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Objectives: Tsukushi (TSK), a member of the small leucine-rich repeat proteoglycan (SLRP) family, plays multifunctional roles by interacting with signaling molecules during development. However, the role of TSK in cancer remains unknown. The aim of the present study was to investigate the biological significance of TSK in lung cancer., Materials and Methods: Immunohistochemistry of lung cancer tissues and reverse transcription polymerase chain reaction (PCR) of lung cancer cell lines were carried out to detect TSK. Then, RNA sequence analysis, Gene Ontology analysis, quantitative real-time PCR, western blotting, cell counting assay, invasion assays, and xenograft studies were done in a human lung adenocarcinoma cell line, H1975 with modification of TSK expression levels, in order to investigate its biological roles, in particular epithelial-mesenchymal transition (EMT) and proliferation., Results: TSK was found to be highly expressed in lung cancer tissues and cell lines. Modification of TSK expression levels in H1975 resulted in changes in molecules related to EMT, including cadherin-1, snail family transcriptional repressor 1, snail family transcriptional repressor 2, and vimentin. The results of cell counting and xenograft assays showed that TSK promotes cell proliferation., Conclusions: In lung cancer cells, TSK is expressed more highly than the other SLRPs family members, and regulates the EMT and proliferation. Thus, TSK may be a key coordinator of multiple pathways and an important structural element in the lung cancer microenvironment., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The detection rate of synchronous multiple lung adenocarcinomas (SMLA), which display multiple ground glass opacity nodules in the peripheral lung, is increasing due to advances in high resolution computed tomography. The backgrounds of multicentric development of adenocarcinoma are unknown. In this study, we quantitated estrogen concentration in the peripheral lungs of postmenopausal female patients with SMLA., Methods: The tissue concentration of estrogens (estrone [E1] and estdadiol [E2]) in the noncancerous peripheral lung were measured with liquid chromatography/electrospray tandem mass spectrometry in postmenopausal female patients with lung adenocarcinoma. The expression levels of CYP19A1 in the normal lung were also quantitated with real-time PCR. Thirty patients with SMLA and 79 cases of control patients with single lung adenocarcinoma were analyzed., Results: The concentrations of E1 and E2 in the noncancerous tissue were significantly higher in SMLA cases than control cases (P = 0.004 and P = 0.02, respectively). The minor allele (A) of single nucleotide polymorphism rs3764221 were significantly associated with higher concentration of E1 and E2 (P = 0.002 and P = 0.01, respectively) and higher CYP19A1 mRNA expression (P = 0.03)., Conclusion: The tissue estrogen concentration of peripheral lung was significantly higher in SMLA than control cases. The high concentration of estrogen may be one of the causes of multicentric development of peripheral lung adenocarcinomas.

Background: Solute carrier family 5 member A8 (SLC5A8) is a sodium-coupled transporter for several chemicals. The SLC5A8 gene has been reported to function as a tumor suppressor gene that contributes to carcinogenesis and tumor progression. The expression of SLC5A8 is silenced in colon neoplasia by hypermethylation of CpG-rich islands located in exon 1. In this study, we assessed the significance of aberrant methylation of the SLC5A8 gene as a prognostic factor for lung adenocarcinoma (AD)., Methods: We analyzed the methylation levels of a consecutive series of 143 node-negative stage I and II lung AD samples using pyrosequencing., Results: The methylation level of exon 1 in the SLC5A8 gene was significantly associated with poor prognosis in cases of node-negative stage I and II lung AD., Conclusions: Gene silencing of SLC5A8 by hypermethylation was associated with poor prognosis in cases of node-negative stage I and II lung AD., (Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Lung adenocarcinoma has never before been reported to be associated with von Hippel-Lindau (VHL) disease. Here, we report a case of VHL disease in a patient who had metachronous multiple lung adenocarcinomas. The patient is a 64-year-old-woman with VHL disease. She underwent surgical resection of one adenocarcinoma and one atypical adenomatous hyperplasia. A second lung adenocarcinoma developed metachronously. A point mutation in the VHL gene was confirmed in DNA from a blood sample, and loss of heterozygosity at the VHL locus was detected in the lung adenocarcinoma. The VHL dysfunction may have a role in the development of multiple lung adenocarcinomas., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The detection rate of multiple lung adenocarcinomas, which display multiple ground glass opacity nodules in the peripheral lung, is increasing because of advances in high resolution computed tomography. The genetic backgrounds of multiple nodules and the mechanisms that underlie their multicentric development are unknown. In this study, we examined single nucleotide polymorphisms (SNPs) of the cytochrome P450 19A1 gene to determine if they are associated with multiple adenocarcinomas risk., Methods: Fifty-one cases of multiple adenocarcinomas with lepidic growth, 62 cases of a single adenocarcinoma with lepidic growth, and 126 control cases were analyzed. Three SNPs were analyzed by using a 5' nuclease assay with TaqMan minor-groove-binder probe. The expression level of CYP19A1 in the noncancerous lung was quantified by real-time reverse transcription polymerase chain reaction (RT-PCR)., Results: A minor allele of SNP rs3764221, which is located in the CYP19A1 gene, was significantly associated with multiple adenocarcinomas risk (adjusted odds ratio = 3.06; P = 0.006). Other polymorphisms of CYP19A1 were not significantly associated with the risk of multiple adenocarcinomas. A minor allele of SNP rs3764221 was also associated with a higher level of CYP19A1 messenger RNA expression (P = 0.03)., Conclusions: SNP rs3764221 contributes to the development of multicentric adenocarcinomas in the peripheral lung by causing higher levels of CYP19A1 expression.

Background: Genome-wide DNA hypomethylation is known to play important roles in genomic instability and carcinogenesis. Methylation in long interspersed nucleotide element 1 (LINE-1) is a good indicator of the global DNA methylation level within a cell. The aim of this study was to evaluate prognostic significance of LINE-1 hypomethylation in lung adenocarcinoma., Methods: A consecutive series of 211 lung adenocarcinoma patients who underwent curative resections without any preoperative chemotherapy or radiotherapy at Kumamoto University Hospital between April 2010 and December 2012 were included. The LINE-1 methylation levels were quantified in tumor and noncancerous tissue by Pyrosequencing assay., Results: Higher histologic grade and positive findings for vascular invasion were significantly associated with lower methylation levels. The disease-free survival in the hypomethylation group was significantly shorter than that of the non-hypomethylation group. The prognostic difference was more obvious in advanced cases (stage II, III) than in stage I cases., Conclusions: The LINE-1 methylation level is associated with histologic grade and vascular invasion of lung adenocarcinoma. Additionally, LINE-1 hypomethylation is a useful biomarker to predict early recurrence of lung adenocarcinoma., (Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: To examine whether segmentectomy is radical for cT1N0M0 non-small cell lung cancer (NSCLC), a prospective single-arm study was performed at a single institution., Methods: The criteria for segmentectomy were as follows: (1) peripheral-type cT1N0M0 NSCLC; (2) intraoperative frozen sections of sentinel nodes identified with isotope showing no metastasis; (3) surgical margins greater than 2 cm; (4) patient choice for segmentectomy; and (5) exclusion of right middle lobe tumors. From 2005 to 2009, of 245 patients with cT1N0M0 NSCLC, 195 (80%) were enrolled in the present study. Of these 195 patients, 179 ultimately underwent segmentectomy with systematic lymph node dissection. Of these 179 patients, 134 (75%) had tumors 2 cm or smaller, and 45 (25%) had tumors 2.1 cm to 3 cm. The median follow-up period was 43 months., Results: All 181 tumors from 179 patients were stage pN0. Of the 179 patients, 6 developed distant site recurrence and 3 local recurrence (ie, 1 developed pulmonary metastases within the same lobe 21 months after segmentectomy and 2 developed local recurrence at the surgical margin 60 and 62 months after segmentectomy, respectively). The 5-year overall survival was 94% for patients with tumors 2 cm or smaller and 81% for those with 2.1-cm to 3-cm tumors. Postoperative pulmonary function was preserved at 90% ± 12% of preoperative levels., Conclusions: Segmentectomy with systematic lymph node dissection with a sufficient surgical margin could be a radical treatment for selected cT1N0M0/pN0 NSCLC while preserving pulmonary function. The surgical margin should be monitored for the development of local recurrence for a long period after segmentectomy., (Copyright © 2012 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Background: The mechanisms of generation and progression of multicentric lung adenocarcinoma (AD), bronchioloalveolar carcinoma (BAC), and atypical adenomatous hyperplasia (AAH) in the peripheral lung is not well known. In this study, we analyzed epidermal growth factor receptor (EGFR) mutations in the cases of multicentric AD, BAC, and AAH to reveal the role of EGFR mutation in their generations and progressions., Method: Ninety-seven AAH, BAC, or AD lesions less than 3 cm in size in 26 patients were surgically resected. Of these, EGFR mutations of the nodules with the highest and the second highest grade of histologic malignancy were examined in each patient by using the peptide nucleic acid-locked nucleic acid polymerase chain reaction (PNA-LNA PCR) clamp method., Results: EGFR mutations could be examined in 48 nodules in the 26 patients. The EGFR mutations were found more frequently in lesions with higher histologic malignancy, ie, 9 of 10 ADs (90%), 16 of 28 BACs (57%), and one of 10 AAHs (10%). In 22 patients who could be examined of EGFR mutations for the two lesions in each patient, only two patients (9%) had the same mutation patterns between the two lesions, whereas 15 patients (68%) had the different statuses and the remaining five (23%) had no mutations., Conclusion: Our data demonstrated that EGFR mutations seem to contribute to the acquisition of malignant potential in the AAH-AD sequence and occur independently in each lesion and in the cases of multicentric AD, BAC, and AAH.

A novel germline transmission of the epidermal growth factor receptor (EGFR) mutation V843I in a family with multiple members with lung cancer is reported. The proband was a 70-year-old woman with multiple adenocarcinomas who exhibited secondary EGFR mutations, either L858R or L861Q, in the specimens of resected tumors, in addition to a germline EGFR V843I mutation. These observations suggest that the germline EGFR V843I mutation might have altered EGFR signaling in the multicentric development of adenocarcinoma, bronchoalveolar carcinoma, and atypical adenomatous hyperplasia and also might have had a role in the development of lung cancer in multiple members of her family.

Background: The histological diagnosis of gastric intramucosal neoplastic lesions (GINLs) is controversial among experienced pathologists. Although the destruction of the epithelial basement membrane (BM) and the invasion of neoplastic epithelial cells into the interstitium of the lamina propria is distinct proof of "intramucosal carcinoma," histological evaluation of GINLs is difficult and ambiguous, especially intestinal-type adenocarcinoma. Type IV collagen is a major component of the BM, and comprises six genetically distinct alpha(IV) chains, alpha1(IV) to alpha6(IV). In several types of carcinomas, the loss of alpha5/alpha6(IV) chains of the epithelial BM at an early invasive stage has been reported. However, the expression of alpha5/alpha6(IV) chains in GINLs is still unclear. We examined the immunohistochemical expression of alpha(IV) chains in GINLs and investigated whether the expression pattern was a diagnostic marker of gastric intramucosal carcinoma., Methods: The expression of alpha(IV) chains and Ki-67 in 60 resected GINL specimens was immunohistochemically examined., Results: In normal gastric epithelium, alpha1(IV), alpha2(IV), alpha5(IV), and alpha6(IV) chains were expressed continuously in the BM. In most tubular adenomas (Japanese classification), these four chains were stained continuously in the BM, whereas in tubular adenocarcinomas (Japanese classification), the alpha5/alpha6(IV) chains had disappeared, partially or completely. The expression of alpha5/alpha6(IV) chains was closely related to the grade of histological atypia. In addition, the loss of alpha5/alpha6(IV) chains was significantly correlated with tumor cell growth activity., Conclusions: The loss of alpha5/alpha6(IV) chains might be a useful diagnostic finding for gastric intramucosal carcinoma in GINL cases.

CD163 is one of the scavenger receptors expressed on macrophages. However, several immunohistochemical studies have demonstrated that CD163 is also detected on cancer cells, and is associated with a poor prognosis. In the present study, we detected CD163 staining on cancer cells in lung adenocarcinoma and squamous cell carcinoma (SCC), and investigated the relationship between CD163 on cancer cells and the clinical prognosis. CD163 staining was seen in 128 of 342 adenocarcinoma cases and 35 of 103 SCC cases. Among the lung adenocarcinoma cases, the progression‐free survival and overall survival were significantly shorter in the CD163 high group than the CD163 low group. A similar trend was observed among the SCC cases, but the difference was not statistically significant. Additionally, a higher number of macrophages was detected in areas with CD163‐positive cancer cells when compared to areas with CD163‐negative cancer cells. In summary, we found that CD163‐positive cancer cells are a predictor of a worse clinical course in lung adenocarcinoma and SCC. [ABSTRACT FROM AUTHOR]

Tumor‐associated calcium signal transducer 2 (TROP2) is a cell‐surface glycoprotein involved in the high malignant potential of several cancers. Antibody‐drug conjugates that target TROP2 represent a promising approach for the treatment of TROP2‐expressing cancers including lung cancer and breast cancer. TROP2 expression was tested by immunohistochemistry in lung adenocarcinoma (ADC) and squamous cell carcinoma samples, and its correlation with clinicopathological factors, including survival rate and p53 mutation, was statistically analyzed. We found that increased TROP2 expression was significantly associated with a poor clinical course in patients with ADC, but not in patients with squamous cell carcinoma. A more significant association with poor outcome was seen in ADC cases with a high histological grade as well as those without the epidermal growth factor receptor (EGFR) mutation. A significant correlation between TROP2 expression and abnormal p53 nuclear accumulation/expression was also found in ADC. In the present study, we discovered a significant correlation between TROP2 expression and p53 mutation in ADC, and that TROP2 expression was a prognostic factor in ADC cases with a high histological grade as well as those without the EGFR mutation. Signals mediated by mutated p53 might influence TROP2 expression in ADC. [ABSTRACT FROM AUTHOR]

The histological diagnosis of gastric intramucosal neoplastic lesions (GINLs) is controversial among experienced pathologists. Although the destruction of the epithelial basement membrane (BM) and the invasion of neoplastic epithelial cells into the interstitium of the lamina propria is distinct proof of “intramucosal carcinoma,” histological evaluation of GINLs is difficult and ambiguous, especially intestinal-type adenocarcinoma. Type IV collagen is a major component of the BM, and comprises six genetically distinct α(IV) chains, α1(IV) to α6(IV). In several types of carcinomas, the loss of α5/α6(IV) chains of the epithelial BM at an early invasive stage has been reported. However, the expression of α5/α6(IV) chains in GINLs is still unclear. We examined the immunohistochemical expression of α(IV) chains in GINLs and investigated whether the expression pattern was a diagnostic marker of gastric intramucosal carcinoma. The expression of α(IV) chains and Ki-67 in 60 resected GINL specimens was immunohistochemically examined. In normal gastric epithelium, α1(IV), α2(IV), α5(IV), and α6(IV) chains were expressed continuously in the BM. In most tubular adenomas (Japanese classification), these four chains were stained continuously in the BM, whereas in tubular adenocarcinomas (Japanese classification), the α5/α6(IV) chains had disappeared, partially or completely. The expression of α5/α6(IV) chains was closely related to the grade of histological atypia. In addition, the loss of α5/α6(IV) chains was significantly correlated with tumor cell growth activity. The loss of α5/α6(IV) chains might be a useful diagnostic finding for gastric intramucosal carcinoma in GINL cases. [ABSTRACT FROM AUTHOR]