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L.K. is a fellow in the Canadian Institutes of Health Research (CIHR) Strategic Training in Advanced Genetic Epidemiology (STAGE) programme and is supported by the CIHR Doctoral Research Award from the Frederick Banting and Charles Best Canada Graduate Scholarships (GSD-137441). Transdisciplinary Research for Cancer in Lung (TRICL) of the International Lung Cancer Consortium (ILCCO) was supported by the National Institutes of Health (U19-CA148127, CA148127S1). Genotyping for the TRICL-ILCCO OncoArray was supported by in-kind genotyping at Centre for Inherited Disease Research (CIDR) (26820120008i-0–6800068-1). Genotyping for the Head and Neck Cancer OncoArray performed at CIDR was funded by the US National Institute of Dental and Craniofacial Research (NIDCR) grant 1X01HG007780–0. CAPUA study was supported by FIS-FEDER/Spain grant numbers FIS-01/310, FIS-PI03–0365 and FIS-07-BI060604, FICYT/Asturias grant numbers FICYT PB02–67 and FICYT IB09–133, and the University Institute of Oncology (IUOPA), of the University of Oviedo and the Ciber de Epidemiologia y Salud Publica. CIBERESP, SPAIN. The work performed in the CARET study was supported by the National Institute of Health (NIH)/National Cancer Institute (NCI): UM1 CA167462 (PI: Goodman), National Institute of Health UO1-CA6367307 (PIs Omen, Goodman); National Institute of Health R01 CA111703 (PI Chen), National Institute of Health 5R01 CA151989 (PI Doherty). The Liverpool Lung Project is supported by the Roy Castle Lung Cancer Foundation. The Harvard Lung Cancer Study was supported by the NIH (National Cancer Institute) grants CA092824, CA090578 and CA074386. The Multiethnic Cohort Study was partially supported by NIH Grants CA164973, CA033619, CA63464 and CA148127. The work performed in MSH-PMH study was supported by the Canadian Cancer Society Research Institute (020214), Ontario Institute of Cancer and Cancer Care Ontario Chair Award to R.J.H. and G.L. and the Alan Brown Chair and Lusi Wong Programs at the Princess Margaret Hospital Foundation. The Norway study was supported by Norwegian Cancer Society, Norwegian Research Council. The work in TLC study has been supported in part the James & Esther King Biomedical Research Program (09KN-15), National Institutes of Health Specialized Programs of Research Excellence (SPORE) Grant (P50 CA119997) and by a Cancer Center Support Grant (CCSG) at the H. Lee Moffitt Cancer Center and Research Institute, an NCI designated Comprehensive Cancer Center (grant number P30-CA76292). The dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Center’s BioVU, which is supported by institutional funding and by the Vanderbilt CTSA grant UL1 TR000445 from NCATS/NIH. Dr Melinda Aldrich is supported by the by NIH/National Cancer Institute 5K07CA172294. The Copenhagen General Population Study (CGPS) was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital. The NELCS study: Grant Number P20RR018787 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). Kentucky Lung Cancer Research Initiative (KLCRI) was supported by the Department of Defense (Congressionally Directed Medical Research Program, U.S. Army Medical Research and Materiel Command Program) under award number: 10153006 (W81XWH-11–1-0781). Views and opinions of, and endorsements by the author(s) do not reflect those of the US Army or the Department of Defense. This research was also supported by unrestricted infrastructure funds from the UK Center for Clinical and Translational Science, NIH grant UL1TR000117 and Markey Cancer Center NCI Cancer Center Support Grant (P30 CA177558) Shared Resource Facilities: Cancer Research Informatics, Biospecimen and Tissue Procurement, and Biostatistics and Bioinformatics. The research undertaken by M.D.T., L.V.W. and M.S.A. was partly funded by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. M.D.T. holds a Medical Research Council Senior Clinical Fellowship (G0902313). The Tampa study was funded by Public Health Service grants P01-CA68384 and R01-DE13158 from the National Institutes of Health. The University of Pittsburgh head and neck cancer case–control study is supported by US National Institutes of Health grants P50 CA097190 and P30 CA047904. The Carolina Head and Neck Cancer Study (CHANCE) was supported by the National Cancer Institute (R01CA90731). The Head and Neck Genome Project (GENCAPO) was supported by the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP; grants 04/12054–9 and 10/51168–0). The authors thank all the members of the GENCAPO team. This publication presents data from the Head and Neck 5000 study. The study was a component of independent research funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research scheme (RP-PG-0707–10034). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Human papillomavirus (HPV) serology was supported by a Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (grant number: C18281/A19169). The Alcohol-Related Cancers and Genetic Susceptibility Study in Europe (ARCAGE) was funded by the European Commission’s fifth framework programme (QLK1– 2001-00182), the Italian Association for Cancer Research, Compagnia di San Paolo/FIRMS, Region Piemonte and Padova University (CPDA057222). The Rome Study was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) awards IG 2011 10491 and IG 2013 14220 to S.B. and by Fondazione Veronesi to S.B. The IARC Latin American study was funded by the European Commission INCO-DC programme (IC18-CT97–0222), with additional funding from Fondo para la Investigacion Cientifica y Tecnologica (Argentina) and the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (01/01768–2). The IARC Central Europe study was supported by the European Commission’s INCO-COPERNICUS Program (IC15-CT98–0332), US NIH/National Cancer Institute grant CA92039 and World Cancer Research Foundation grant WCRF 99A28. The IARC Oral Cancer Multicenter study was funded by grant S06 96 202489 05F02 from Europe against Cancer; grants FIS 97/0024, FIS 97/0662 and BAE 01/5013 from Fondo de Investigaciones Sanitarias, Spain; the UICC Yamagiwa-Yoshida Memorial International Cancer Study; the National Cancer Institute of Canada; Associazione Italiana per la Ricerca sul Cancro; and the Pan-American Health Organization. Coordination of the EPIC study is financially supported by the European Commission (DG SANCO) and the International Agency for Research on Cancer.

The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Through machine learning and multi-omics factor analysis, we compare and contrast the genomic profiles of 116 pulmonary carcinoids (including 35 atypical), 75 large-cell neuroendocrine carcinomas (LCNEC), and 66 small-cell lung cancers. Here we report that the integrative analyses on 257 lung neuroendocrine neoplasms stratify atypical carcinoids into two prognostic groups with a 10-year overall survival of 88% and 27%, respectively. We identify therapeutically relevant molecular groups of pulmonary carcinoids, suggesting DLL3 and the immune system as candidate therapeutic targets; we confirm the value of OTP expression levels for the prognosis and diagnosis of these diseases, and we unveil the group of supra-carcinoids. This group comprises samples with carcinoid-like morphology yet the molecular and clinical features of the deadly LCNEC, further supporting the previously proposed molecular link between the low- and high-grade lung neuroendocrine neoplasms., The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Here, Alcala and colleagues present a multi-omics analysis of these tumours, revealing distinct molecular and prognostic subgroups.

Neuroendocrine lung tumors (NET) include typical carcinoids (TC), atypical carcinoids (AC), large cell NE carcinoma (LCNEC) and small-cell carcinoma (SCLC), with different clinicopathological profiles and relative grades of malignancy. Although differences between carcinoids and high grade carcinomas are recognized, precise differences and behavior of TC and AC have not been clearly defined. The aim of this study was to better define the differences in the clinical behavior of TC and AC, and to establish new prognostic factors of overall survival (OS), by determining the levels of genetic expression of IGF1R, ERCC1, Bax, p53, Bcl2 and Bcl2/Bax ratio.The histopathological diagnosis of 52 surgically resected pulmonary carcinoid tumors was made according to the WHO classification. Gene expressions were evaluated by quantitative real-time PCR.The confirmed prognostic factors for overall survival (OS) were pTNM T (p0.01), pTNM N (p0.05), clinical stage (p0.05), type of surgery (p0.01) and histopathological (HP) tumor type (p0.05). Bcl2 mRNA level and Bcl2/Bax ratio were found to have a potential for discrimination of the HP type of tumor (AC vs TC, Receiver Operating Characteristics (ROC) cut-off values 0.1451 and 0.3015, respectively), but without statistically significant impact on OS.In patients with NETs, smaller primary tumor, absence of positive lymph nodes, and TC type of tumor predicted longer OS. Type of resection has influence on OS. Bcl2 expression and Bcl2/Bax ratio might be valuable as independent diagnostic parametars in lung carcinoids. Therapeutic approaches using attenuation of Bcl2 or upregulation of Bax might prove useful in lung NETs.

Prognostic significance of immune microenvironment has been emphasized using the most advanced analysis, with consecutive attempts to reveal prognostic impact of this findings. The aim of this study was to compare and define prognostic significance of clinical parameters, microvessel density (MVD) in tumour tissue and expression of CD44s as adhesive molecule on tumour cells in diffuse large B cell lymphoma-DLBCL, primary central nervous system DLBCL-CNS DLBCL and follicular lymphoma-FL. A total of 202 histopathological samples (115 DLBCL/65 FL/22 CNS DLBCL) were evaluated. Overall response (complete/partial remission) was achieved in 81.3 % DLBCL patients, 81.8 % primary CNS DLBCL and 92.3 % FL. Absolute lymphocyte count-ALC/Absolute monocyte count-AMC2.6 in DLBCL and ALC/AMC ≥ 4.7 in FL were associated with better event-free survival (EFS) and overall survival (OS) (p 0.05). In DLBCL, MVD 42 blood vessels/0.36 mm(2) correlated with primary resistant disease (p 0.0001), poorer EFS and OS (p = 0.014). High CD44s expression in FL correlated with inferior EFS and OS (p 0.01). In DLBCL, multivariate Cox regression analysis showed that ALC/AMC was independent parameter that affected OS (HR 3.27, 95 % CI 1.51-7.09, p = 0.003) along with the NCCN-IPI (HR 1.39, 95 % CI 1.08-1.79, p = 0.01). Furthermore, in FL, ALC/AMC mostly influenced OS (HR 5.21, 95 % CI 1.17-23.21, p = 0.03), followed with the FLIPI (HR 3.98, 95 % CI 1.06-14.95, p = 0.041). In DLBCL and FL, ALC/AMC is simple and robust tool that is, with current prognostic scores, able to define long-term survival and identify patients with inferior outcome. The introduction of immunochemotherapy might altered the prognostic significance of microenvionmental biomarkers (MVD and CD44s).

Background In spite of the progress made in neoadjuvant therapy for operable non small‐cell lung cancer (NSCLC), many issues remain unsolved, especially in locally advanced stage IIIA. Methods Retrospective data of 163 patients diagnosed with stage IIIA NSCLC after surgery was analyzed. The patients were divided into two groups: a preoperative chemotherapy group including 59 patients who received platinum‐etoposide doublet treatment before surgery, and an upfront surgery group including 104 patients for whom surgical resection was the first treatment step. Adjuvant chemotherapy or/and radiotherapy was administered to 139 patients (85.3%), while 24 patients (14.7%) were followed‐up only. Results The rate of N2 disease was significantly higher in the upfront surgery group (P < 0.001). The one‐year relapse rate was 49.5% in the preoperative chemotherapy group compared to 65.4% in the upfront surgery group. There was a significant difference in relapse rate in relation to adjuvant chemotheraphy treatment (P = 0.007). The probability of relapse was equal whether radiotherapy was applied or not (P = 0.142). There was no statistically significant difference in two‐year mortality (P = 0.577). The median survival duration after two years of follow‐up was 19.6 months in the preoperative chemotherapy group versus 18.8 months in the upfront surgery group (P = 0.608 > 0.05). Conclusion There was significant difference in preoperative chemotherapy group regarding relapse rate and treatment outcomes related to the lymph node status comparing to the upfront surgery group. Neoadjuvant/adjuvant chemo‐therapy is a part of treatment for patients with stage IIIA NSCLC, but further investigation is required to determine optimal treatment.

Nonspecific interstitial pneumonia (NSIP) is often associated with connective tissue diseases (CTD). The diagnosis of NSIP was confirmed in a 63-year-old man by high-resolution computed tomography and an open lung biopsy. Anti-Golgi complex autoantibodies (AGA) and anti-Ro52 antibodies were simultaneously detected at high concentrations. Autoantibodies to aminoacyl-tRNA synthetases (ARS) were negative. The patient was treated with corticosteroids for six months. During the seven-year follow-up, NSIP had a slow progression and patient had not developed the clinical features of CTD. The present study potentially demonstrates that the autoimmune process elicited by AGA and/or Ro/SSA may play a role in promoting idiopathic NSIP independently of the typical ARS routes, which has not been reported thus far.

Background For patients with two or more primary cancers a correct diagnosis is critically important because prognosis and treatment vary considerably between multiple primary cancers and metastatic disease. Case report Two bilateral synchronous primary lung malignancies of different histological types were diagnosed and immunohistochemically confirmed in a 60-year-old woman. In biopsy specimens of the right lung pure squamous cell carcinoma was detected (stage IIIa). The tumor expressed AE1/AE3, cytokeratin 5 and 34βE12. In biopsy specimens of the left lung small cell carcinoma was detected (stage IIIa). The small cells expressed synaptophysin, chromogranin A and CD56. DNA was extracted from paraffin-embedded tissue of both tumors. Exons 5–9 of the TP53 gene were examined for genetic mutations by polymerase chain reaction and DNA sequencing analysis. Direct sequencing of DNA isolated from the small cell carcinoma revealed a TGC to TTC mutation at codon 404 of TP53 exon 5. In DNA isolated from the squamous cell carcinoma no TP53 mutation was found. The tumors' different response to chemotherapy also suggested that they belonged to different histological types. The patient lived 24 months after the diagnosis, which is more typical for stage III than for stage IV lung carcinoma. Conclusion Discrimination of synchronous primary lung cancers from intrapulmonary metastases based only on clinical findings can be very difficult. Multidisciplinary diagnostic evaluation is therefore very helpful in cases like this, because a correct diagnosis will determine the best treatment for the patient and consequently a better prognosis.

The inactivation of p53 and PTEN tumor suppressor genes is a common genetic event in lung cancer. However, data on the effect of the joint inactivation of tumor-suppressor genes in non-small cell lung carcinoma (NSCLC) are lacking. The purpose of this study was to investigate the alterations in PTEN and p53 genes, as well as to evaluate their mutual role in NSCLC pathogenesis and their impact on survival rate. To that end, polymerase chain reaction single-strand conformational polymorphism (PCR-SSCP), sequencing, methylation-specific PCR, and fragment analysis were used. The results obtained were correlated with clinicopathologic parameters, the level of genomic instability, and patient survival. Overall, 13% of specimens had aberrant p53 only, 13% had inactive PTEN only, and 50% of samples had both genes altered. Correlation analyses showed that the mutual inactivation of p53 and PTEN was a frequent event that was associated significantly with the increased level of genomic instability and lymph node invasion implying their synergistic effect in promoting metastatic phenotype of this kind of cancer. In addition, our results revealed a significant association of joint alterations of these genes with dramatically shortened survival indicating that aberrant p53 and PTEN could be used as an adverse prognostic factor for NSCLC patients' outcome. Our findings established the relevance of the combinatorial inactivation of p53 and PTEN in NSCLC progression and identified a subgroup of patients with a particularly aggressive disease.

Introduction. Lung cancer is the leading cause of death from malignancy in Serbia. Objective. This is a retrospective analysis of lung cancer epidemiological changes regarding to its histological type and patients’ age of both genders. Data were based on surgically treated lung cancer patients from 1985 to 2005. Methods. Data were collected from 972 pathohistological reports of operated patients of both genders divided into age groups. Histological types of lung cancer were distributed in four major groups: squamous cell cancer (SCC), adenocarcinoma (AC), small cell cancer (SCLC) and other rare histological types. Both genders together and separately were analysed. Chi-square with the level of significance p

Introduction. Sarcoidosis is a multisystem, granulomatous disease of unknown etiology. Sarcoid granulomas appear as immunological response to a particular but still unknown agent of the human body. Objective. The main purpose of this study was to point out the important fact that the exact diagnosis of sarcoidosis must be estimated by clinical and pathological correlation, and team cooperation between the clinician and the pathologist. Methods. Of 751 patients referred with the suspected diagnosis of sarcoidosis, from 1995 to1999, 663 (431 female and 232 male) were analyzed and confirmed as having sarcoidosis stage I-III based on biopsy findings obtained by bronchoscopy, open lung biopsy, skin biopsy, liver biopsy or splenectomy. Results. Diagnosis of sarcoidosis was made in 663 patients, 431 females and 232 males (ratio 1.9:1). The average age of patients varied from 16 to 67 years, with those below age 50 years being predominant (78.4%). The highest number of patients was diagnosed in stage I of lung sarcoidosis (81.7%). Sarcoidosis was the most common cause of hilar and mediastinal lymphadenopathy (72.2%). Conclusion. Biopsy is a necessary diagnostic procedure for pathological diagnosis of sarcoid granu- loma before treatment even in patients where clinical, radiological, biochemical and immunological tests imply the diagnosis of sarcoidosis.

Lung cancer is the most common cause of neoplasia-related death worldwide. One of the crucial early events in carcinogenesis is the induction of genomic instability and mutator phenotype. We investigated genomic instability in 30 patients with non-small-cell lung cancer (NSCLC) by comparing DNA fingerprints of paired tumor and normal tissues using arbitrarily primed polymerase chain reaction (AP-PCR). Selected 21 DNA bands with altered mobility were isolated from polyacrylamide gels, cloned and sequenced. Obtained sequences were submitted to homology search in GenBank database which revealed the following genes: TSPAN14, CDH12, RDH10, CYP4Z1, KIR, E2F4, PHACTR3, PHF20, PRAME family member and SLC2A13. Following the identification of these genes we examined their relation to the clinicopathological parameters and survival of the patients. Our study revealed that genetic alterations of TSPAN14, SLC2A13 and PHF20 appeared prevalently in tumors of grade 1, stage I suggesting that structural changes of these genes could play a role in NSCLC promotion. Contrary to this CYP4Z1, KIR and RDH10 were prevalently mutated in tumors of grade 3, stage III suggesting that they could play a role in NSCLC progression. E2F4, PHACTR3, PRAME family member and CDH12 most probably play important role in NSCLC geneses. In conclusion, our study revealed altered genes previously not described in regard to this type of cancer.

UNLABELLED Patients with advanced non-small cell lung cancer (NSCLC) usually undergo toxic treatment (chemotherapy and/or radiotherapy). They can experience devastating effects of illness and therapies on their psychological and emotional well-being. On the other hand, untreated psychological distress is associated with reduced quality of life and inadequate palliation of physical symptoms. In order to estimate frequency of anxiety and depressive symptoms and influence of demographic, socioeconomic and clinical factors on psychological well-being, we performed this cross-sectional study in group of 100 patients with advanced stage of disease. Symptoms of anxiety and depression were assessed using the Hamilton Anxiety Rating Scale (HARS) and Hamilton Depression Rating scale (HDRS). Health-related quality of life data are obtained by EORTC QLC C30 and SF 36. Patients with poor performance status (PS) experienced significantly more anxiety and depressive symptoms (p=0.001) and worse emotional (p=0.001) and mental functioning (p=0.001). Treated patients had significantly better mental (p=0.011) and emotional (p=0.001) functioning in compared to newly diagnosed ones. Somewhat unusual, unemployed participants reported significantly less anxiety (p=0.029) and depressive (p=0.002) symptoms, better mental (p=0.030) and emotional functioning (p=0.007). Additionally, nausea and vomiting adversely affected mental health and emotional functioning and correlated significantly positively with HARS and HDRS scores. Our findings suggest significant impact of some disease-related factors (PS, active treatment) and treatment-related factors (chemotherapy -induced nausea and vomiting) on psychological well-being of patients with advanced NSCLC. This should be taking an account when appropriate interventions are planned. KEYWORDS lung cancer, anxiety, depression, quality of life, chemotherapy, chemotherapy-induced nausea and vomiting.

Acquired pure red-cell aplasia (PRCA) is an uncommon disorder of erythrocytopoiesis that can develop in association with thymic tumors. We present the very rare case of a severely anemic 62-year-old man with PRCA and a concurrent neuroendocrine carcinoid tumor of the thymus. The anterior mediastinal thymus tumor was completely excised, and following histological and immunohistochemical analyses (showing positive staining for cytokeratin, chromogranin A, synaptophysin, and neuron-specific enolase) the diagnosis of a (grade I; T(1)N(0)M(0)) typical carcinoid tumor of the thymus was made. Postoperatively the anemia persisted despite no signs of residual tumor on CT chest. A hematological work up found: normocellularity with

The patient suffered loss of consciousness, dysarthria and right sided hemiparesis. The CT scan and MRI scans were negative. These findings are more in keeping with a diagnosis of Transient Ischemic Attack (TIA) or mild CVA. Hypoglycemia per se does not usually cause hemiparesis. The blood glucose level was low but I am not sure if one can conclude that hypoglycemia caused the above noted neurological signs and symptoms. The authors do not present any data to prove that this patient had "hypoglycemic coma".

The aim of the study was to assess the expression and significance of HER2 and HER3, and Ile/Val single nucleotide polymorphism (SNP) of HER2 in lung cancer patients. Thirty seven cases of lung cancer were investigated immunohistochemically for HER2 and HER3 expression. PCR followed by restriction fragment length polymorphism (RFLP) was used to analyze the presence of HER-2 SNP at codon 655 in 20 samples. The results were compared with clinical and pathological parameters of investigated patients. We found that 100 % of the cases were negative for HER2, 29.7 % were with moderate or strong HER3 expression and 70.3 % of the tumors—without or with low expression for HER3. Lymph node metastasis were found in 40 % of HER3 positive cases (χ2 = 4.752; p = 0.029). Moderately-differentiated tumors do not express neither of investigated markers (χ2 = 6.719; p = 0.035). HER2 RFLP—PCR analysis showed genotype AG in five patients (25 %) and the rest of 15 cases (75 %) had АА (Ile/Ile) genotype. Patients with metastasis had genotype АА (Ile/Ile) in 80 % and genotype AG (Ile/Val) in 20 % (χ2 = 2.857; p = 0.091). Our results indicate that SNP in HER2 codon 655 and investigation of HER2 and HER3 expression could be helpful to outline the prognosis for patients with lung adenocarcinoma.

Introduction Clinical studies indicate involvement of the liver and spleen in approximately 20-30% of patients affected with sarcoidosis and their detection should be based on a standardized diagnostic procedure. Diagnostic procedures Ultrasonography is a reliable and safe method to assess changes related to size and structure of the affected organs that are pathognomonic for sarcoidosis. Further evaluation may include computerized tomography or magnetic resonance, while percutaneous needle aspiration biopsy or laparoscopy may also be applied when indicated. The most important criterion used for final diagnosis is pathohistological evidence of epithelioid noncaseating granuloma in bioptic material along with already established sarcoidosis of the lungs or some other organ. Material and methods The study on the incidence of liver and spleen sarcoidosis included a group of 130 patients affected with sarcoidosis hospitalized at the Institute of Pulmonary Diseases and Tuberculosis, Clinical Center of Serbia, over the period 2002-2003. Results The analysis evidenced that 31.5% of sarcoidosis patients had pathognomonic echographic findings of abdominal organs: splenomegaly (13%), hepatomegaly (10.8%) and hepatosplenomegaly (7.7%). Three patients underwent surgical treatment of liver and spleen sarcoidosis. Conclusion Pathognomonic findings of liver and spleen sarcoidosis were evidenced in approximately one third of sarcoidosis cases and they represented a significant parameter for further therapy, particularly in chronic patients.

Lung cancer is the most common cause of neoplasia-related death worldwide. Accounting for approximately 80\% of all lung carcinomas, the non-small cell lung carcinoma (NSCLC) is the most common clinical form with its two predominant histological types, adenocarcinoma (ADC) and squamous cell carcinoma (SCC). Although surgical resection is the most favorable treatment for patients with NSCLC, relapse is still high, so neoadjuvant chemotherapy (NAC) is an accepted treatment modality. In this study we examined whether some of the key molecules associated with the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR signaling pathways could have predictive and prognostic value for the NAC application. To that end we examined the expression status of PTEN, pAKT, pERK and loss of heterozygosity (LOH) of PTEN in two groups of NSCLC patients, those who received and those who did not receive NAG LOH PTEN and low pERK expression is shown to be correlated with the longest survival of patients with SCC and ADC, respectively, who received NAC. These results point that the application of NAC is beneficial in the NSCLC patients with specific molecular alterations which could further help to improve constant search for the druggable molecular targets used in personalized therapy. (C) 2014 Elsevier Inc. All rights reserved. Ministry of Education, Science and Technological Development of the Republic of Serbia {[}III41031]

Anaplastic thyroid carcinoma (ATC) is a rare, but aggressive and chemoresistant tumor with dismal prognosis. Most ATCs harbor mutations that activate RAS/MAPK/ERK and PI3K/AKT/mTOR pathways. Therefore, we investigated and correlated the expression of phosphatase and tensin homolog, pERK, and pAKT proteins as well as mutations of BRAF, RAS, and p53 genes in samples of patients with ATC. Furthermore, we evaluated the potential of inhibition of these pathways on chemosensitization of ATC using 2 thyroid carcinoma cell lines (FRO and SW1736). Our results revealed a negative correlation between the activity of RAS-MAPK-ERK and PI3K-AKT-mTOR pathways in samples of patients. To be specific, the PI3K-AKT-mTOR pathway was suppressed in patients with activated NRAS or high pERK expression. In vitro results suggest that the inhibition of either RAS-MAPK-ERK or PI3K-AKT-mTOR components may confer sensitivity of thyroid cancer cells to classic chemotherapeutics. This may form a basis for the development of novel genetic-based therapeutic approach for this cancer type. Ministry of Education, Science and Technological Development, Republic of Serbia {[}III41031]

An association between sarcoidosis and lymphoproliferative diseases (LD), the sarcoidosis-lymphoma syndrome, has been previously described, and may be attributed to the underlying immunological abnormalities that occur during the sarcoidosis disease process. We report two patients who developed Hodgkin's disease and diffuse large B-cell non-Hodgkin's lymphoma (NHL) subsequent to their diagnosis of sarcoidosis after latency periods of 6 years and 18 years respectively. Both patients developed histologically-proven sarcoidosis late in life, at 46 years and 58 years, and had differing clinical courses. The first had radiographically staged II chronic progressive respiratory sarcoidosis (RS) and required long-term methotrexate to control the disease, while the second achieved a spontaneous remission of her stage I intrathoracic RS. After treatment, the patient with Hodgkin's disease remains in remission 2.5 years following six cycles of ABVD protocol chemotherapy and involved-field radiotherapy, while the NHL patient remains in remission at 3 years following six cycles of R-COP protocol chemotherapy. Clinicians should be aware of the potential risks of malignancy, and especially of LD in sarcoidosis patients. They should be alerted to the possibility of additional pathology by any atypical clinical features, and should biopsy new lesions and adenopathy to exclude any coexistent neoplasm.

p16 and PTEN are tumor suppressors that are commonly inactivated in human cancers. Loss of each of these molecules is widely studied in lung cancer, including non-small cell lung carcinoma (NSCLC), its most common clinical form. However, the importance of their mutual alterations for NSCLC pathogenesis has been barely examined so far. In this study we tested hypothesis that aberrant p16 might cooperate with inactive PTEN during pathogenesis of NSCLC, particularly in promoting tumor aggressiveness and invasiveness. Initially, we screened NSCLC tumor samples from patients for the presence of the most common genetic and epigenetic alterations of p16 and further correlated them with previously detected aberrations in PTEN gene. Statistical analyses showed that aberrant p16 directly correlated with altered PTEN. Such significant correlation was also observed in groups of patients with high genomic instability, with squamocellular histological subtype, with disease grade 2 and with lymph node invasion. Finally, survival analyses revealed dramatic decrease in survival rate of patients with mutual alterations of p16 and PTEN, but without prognostic significance. Overall results implicate cooperation between aberrant p16 and PTEN in pathogenesis of NSCLC and suggest that their combination might be considered as potential molecular marker for specific subgroups of NSCLC patients.

Non–small-cell lung carcinoma (NSCLC) (n = 65) were analyzed for promoter methylation of RASSF1A, CDH13, MGMT, ESR1, and DAPK genes in matching lung tumors, normal lung tissue, and blood samples. Aberrant methylation in CDH13 and MGMT was associated with clinicopathologic features of NSCLC. Hypermethylation detected in primary tumors was not observed in corresponding blood samples, which rendered this an unsuitable blood-based test for NSCLC detection.Systemic methylation changes may be a diagnostic marker for tumor development or prognosis. Here, we investigate the relationship between gene methylation in lung tumors relative to normal lung tissue and whether DNA methylation changes can be detected in paired blood samples.Sixty-five patients were enrolled in a surgical case series of non-small-cell lung carcinoma at a single institution. By using bisulfite pyrosequencing, CpG methylation was quantified at 5 genes (RASSF1A, CDH13, MGMT, ESR1, and DAPK) in lung tumor, pathologically normal lung tissue, and circulating blood from enrolled cases.The analyses of methylation in tumors compared with normal lung tissue identified higher methylation of CDH13, RASSF1A, and DAPK genes, whereas ESR1 and MGMT methylation did not differ significantly between these tissue types. We then examined whether the 3 aberrantly methylated genes could be detected in blood. The difference in methylation observed in tumors was not reflected in methylation status of matching blood samples, which indicated a low feasibility of detecting lung cancer by analyzing these genes in a blood-based test. Lastly, we probed whether tumor methylation was associated with clinical and demographic characteristics. Histology and sex were associated with methylation at the CDH13 gene, whereas, stage was associated with methylation at MGMT.Our results showed higher methylation of RASSF1A, CDH13, and DAPK genes in lung tumors compared with normal lung. The lack of reflection of these methylation changes in blood samples from patients with non-small-cell lung carcinoma indicates their poor suitability for a screening test.

Background beside the well known predominance of distant vs. loco-regional relapse, several aspects of the relapse pattern still have not been fully elucidated. Methods prospective, controlled study on 88 patients operated for non-small cell lung cancer (NSCLC) in a 15 months period. Stage IIIA existed in 35(39.8%) patients, whilst stages IB, IIA and IIB existed in 10.2%, 4.5% and 45.5% patients respectively. Inclusion criteria: stage I-IIIA, complete resection, systematic lymphadenectomy with at least 6 lymph node groups examined, no neoadjuvant therapy, exact data of all aspects of relapse, exact data about the outcome of the treatment. Results postoperative lung cancer relapse occurred in 50(56.8%) patients. Locoregional, distant and both types of relapse occurred in 26%, 70% and 4% patients respectively. Postoperative cancer relapse occurred in 27/35(77.1%) pts. in the stage IIIA and in 21/40(52.55) pts in the stage IIB. In none of four pts. in the stage IIA cancer relapse occurred, unlike 22.22% pts. with relapse in the stage IB. The mean disease free interval in the analysed group was 34.38 ± 3.26 months. The mean local relapse free and distant relapse free intervals were 55 ± 3.32 and 41.62 ± 3.47 months respectively Among 30 pts. with the relapse onset inside the first 12 month after the lung resection, in 20(66.6%) pts. either T3 tumours or N2 lesions existed. In patients with N0, N1 and N2 lesions, cancer relapse occurred in 30%, 55.6% and 70.8% patients respectively Radiographic aspect T stage, N stage and extent of resection were found as significant in terms of survival. Related to the relapse occurrence, although radiographic aspect and extent of resection followed the same trend as in the survival analysis, only T stage and N stage were found as significant in the same sense as for survival. On multivariate, only T and N stage were found as significant in terms of survival. Specific oncological treatment of relapse was possible in 27/50(54%) patients. Conclusion the intensified follow up did not increase either the proportion of patients detected with asymptomatic relapse or the number of patients with specific oncological treatment of relapse.

We present a case of large cell lung carcinoma in sixty-one year old male with typical lung cancer symptoms but unusual radiological presentation and immunophenotype. Tumor morphological finding related to its radiological finding was suggestive for large cell lymphoma or carcinoma, but its immunophenotype made confusion for pathological diagnosis. No p53 mutations were detected in genetic investigation. Multidisciplinary diagnostic approach to some tumors is useful for their final diagnosis.

The aim of the study was to analyse changes in histological type and age of presentation in female lung cancer patients during a period of 20 years. The obtained results are compared with those available from the literature published in various parts of the world.

We report a case of mucous gland adenoma arising in the left main bronchus which was initially misdiagnosed as asthma and review the previous reported cases of this rare tumor published in the available literature.

Background It is still not clear whether an intrapericardial pneumonectomy indicates a more advanced stage of the disease compared to a standard pneumonectomy. Methods This was a retrospective study of 164 patients who underwent a pneumonectomy for lung cancer. The first group consisted of 82 patients who had a standard pneumonectomy and the second group was 38 patients who had a intrapericardial pneumonectomy, for both groups in the latest 5-year period. The third group was 44 patients with had a sleeve pneumonectomy in the latest 10-year period. The groups were compared in relation to the overall and stage-related survival, influence of T and N factors, operative morbidity and mortality. The statistics used were Kaplan–Meier, U-test, t-test, χ2 test. Results There was no statistically significant difference in stage distribution between standard and intrapericardial pneumonectomies; stages I, II, IIIA and IIIB occurred for 10.9% vs 2.6%, 30.5% vs 26.3%, 46.4% vs 65.8% and 12.2% vs 5.3% of patients, respectively. For patients who had a sleeve pneumonectomy, stage IIIA was significantly more frequent. Although the overall survival (63.5% vs 57.6%) and stage-related 5-year survival were better in the first compared to the second group, especially for stage IIIA (58.6% vs 42.6%), these differences were not statistically significant. There were no significant differences in operative morbidity and mortality between groups 1 and 2, but both were significantly higher in the third group (35.7% and 15.9%). Conclusions An intrapericardial pneumonectomy does not always indicate a more advanced stage of the disease. The need for an intrapericardial pneumonectomy, either established preoperatively or during the operation, as a single factor, even for marginal surgical candidates, is not strong enough to reject these patients for surgery.

Summary Background Connective tissue diseases (CTD) might be associated with various malignancies, and one of the most frequent is lung cancer (LC). Despite our understanding of pathogenesis, this association remains still unclear. The aim of the present study is to describe the clinical characteristics of patients with CTD who developed LC. Methods Of 375 successive patients with CTD followed up to University Hospital between 1995 and 2004, 24 patients were diagnosed with LC: 11 (46%) had systemic sclerosis (SSc), 6 (25%) rheumatoid arthritis (RA), 6 (25%) systemic lupus erythematosus (SLE), and 1 (4%) dermatomyositis. We analyzed LC stage, radiological presentation, histological type, patients’ smoking status, method of diagnosis, treatment applied, and disease outcome. Results Average duration of CTD was 13.95 (range 0–30) years. Non-small cell lung cancer (NSCLC) was significantly more frequent than small-cell lung cancer (SCLC). Among patients with NSCLC, 21 patients (85%) presented with stage III or IV. With regard to treatment, 13% patients underwent surgery, 25% chemotherapy, 4% patients combined chemo- and radiotherapy and 58% patients had only supportive therapy. The median survival was 5 months (range 1–96 months). Conclusion The majority of CTD patients who developed LC were diagnosed at advanced stage and had poor survival. Efforts for early detection of LC in CTD patients’ group are warranted.

Introduction: Tracheobronchial tumours usually cause an airway obstruction and secondary pulmonary infections. Although rare, they are an important differential diagnosis as they may mimic other conditions and diseases. This paper aims to analyse clinical, radiological and histological characteristics of the patients with tracheobronchial tumours diagnosed for a period of 7 years. Materials and Methods: In this retrospective, observational study, we carefully reviewed 65 patients who were diagnosed with tracheal and endobronchial tumours, and performed statistical analysis on the results. Results: Among these 65 patients (36 men and 29 women) with a mean age of 48.8 years (range, 15 to 75), 50 had malignant tumours while 15 had benign ones. The most common symptoms were cough, chest pain and haemoptysis. Cough was a more frequent symptom in patients with benign tumours (P