8th Edition Tumor, Node, and Metastasis T-Stage Prognosis Discrepancies: Solid Component Diameter Predicts Prognosis Better than Invasive Component Diameter

The biggest change in the 8th edition of the tumor, lymph node, and metastasis (TNM) classification is the recommendation of the solid component diameter and invasive size for determining the clinical and pathological T-factor, respectively. Here, we validated new proposals for the Lung Cancer TNM classification’s revision and compared clinical and pathological T-stages. We retrospectively analyzed 177 cases of non-small cell lung cancers without lymph node metastasis, and involving complete resection, that occurred in our department between January 2017 and March 2019. We reviewed the overall tumor diameter, solid component diameter, and clinical T-factor on computed tomography (CT), and the pathological tumor diameter, pathological invasion diameter, pathological T-factor, and prognosis. The difference between the pathological invasive size and solid size on CT was within 5 mm in 99 cases (56%). At a two-year recurrence-free survival rate, the clinical T-stage demonstrated a better prognostic outcome than the pathological T-stage. Despite including the benign findings, the solid component diameter was better correlated with prognosis than the invasive size. Therefore, in cases of discrepancies of clinically and pathologically detected tumor size, the solid CT size should also be used for the pathological T classification

Left upper lobectomy with combined distal aortic arch and left subclavian artery resection after neoadjuvant chemoradiotherapy for locally advanced lung squamous cell carcinoma

Abstract T4 locally advanced non‐small cell lung cancer (NSCLC) is a heterogeneous group with a great variety of involved organs and is associated with a poor prognosis. However, appropriately selected patients benefit from surgical resection. The surgical indication must be carefully considered based on the risk–benefit between high surgical stress and expected prognosis, particularly in cases with probable aortic involvement. Here, we report a long‐term survival case of left upper lobe squamous cell carcinoma, in which lobectomy and combined distal aortic arch and left subclavian artery resection achieved a complete resection after induction chemoradiotherapy (CRT). Appropriate patient selection considering expected prognosis, induction CRT and complete resection under well‐planned cardiopulmonary bypass are essential to achieve a long‐term survival on T4 NSCLC with a probable aortic involvemen

POLQ Overexpression Is Associated with an Increased Somatic Mutation Load and PLK4 Overexpression in Lung Adenocarcinoma

DNA Polymerase Theta (POLQ) is a DNA polymerase involved in error-prone translesion DNA synthesis (TLS) and error-prone repair of DNA double-strand breaks (DSBs). In the present study, we examined whether abnormal POLQ expression may be involved in the pathogenesis of lung adenocarcinoma (LAC). First, we found overexpression of POLQ at both the mRNA and protein levels in LAC, using data from the Cancer Genome Atlas (TCGA) database and by immunohistochemical analysis of our LAC series. POLQ overexpression was associated with an advanced pathologic stage and an increased total number of somatic mutations in LAC. When H1299 human lung cancer cell clones overexpressing POLQ were established and examined, the clones showed resistance to a DSB-inducing chemical in the clonogenic assay and an increased frequency of mutations in the supF forward mutation assay. Further analysis revealed that POLQ overexpression was also positively correlated with Polo Like Kinase 4 (PLK4) overexpression in LAC, and that PLK4 overexpression in the POLQ-overexpressing H1299 cells induced centrosome amplification. Finally, analysis of the TCGA data revealed that POLQ overexpression was associated with an increased somatic mutation load and PLK4 overexpression in diverse human cancers; on the other hand, overexpressions of nine TLS polymerases other than POLQ were associated with an increased somatic mutation load at a much lower frequency. Thus, POLQ overexpression is associated with advanced pathologic stage, increased somatic mutation load, and PLK4 overexpression, the last inducing centrosome amplification, in LAC, suggesting that POLQ overexpression is involved in the pathogenesis of LAC

Visceral Pleural Invasion Classification in Non–Small-Cell Lung Cancer in the 7th Edition of the Tumor, Node, Metastasis Classification for Lung Cancer: Validation Analysis Based on a Large-Scale Nationwide Database

ObjectiveIn the 7th tumor, node, metastasis (TNM) classification, visceral pleural invasion (VPI) is defined as invasion beyond the elastic layer, including invasion to the visceral pleural surface, and T1 tumors with VPI are upgraded to T2a. To validate this, we analyzed the survival of non–small-cell lung cancer patients from a nationwide database and evaluated the prognostic impact of VPI.MethodsThe clinicopathological characteristics and prognosis of 4995 patients who were included in the registry study of the Japanese Joint Committee of Lung Cancer Registry were retrospectively analyzed with a special interest in the prognostic impact of VPI. These patients underwent surgery in 2004 and were pathologically staged as T1a-3N0. VPI was defined as including PL1 and PL2 according to the 7th TNM Classification, but the Japanese Joint Committee of Lung Cancer Registry did not collect data regarding staining or how extensively VPI was evaluated in each participating institution.ResultsThe survival differences were statistically significant between PL0 and PL1, PL1 and PL2, as well as PL2 and T3. There were no significant survival differences between T1a with VPI and T1b without VPI, or between T1a with VPI and T2a without VPI. There were no significant survival differences between T1b with VPI and T2a without VPI, or between T1b with VPI and T2b without VPI. There were no significant survival differences between T2a with VPI and T2b without VPI, or between T2b with VPI and T2b without VPI. T3 showed significantly worse prognosis than T2a with VPI and T2b with VPI.ConclusionsIn addition to the current TNM classification recommendations, in which T1 tumors with VPI are upgraded to T2a, T2a tumors with VPI should be classified as T2b

Ubiquitin-like 3 as a new protein-sorting factor for small extracellular vesicles

Ubiquitin-like 3 (UBL3) is a well-conserved ubiquitin-like protein (UBL) in eukaryotes and regulates the ubiquitin cascade, but the significant roles of UBL3 in cellular processes remained unknown. Recently, UBL3 was elucidated to be a post-translational modification factor that promotes protein sorting to small extracellular vesicles (sEVs). Proteins sorted into sEVs have been studied as etiologies of sEV-related diseases. Also, there have been attempts to construct drug delivery systems (DDSs) by loading proteins into sEVs. In this review, we introduce the new concept that UBL3 has a critical role in the protein-sorting system and compare structure conservation between UBL3 and other UBLs from an evolutionary perspective. We conclude with future perspectives for the utility of UBL3 in sEV-related diseases and DDS. Key words: UBL3, small extracellular vesicles, protein sorting, ubiquitin-like protein, post-translational modificatio

CD200 and CD200R1 are differentially expressed and have differential prognostic roles in non-small cell lung cancer

CD200, a member of the immunoglobulin superfamily, interacts with its receptor CD200R1 to modulate cancer immune microenvironments. Here, we explored the clinicopathological and prognostic implications of the CD200/CD200R1 axis in non-small-cell lung cancer (NSCLC) patients. We evaluated CD200/CD200R1 expression in the tumors and stroma of 632 NSCLC patients using immunohistochemistry. Associations between CD200/CD200R1 expression levels and clinicopathological data were analyzed. We also examined their expression in lung cancer cell lines. Changes in endogenous immune-related factors and cell proliferation were evaluated by CD200 and CD200R1 knockdown and CD200Fc fusion protein administration. CD200 expression was observed mainly in the tumor, and also in the stroma among a few cases, whereas CD200R1 expression was observed in both the tumor and stroma. High tumoral CD200 expression was significantly associated with female sex, never-smoking status, adenocarcinoma histology, EGFR mutation, and a low density of tumor-infiltrating lymphocytes. Meanwhile, high CD200R1 expression in the tumor and stroma was associated with ever smoking, non-adenocarcinoma histology, and increased tumor-infiltrating lymphocytes. High CD200R1 expression was associated with worse survival (log-rank, P <.001 for both tumor and stroma), whereas high CD200 expression was associated with better survival outcomes (log-rank, P <.001). The transient knockdown of CD200R1 in lung cancer cell lines impaired cell proliferation, and the in vitro modulation of CD200 and CD200R1 altered endogenous oncogenic and inflammation-related gene expression. CD200R1 expression was associated with poor prognosis, whereas CD200 expression was an independent favorable prognostic factor. Our results suggest the importance of CD200 and CD200R1 in lung cancer biology

Identification and Characterization of Cancer Mutations in Japanese Lung Adenocarcinoma without Sequencing of Normal Tissue Counterparts

<div><p>We analyzed whole-exome sequencing data from 97 Japanese lung adenocarcinoma patients and identified several putative cancer-related genes and pathways. Particularly, we observed that cancer-related mutation patterns were significantly different between different ethnic groups. As previously reported, mutations in the EGFR gene were characteristic to Japanese, while those in the KRAS gene were more frequent in Caucasians. Furthermore, during the course of this analysis, we found that cancer-specific somatic mutations can be detected without sequencing normal tissue counterparts. 64% of the germline variants could be excluded using a total of 217 external Japanese exome datasets. We also show that a similar approach may be used for other three ethnic groups, although the discriminative power depends on the ethnic group. We demonstrate that the ATM gene and the PAPPA2 gene could be identified as cancer prognosis related genes. By bypassing the sequencing of normal tissue counterparts, this approach provides a useful means of not only reducing the time and cost of sequencing but also analyzing archive samples, for which normal tissue counterparts are not available. </p> </div