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Background Recently, anti–programmed cell death 1 (PD-1) and anti–programmed cell death ligand 1 (PD-L1) immunotherapies have yielded promising outcomes for patients with advanced non–small cell lung cancer (NSCLC) and led to great interest in applying these agents to treat resectable early-stage NSCLC. The objective of our study was to evaluate PD-L1 protein expression in resectable early-stage NSCLC specimens from a large Northern European cohort, examine the relationship to clinical characteristics, and demonstrate the prognostic role in resected NSCLC. Materials and Methods A large cohort of 875 NSCLC tumors consisted of 337 patients from Sweden and 538 patients from Norway was studied. All the patients had undergone pulmonary resection, and most patients had had early-stage NSCLC. PD-L1 protein expression was assessed by immunohistochemistry using the Dako PD-L1 22C3 pharmDx kit. The tumor proportion score for PD-L1 protein expression was compared with comprehensive demographic and clinicopathologic data. Results The overall prevalence of PD-L1 protein expression in the resectable NSCLC cohort was 9.5% at a tumor proportion score cutoff of ≥ 50%. Stage I NSCLC had lower PD-L1 expression compared with that of the other stages (P = .0012). PD-L1 expression correlated with wild-type EGFR gene expression (P = .0156) and mutated KRAS gene expression (P = .0004). No significant association was found between PD-L1 expression and mortality after multivariable adjustment for clinical characteristics, although the survival curves showed PD-L1 expression significantly correlated with a poor prognosis in the total NSCLC cohort and in the adenocarcinoma subgroup. Conclusion PD-L1 expression in the present large cohort of resectable NSCLC was relatively low compared with data from clinical trials of advanced NSCLC. PD-L1 expression correlated positively with tumor stage, wild-type EGFR, and KRAS mutation. PD-L1 expression was not found as an independent prognostic factor in the present study. These findings could be important in the future when evaluating the role of anti–PD-1/PD-L1 immunotherapy in the setting of neoadjuvant or adjuvant trials for early-stage resectable NSCLC.

Objectives: A prerequisite for utilizing the tumour, lymph-nodes, and metastases (TNM) for the staging of lung cancer patients is a high quality of the reported data on which the staging is based. The aim of this study was to investigate the concordance between the clinical, cTNM and the pathology, pTNM staging for lung cancer, version 8 as reported to the Cancer Registry of Norway (CRN). Materials and Methods: A total of 1284 patients who underwent surgery 2018–2019 with sufficient data regarding both clinical and pathology T and N descriptors were included. Results: The differences in tumour diameter reported in the clinical and the pathology notifications were ≤5 mm and ≤10 mm in 65.9 % and in 84.4 % of the cases, respectively. For the c- and pT categories, there was concordance in 53.4 % while 28.4 % were upstaged and 18.2 % were downstaged. For N categories there was concordance in 83.3 % while 13.7 % were upstaged and 3.0 % were downstaged. Unforeseen pN2 was found in 6.2 % of the cases. For TNM staging groups there was concordance in 48.1 % of the cases, while 33.4 % were upstaged and 18.5 % were downstaged. The calculated sensitivity and specificity for reported cTNM staging as diagnostic test for being eligible for adjuvant treatment (stage II–IIIA) were 0.65 and 0.91, respectively. Conclusions: These data on staging for lung cancer, as reported to the CRN, shows a disappointingly low precision and concordance in c- and pTNM staging. This urges a strategy for a marked improvement.

Dysregulation of microRNAs is a common mechanism in the development of lung cancer, but the relationship between microRNAs and expression subtypes in non‐small‐cell lung cancer (NSCLC) is poorly explored. Here, we analyzed microRNA expression from 241 NSCLC samples and correlated this with the expression subtypes of adenocarcinomas (AD) and squamous cell carcinomas (SCC) to identify microRNAs specific for each subtype. Gene set variation analysis and the hallmark gene set were utilized to calculate gene set scores specific for each sample, and these were further correlated with the expression of the subtype‐specific microRNAs. In ADs, we identified nine aberrantly regulated microRNAs in the terminal respiratory unit (TRU), three in the proximal inflammatory (PI), and nine in the proximal proliferative subtype (PP). In SCCs, 1, 5, 5, and 9 microRNAs were significantly dysregulated in the basal, primitive, classical, and secretory subtypes, respectively. The subtype‐specific microRNAs were highly correlated to specific gene sets, and a distinct pattern of biological processes with high immune activity for the AD PI and SCC secretory subtypes, and upregulation of cell cycle‐related processes in AD PP, SCC primitive, and SCC classical subtypes were found. Several in silico predicted targets within the gene sets were identified for the subtype‐specific microRNAs, underpinning the findings. The results were significantly validated in the LUAD (n = 492) and LUSC (n = 380) TCGA dataset (False discovery rates‐corrected P‐value, Aberrant expression of microRNAs is an important factor in lung cancer development and differs across different lung cancer expression subtypes. In this study, we identified subtype‐specific microRNAs which may be involved in essential processes characterizing the expression subtypes of ADs and SCCs. Several in silico predicted targets were found within the specific processes.

The impact of the tumor immune microenvironment on overall survival in non‐small cell lung cancer (NSCLC) has been studied, but there is little information on its relevance for risk of relapse after surgery. Understanding more about the immune microenvironment in previously untreated NSCLC could help in identifying high‐risk patients and patients more likely to benefit from neoadjuvant/adjuvant immunotherapy. Here, we examined gene expression in 399 surgically derived NSCLC samples and 47 samples from normal lung, using Agilent microarray and RNA sequencing. In 335 of the tumor samples, programmed death‐ligand 1 (PD‐L1) expression was evaluated by immunohistochemistry. Gene expression was used to estimate content of immune cells and to calculate an immune score. Properties of the immune microenvironment, and its impact on prognosis, were compared in histological subgroups and gene expression subtypes. Tumors with an active immune microenvironment were found for both adenocarcinomas (AD) and squamous cell carcinomas (SCC). In AD, high immune score and high estimates of several immune cell types belonging to the adaptive immune system were associated with better progression‐free survival (PFS), while in SCC, no association between immune characteristics and PFS was found. The immune microenvironment, including PD‐L1 expression, and its impact on prognosis showed clear differences in AD and SCC gene expression subtypes. In conclusion, the NSCLC immune microenvironment is predictive of prognosis after surgery. Lung AD and SCC gene expression subtypes should be investigated as potential prognostic biomarkers in patients treated with immune checkpoint inhibitors.

Background Genetic alterations are common in non-small cell lung cancer (NSCLC), and DNA mutations and translocations are targets for therapy. Copy number aberrations occur frequently in NSCLC tumors and may influence gene expression and further alter signaling pathways. In this study we aimed to characterize the genomic architecture of NSCLC tumors and to identify genomic differences between tumors stratified by histology and mutation status. Furthermore, we sought to integrate DNA copy number data with mRNA expression to find genes with expression putatively regulated by copy number aberrations and the oncogenic pathways associated with these affected genes. Methods Copy number data were obtained from 190 resected early-stage NSCLC tumors and gene expression data were available from 113 of the adenocarcinomas. Clinical and histopathological data were known, and EGFR-, KRAS- and TP53 mutation status was determined. Allele-specific copy number profiles were calculated using ASCAT, and regional copy number aberration were subsequently obtained and analyzed jointly with the gene expression data. Results The NSCLC tumors tissue displayed overall complex DNA copy number profiles with numerous recurrent aberrations. Despite histological differences, tissue samples from squamous cell carcinomas and adenocarcinomas had remarkably similar copy number patterns. The TP53-mutated lung adenocarcinomas displayed a highly aberrant genome, with significantly altered copy number profiles including gains, losses and focal complex events. The EGFR-mutant lung adenocarcinomas had specific arm-wise aberrations particularly at chromosome7p and 9q. A large number of genes displayed correlation between copy number and expression level, and the PI(3)K-mTOR pathway was highly enriched for such genes. Conclusions The genomic architecture in NSCLC tumors is complex, and particularly TP53-mutated lung adenocarcinomas displayed highly aberrant copy number profiles. We suggest to always include TP53-mutation status when studying copy number aberrations in NSCLC tumors. Copy number may further impact gene expression and alter cellular signaling pathways.

Personalised cancer treatment depends on identification of therapeutically relevant biological subgroups of patients for assessing effect of treatment and to discover new therapeutic options. By analyses in heterogeneous patient populations, the effects may be lost in noise. Squamous cell carcinoma of the lung is a major killer worldwide. Despite recent advances, mortality is high and response to therapies varies greatly from patient to patient. Target search in biologically relevant subgroups may identify treatment options not so far discovered. A total of 198 patients undergoing surgery for squamous cell carcinomas of the lung were included in the study. The tumours were analysed for copy number alterations (n = 152) and gene expression from tumour (n = 188) and normal lung (n = 21), with both data levels present in 140 patients. We studied alterations in tumours harbouring mutations in TP53 and in previously published gene expression subtypes. Genes with consistent alterations in both genomic levels were identified as putative biomarkers. Results were validated in TCGA. The most convincing biomarker in TP53 mutated squamous cell carcinomas of the lung was BIRC5 with amplification in 36% of mutated samples, 5% in wild‐type samples and a 17%‐fold change of expression between TP53 mutated tumours and normal lung tissue. BIRC5 was significantly altered in the classical and primitive subtypes. We suggest BIRC5 as a putative predictive biomarker and putative druggable target in squamous cell lung carcinomas harbouring TP53 mutation or classified as classical and primitive subtypes., What's new? This study presents a target gene search combining copy number alteration and gene expression to identify putative genes for therapeutic and predictive approaches in TP53 mutated lung squamous cell carcinoma (SCC) and published gene expression subtypes with high percentages of TP53 mutations. Several potential biomarkers and therapeutic targets emerged from these pre‐defined biological subgroups. The results suggest that BIRC5 is one of the most appealing targets in TP53 mutated cancers and in the classical and primitive subtypes and should be tested clinically in these subgroups. Testing in biologically defined subgroups may increase likelihood of discovering clinically relevant treatment effects.

Introduction There have been significant changes in both diagnostic procedures and therapy for lung cancer since the beginning of the millennium. National incidence and survival data from 2000 through 2016 are studied. Methods National data on cancer incidence and vital status are virtually complete. Changes in incidence and survival are described by absolute numbers, percentages, and calculation of relative survival (period analysis). Results A total of 44,825 individuals were diagnosed with lung cancer in Norway in the study period. The number of incident cases increased with 49% whereas the prevalence increased with 136% from 2000 to 2016. Age-standardised rates rose markedly for women and levelled off for men. In 2016, adenocarcinoma accounted for about 50% of all lung cancers, slightly more for women than for men. The entity “NSCLC not otherwise specified” declined from 24% to 13%, and the fraction of patients with metastatic disease decreased from 54% to 46% during the period, for both sexes combined. The overall median survival time doubled for women and men, reaching 14.3 months and 11.4 months, respectively. For patients with metastatic disease, median survival time showed a small increase but remained less than 6 months. The overall 5-year relative survival increased from 16% to 26% in women and from 16% to 22% in men. The corresponding improvements for the subgroup of non-surgically treated cases with localised disease, were up from 25% to more than 40% in females, and from 10% to almost 40% in males. Conclusion There have been notable changes in incidence patterns and a remarkable improvement in survival for lung cancer over the last 17 years, most markedly for patients without distant metastases at the time of diagnosis. Hopefully, survival will improve even more when immunotherapy is implemented.

Background The previously reported SECA study demonstrated a dramatic 5-year survival improvement in patients with unresectable colorectal liver metastases (CLM) treated with liver transplantation (LT) compared with chemotherapy. The objective of this study was to assess whether immunosuppressive therapy accelerates the growth of pulmonary metastases in patients transplanted for unresectable CLM. Methods Chest CT scans from 11 patients in the SECA study resected for 18 pulmonary metastases were reviewed retrospectively. Tumour diameter, volume and CT characteristics were registered and tumour volume doubling time was calculated. Findings in the SECA group were compared with those of a control group consisting of 12 patients with non-transplanted rectal cancer resected for 26 pulmonary metastases. Disease-free survival (DFS) and overall survival (OS) after first pulmonary resection were determined. Results Median doubling time based on tumour diameter and volume in the SECA and control groups were 125 and 130 days (P = 0·658) and 110 and 129 days (P = 0·632) respectively. The metastases in both groups were distributed to all lung lobes and were mostly peripheral. Median DFS after LT in the SECA group and after primary pelvic surgery in the control group was 17 (range 6–42) and 18 (2–57) months respectively (P = 0·532). In the SECA group, estimated 5-year DFS and OS rates after first pulmonary resection were 39 and 51 per cent respectively. Conclusion Patients treated by LT for unresectable CLM have a good prognosis following resection of pulmonary metastases. Doubling time did not appear to be worse with the immunosuppression used after LT.

Lung cancer is the leading cause of cancer related death, and the past years' improved insight into underlying molecular events has significantly improved outcome for specific subsets of patients. In particular, several new therapies that target protein kinases have been implemented, and many more are becoming available. We have investigated lung cancer specimens for somatic mutations in a targeted panel of 612 human genes, the majority being protein kinases. The somatic mutation profiles were correlated to profiles of immune cell infiltration as well as relapse-free survival. Targeted deep sequencing was performed on 117 tumour/normal pairs using the SureSelect Human Kinome kit (Agilent Technologies), with capture probes targeting 3.2 Mb of the human genome, including exons and untranslated regions of all known kinases, kinase receptors and selected cancer-related genes (612 genes in total). CD8 staining was determined using Ventana Benchmark. Survival analyses were performed using SPSS. The number of mutations per sample ranged from 0 to 50 (within the 612 genes tested), with a median of nine. The prognosis was worse for patients with more than the median number of mutations. A significant correlation was found between mutations in one of selected DNA-repair genes and the total number of mutations in that tumour (p

Objectives Mutation in the PIK3CA gene is reported frequent in squamous cell carcinomas of the lung, but its potential prognostic role is still obscure. We have studied the prognostic importance of PIK3CA mutations as well as the relation to other markers in a large number of early stage lung cancers of squamous carcinoma subtype. Patients and methods Tumour tissue was obtained from 308 consecutively operated lung cancer patients with squamous cell carcinoma in the period 2003–2013. DNA was isolated according to standard procedures, and mutation analysis was done with either the SnapShot method and/or using PIK3CA specific primers in the Cobas system. PD-L1-expression was analysed with immunohistochemistry After thorough follow-up (median 67.6 months), overall survival and time to relapse was calculated. Results Tumour tissue from 102 females and 206 males were analysed. 167 (54.2%) were in stage I, 96 (31.2%) in stage II and 45 (14.6%) in stage III. PIK3CA mutation was found in 35 (11.4%) patients, most frequently in exon 20. There were no differences in sex, stage or smoking behaviour between mutated and non-mutated cases. Patients with PIK3CA mutations had a significantly longer overall survival (p = 0.042) and time to relapse (p = 0.030) than non-mutated cases, and the difference in time to relapse was also retained in stage I-cases (p = 0.044). PD-L1-expression was less frequent among mutated cases. Conclusion Our results indicate that PIK3CA mutations may confer a survival advantage in early stage squamous cell lung cancers, but further work is needed to confirm this finding.

Objective To determine overall survival and disease-free survival in selected patients with nonresectable liver-only colorectal cancer receiving liver transplantation. Background Patients with nonresectable colorectal cancer receiving palliative chemotherapy has a 5-year overall survival of about 10%. Liver transplantation provided an overall survival of 60% in a previous study (SECA-I). Risk factors for death were carcinoembryonic antigen (CEA) >80 μg/L, progressive disease on chemotherapy, size of largest lesion>5.5 cm, and less than 2 years from resection of the primary tumor to transplantation. Methods In this prospective (SECA-II) study, we included colorectal cancer patients with nonresectable liver-only metastases determined by computed tomography (CT)/magnetic resonance imaging/positron emission tomography scans and at least 10% response to chemotherapy. Time from diagnosis to liver transplant was required to be more than 1 year. Results At a median follow-up of 36 months, Kaplan-Meier overall survival at 1, 3, and 5 years were 100%, 83%, and 83%, respectively. Disease-free survival at 1, 2, and 3 years were 53%, 44%, and 35%, respectively. Overall survival from time of relapse at 1, 2, and 4 years were 100%, 73%, and 73%, respectively. Recurrence was mainly slow growing pulmonary metastases amenable to curative resection. Fong Clinical Risk Score of 1 to 2 at the time of diagnosis resulted in longer disease-free survival than score 3 to 4 (P = 0.044). Patients included in the present study had significantly better prognostic factors than the previous SECA-I study. Conclusion Liver transplantation provides the longest overall survival reported in colorectal cancer patient with nonresectable liver metastases. Improved selection criteria give patients with nonresectable colorectal liver metastases a 5-year overall survival comparable to other indications for liver transplantation.

Background Protein expression is deregulated in cancer, and the proteomic changes observed in lung cancer may be a consequence of mutations in essential genes. The purpose of this study was to identify protein expression associated with prognosis in lung cancers stratified by smoking status, molecular subtypes, and EGFR-, TP53- and KRAS-mutations. Methods We performed profiling of 295 cancer-relevant phosphorylated and non-phosphorylated proteins, using reverse phase protein arrays. Biopsies from 80 patients with operable lung adenocarcinomas were analyzed for protein expression and association with progression free survival (PFS) were studied. Results Spearman rank correlation analysis identified 56 proteins with significant association to PFS (p

We have studied the alterations in the use of curative treatment and the outcome for lung cancer patients in Norway 2001–2016. The Cancer Registry of Norway has a practically complete registration of all cancer diagnoses, treatments given and deaths. For the years 2001–2016, 43,137 patients were diagnosed with lung cancer. Stereotactic radiotherapy was established nationwide from 2008 and its use has increased, and in 2016, 8.8% were given this treatment. In addition 20.6% were operated and 8.5% were treated with conventional radiotherapy. Thus 37.9% of those diagnosed were treated with intention to cure, compared to 22.9% in 2001 (p

Pulmonary large-cell neuroendocrine carcinomas (LCNECs) have similarities with other lung cancers, but their precise relationship has remained unclear. Here we perform a comprehensive genomic (n = 60) and transcriptomic (n = 69) analysis of 75 LCNECs and identify two molecular subgroups: “type I LCNECs” with bi-allelic TP53 and STK11/KEAP1 alterations (37%), and “type II LCNECs” enriched for bi-allelic inactivation of TP53 and RB1 (42%). Despite sharing genomic alterations with adenocarcinomas and squamous cell carcinomas, no transcriptional relationship was found; instead LCNECs form distinct transcriptional subgroups with closest similarity to SCLC. While type I LCNECs and SCLCs exhibit a neuroendocrine profile with ASCL1high/DLL3high/NOTCHlow, type II LCNECs bear TP53 and RB1 alterations and differ from most SCLC tumors with reduced neuroendocrine markers, a pattern of ASCL1low/DLL3low/NOTCHhigh, and an upregulation of immune-related pathways. In conclusion, LCNECs comprise two molecularly defined subgroups, and distinguishing them from SCLC may allow stratified targeted treatment of high-grade neuroendocrine lung tumors., The molecular nature of large-cell neuroendocrine lung carcinomas (LCNEC) has remained unclear. Here, the authors show LCNECs represent a distinct transcriptional subgroup among lung cancers and comprise two molecular subgroups, type I (TP53 and STK11/KEAP1 alterations) and type II (TP53 and RB1 inactivation).

Background Patients need information about the course of recovery after surgery for lung cancer, but knowledge about symptoms in this period is limited. Objective The purpose of this study was to assess for changes in symptom occurrence rates and severity scores from the preoperative period to 1 month after surgery. Methods Patients (n = 228) completed questionnaires before and at 1 month after surgery. McNemar tests were used to evaluate for changes over time in symptom occurrence rates and paired t tests for changes in symptom severity scores. General linear model was used to determine if select demographic and clinical characteristics were associated with the number of symptoms after surgery. Results The total number of symptoms increased significantly from the preoperative (mean, 9.4) to the postoperative (mean, 13.1) assessment. Of the 11 symptoms that occurred in 50% or more of the patients 1 month after surgery, 8 increased significantly in both occurrence and severity. Four symptoms were experienced by more than 80% of the patients 1 month after surgery: shortness of breath (85.5%), lack of energy (83.8%), pain (83.8%), and feeling drowsy (82.5%). Conclusions Patients experienced a high number of symptoms after lung cancer surgery. The only characteristic that was associated with a higher number of symptoms 1 month after surgery was the number of symptoms reported preoperatively. Implications for practice These findings can be used to educate patients about the normal course of postoperative recovery. Clinicians need to assess for these symptoms and develop effective interventions to improve symptom management for these patients.

Introduction: Surgical resection is recommended treatment in patients with early-stage non-small cell lung cancer (NSCLC). In addition to tumor stage and biology, various risk factors contribute to postoperative mortality. Aims and objectives: We have investigated risk factors for all-cause mortality. In addition we evaluated risk factors for specific causes of death due to lung cancer, cardiovascular disease and other causes. Methods: We individually assessed risk factors affecting overall and cause-specific mortality in a Cox’ proportional hazards model in a cohort of stage I/II NSCLC patients (n=756, 381 females, 375 males, -mean age at surgery 66 years) treated from 2007-2015 in a tertiary university center. Median follow-up was 7.3 years and ended at 9.3 years. Results: Risk factors predicting mortality for all causes of death and death due to NSCLC were increasing age, severely reduced lung function, ECOG ≥2, preoperative examination without FDG-PET/CT, tumor histology (large cell carcinoma, adenosquamous cell carcinoma, carcinoma-NOS) and increasing tumor stage. Patients dying of cardiovascular disease were few (n=19) and therefore included in the other cause group. In patients dying of other causes, age, gender, BMI, smoking and ECOG ≥2 affected mortality. At the end of follow-up there was 35% risk of dying from lung cancer and 20% risk of dying of other causes. Risk of cardiovascular death was 3%. Overall survival was 74%, 62% and 41% at 3, 5 and 9 years, respectively. Conclusions: Our study documented continued risk of lung cancer death beyond 5 years after resection. This may contribute to future guidelines, especially in terms of duration of follow-up in surgically resected lung cancer patients.

Objectives Surgical resection is the recommended treatment for patients with early-stage non-small-cell lung cancer. However, it is believed that causes other than lung cancer can lead to death following surgical resection. Investigating the risk factors for overall mortality and analysing the specific causes of death may indicate the degree of influence of other causes of death. Methods We assessed individual risk factors affecting overall and cause-specific mortality in a Cox proportional hazards model in a cohort of patients with resected Stage I/II non-small-cell lung cancer (n = 756) from 2007 to 2015 in a tertiary university centre. The follow-up period ranged from 3 days to 9.3 years. Median survival time was 7.3 years (95% confidence interval 6.0-7.9). A few patients died of cardiovascular disease (n = 19) and were included in the group 'other cause'. In a competing risk model, we evaluated the risk factors for specific causes of death in patients dying of lung cancer and dying of non-lung cancer specific conditions. Results The overall survival was 94%, 62% and 50% at 1, 5 and 7 years, respectively. At the end of the follow-up period, the risk of having died of, respectively, lung cancer or other causes was 36% and 24%. The cumulative incidence of death of lung cancer increased continuously during the study. Risk factors predicting death of all causes and death of non-small-cell lung cancer were increasing age, severely reduced lung function, Eastern Cooperative Oncology Group Performance Status ≥2, preoperative examination without positron emission tomography/computed tomography, histological tumour diagnosis other than adenocarcinoma and squamous cell carcinoma and increasing disease stage. In patients dying of other causes, age, gender, body mass index, smoking and Eastern Cooperative Oncology Group Performance Status ≥2 affected the mortality rate. Conclusions The probability of having died of lung cancer continued to increase beyond 5 years after the operation. Surveillance of risk factors associated with an increased mortality rate should be considered in the postoperative follow-up examination after lung cancer resection.

Background Non-small cell lung cancer is a major killer world-wide. While some lung adenocarcinomas have mutations qualifying for targeted therapy, this is not the case for the squamous cell carcinomas (SqCC). TP53 mutations exist in around 85% of squamous cell carcinomas, but the mutations are difficult to target directly. We explore the biology of TP53 mutated SqCC and search for putative targets for therapy. Methods Patients undergoing surgery for squamous cell lung carcinoma from 2006 to 2015 were included in the study (n = 198). Tumours were analysed using Illumina SNP6 for copy number alterations and Agilent 60K arrays for gene expression. TP53 mutations were analysed by Sanger sequencing. For 140 patients both gene expression and copy number data were available. Results Frequency plots for tumours harbouring TP53 mutations and TP53 wild type tumours were generated separately identifying genomic regions with differential frequency of copy number alterations. TP53 mutations are more frequent in the previously published gene expression subtypes Classical and Primitive compared with Basal and Secretory, but this does not seem to affect survival. Amplifications are particularly frequent in the Classical subtype. Target gene search was performed, identifying 148 genes with amplification and over-expression in TP53 mutated tumours compared with wild type tumours. Several of these putative target genes are previously studied as putative targets of therapy. The majority of the putative target genes are located on the chromosomal arms 2p for samples of the Secretory subtype, 2q for samples of the Primitive subtype and on 12p and 17q for samples of the Classical subtype. Conclusions There are distinct copy number alterations and gene expression patterns in TP53 mutated squamous cell lung cancers that can be used to identify novel targets of therapy. Legal entity responsible for the study Oslo University Hospital. Funding The Norwegian Cancer Society, South-Eastern Norway Regional Health Authority. Disclosure All authors have declared no conflicts of interest.

Objectives This research aims to study how carotid atherosclerosis is related to growth of infrarenal aortic diameter and aneurysmal formation. Design Population-based follow-up study. Materials and methods At baseline, ultrasound examination of the carotid artery and the abdominal aorta was performed in 4241 persons from a general population with no evidence of abdominal aortic aneurysm (AAA). The burden of atherosclerosis was assessed as carotid total plaque area (TPA). After a mean follow-up of 6.3 years, a new ultrasound examination was performed and measurements of the aortic diameter and carotid TPA were repeated. The effects on aortic diameter progression, follow-up diameter and risk for AAA were assessed in multiple linear and logistic regression models according to carotid TPA, adjusted for known risk factors. Results When analysing AAA as a dichotomous variable, a borderline association between atherosclerosis and AAA could be demonstrated. When modelling aortic diameter as a continuous variable, a 1-SD increase in 5 years' carotid plaque area (ΔTPA) was associated with a 0.12-mm growth in infrarenal aortic diameter (standard error (SE) 0.04) and a 0.20-mm wider aorta at follow-up (SE 0.06). No independent relation was seen for baseline atherosclerosis. Conclusions Carotid plaque progression was positively related to growth in infrarenal aortic diameter and aortic diameter at follow-up. Whether this co-variation between plaque growth and aortic diameter growth is causally related or independent events is still an open question.

Background: Asbestos-related malignant pleural mesothelioma is one of the most lethal tumor types. The advent of antimetabolite treatment as pemetrexed, introduced in the early 2000s, may have increased survival on a population basis. In this study, we have analyzed population-based incidence and survival data over the last 40 years. Methods: Complete national data on 1686 patients from the Cancer Registry of Norway sampled from 1970 to 2009 are presented, with incidence rates in 5-year periods. Relative survival for 1 year and 3 years and median survival in 5-year intervals were calculated. Results: The incidence of malignant pleural mesothelioma has been significantly and steadily increasing from 1970 until 2009, with 50 patients diagnosed in the period 1970–1974 and 377 diagnosed in 2005–2009. The incidence was highest among men in all time periods. A slight decline was observed in the last period. The 1-year survival rate increased from 20.7% to 44.0% during the period 1970–2009, whereas the 3-year survival rate remained below 10%. Median survival increased from 4.0 months in the first period to 9.3 months in the last period. Conclusions: The incidence of malignant pleural mesothelioma follows the curve of asbestos exposure with a 20- to 40-year lag. There has been a significant increase in survival, most likely because of earlier diagnosis and improvements in cytostatic treatment.

Extensive prior research focused on somatic copy-number alterations (SCNAs) affecting cancer genes, yet the extent to which recurrent SCNAs exert their influence through rearrangement of cis-regulatory elements (CREs) remains unclear. Here we present a framework for inferring cancer-related gene overexpression resulting from CRE reorganization (e.g., enhancer hijacking) by integrating SCNAs, gene expression data and information on topologically associating domains (TADs). Analysis of 7,416 cancer genomes uncovered several pan-cancer candidate genes, including IRS4, SMARCA1 and TERT. We demonstrate that IRS4 overexpression in lung cancer is associated with recurrent deletions in cis, and we present evidence supporting a tumor-promoting role. We additionally pursued cancer-type-specific analyses and uncovered IGF2 as a target for enhancer hijacking in colorectal cancer. Recurrent tandem duplications intersecting with a TAD boundary mediate de novo formation of a 3D contact domain comprising IGF2 and a lineage-specific super-enhancer, resulting in high-level gene activation. Our framework enables systematic inference of CRE rearrangements mediating dysregulation in cancer.

Lung cancer is the leading cause of cancer death worldwide. The incidence and mortality rate of lung cancer in women has increased. Studies have indicated that females with non-small cell lung cancer (NSCLC) have better survival than males. We aimed to examine the impact of gender on 1-, 5- and 10-year survival after surgery for stage I and II NSCLC.During the period 2003-2013, 692 patients operated for stage I and II NSCLC were prospectively registered. Patients were stratified into four groups according to gender and age over or less than 66 years. The relationship between gender and age on overall survival was investigated. Adjustment for multiple confounders was performed using the Cox proportional hazard regression model.Surgical resection was performed in 368 (53.2%) males and 324 (46.8%) females. During the study period, mortality was 35.2% in younger females, 34.9% in younger males, 42.8% in older females and 51.2% in older males. Stratified by age, there were no significant gender differences with regard to survival [hazard ratio (HR) 1.16, 95% confidence interval (CI) 0.91-1.46, p = .23]. Comparing the younger and the older patients adjusted for confounders, the mortality risk was significantly increased in elderly patients [females, adjusted HR 1.60, 95% CI 1.12-2.28]. Compared with population data, standardized mortality ratio was increased to 4.1 (95% CI 3.5-4.7) in males and to 6.5 (95% CI 5.4-7.6) in females.Overall survival did not differ significantly between males and females. Adjusted for confounding factors, we found a significantly increased mortality risk in elder patients compared to their younger counterparts. However, five-year overall survival of more than 50% for older patients with NSCLC should encourage surgical treatment also in elderly lung cancer patients.

Published version. Source at http://dx.doi.org/10.1186/s13000-016-0504-4 Background: The regional lymph node involvement is a major prognostic factor in patients with non-small cell lung cancer (NSCLC) undergoing surgical resection. Disease relapse is common, suggesting that early disseminated disease is already present in the regional lymph nodes at the time of surgery, and that the current nodal staging classification might be suboptimal. Early detection of disseminated tumor cells (DTCs) in lymph nodes could potentially enable identification of subcategories of patients with high risk of disease relapse. Method: Lymph node samples were collected from 128 NSCLC patients at the time of surgery and the presence of DTCs determined by immunomagnetic selection (IMS) using the MOC31 antibody recognizing EpCAM. Results obtained with IMS were compared to the pathological staging obtained by histopathology. Associations between the presence of DTCs and clinicopathological variables and patient outcome were investigated. Results: DTCs were detected in 40 % of the lymph node samples by IMS. Their presence was significantly associated with pN status as assessed by histopathology, and samples from 83 % of the patients with lymph node metastases (pN1-2) had detectable DTCs. In the group of patients who were negative for lymph node metastases by standard histopathology (pN0) DTCs were detected in 32 %. The presence of DTCs was not associated with any other clinicopathological variables. Patients with IMS-positive samples showed decreased relapse free survival compared to patients with IMS-negative samples, but the difference was not statistically significant. The pN status was significantly associated with both relapse free and overall survival, but the presence of DTCs had no prognostic impact in the subcategory of patients with pN0 status. Conclusion: Our findings do not support further development of lymph node DTC detection for clinical use in early stage NSCLC.

Small-cell lung cancer (SCLC) is an aggressive lung tumor subtype with poor prognosis(1-3). We sequenced 29 SCLC exomes, 2 genomes and 15 transcriptomes and found an extremely high mutation rate of 7.4 +/- 1 protein-changing mutations per million base pairs. Therefore, we conducted integrated analyses of the various data sets to identify pathogenetically relevant mutated genes. In all cases, we found evidence for inactivation of TP53 and RB1 and identified recurrent mutations in the CREBBP, EP300 and MLL genes that encode histone modifiers. Furthermore, we observed mutations in PTEN, SLIT2 and EPHA7, as well as focal amplifications of the FGFR1 tyrosine kinase gene. Finally, we detected many of the alterations found in humans in SCLC tumors from Tp53 and Rb1 double knockout mice(4). Our study implicates histone modification as a major feature of SCLC, reveals potentially therapeutically tractable genomic alterations and provides a generalizable framework for the identification of biologically relevant genes in the context of high mutational background.

Surgery is the gold standard of lung carcinoid treatment. However, bronchoscopic treatment may provide a complete cure in selected patients. The aim of the study was to review the results of laser treatment of bronchial carcinoids and to compare the outcome after laser resection against the outcome after surgical resection.Seventy-three patients, 29 men and 44 women, median age 53 years (range, 23 to 78 y), with bronchial carcinoids were treated by surgical resection (n=48) or endobronchial ablation (n=25). Bronchoscopic treatment was also performed in 5 of 48 surgical patients as a part of the surgical treatment strategy.Among 25 patients treated endoscopically, 16 were successfully treated with laser, whereas 9 were operated subsequently. One major complication was registered, as an inadvertent ventilation caused a nonfatal fire of the bronchoscope during Nd:YAG laser procedure. Forty-eight patients underwent surgical resection. Most of the patients underwent lobectomy and bilobectomy (30 and 5 patients, respectively). Four of the patients were dead by the end of the study, 1 was treated with laser, and 3 treated with surgical resection. The overall survival was 94.5% in the surgical group and 94.4% in the group treated with endoscopic ablation (P=0.9). None of the 69 survivors had any sign of recurrence on computed tomographic scans and bronchoscopy by the end of the study.This is a retrospective study and no randomization has been performed. However, the results add evidence to the view that transbronchial laser treatment may be offered as a safe, stand-alone procedure in the treatment of typical carcinoid tumor in the central airways.

In a study of 41 surgically removed colorectal adenomas of unselected size, the dysplasia was graded as mild in 9, as moderate in 22, and severe in 10 cases. Twenty-four of the lesions were classified as tubular adenomas and 17 as tubulo-villous. The presence of O-acylated sialic mucin was for each of the adenomas assessed as normal (19 cases), intermediate (13 cases) or absent (9 cases). The absence of O-acylated mucin was in the present study found to be highly predictive for severe dysplasia (89%). The morphometric measurements of epithelial structures showed that nuclear shape factor and nuclear stratification index were most significantly related to the grades of dysplasia. In a multivariate analysis, the grading of O-cylated sialic mucin most significantly contributed to the grade of dysplasia, and to a lesser degree, nuclear shape factor and nuclear stratification index. The presence of villous elements and the size of the adenomas had no independent influence on the grade of dysplasia in this statistical analysis.

In 4649 autopsies performed, in 1972–1985, 824 cases of acute myocardial infarction were found. Of these, 104 (12.6%) had cardiac rupture. Ten cases had rupture of the interventricular septum. The clinical and pathological records were reviewed, and the rupture group was compared with a control group of 100 patients who died from acute myocardial infarction without rupture. Of the patients with rupture, 85% died during the first week after the onset of myocardial infarction; three patients with rupture died suddenly without previous clinical evidence of myocardial infarction. Rupture occurred only in hearts with transmural infarcts, and predominantly in the anteroseptal wall. Patients with rupture had significantly higher blood pressure, fewer previous infarcts, higher frequency of coronary thrombi, less myocardial scar tissue and lower heart weight compared to the control group. There were no significant differences regarding age and sex distribution, physical effort at the symptom debut or death, medication, previous and present diseases other than infarcts, complications or the degree of atherosclerosis in the coronary arteries or aorta.

Background Extensive research has increased our understanding of the molecular alterations needed for non-small cell lung cancer (NSCLC) development. Deregulation of a pathway including MYCN, HMGA2 and CDKN2A, with the participation of DICER1, is of importance in several solid tumours, and may also be of significance in the pathogenesis of NSCLC. Methods Gene expression of MYCN, HMGA2, CDKN2A and DICER1 were investigated with RT-qPCR in surgically resected NSCLC tumour tissue from 175 patients. Expression of the let-7 microRNA family was performed in 78 adenocarcinomas and 16 matching normal lung tissue samples using microarrays. The protein levels of HMGA2 were determined by immunohistochemistry in 156 tumour samples and the protein expression was correlated with gene expression. Associations between clinical data, including time to recurrence, and expression of mRNA, protein and microRNAs were analysed. Results Compared to adenocarcinomas, squamous cell carcinomas had a median 5-fold increase in mRNA expression of HMGA2 (p = 0.003). A positive correlation (r = 0.513, p

Background The best curable therapy for lung cancer is surgical resection. Chronic obstructive pulmonary disease (COPD) may influence survival, and lung function is crucial in the preoperative assessment. We hypothesized that COPD would influence survival after lung cancer resection. Methods During the period 2003 to 2013, 688 patients were operated on for stage I and II non-small cell lung cancer and prospectively registered. Spirometry was performed, and COPD categorized according to the definition by the Global Initiative for Chronic Obstructive Lung Disease. An explanatory strategy was used to investigate the relationship between severe COPD and survival. Results COPD was present in 455 patients (66.1%) and was severe in 51 (7.4%) and mild to moderate in 404 (58.7%), whereas 233 patients (33.9%) had normal lung function. Cumulative survival was similar in patients with normal lung function and patients with mild to moderate COPD. Patients with severe COPD had significantly reduced cumulative survival after 2 and 5 years of 63.5% (95% confidence interval [CI], 48.4% to 75.2%) and 41.8% (95% CI, 26.5% to 56.3%), respectively, compared with nonsevere COPD at 81.7% (95% CI, 77.4% to 85.2%) and 61.3% (95% CI, 55.3% to 66.6%), respectively. Severe COPD was associated with a 69% increased risk of mortality (adjusted hazard ratio, 1.69; 95% CI, 1.12 to 2.55). Conclusions With careful preoperative selection, surgical resection may safely be offered to lung cancer patients with severe COPD. However, these patients have decreased long-term overall survival. Similar survival between patients with normal lung function and mild to moderate COPD suggests that similar indications for lung cancer operations may be applied.

Immunoscore is a prognostic tool defined to quantify in situ immune cell infiltrates and appears highly promising as a supplement to the tumor-node-metastasis (TNM) classification of various tumors. In colorectal cancer, an international task force has initiated prospective multicenter studies aiming to implement TNM-Immunoscore (TNM-I) in a routine clinical setting. In breast cancer, recommendations for the evaluation of tumor-infiltrating lymphocytes (TILs) have been proposed by an international working group. Regardless of promising results, there are potential obstacles related to implementing TNM-I into the clinic. Diverse methods may be needed for different malignancies and even within each cancer entity. Nevertheless, a uniform approach across malignancies would be advantageous. In nonsmall-cell lung cancer (NSCLC), there are several previous reports indicating an apparent prognostic importance of TILs, but studies on TILs in a TNM-I setting are sparse and no general recommendations are made. However, recently published data is promising, evoking a realistic hope of a clinical useful NSCLC TNM-I. This review will focus on the TNM-I potential in NSCLC and propose strategies for clinical implementation of a TNM-I in resected NSCLC.

Background: DNA methylation alterations are early events in tumorigenesis and important in the regulation of gene expression in cancer cells. Lung cancer patients have in general a poor prognosis, and a deeper insight into the epigenetic landscape in lung adenocarcinoma tumors and its prognostic implications is needed. Results: We determined whole‐genome DNA methylation profiles of 164 fresh frozen lung adenocarcinoma samples and 19 samples of matched normal lung tissue using the Illumina Infinium 450K array. A large number of differentially methylated CpGs in lung adenocarcinoma tissue were identified, and specific methylation profiles were observed in tumors with mutations in the EGFR‐, KRAS‐ or TP53 genes and according to the patients' smoking status. The methylation levels were correlated with gene expression and both positive and negative correlations were seen. Methylation profiles of the tumor samples identified subtypes of tumors with distinct prognosis, including one subtype enriched for TP53 mutant tumors. A prognostic index based on the methylation levels of 33 CpGs was established, and was significantly associated with prognosis in the univariate analysis using an independent cohort of lung adenocarcinoma patients from The Cancer Genome Atlas project. CpGs in the HOX B and HOX C gene clusters were represented in the prognostic signature. Conclusions: Methylation differences mirror biologically important features in the etiology of lung adenocarcinomas and influence prognosis., Highlights Extensive DNA methylation changes linked to immune signaling.DNA methylation in EGFR‐mutated tumors associated with oncogenic pathways.DNA methylation with both positive and negative correlation with mRNA expression.DNA methylation signature with prognostic information.

We characterized genome alterations in 1255 clinically annotated lung tumors of all histological subgroups to identify genetically defined and clinically relevant subtypes. More than 55% of all cases had at least one oncogenic genome alteration potentially amenable to specific therapeutic intervention, including several personalized treatment approaches that are already in clinical evaluation. Marked differences in the pattern of genomic alterations existed between and within histological subtypes, thus challenging the original histomorphological diagnosis. Immunohistochemical studies confirmed many of these reassigned subtypes. The reassignment eliminated almost all cases of large cell carcinomas, some of which had therapeutically relevant alterations. Prospective testing of our genomics-based diagnostic algorithm in 5145 lung cancer patients enabled a genome-based diagnosis in 3863 (75%) patients, confirmed the feasibility of rational reassignments of large cell lung cancer, and led to improvement in overall survival in patients with EGFR-mutant or ALK-rearranged cancers. Thus, our findings provide support for broad implementation of genome-based diagnosis of lung cancer.

Genomic translocation events frequently underlie cancer development through generation of gene fusions with oncogenic properties. Identification of such fusion transcripts by transcriptome sequencing might help to discover new potential therapeutic targets. We developed TRUP (Tumor-specimen suited RNA-seq Unified Pipeline) (https://github.com/ruping/TRUP), a computational approach that combines split-read and read-pair analysis with de novo assembly for the identification of chimeric transcripts in cancer specimens. We apply TRUP to RNA-seq data of different tumor types, and find it to be more sensitive than alternative tools in detecting chimeric transcripts, such as secondary rearrangements in EML4-ALK-positive lung tumors, or recurrent inactivating rearrangements affecting RASSF8. Electronic supplementary material The online version of this article (doi:10.1186/s13059-014-0558-0) contains supplementary material, which is available to authorized users.

Objectives: to assess intra- and interobserver variability in the measurement of aortic and common iliac artery diameter by means of computed tomography (CT). Design: reproducibility study. Material and Methods: three radiologists performed measurements of aortic diameter at five different levels and of both common iliac arteries with CT. Fifty-nine subjects were examined, 29 with and 30 without abdominal aortic aneurysms (AAA) as assessed by ultrasound. Results: intraobserver variability varied between radiologists, measurement plane (anterior-posterior vs transverse) and measurement level. The interobserver variability was markedly higher at the bifurcation than at the suprarenal level and higher than intraobserver variability for measurements at all levels. Both intraobserver and interobserver variability increased with increasing vessel diameter and were largest in patients with AAA. The absolute intraobserver difference of the maximal infrarenal aortic diameter was 2 mm or less in 94% of intraobserver pairs. The corresponding interobserver difference was 82%. Conclusions: interobserver variability of CT measurements of aortic and common iliac artery diameter is not negligible and should be taken into account when making clinical decisions. When assessing change in aortic diameter, previous CT-scans should be reviewed simultaneously as a routine to exclude interobserver variability. Eur J Vasc Endovasc Surg 25 , 399-407 (2003)

Background Acute renal failure (ARF) after cardiac surgery is associated with high costs and a poor prognosis. Based on the results of a large US study, an algorithm has been developed for predicting ARF from pre-operative risk factors. The aim of this study was to cross-validate this algorithm in a patient population from Europe, and to assess its usefulness as a clinical tool. Methods All coronary bypass and valvular surgery patients from a 5-year period were included. Data on pre-operative risk factors for all patients who developed dialysis-dependent ARF and for a random sample of patients without ARF were retrospectively obtained from hospital databases and medical records. For each patient, a risk score for ARF was calculated on the basis of the algorithm. The sensitivity, specificity, positive and negative predictive values and area under receiver operating characteristic (ROC) curve of the score's ability to predict ARF were estimated. Results 2037 patients were included. The risk of ARF was 1.9%, and the area under the ROC curve 0.71. For a risk score of 6 or higher, the sensitivity was 0.53, the specificity 0.71, the positive predictive value 0.03 and the negative predictive value 0.99. Conclusions The validity of the algorithm was confirmed in a population differing in several aspects from the US populations where it was developed. Although it is useful for estimating the risk of ARF in groups of patients, the low risk of ARF limits the algorithm's ability to predict the outcome for individual patients.