases is not established. Here, we examined the mechanism of tumour vascularization in 164 human lung metastasis specimens (composed of breast, colorectal and renal cancer lung metastasis cases). We identified four distinct histopathological growth patterns (HGPs) of lung metastasis (alveolar, interstitial, perivascular cuffing, and pushing), each of which vascularized via a different mechanism. In the alveolar HGP, cancer cells invaded the alveolar air spaces, facilitating the co-option of alveolar capillaries. In the interstitial HGP, cancer cells invaded the alveolar walls to co-opt alveolar capillaries. In the perivascular cuffing HGP, cancer cells grew by co-opting larger vessels of the lung. Only in the pushing HGP did the tumours vascularize by angiogenesis. Importantly, vessel co-option occurred with high frequency, being present in >80% of the cases examined. Moreover, we provide evidence that vessel co-option mediates resistance to the anti-angiogenic drug sunitinib in preclinical lung metastasis models. Assuming that our interpretation of the data is correct, we conclude that vessel co-option in lung metastases occurs through at least three distinct mechanisms, that vessel co-option occurs frequently in lung metastases, and that vessel co-option could mediate resistance to anti-angiogenic therapy in lung metastases. Novel therapies designed to target both angiogenesis and vessel co-option are therefore warranted. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

[Minimally invasive resection of nonpalpable pulmonary nodules after wire- and isotope-guided localization]. / Nem tapintható tüdogócok drót- és izotópjelölés segítségével történo minimálinvazív mutéti eltávolítása.

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.

[The start of the Hungarian lung transplantation program and the first results]. / A magyar tüdotranszplantációs program indulása és elso eredményei.

The first lung transplantation in Hungary was performed on 12th of December, 2015. It was a joint effort of the National Institute of Oncology and the Semmelweis University. Hereby we summarise the results and experiences from the first three years. Until August, 2018, 55 lung transplantations were performed in Hungary. This was a retrospective analysis. All patients were listed according to the recommendation of the Lung Transplantation Committee. All implanted lungs have been procured from brain dead donors. Postoperative treatment and rehabilitation of the patients were continued at the Semmelweis University. Between 12. 12. 2015 and 31. 07. 2018, our team performed 76 organ retrievals: out of 45 Hungarian offers, 23 came from Eurotransplant countries and 8 outside of the Eurotransplant region. From these donations, 54 double and 1 single side transplantations were successfully performed. The surgical approach was single side thoracotomy (n = 1), bilateral thoracotomy (n = 1) and in the majority of the cases clamshell incision (n = 53). For the intraoperative veno-arterial extracorporeal membrane oxygenation support was used. The extracorporeal membrane oxygenation support had to be prolonged in 3 patients into the early postoperative period, two other recipients were bridged to transplant with extracorporeal membrane oxygenation. In the same time period, one combined lung-kidney transplantation was also performed. The distribution of recipients according to the underlying disease was: chronic obstructive pulmonary disease (n = 28); idiopathic pulmonary fibrosis (n = 8); cystic fibrosis (n = 12); primary pulmonary hypertension (n = 2); hystiocytosis-X (n = 1); bronchiectasis (n = 2); lymphangioleiomyomatosis (n = 1); and re-transplantation following bronchiolitis obliterans syndrome (n = 1), respectively. The mean age of recipients was 47.5 ± 15.18 years. The youngest recipient was 13 years old. We unfortunately lost 12 patients on our waiting list. The mean intensive care unit stay was 24.6 ± 18.18 days. Two patients were lost in the early postoperative phase. Tracheostomy was necessary in 13 cases due to the need of prolonged ventilation. 1-year survival of the recipients was 82.96% (until 31. 07. 2018). When looking at the first three years of the program, the case numbers elevated quickly throughout the years which is rather unique when compared to other centres in their starting period. Perioperative mortality and morbidity is comparable with high-volume lung transplantation centres. In the future we would like to increase the number of patients on the waiting list, thus increasing the total number of transplantations performed, and we are also planning to implement the use of the ex vivo lung perfusion system (EVLP) in our program. Orv Hetil. 2018; 159(46): 1859-1868.

[Excerpts from the collaborative lung cancer research program of Semmelweis University, the National Institute of Oncology and Korányi Institute of TB and Pulmonology (2010-2015)]. / Szemelvények a Semmelweis Egyetem, az Országos Onkológiai Intézet és az Országos Korányi Tbc és Pulmonológiai Intézet együttmûködésén alapuló tüdõrák-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.

[Surgical possibilities in the treatment of advanced and locally recurrent breast cancers]. / A távoli áttétképzo és lokálisan kiújult emlorákok sebészi kezelésének lehetoségei.

Stage IV breast cancer is an incurable but treatable condition. Therapy of distant metastatic disease consists primarily of systemic and symptomatic treatments, while the role of surgery is subordinate. Conventional medical treatments result in 18-24 months average overall survival, and about 5-20% 5-year overall survival. However, it seems that in selected cases with solitary or oligometastases, mainly in those which respond well to drug therapy, the aggressive surgical removal of both the primary tumour and visceral metastases results in a survival advantage. After accurate evaluation of the patients, the indication for surgical treatment should be established through a biological and multidisciplinary approach. Other possible indications for surgical treatment are ulceration, bleeding, hygienic conditions undignified of human life, central nervous system metastases, acute neurological disorders, hydro- and pneumothorax greatly reducing respiratory surface and impending fractures. Surgical procedures include simple pleural drainage, minimal invasive techniques, large body cavity surgeries, extensive resection of soft tissue and chest wall due to the primary tumor, and plastic surgical reconstruction as well. Scientific assessment of the oncological value of surgical oncological interventions in stage IV. breast cancer require further multicentric prospective comparative studies. The present paper provides a broad review of the literature on surgical interventions and results in patients with breast cancer and remote metastases, and the surgical options of locally recurrent tumours.

[Lung transplantation program for Hungarian patients]. / Tüdotranszplantáció 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.

[Quality assurance of rapid on-site evaluation of CT-guided fine-needle aspiration cytology of lung nodules]. / A CT-vezérelt vékonytu-aspirációs citológiai vizsgálat minoségbiztosítása a tüdodaganatok diagnosztikájában.

INTRODUCTION: The methods available for the diagnosis of lung cancer include radiologic, cytologic and pathologic procedures. AIMS: The aim of this study was to determine the quality assurance of CT guided fine needle aspiration cytology of lung nodules. METHODS: Cytology results were rated to 4 categories (positive; suspicious; negative; not representative). All cytology reports were compared with the final histology diagnosis. RESULTS: A total of 128 patients underwent CT-guided percutaneous fine-needle aspiration biopsy cytology (63 males; 65 females; mean age 62.8 years). Smears were adequate in 99 cases and inadequate in 29 cases. The average diameter of the nodules was 3.28 cm. Thirty three (25.6%) of the cases were histologically verified and 2 falsely negative and 2 falsely positive cases were detected. The sensitivity and the positive predictive value were 88.8% and 88.8%, respectively. Pneumothorax developed in 7 (5.4%) cases. CONCLUSION: These results suggest that CT-guided transthoracic fine needle aspiration cytology has a high diagnostic accuracy and an acceptable complication rate. The auditing valves of the results meet the proposed threshold values.

[Optimal treatment of the axilla after positive sentinel lymph node biopsy in early invasive breast cancer. Early results of the OTOASOR trial]. / Az axilla optimális kezelése pozitív orszemnyirokcsomó esetén korai invazív emlorákban. Az OTOASOR vizsgálat elozetes eredményei.

INTRODUCTION: Sentinel lymph node biopsy alone has become an acceptable alternative to elective axillary lymph node dissection in patients with clinically node-negative early-stage breast cancer. Approximately 70 percent of the patients undergoing breast surgery develop side effects caused by the axillary lymph node dissection (axillary pain, shoulder stiffness, lymphedema and paresthesias). AIM: The current standard treatment is to perform completion axillary lymph node dissection in patients with positive sentinel lymph node biopsy. However, randomized clinical trials of axillary dissection versus axillary irradiation failed to show survival differences between the two types of axillary treatment. The National Institute of Oncology, Budapest conducted a single centre randomized clinical study. The OTOASOR (Optimal Treatment of the Axilla - Surgery or Radiotherapy) trial compares completion axillary lymph node dissection to axillary nodal irradiation in patients with sentinel lymph node-positive primary invasive breast cancer. METHOD: Patients with primary invasive breast cancer (clinically lymph node negative and less than or equal to 3 cm in size) were randomized before surgery for completion axillary lymph node dissection (arm A-standard treatment) or axillary nodal irradiation (arm B-investigational treatment). Sentinel lymph node biopsy was performed by the radio-guided method. The use of blue-dye was optional. Sentinel lymph nodes were investigated with serial sectioning at 0.5 mm levels by haematoxylin and eosin staining. In the investigational treatment arm patients received 50Gy axillary nodal irradiation instead of completion axillary lymph node dissection. Adjuvant treatment was recommended and patients were followed up according to the actual institutional guidelines. RESULTS: Between August 2002 and June 2009, 2106 patients were randomized for completion axillary lymph node dissection (1054 patients) or axillary nodal irradiation (1052 patients). The two arms were well balanced according to the majority of main prognostic factors. Sentinel lymph node was identified in 2073 patients (98.4%) and was positive in 526 patients (25.4%). Fifty-two sentinel lymph node-positive patients were excluded from the study (protocol violation, patient's preference). Out of the remaining 474 patients, 244 underwent completion axillary lymph node dissection and 230 received axillary nodal irradiation according to randomization. The mean length of follow-up to the first event and the mean total length of follow-up were 41.9 and 43.3 months, respectively, and there were no significant differences between the two arms. There was no significant difference in axillary recurrence between the two arms (0.82% in arm A and 1.3% in arm B). There was also no significant difference in terms of overall survival between the arms at the early stage follow-up. CONCLUSIONS: The authors conclude that after a mean follow-up of more than 40 months axillary nodal irradiation may control the disease in the axilla as effectively as completion axillary lymph node dissection and there was also no difference in terms of overall survival.

[Small cell lung cancer heterogeneity and molecular subtypes: biological and clinical relevance]. / A molekuláris altípusok szerinti heterogenitás biológiai és klinikai jelentosége kissejtes tüdorákban.

Small-cell lung cancer (SCLC) is a highly aggressive malignancy characterised by genomic instability and early metastatic spread. Patients are typically diagnosed at advanced disease stage, when platinum-based chemotherapy with immunotherapy represents the standard therapeutic approach. The role of radiotherapy with concomitant systemic therapy is also well established in the management of SCLC patients. Although these therapeutic approaches are initially effective, most patients rapidly develop resistance. This clearly highlights the need to improve therapeutic efficacy and broaden the scope of current therapeutic strategies. Recent advances in the study of this disease, once considered homogeneous, have led to a new model of the SCLC classification scheme based on the relative expression of certain transcriptional regulators and inflammatory characteristics. New biological insights into the molecular subtypes of SCLC could lead to the implementation of subtype-specific therapeutic approaches. Here, we summarise our key findings concerning the biological and clinical relevance of SCLC molecular subtypes.

Comparative expression analysis of immune-related markers in surgically resected lung neuroendocrine neoplasms.

BACKGROUND: Although immunotherapy has led to a paradigm shift in the treatment of lung cancer, the therapeutic approaches for lung neuroendocrine neoplasms (LNENs) are still limited. Our aim was to explore the immunological landscape and the expression of immune checkpoint markers in LNENs. METHODS: Surgically removed tumor samples of 26 atypical carcinoid (AC), 30 large cell neuroendocrine carcinoma (LCNEC) and 29 small cell lung cancer (SCLC) patients were included. The immune phenotype of each tumor type was assessed by using a panel of 15 immune-related markers. As these markers are potentially expressed by immune cells and/or tumor cells, they might serve as putative targets for immunotherapy. Expression patterns were measured by immunohistochemistry and correlated with clinicopathological parameters and prognosis. RESULTS: Unsupervised hierarchical clustering revealed distinct immunologic profiles across tumor types. Specifically, AC tumors were characterized by high tumor cell CD40 expression and low levels of immune infiltrates whereas SCLC samples had a high CD47 and Inducible T Cell Costimulator (ICOS) expression in tumor cells and immune cells, respectively. High CD70 and CD137 expression by tumor cells as well as elevated expression of CD27, Lymphocyte Activation Gene 3 (LAG3), and CD40 by immune cells were characteristic for LCNEC samples. Overall, SCLC and LCNEC tumors had a more immunogenic phenotype than AC samples. High tumor cell CD47 and CD40 expressions were associated with impaired and improved survival outcomes, respectively. CONCLUSIONS: By providing insights into the widely divergent immunologic profiles of LNENs, our results might serve as a basis for the development of novel immunotherapy-related approaches in these devastating malignancies.

Unfolding the secrets of small cell lung cancer progression: Novel approaches and insights through rapid autopsies.

The understanding of small cell lung cancer (SCLC) biology has increased dramatically in recent years, but the processes that allow SCLC to progress rapidly remain poorly understood. Here, we advocate the integration of rapid autopsies and preclinical models into SCLC research as a comprehensive strategy with the potential to revolutionize current treatment paradigms.