| 11. |
- Moreira, Andre L., et al.
(författare)
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A Grading System for Invasive Pulmonary Adenocarcinoma : A Proposal From the International Association for the Study of Lung Cancer Pathology Committee
- 2020
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Ingår i: Journal of Thoracic Oncology. - : ELSEVIER SCIENCE INC. - 1556-0864 .- 1556-1380. ; 15:10, s. 1599-1610
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: A grading system for pulmonary adenocarcinoma has not been established. The International Association for the Study of Lung Cancer pathology panel evaluated a set of histologic criteria associated with prognosis aimed at establishing a grading system for invasive pulmonary adenocarcinoma. Methods: A multi-institutional study involving multiple cohorts of invasive pulmonary adenocarcinomas was conducted. A cohort of 284 stage I pulmonary adenocarcinomas was used as a training set to identify histologic features associated with patient outcomes (recurrence-free survival [RFS] and overall survival [OS]). Receiver operating characteristic curve analysis was used to select the best model, which was validated (n = 212) and tested (n = 300, including stage I-III) in independent cohorts. Reproducibility of the model was assessed using kappa statistics. Results: The best model (area under the receiver operating characteristic curve [AUC] = 0.749 for RFS and 0.787 for OS) was composed of a combination of predominant plus high-grade histologic pattern with a cutoff of 20% for the latter. The model consists of the following: grade 1, lepidic predominant tumor; grade 2, acinar or papillary predominant tumor, both with no or less than 20% of high-grade patterns; and grade 3, any tumor with 20% or more of high-grade patterns (solid, micropapillary, or complex gland). Similar results were seen in the validation (AUC = 0.732 for RFS and 0.787 for OS) and test cohorts (AUC = 0.690 for RFS and 0.743 for OS), confirming the predictive value of the model. Interobserver reproducibility revealed good agreement (k = 0.617). Conclusions: A grading system based on the predominant and high-grade patterns is practical and prognostic for invasive pulmonary adenocarcinoma. (C) 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
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| 12. |
- Sholl, Lynette, et al.
(författare)
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The Promises and Challenges of Tumor Mutation Burden as an Immunotherapy Biomarker : A Perspective from the International Association for the Study of Lung Cancer Pathology Committee
- 2020
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Ingår i: Journal of Thoracic Oncology. - : ELSEVIER SCIENCE INC. - 1556-0864 .- 1556-1380. ; 15:9, s. 1409-1424
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Forskningsöversikt (refereegranskat)abstract
- Immune checkpoint inhibitor (ICI) therapies have revolutionized the management of patients with NSCLC and have led to unprecedented improvements in response rates and survival in a subset of patients with this fatal disease. However, the available therapies work only for a minority of patients, are associated with substantial societal cost, and may lead to considerable immune-related adverse events. Therefore, patient selection must be optimized through the use of relevant biomarkers. Programmed death-ligand 1 protein expression by immunohistochemistry is widely used today for the selection of programmed cell death protein 1 inhibitor therapy in patients with NSCLC; however, this approach lacks robust sensitivity and specificity for predicting response. Tumor mutation burden (TMB), or the number of somatic mutations derived from next-generation sequencing techniques, has been widely explored as an alternative or complementary biomarker for response to ICIs. In theory, a higher TMB increases the probability of tumor neoantigen production and therefore, the likelihood of immune recognition and tumor cell killing. Although TMB alone is a simplistic surrogate of this complex interplay, it is a quantitative variable that can be relatively readily measured using currently available sequencing techniques. A large number of clinical trials and retrospective analyses, employing both tumor and blood-based sequencing tools, have evaluated the performance of TMB as a predictive biomarker, and in many cases reveal a correlation between high TMB and ICI response rates and progression-free survival. Many challenges remain before the implementation of TMB as a biomarker in clinical practice. These include the following: (1) identification of therapies whose response is best informed by TMB status; (2) robust definition of a predictive TMB cut point; (3) acceptable sequencing panel size and design; and (4) the need for robust technical and informatic rigor to generate precise and accurate TMB measurements across different laboratories. Finally, effective prediction of response to ICI therapy will likely require integration of TMB with a host of other potential biomarkers, including tumor genomic driver alterations, tumor-immune milieu, and other features of the host immune system. This perspective piece will review the current clinical evidence for TMB as a biomarker and address the technical sequencing considerations and ongoing challenges in the use of TMB in routine practice. (c) 2020 Published by Elsevier Inc. on behalf of International Association for the Study of Lung Cancer.
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| 13. |
- Sun, Ryan, et al.
(författare)
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Integration of multiomic annotation data to prioritize and characterize inflammation and immune-related risk variants in squamous cell lung cancer
- 2021
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Ingår i: Genetic Epidemiology. - : John Wiley & Sons. - 0741-0395 .- 1098-2272. ; 45:1, s. 99-114
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Tidskriftsartikel (refereegranskat)abstract
- Clinical trial results have recently demonstrated that inhibiting inflammation by targeting the interleukin-1 beta pathway can offer a significant reduction in lung cancer incidence and mortality, highlighting a pressing and unmet need to understand the benefits of inflammation-focused lung cancer therapies at the genetic level. While numerous genome-wide association studies (GWAS) have explored the genetic etiology of lung cancer, there remains a large gap between the type of information that may be gleaned from an association study and the depth of understanding necessary to explain and drive translational findings. Thus, in this study we jointly model and integrate extensive multiomics data sources, utilizing a total of 40 genome-wide functional annotations that augment previously published results from the International Lung Cancer Consortium (ILCCO) GWAS, to prioritize and characterize single nucleotide polymorphisms (SNPs) that increase risk of squamous cell lung cancer through the inflammatory and immune responses. Our work bridges the gap between correlative analysis and translational follow-up research, refining GWAS association measures in an interpretable and systematic manner. In particular, reanalysis of the ILCCO data highlights the impact of highly associated SNPs from nuclear factor-kappa B signaling pathway genes as well as major histocompatibility complex mediated variation in immune responses. One consequence of prioritizing likely functional SNPs is the pruning of variants that might be selected for follow-up work by over an order of magnitude, from potentially tens of thousands to hundreds. The strategies we introduce provide informative and interpretable approaches for incorporating extensive genome-wide annotation data in analysis of genetic association studies.
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| 14. |
- Thunnissen, Erik, et al.
(författare)
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Defining Morphologic Features of Invasion in Pulmonary Nonmucinous Adenocarcinoma With Lepidic Growth : A Proposal by the International Association for the Study of Lung Cancer Pathology Committee
- 2023
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Ingår i: Journal of Thoracic Oncology. - : Elsevier. - 1556-0864 .- 1556-1380. ; 18:4, s. 447-462
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Since the eight edition of the Union for In-ternational Cancer Control and American Joint Committee on Cancer TNM classification system, the primary tumor pT stage is determined on the basis of presence and size of the invasive components. The aim of this study was to identify histologic features in tumors with lepidic growth pattern which may be used to establish criteria for distinguishing invasive from noninvasive areas.Methods: A Delphi approach was used with two rounds of blinded anonymized analysis of resected nonmucinous lung adenocarcinoma cases with presumed invasive and nonin-vasive components, followed by one round of reviewer de-anonymized and unblinded review of cases with known outcomes. A digital pathology platform was used for measuring total tumor size and invasive tumor size. Results: The mean coefficient of variation for measuring total tumor size and tumor invasive size was 6.9% (range: 1.7%-22.3%) and 54% (range: 14.7%-155%), respectively, with substantial variations in interpretation of the size and location of invasion among pathologists. Following the presentation of the results and further discussion among members at large of the International Association for the Study of Lung Cancer Pathology Committee, extensive epithelial proliferation (EEP) in areas of collapsed lepidic growth pattern is recognized as a feature likely to be associated with invasive growth. The EEP is characterized by multilayered luminal epithelial cell growth, usually with high-grade cytologic features in several alveolar spaces.Conclusions: Collapsed alveoli and transition zones with EEP were identified by the Delphi process as morphologic features that were a source of interobserver variability. Definition criteria for collapse and EEP are proposed to improve reproducibility of invasion measurement.(c) 2022 International Association for the Study of Lung Cancer.
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| 15. |
- Thunnissen, Erik, et al.
(författare)
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The Use of Immunohistochemistry Improves the Diagnosis of Small Cell Lung Cancer and Its Differential Diagnosis. An International Reproducibility Study in a Demanding Set of Cases
- 2017
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Ingår i: Journal of Thoracic Oncology. - : Elsevier BV. - 1556-0864 .- 1556-1380. ; 12:2, s. 334-346
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The current WHO classification of lung cancer states that a diagnosis of SCLC can be reliably made on routine histological and cytological grounds but immunohistochemistry (IHC) may be required, particularly (1) in cases in which histologic features are equivocal and (2) in cases in which the pathologist wants to increase confidence in diagnosis. However, reproducibility studies based on hematoxylin and eosin-stained slides alone for SCLC versus large cell neuroendocrine carcinoma (LCNEC) have shown pairwise K scores ranging from 0.35 to 0.81. This study examines whether judicious use of IHC improves diagnostic reproducibility for SCLC.Methods: Nineteen lung pathologists studied interactive digital images of 79 tumors, predominantly neuroendocrine lung tumors. Images of resection and biopsy specimens were used to make diagnoses solely on the basis of morphologic features (level 1), morphologic features along with requested IHC staining results (level 2), and all available IHC staining results (level 3).Results: For the 19 pathologists reading all 79 cases, the rate of agreement for level 1 was 64.7%, and it increased to 73.2% and 77.5% in levels 2 and 3, respectively. With IHC, K scores for four tumor categories (SCLC, LCNEC, carcinoid tumors, and other) increased in resection samples from 0.43 to 0.60 and in biopsy specimens from 0.43 to 0.64.Conclusions: Diagnosis using hematoxylin and eosin staining alone showeds moderate agreement among pathologists in tumors with neuroendocrine morphology, but agreement improved to good in most cases with the judicious use of IHC, especially in the diagnosis of SCLC. An approach for IHC in the differential diagnosis of SCLC is provided. (C) 2017 International Association for the Study of Lung Cancer.
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| 16. |
- Tsao, Ming Sound, et al.
(författare)
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PD-L1 Immunohistochemistry Comparability Study in Real-Life Clinical Samples : Results of Blueprint Phase 2 Project
- 2018
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Ingår i: Journal of Thoracic Oncology. - : Elsevier BV. - 1556-0864 .- 1556-1380. ; 13:9, s. 1302-1311
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The Blueprint (BP) Programmed Death Ligand 1 (PD-L1) Immunohistochemistry Comparability Project is a pivotal academic/professional society and industrial collaboration to assess the feasibility of harmonizing the clinical use of five independently developed commercial PD-L1 immunohistochemistry assays. The goal of BP phase 2 (BP2) was to validate the results obtained in BP phase 1 by using real-world clinical lung cancer samples.Methods: BP2 were conducted using 81 lung cancer specimens of various histological and sample types, stained with all five trial-validated PD-L1 assays (22C3, 28-8, SP142, SP263, and 73-10); the slides were evaluated by an international panel of pathologists. BP2 also assessed the reliability of PD-L1 scoring by using digital images, and samples prepared for cytological examination. PD-L1 expression was assessed for percentage (tumor proportional score) of tumor cell (TC) and immune cell areas showing PD-L1 staining, with TCs scored continuously or categorically with the cutoffs used in checkpoint inhibitor trials.Results: The BP2 results showed highly comparable staining by the 22C3, 28-8 and SP263 assays; less sensitivity with the SP142 assay; and higher sensitivity with the 73-10 assay to detect PD-L1 expression on TCs. Glass slide and digital image scorings were highly concordant (Pearson correlation >0.96). There was very strong reliability among pathologists in TC PD-L1 scoring with all assays (overall intraclass correlation coefficient [ICC] = 0.86–0.93), poor reliability in IC PD-L1 scoring (overall ICC = 0.18–0.19), and good agreement in assessing PD-L1 status on cytological cell block materials (ICC = 0.78–0.85).Conclusion: BP2 consolidates the analytical evidence for interchangeability of the 22C3, 28-8, and SP263 assays and lower sensitivity of the SP142 assay for determining tumor proportion score on TCs and demonstrates greater sensitivity of the 73-10 assay compared with that of the other assays.
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| 17. |
- Wang, Tao, et al.
(författare)
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Pleiotropy of genetic variants on obesity and smoking phenotypes : Results from the Oncoarray Project of The International Lung Cancer Consortium
- 2017
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:9, s. 0185660-0185660
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Tidskriftsartikel (refereegranskat)abstract
- Obesity and cigarette smoking are correlated through complex relationships. Common genetic causes may contribute to these correlations. In this study, we selected 241 loci potentially associated with body mass index (BMI) based on the Genetic Investigation of ANthropometric Traits (GIANT) consortium data and calculated a BMI genetic risk score (BMI-GRS) for 17,037 individuals of European descent from the Oncoarray Project of the International Lung Cancer Consortium (ILCCO). Smokers had a significantly higher BMI-GRS than never-smokers (p = 0.016 and 0.010 before and after adjustment for BMI, respectively). The BMI-GRS was also positively correlated with pack-years of smoking (p<0.001) in smokers. Based on causal network inference analyses, seven and five of 241 SNPs were classified to pleiotropic models for BMI/smoking status and BMI/pack-years, respectively. Among them, three and four SNPs associated with smoking status and pack-years (p<0.05), respectively, were followed up in the ever-smoking data of the Tobacco, Alcohol and Genetics (TAG) consortium. Among these seven candidate SNPs, one SNP (rs11030104, BDNF) achieved statistical significance after Bonferroni correction for multiple testing, and three suggestive SNPs (rs13021737, TMEM18; rs11583200, ELAVL4; and rs6990042, SGCZ) achieved a nominal statistical significance. Our results suggest that there is a common genetic component between BMI and smoking, and pleiotropy analysis can be useful to identify novel genetic loci of complex phenotypes.
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| 18. |
- Yatabe, Yasushi, et al.
(författare)
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Best Practices Recommendations for Diagnostic Immunohistochemistry in Lung Cancer
- 2019
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Ingår i: Journal of Thoracic Oncology. - : Elsevier BV. - 1556-0864 .- 1556-1380. ; 14:3, s. 377-407
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Tidskriftsartikel (refereegranskat)abstract
- Since the 2015 WHO classification was introduced into clinical practice, immunohistochemistry (IHC) has figured prominently in lung cancer diagnosis. In addition to distinction of small cell versus non-small cell carcinoma, patients' treatment of choice is directly linked to histologic subtypes of non-small cell carcinoma, which pertains to IHC results, particularly for poorly differentiated tumors. The use of IHC has improved diagnostic accuracy in the classification of lung carcinoma, but the interpretation of IHC results remains challenging in some instances. Also, pathologists must be aware of many interpretation pitfalls, and the use of IHC should be efficient to spare the tissue for molecular testing. The International Association for the Study of Lung Cancer Pathology Committee received questions on practical application and interpretation of IHC in lung cancer diagnosis. After discussions in several International Association for the Study of Lung Cancer Pathology Committee meetings, the issues and caveats were summarized in terms of 11 key questions covering common and important diagnostic situations in a daily clinical practice with some relevant challenging queries. The questions cover topics such as the best IHC markers for distinguishing NSCLC subtypes, differences in thyroid transcription factor 1 clones, and the utility of IHC in diagnosing uncommon subtypes of lung cancer and distinguishing primary from metastatic tumors. This article provides answers and explanations for the key questions about the use of IHC in diagnosis of lung carcinoma, representing viewpoints of experts in thoracic pathology that should assist the community in the appropriate use of IHC in diagnostic pathology.
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| 19. |
- Zhu, Ying, et al.
(författare)
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Elevated Platelet Count Appears to Be Causally Associated with Increased Risk of Lung Cancer : A Mendelian Randomization Analysis
- 2019
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research (AACR). - 1055-9965 .- 1538-7755. ; 28:5, s. 935-942
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Tidskriftsartikel (refereegranskat)abstract
- Background: Platelets are a critical element in coagulation and inflammation, and activated platelets are linked to cancer risk through diverse mechanisms. However, a causal relationship between platelets and risk of lung cancer remains unclear. Methods: We performed single and combined multiple instrumental variable Mendelian randomization analysis by an inverse-weighted method, in addition to a series of sensitivity analyses. Summary data for associations between SNPs and platelet count are from a recent publication that included 48,666 Caucasian Europeans, and the International Lung Cancer Consortium and Transdisciplinary Research in Cancer of the Lung data consisting of 29,266 cases and 56,450 controls to analyze associations between candidate SNPs and lung cancer risk. Results: Multiple instrumental variable analysis incorporating six SNPs showed a 62% increased risk of overall nonsmall cell lung cancer [NSCLC; OR, 1.62; 95% confidence interval (CI), 1.15-2.27; P = 0.005] and a 200% increased risk for small-cell lung cancer (OR, 3.00; 95% CI, 1.27-7.06; P = 0.01). Results showed only a trending association with NSCLC histologic subtypes, which may be due to insufficient sample size and/or weak effect size. A series of sensitivity analysis retained these findings. Conclusions: Our findings suggest a causal relationship between elevated platelet count and increased risk of lung cancer and provide evidence of possible antiplatelet interventions for lung cancer prevention. Impact: These findings provide a better understanding of lung cancer etiology and potential evidence for antiplatelet interventions for lung cancer prevention.
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