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.

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.

[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.

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.

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.

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.

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.

Post-COVID Subacute Thyroiditis and Bronchiolitis in a Lung Transplant Recipient: A Case Report.

Lung transplant recipients are at risk for life-threatening infections including severe acute respiratory syndrome coronavirus 2-associated COVID-19. Several viral infections have been associated with the development of chronic lung allograft dysfunction. Long-term outcomes of COVID-19 on graft function are not known. A 53-year-old female patient, who underwent bilateral lung transplantation 3 years before because of stage IV sarcoidosis and secondary pulmonary hypertension was admitted in the second wave of the pandemic because of COVID-19 with symptoms including dry cough. Chest computed tomography showed ground glass opacities affecting 25% to 50% of the lung parenchyma. She was admitted to the COVID-19 Unit of our clinic. She received oxygen via nasal cannula, remdesivir, and low-dose methylprednisolone while mycofenolate acid administration was stopped. Her clinical condition improved. The first follow-up visit 1 month after the infection demonstrated deterioration in lung function. Computed tomography scan showed almost complete resolution; transbronchial biopsy was performed and proved acute allograft rejection. During the hospitalization a new onset atrial fibrillation was confirmed. In the background of atrial fibrillation and simultaneous neck pain, severe hyperthyroidism was proven. Because of thyroiditis and lung allograft rejection, high-dose steroid treatment was initiated and everolimus was added to the immunosuppressive therapy. Donor specific antibodies were also detected, hence plasmapheresis was indicated and continued with photoferesis. On the follow-up spirometry the values were stable; however, they did not reach pre-COVID levels. In lung transplant recipients COVID-19 might trigger allograft rejection in addition to virus-related thyroid disease.

Sleeve lobectomy in patients with non-small-cell lung cancer: a report from the European Society of Thoracic Surgery database 2021.

OBJECTIVES: For centrally located lung tumours, sleeve lobectomy is preferred over pneumectomy. We report on the surgical practices and perioperative outcomes of sleeve resections based on data from the European Society of Thoracic Surgeons database. METHODS: We retrieved data of patients undergoing sleeve lobectomy or bilobectomy from 2007 to 2021. We evaluated baseline characteristics, surgical approach, neoadjuvant treatments, morbidity and postoperative outcomes of open and video-assisted thoracoscopic surgery (VATS) procedures. RESULTS: In total, 1652 patients (median age: 63 years; females/males: 446/1206) underwent sleeve lobectomy (n = 1536) or bilobectomy (n = 116) by open thoracotomy (n = 1491; 90.2%) or VATS (n = 161; 9.8%) with a thoracotomy conversion rate of 21.1% (n = 34); 398 (24.1%) patients received neoadjuvant treatment. Overall morbidity and 30-day mortality were 40.6% and 2.2%, respectively. Bronchial anastomotic complications occurred in 29 patients (1.8%) with conservative treatment in 6 cases (20.7%) and operative management in 23 (79.3%). On multivariable analysis, factors related to the elevated risk of cardiopulmonary complications were body mass index < 20 [odds ratio (OR): 2.26; P < 0.001] and bilobectomy (OR : 2.28, P < 0.001). Age <60 years (OR: 0.71, P = 0.013), female sex (OR: 0.54, P < 0.001) and VATS (0.64, P < 0.001) were associated with decreased risk. Neoadjuvant treatment was not associated with increased risks of cardiopulmonary complications (OR: 1.05; P = 0.664). Compared to open thoracotomy, VATS was associated with significantly decreased overall morbidity (30.4% vs 41.7%, P = 0.006) and length of stay (median: 5 days vs 8 days; P < 0.001). CONCLUSIONS: Sleeve lobectomies can be safely performed after neoadjuvant treatment. The VATS approach fosters shorter length of stay and decreased morbidity.

Unilateral video-assisted thoracoscopic thymoma resection ­ Indications, early and mid-term results / Az unilateralis videoasszisztált torakoszkópos thymomaeltávolítás javallata, korai és középtávú eredményei

Introduction. Thymoma is the most common tumour of the anterior mediastinum. Video-Assisted Thoracic Surgery technique of thymoma resection is spreading world-wide, but the thoracoscopic method is still contentious in many ways. Authors evaluate the early and mid-term results of a 17 years period of VATS unilateral approach at 2 Hungarian thoracic surgical centers. Method. Depending on the anatomical situation of the thymoma, we performed thymectomy, or partial thymectomy (thymomectomy) for the Masaoka­Koga I­II­III stage thymoma from the right or left side through 2 or 3 intercostal ports. We managed the operations with ultrasonic dissector and electrocauter. By using international standards we evaluated perioperative morbidity, mid-term oncological results and clinical symptoms of myasthenia. Results. 23 of the 54 patients were man, 31 were woman, the average age was 58 (26­79) years, 23 of them had myasthenia. The conversion rate was 11,5% (7/61). The average operation time was 84 (39­150) minutes. The average hospitalisation time was 5.5 (3­19) days. The average size of the thymomas was 46 (18­90) mm. The histology resulted thymoma type A in 2 cases, AB in 19 cases, B1/2/3 in 11/11/1 cases, mixed B in 10 cases. The examination of the resection line was R0/1/2 in 42/11/1 cases. The Masaoka­Koga stages were: I (17), IIA (28), IIB (2), III (7). There was 25 thymomectomies, and 29 thymectomies. In seven cases there were extension of the operation to the pericardium (2), to the lung (2), to the phrenic nerve (6), and to innominate vein (1). The in-hospital mortality over 30 day was in 1 case (1.85%). The morbidity was 11/54 (20.4%). The average follow-up time was 62.56 (5­198) months. In the group with myasthenia the effectivity of the operation was 18/21 (85.7%), including complete remission of 5/21 (23.8%). Post-thymectomy myasthenia gravis developed in 2/31 cases (6.5%). The average 5 years survival was 100%, tumour-free 5 years survival was 96%. Conclusions. The higher proportion of the thymomectomy in the early results, higher conversion rate and lower R0 proportion might be in connection with the attitude of the surgeons, with the learning curve and with the limitations of the unilateral method. After a longer follow-up time late results may become more real and comparable. Instead of unilateral VATS technique we have changed to the subxyphoideal approach of VATS because of its better visualisation.

Lymphocyte-to-monocyte ratio is an independent prognostic factor in surgically treated small cell lung cancer: An international multicenter analysis.

INTRODUCTION: The prognostic value of lymphocyte-to-monocyte ratio (LMR) has already been evaluated in a wide range of malignancies including patients with non-surgically managed small cell lung cancer (SCLC). However, the impact of LMR on survival in surgically treated SCLC patients has not yet been assessed. The aim of this study was to determine the clinical role of LMR in patients undergoing surgical resection for SCLC. MATERIALS AND METHODS: In this retrospective study, individuals receiving radical surgery for SCLC between January 2000 and December 2019 from three participating European institutions were included. LMR was calculated from the most recent blood test prior to surgery. Optimal cut-off values for LMR were determined and correlated with clinical data and survival outcomes. RESULTS: In total, 101 patients underwent surgical resection for SCLC during the study period. 76 (75.2%) received anatomic lung resection (defined as lobectomy or pneumonectomy), 63 (62.4%) were male and the median age was 63 (range 41-80) years. LMR > 2.50 significantly associated with improved overall survival (OS) (35.3 vs. 20.7 months, p = 0.032) and disease-free survival (DFS) (25.8 vs 18.5 months, p = 0.011). Moreover, multivariate Cox proportional hazard model identified LMR > 2.50 as an independent prognostic factor of longer OS (hazard ratio (HR) 0.617; 95% confidence interval (CI) 0.383-0.993; p = 0.047) and DFS (HR 0.505; 95% CI 0.266-0.959; p = 0.037). CONCLUSION: Preoperatively elevated LMR is a robust prognostic factor associated with improved OS and DFS in patients undergoing surgery for SCLC. Further studies are warranted to better understand the overall impact of LMR when applying surgery in these patients.

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.

Covid-19-fertozés klinikai jelentosége tüdorák és egyéb malignus mellkasi daganatok esetén.

The COVID-19 pandemic has posed significant challenges to healthcare systems worldwide. Patients with cancer, and particularly those with lung malignancies, represent a highrisk group for COVID-19 since they are more susceptible to infection and have a higher risk of severe outcomes. However, the restructuration of the healthcare environment, the development of guidelines for treatment and surveillance, and the improvement of vaccination coverage allowed adequate patient shielding and continuity of oncological care of cancer patients. By shedding light on the characteristics of COVID-19 patients with thoracic malignancies, recent studies also contributed to the development of personalized therapeutic strategies. Accordingly, several determinants were identified to predict disease outcomes. These include the ECOG performance status, the levels of C-reactive protein, neutrophils and procalcitonin, the disease stage, and the presence of pneumonia. COVID-19 vaccines are safe in patients with lung cancer. In order to obtain adequate immunization, the booster dose is recommended in these patients.

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%.

Bone-Specific Metastasis Pattern of Advanced-Stage Lung Adenocarcinoma According to the Localization of the Primary Tumor.

Background: Patients with advanced-stage lung adenocarcinoma (LADC) often develop distant metastases in the skeletal system. Yet, the bone-specific metastasis pattern is still controversial. We, therefore, aimed to examine how the primary tumor location affects bone specificity and survival in LADC patients diagnosed with skeletal metastases. Methods: In total, 209 bone-metastatic Caucasian LADC patients from two thoracic centers were included in this study. Focusing on the specific location of primary tumors and bone metastatic sites, clinicopathological variables were included in a common database and analyzed retrospectively. Skeletal metastases were diagnosed according to the contemporary diagnostic guidelines and confirmed by bone scintigraphy. Besides region- and side-specific localization, primary tumors were also classified as central or peripheral tumors based on their bronchoscopic visibility. Results: The most common sites for metastasis were the spine (n = 103) and the ribs (n = 60), followed by the pelvis (n = 36) and the femur (n = 22). Importantly, femoral (p = 0.022) and rib (p = 0.012) metastases were more frequently associated with peripheral tumors, whereas centrally located LADCs were associated with humeral metastases (p = 0.018). Moreover, we deduced that left-sided tumors give rise to skull metastases more often than right-sided primary tumors (p = 0.018). Of note, however, the localization of the primary tumor did not significantly influence the type of affected bones. Multivariate Cox regression analysis adjusted for clinical parameters demonstrated that central localization of the primary tumor was an independent negative prognostic factor for overall survival (OS). Additionally, as expected, both chemotherapy and bisphosphonate therapy conferred a significant benefit for OS. Conclusion: The present study demonstrates unique bone-specific metastasis patterns concerning primary tumor location. Peripherally located LADCs are associated with rib and femoral metastases and improved survival outcomes. Our findings might contribute to the development of individualized follow-up strategies in bone-metastatic LADC patients and warrant further clinical investigations on a larger sample size.

Clinical relevance of circulating activin A and follistatin in small cell lung cancer.

OBJECTIVES: Circulating levels of activin A (ActA) and follistatin (FST) have been investigated in various disorders including malignancies. However, to date, their diagnostic and prognostic relevance is largely unknown in small cell lung cancer (SCLC). Our aim was to evaluate circulating ActA and FST levels as potential biomarkers in this devastating disease. METHODS: Seventy-nine Caucasian SCLC patients and 67 age- and sex-matched healthy volunteers were included in this study. Circulating ActA and FST concentrations were measured by ELISA and correlated with clinicopathological parameters and long-term outcomes. RESULTS: Plasma ActA and FST concentrations were significantly elevated in SCLC patients when compared to healthy volunteers (p < 0.0001). Furthermore, extensive-stage SCLC patients had significantly higher circulating ActA levels than those with limited-stage disease (p = 0.0179). Circulating FST concentration was not associated with disease stage (p = 0.6859). Notably, patients with high (≥548.8 pg/ml) plasma ActA concentration exhibited significantly worse median overall survival (OS) compared to those with low (<548.8 pg/ml) ActA levels (p = 0.0009). Moreover, Cox regression analysis adjusted for clinicopathological parameters revealed that high ActA concentration is an independent predictor of shorter OS (HR: 1.932; p = 0.023). No significant differences in OS have been observed with regards to plasma FST levels (p = 0.1218). CONCLUSION: Blood ActA levels are elevated and correlate with disease stage in SCLC patients. Measurement of circulating ActA levels might help in the estimation of prognosis in patients with SCLC.

[Predictive relevance of KRAS mutational status in bone metastatic lung adenocarcinoma treated with bisphosphonate therapy]. / A KRAS-mutációs státusz prediktív szerepe biszfoszfonáttal kezelt, csontáttétet képzo tüdo-adenokarcinómában.

The therapeutic impact of KRAS mutations remains controversial in bone metastatic lung adenocarcinoma (LADC). Therefore, our aim was to investigate the effects of KRAS mutational status on overall survival (OS) in these patients according to bisphosphonate therapy (BTx) and radiation therapy (RTx). In total, 134 LADC patients diagnosed with simultaneous bone metastasis were included in this study. The results of the univariate (p=0.008) and multivariate (p=0.004) survival analyses indicated that KRAS mutation is a negative prognostic factor. Both BTx and RTx can increase the OS with a pronounced benefit for patients with KRAS wild-type tumors. Importantly, the concomitant use of BTx and RTx might increase the OS irrespective of KRAS status compared to BTx or RTx alone. In summary, our results might contribute to the development of new therapeutic approaches with regards to KRAS mutational status in bone metastatic LADC.

Prognostic impact of PD-1 and PD-L1 expression in malignant pleural mesothelioma: an international multicenter study.

BACKGROUND: Programmed cell death 1/programmed death ligand 1 (PD-1/PD-L1) immune-checkpoint blockade is a promising new therapeutic strategy in cancer. However, expression patterns and prognostic significance of PD-L1 and PD-1 are still controversial in human malignant pleural mesothelioma (MPM). METHODS: Formalin-fixed paraffin-embedded (FFPE) tumor samples from 203 MPM patients receiving standard treatment without immunotherapy were collected from 5 European centers. PD-L1 and PD-1 expression of tumor cells (TCs) and tumor-infiltrating lymphocytes (TILs) were measured by immunohistochemistry and correlated with clinical parameters and long-term outcome. RESULTS: High (>10%) PD-L1 TC and PD-1 TILs expressions were found in 18 (8%) and 39 (24%) patients, respectively. PD-L1 was rarely expressed by TILs [≥1%, n=13 (8%); >10%, n=1]. No significant associations were found between the PD-L1 or PD-1 expression of TCs or TILs and clinicopathological parameters such as stage or histological subtype. Notably, patients with high (>10%) TC-specific PD-L1 expression exhibited significantly worse median overall survival (OS) (6.3 vs. 15.1 months of those with low TC PD-L1 expression; HR: 2.51, P<0.001). In multivariate cox regression analysis adjusted for clinical parameters, high TC PD-L1 expression (>10%) proved to be an independent negative prognostic factor for OS (HR: 2.486, P=0.005). There was no significant correlation between PD-L1 or PD-1 expression of TILs and OS. CONCLUSIONS: In this multicenter cohort study, we demonstrate that high (>10%) PD-L1 expression of TCs independently predicts worse OS in MPM. Further studies are warranted to investigate the value of PD-L1/PD-1 expression as a marker for treatment response in MPM patients receiving immunotherapy.

The effects of bisphosphonate and radiation therapy in bone-metastatic lung adenocarcinoma: the impact of KRAS mutation.

BACKGROUND: KRAS mutation is the most common genetic alteration in lung adenocarcinoma (LADC) in Western countries and is associated with worse outcome in bone-metastatic cases. Yet, to date, no effective treatment guidelines were developed for these patients. Accordingly, our aim was to investigate the impact of KRAS mutation on bisphosphonate (BTx) and radiation therapy (RTx) in bone-metastatic LADC patients. METHODS: Clinicopathological variables of 134 consecutive LADC patients with bone metastases at diagnosis and known KRAS status were retrospectively analyzed. The effects of BTx, RTx and KRAS mutation on overall survival (OS) were investigated. RESULTS: Of the total cohort, 93 patients were identified as KRAS wild-type (WT) (69.4%) and 41 (30.6%) as KRAS mutant patients. The presence of KRAS mutation was associated with significantly reduced median OS (5.1 vs. 10.2 months in KRAS WT patients; P=0.008). Irrespective of KRAS mutational status both BTx (P=0.007) and RTx (P=0.021) conferred a significant benefit for OS. Notably, however, when analyzing the patients with KRAS-mutant and KRAS WT tumors separately, the benefit from BTx and RTx on OS remained statistically significant only in KRAS WT patients (P=0.032 and P=0.031, respectively). CONCLUSIONS: KRAS mutation is a strong negative prognostic factor in bone-metastatic LADC patients. Both BTx and RTx can increase the OS with a pronounced benefit for patients with KRAS WT tumors. Altogether, KRAS mutational status should be considered during therapeutic decision making in bone-metastatic LADC patients.

EGFR variant allele frequency predicts EGFR-TKI efficacy in lung adenocarcinoma: a multicenter study.

BACKGROUND: Although lung adenocarcinoma (LADC) with sensitizing mutations of the epidermal growth factor receptor (EGFR) is highly sensitive to EGFR tyrosine kinase inhibitors (EGFR-TKIs), in most cases disease progression inevitably occurs. Our aim was to investigate the predictive and prognostic significance of adjusted tumoral EGFR variant allele frequency (EGFR-aVAF) in the above setting. METHODS: Eighty-nine Caucasian advanced-stage LADC patients with known exon-specific EGFR mutations undergoing EGFR-TKI treatment were included. The correlations of EGFR-aVAF with clinicopathological variables including progression-free and overall survival (PFS and OS, respectively) were retrospectively analyzed. RESULTS: Of 89 EGFR-mutant LADC patients, 46 (51.7%) had exon 19 deletion, while 41 (46.1%) and 2 (2.2%) patients had exon 21- and exon 18-point mutations, respectively. Tumoral EGFR-aVAF was significantly higher in patients harboring EGFR exon 19 mutations than in those with exon 21-mutant tumors (P<0.001). Notably, patients with EGFR exon 19 mutant tumors demonstrated significantly improved PFS (P=0.003) and OS (P=0.02) compared to patients with exon 21 mutations. Irrespective of specific exon mutations, a statistically significant positive linear correlation was found between EGFR-aVAF of tumoral tissue and PFS (r=0.319; P=0.002). High (≥70%) EGFR-aVAF was an independent predictor of longer PFS [vs. low (<70%) EGFR-aVAF; median PFSs were 52 vs. 26 weeks, respectively; P<0.001]. Additionally, patients with high EGFR-aVAF also had significantly improved OS than those with low EGFR-aVAF (P=0.011). CONCLUSIONS: Our study suggests that high (≥70%) EGFR-aVAF of tumoral tissue predicts benefit from EGFR-TKI treatment in advanced LADC and, moreover, that exon 19 EGFR mutation is associated with high EGFR-aVAF and improved survival outcomes.