In 2011, the U.S. National Lung Cancer Screening Trial (NLST) reported a 20% reduction of lung cancer mortality after regular screening by low‐dose computed tomography (LDCT), as compared to X‐ray ...screening. The introduction of lung cancer screening programs in Europe awaits confirmation of these first findings from European trials that started in parallel with the NLST. The German Lung cancer Screening Intervention (LUSI) is a randomized trial among 4,052 long‐term smokers, 50–69 years of age, recruited from the general population, comparing five annual rounds of LDCT screening (screening arm; n = 2,029 participants) with a control arm (n = 2,023) followed by annual postal questionnaire inquiries. Data on lung cancer incidence and mortality and vital status were collected from hospitals or office‐based physicians, cancer registries, population registers and health offices. Over an average observation time of 8.8 years after randomization, the hazard ratio for lung cancer mortality was 0.74 (95% CI: 0.46–1.19; p = 0.21) among men and women combined. Modeling by sex, however showed a statistically significant reduction in lung cancer mortality among women (HR = 0.31 95% CI: 0.10–0.96, p = 0.04), but not among men (HR = 0.94 95% CI: 0.54–1.61, p = 0.81) screened by LDCT (pheterogeneity = 0.09). Findings from LUSI are in line with those from other trials, including NLST, that suggest a stronger reduction of lung cancer mortality after LDCT screening among women as compared to men. This heterogeneity could be the result of different relative counts of lung tumor subtypes occurring in men and women.
What's new?
Low‐dose computed tomography (LDCT) is an emerging tool for early lung cancer detection. Here, as part of the German Lung Cancer Screening Intervention trial, the benefits of annual LDCT screening were examined in long‐term smokers ages 50 to 69. In men and women combined, no statistically significant reduction in lung cancer mortality was observed after five annual rounds of LDCT screening compared to controls. Separate analyses by sex, however, revealed significant reductions in lung cancer mortality among the women who underwent LDCT. The findings support the systematic use of LDCT in lung cancer screening, though critical optimization strategies await investigation.
The treatment of patients with pulmonary metastases from colorectal cancer continues to evolve. Recently the use of novel agents as a first-line treatment in metastatic colorectal disease has ...generated cautious optimism in the oncological community. However, pulmonary metastasectomy remains a mainstay in a multidisciplinary concept for a highly selected subset of patients. A selected group of patients with metastases limited to the lungs may benefit from pulmonary metastasectomy with a 5-year survival rate of up to more than 50%. This review evaluates the current status of surgical resection in pulmonary metastases from colorectal cancer, with special emphasis on prognostic factors that influence survival, as well as on surgical approach and lymph node dissection and its impact on the management of patients with metastatic colorectal disease.
Abstract Patients with stage IV metastatic non-small cell lung cancer (NSCLC) are generally believed to have an incurable disease. Patients with oligometastatic disease represent a distinct subset of ...patients among those with metastatic disease. There is evidence that these patients have synchronous or metachronous satellite nodules in different pulmonary lobes or have solitary extrapulmonary metastases. In these cases, evidence has shown that surgical resection may provide patients with survival benefit. This article discusses the biology of the oligometastatic state in patients with lung cancer and the selection of patients for surgery, as well as the prognostic factors that influence survival of the patient. To properly select patients for an aggressive local treatment regime, accurate clinical staging is of prime importance. The use of FDG-PET should be considered for restaging if oligometastatic disease is suspected based on a patient's CT scan. A limitation of retrospective clinical studies for oligometastatic disease is that it is difficult to summarize and evaluate the available evidence for the effectiveness of surgical resection due to selection bias, and to a high degree of variability among different clinical studies. Nevertheless, we can certainly learn from the clinical experience acquired from retrospective case series to identify prognostic factors. Following surgical resection, the overall 5-year actuarial survival rate is about 28% for patients with satellite nodules and 21% for patients with ipsilateral nodules. Patients with resected brain metastasis achieve 5-year survival rates between 11% and 30%, and those with adrenalectomy for adrenal metastasis achieve 5-year survival rates of 26%.
Tumor spread, in general, is the most important factor determining outcome in almost all malignant tumors. Lung tumors are unique with respect to potential routes for tumor dissemination, as apart ...from vascular, nodal, and distant spread of tumor cells, tumor spread through air spaces (STAS) might also occur. However, morphologic criteria for STAS and its prognostic impact have not been defined yet. We evaluated a series of 569 resected pulmonary adenocarcinomas (ADCs) for predefined morphologic criteria of limited and extensive STAS and correlated our findings with clinical, morphologic, molecular, and outcome data. Limited (21.6%) or extensive (29%) STAS was present in roughly half of all ADCs. The presence and type of STAS was tightly linked to specific growth patterns (P<0.001). STAS was much more prevalent in high-stage (P<0.001), nodal-positive (P<0.001) ADC with distant metastasis (P=0.010). STAS was associated with lower rates of EGFR (P=0.009) but higher rates of BRAF (P=0.016) mutations. Furthermore, STAS was associated with significantly reduced overall (P=0.020) and disease-free survival (P=0.004), which was growth pattern but not stage independent. We analyzed morphologic characteristics of a yet underestimated type of tumor spread of pulmonary ADC through air spaces. STAS is a novel morphologic prognosticator, which should be further validated and considered for implementation in routine diagnostic evaluation and reporting.
Myeloid-derived suppressor cell (MDSC) expansion has been found to play a role in disease progression in patients with cancer. However, the characteristics of MDSCs in lung cancer are poorly ...understood.
We prospectively investigated MDSCs and inflammatory factors in tumor and peripheral blood samples from patients with resectable non-small cell lung cancer and studied their correlations with the disease prognosis.
A complex analysis of MDSC subsets and inflammatory mediators was performed using flow cytometry and a Bio-Plex assay.
A significant increase in the frequency of circulating monocytic (M)-MDSCs was observed in the patients with non-small cell lung cancer compared with the healthy donors (HDs). Moreover, the frequencies of M- and polymorphonuclear (PMN)-MDSCs were higher in tumors than in the peripheral blood of the same patients. This accumulation was associated with elevated concentrations of inflammatory mediators involved in MDSC migration to and activation in the tumor microenvironment. An analysis of the MDSC immunosuppressive pattern showed increased programmed death-ligand 1 expression on circulating cells from patients compared with HDs. Tumor PMN-MDSCs displayed higher programmed death-ligand 1 expression levels than the same cells in the peripheral blood. The frequency of CCR5 (C-C chemokine receptor 5) expression on circulating M-MDSCs was significantly higher in the patients than in the HDs. Clinical data analysis revealed negative correlations between recurrence-free survival and the frequencies of PMN-MDSCs and CCR5
M-MDSCs in the circulation but not in tumors.
Our findings suggest that the level of MDSCs in the peripheral blood but not in tumor tissues predicts recurrence after surgery.
DNA methylation is a dynamic and reversible process that governs gene expression during development and disease. Several examples of active DNA demethylation have been documented, involving ...genome-wide and gene-specific DNA demethylation. How demethylating enzymes are targeted to specific genomic loci remains largely unknown. We show that an antisense lncRNA, termed TARID (for TCF21 antisense RNA inducing demethylation), activates TCF21 expression by inducing promoter demethylation. TARID interacts with both the TCF21 promoter and GADD45A (growth arrest and DNA-damage-inducible, alpha), a regulator of DNA demethylation. GADD45A in turn recruits thymine-DNA glycosylase for base excision repair-mediated demethylation involving oxidation of 5-methylcytosine to 5-hydroxymethylcytosine in the TCF21 promoter by ten-eleven translocation methylcytosine dioxygenase proteins. The results reveal a function of lncRNAs, serving as a genomic address label for GADD45A-mediated demethylation of specific target genes.
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•TARID, a TCF21 antisense lncRNA, is downregulated in cancer cells•TARID binds to the TCF21 promoter and mediates transcriptional activation•TARID recruits GADD45A/TDG, thus promoting base excision-mediated demethylation•A lncRNA can serve as an address label for DNA demethylation
The function of most long noncoding RNAs (lncRNAs) is unknown. Arab et al. characterize TARID, a lncRNA that is antisense to the tumor suppressor TCF21, and find that it specifically directs demethylation and activation of TCF21 via GADD45A.
A novel classification of pulmonary adenocarcinoma (ADC) distinguishing five growth patterns has been established by the International Association for the Study of Lung Cancer/American Thoracic ...Society/European Respiratory Society. There is evidence that an additional cribriform pattern associates with a distinct clinical behavior.
We evaluated the predominant growth pattern of 674 resected ADC as recommended by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society, including the cribriform pattern. The predominant pattern type was correlated with clinical, molecular, and survival data.
Two hundred forty-eight (36.8%) of the pulmonary ADC were solid, 207 (30.6%) were acinar, 101 (15%) were papillary, 55 (8.2%) were micropapillary, 35 (5.2%) were lepidic, and 28 cases (4.2%) were cribriform predominant (cpADC). Minor cribriform components were frequently observed (28.6% of all cases). cpADC showed the second highest proliferative capacity of all patterns, no somatic mutations in the epidermal growth factor receptor (p = 0.001) and a high rate of KRAS mutations. Overall survival (OS) of patients with cpADC (mean OS: 62.7 months) ranged in between survival times of patients with acinar (mean OS: 71.3 months) and solid predominant ADC (mean OS: 54.5 months); cpADC was associated with the worst disease-free survival (DFS) of all patterns (mean DFS: 36.9 months). Both associations were confirmed by multivariate analysis (p < 0.01 for both OS and DFS). Hazard ratios for cpADC were 1.72 for OS and 2.99 for DFS, with lepidic predominant ADC set as reference (hazard ratio: 1).
Our data support the introduction of cpADC as a novel category into future morphology based on pulmonary ADC classifications. Further international studies are required to validate the reported clinicopathological associations of the cribriform pattern.
Non‐small cell lung cancer (NSCLC) is the leading cause of cancer death globally. To develop better diagnostics and more effective treatments, research in the past decades has focused on ...identification of molecular changes in the genome, transcriptome, proteome, and more recently also the metabolome. Phospholipids, which nevertheless play a central role in cell functioning, remain poorly explored. Here, using a mass spectrometry (MS)‐based phospholipidomics approach, we profiled 179 phospholipid species in malignant and matched non‐malignant lung tissue of 162 NSCLC patients (73 in a discovery cohort and 89 in a validation cohort). We identified 91 phospholipid species that were differentially expressed in cancer versus non‐malignant tissues. Most prominent changes included a decrease in sphingomyelins (SMs) and an increase in specific phosphatidylinositols (PIs). Also a decrease in multiple phosphatidylserines (PSs) was observed, along with an increase in several phosphatidylethanolamine (PE) and phosphatidylcholine (PC) species, particularly those with 40 or 42 carbon atoms in both fatty acyl chains together. 2D‐imaging MS of the most differentially expressed phospholipids confirmed their differential abundance in cancer cells. We identified lipid markers that can discriminate tumor versus normal tissue and different NSCLC subtypes with an AUC (area under the ROC curve) of 0.999 and 0.885, respectively. In conclusion, using both shotgun and 2D‐imaging lipidomics analysis, we uncovered a hitherto unrecognized alteration in phospholipid profiles in NSCLC. These changes may have important biological implications and may have significant potential for biomarker development.
What's new?
Cellular membranes are subject to extensive modification in cancer, often with marked alterations in phospholipid metabolism. The extent and nature of those changes are not fully known, however, particularly for non‐small cell lung cancer (NSCLC). In this study, lipidomics analysis of phospholipid profiles uncovered dramatic differences between NSCLC and normal lung tissue. The differences were confirmed via 2D‐imaging lipidomics in tissue sections. Lipid markers capable of discriminating between tumor and normal tissue and between different NSCLC subtypes were identified. The observed alterations in NSCLC phospholipid profiles may be biologically significant.
Aims
Molecular characterization of non‐small‐cell lung cancer (NSCLC) has revealed multiple druggable mutations for targeted therapies. Recently, chromosomal rearrangements involving c‐ros oncogene ...1, receptor tyrosine kinase (ROS1) were identified, and patients seem to benefit from crizotinib treatment. The aim of this study was to identify the clinicopathological characteristics of NSCLC with ROS1 expression and translocation.
Methods and results
We screened 1478 NSCLCs with a ROS1‐specific antibody, and tested positive cases with FISH. All positive cases were analysed for associated clinicopathological characteristics, including survival and molecular tumour composition. Sixty‐eight cases (4.6%) showed ROS1 immunoreactivity, and ROS1 translocations were confirmed in nine cases (0.6%). ROS1 expression was predominantly found in female adenocarcinoma patients, in patients with low T stages, and in association with TTF1 and napsin expression, and certain histomorphological adenocarcinoma patterns (lepidic, acinar, and solid). ROS1 translocations occurred in conjunction with other driver mutations (EGFR, KRAS, and BRAF). ROS1 expression was found to be a stage‐independent predictor of favourable survival.
Conclusions
ROS1 translocations are rare events in resected NSCLCs from Caucasian patients. Immunohistochemical screening for ROS1 expression and clinicopathological parameters, including female sex, early tumour stages, adenocarcinomas with TTF1 and/or napsin expression, and a distinct histomorphological growth pattern, strongly facilitate case enrichment. Molecularly driven multistep concepts might not be optimal for case selection.
Lung cancer remains one of the most prominent public health challenges, accounting for the highest incidence and mortality among all human cancers. While pulmonary invasive mucinous adenocarcinoma ...(PIMA) is one of the most aggressive types of non-small cell lung cancer, transcriptional drivers of PIMA remain poorly understood. In the present study, we found that Forkhead box M1 transcription factor (FOXM1) is highly expressed in human PIMAs and associated with increased extracellular mucin deposition and the loss of NKX2.1. To examine consequences of FOXM1 expression in tumor cells in vivo, we employed an inducible, transgenic mouse model to express an activated FOXM1 transcript in urethane-induced benign lung adenomas. FOXM1 accelerated tumor growth, induced progression from benign adenomas to invasive, metastatic adenocarcinomas, and induced SOX2, a marker of poorly differentiated tumor cells. Adenocarcinomas in FOXM1 transgenic mice expressed increased MUC5B and MUC5AC, and reduced NKX2.1, which are characteristics of mucinous adenocarcinomas. Expression of FOXM1 in KrasG12D transgenic mice increased the mucinous phenotype in KrasG12D-driven lung tumors. Anterior Gradient 2 (AGR2), an oncogene critical for intracellular processing and packaging of mucins, was increased in mouse and human PIMAs and was associated with FOXM1. FOXM1 directly bound to and transcriptionally activated human AGR2 gene promoter via the -257/-247 bp region. Finally, using orthotopic xenografts we demonstrated that inhibition of either FOXM1 or AGR2 in human PIMAs inhibited mucinous characteristics, and reduced tumor growth and invasion. Altogether, FOXM1 is necessary and sufficient to induce mucinous phenotypes in lung tumor cells in vivo.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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