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Tumor budding in the cancer stroma has been reported to be a prognostic factor in non-small cell lung cancer. Micronest in cancer stroma (MICS) is often observed as a formation that is larger and more conspicuous than budding, but its clinicopathologic significance is unclear. In this study, we aimed to examine the clinicopathological significance of MICS in lung squamous cell carcinoma (LSqCC). A total of 198 consecutive patients with pathologically diagnosed LSqCC (anyT N0-1M0) were enrolled in this study. MICS were defined as those that met the following criteria: (1) consisting of 5-200 tumor cells or less than 200 μm in diameter and (2) more than 200 μm away from the adjacent main lesion. The prognostic impact of the presence or absence of MICS and the characteristics of MICS-forming cancer cells were evaluated by immunohistochemistry (IHC). MICS was observed in 57 patients (28.8%), and overall survival (OS) and recurrence-free survival (RFS) were significantly shorter in the MICS-positive group (OS: 44.4% vs. 84.4%, p < 0.001; RFS: 30.0% vs. 82.6%, p < 0.001). Univariate and multivariate analyses revealed that the presence of MICS was an independent poor prognostic factor for OS (hazard ratio [HR] 3.54, p < 0.001) and RFS (HR 4.99, p < 0.001). Immunohistochemistry showed that the expression levels of the cell-cell adhesion molecule E-cadherin and hypoxia-induced protein GLUT-1 were significantly decreased in cancer cells forming MICS lesions compared to the tumor component excluding MICS within the same tumor (non-MICS lesions). Our data show that MICS is a distinct morphological feature with important biological and prognostic significance., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest related to the present study., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The JCOG0804/WJOG4507L single-arm confirmatory trial indicated a satisfactory 10-year prognosis for patients who underwent limited resection for radiologically less-invasive lung cancer. However, only one prospective trial has reported a 10-year prognosis., Methods: We conducted a multicenter prospective study coordinated by the National Cancer Center Hospital East and Kanagawa Cancer Center. We analyzed the long-term prognosis of 100 patients who underwent limited resection of a radiologically less-invasive lung cancer in the peripheral lung field. We defined radiologically less-invasive lung cancer as lung adenocarcinoma with a maximum tumor diameter of ≤2 cm, tumor disappearance ratio of ≥0.5 and cN0. The primary endpoint was the 10-year local recurrence-free survival., Results: Our patients, with a median age of 62 years, included 39 males. A total of 58 patients were non-smokers; 87 had undergone wide wedge resection and 9 underwent segmentectomy. A total of four cases were converted to lobectomy because of the presence of poorly differentiated components in the frozen specimen or insufficient margin with segmentectomy. The median follow-up duration was 120.9 months. The 10-year recurrence-free survival and overall survival rates of patients with lung cancer were both 96.0%. Following the 10-year long-term follow-up, two patients experienced recurrences at resection ends after wedge resection., Conclusions: Limited resection imparted a satisfactory prognosis for patients with radiologically less-invasive lung cancer, except two cases of local recurrence >5 years after surgery. These findings suggest that patients with this condition who underwent limited resection may require continued follow-up >5 years after surgery., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: The developments of perioperative treatments for patients with high-risk early-stage lung cancer are ongoing, however, real-world data and evidence of clinical significance of genetic aberration are lacking in this population. This study aimed to identify patients with early-stage lung adenocarcinoma at high risk for recurrence based on pathological indicators of poor prognosis, including the International Association for the Study of Lung Cancer (IASLC) grade, and elucidate the prognostic impact of epidermal growth factor receptor mutation (EGFRm) status., Methods: This retrospective study included 494 consecutive patients who underwent complete resection for pathological stage I lung adenocarcinoma between 2011 and 2016. The patients were evaluated for EGFRm and IASLC grade. Multivariable analysis was used to identify pathological factors for poor prognosis associated with recurrence-free survival (RFS) and overall survival (OS). Patients with any one of these factors were classified into the high-risk group. The prognostic impact of EGFRm was evaluated using RFS, OS, and cumulative recurrence proportion., Results: Multivariable analysis for RFS and OS revealed that IASLC grade 3, pathological invasion size>2 cm, and presence of lymphovascular invasion were indicators of poor prognosis. EGFRm-positive patients had a higher incidence of all types of recurrence, including central nervous system (CNS) metastasis and distant metastasis in high-risk group, but not in low-risk group., Conclusions: This study provides evidence that patients with EGFRm-positive stage I lung adenocarcinoma in the high-risk group have an increased risk of recurrence, including CNS metastasis. These findings highlight the need for development of adjuvant treatment in this population., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Sarcomatoid carcinoma (SC), which can occur in any organ, is a rare disease. To elucidate common characteristics of SC beyond organs, we evaluated clinicopathological and immunological features of SC defined by the single histological criterion beyond organs compared to randomly matched conventional carcinoma (non-SC) adjusted for the disease stage. Immunological features were assessed by multiplex immunohistochemistry, comparing immune cell density in tumor tissues and tumor programmed death-ligand 1 (PD-L1) expression. A total of 101 patients with SC or non-SC (31 lung, 19 esophagus, 22 pancreas, 15 liver, 4 bile duct, 6 kidney, 2 uterus and 2 ovary) were identified among 7197 patients who underwent surgery at our institute (1997-2020). SC was significantly associated with worse survival (HR: 1.571; 95% CI: 1.084-2.277; P = .017). The frequency of postoperative progression within 6 months was significantly higher for SC patients (54% vs 28%; P = .002). The immune profiling revealed the densities of CD8 + T cells (130 vs 72 cells/mm 2 ; P = .004) and tumor-associated macrophages (566 vs 413 cells/mm 2 ; P < .0001) and the tumor PD-L1 expression score (40% vs 5%; P < .0001) were significantly higher in SCs than in non-SCs. Among 73 SC patients with postoperative progression, multivariate Cox regression analysis showed that immunotherapy tended to be associated with favorable survival (HR: 0.256; 95% CI: 0.062-1.057; P = .060). Collectively, SCs shared clinicopathological and immunological features across organs. Our study can initiate to standardize the pathological definition of SC and provide a rationale for the investigation and development for this rare disease in a cross-organ manner., (© 2023 UICC.)

The prognostic significance and role of extratumoral alveolar macrophages (exAMs) in lung adenocarcinoma (LUAD) patients remain unknown. In this study, we investigated the prognostic impact and gene expression of exAMs in LUAD patients. The density of alveolar macrophages (AMs) in the peri-tumoral lung field (p-exAMs) and distant lung field (d-exAMs) was evaluated in 217 LUAD patients with lymph node metastasis. Patients with high p-exAMs showed significantly shorter recurrence-free (RFS) and shorter overall survival (OS) than those with low p-exAMs (p = 0.02 and p = 0.03, respectively), whereas there was no survival difference between patients with high d-exAMs and those with low d-exAMs. Multivariate analysis revealed that high p-exAMs was an independent predictive factor for RFS (HR: 1.54; 95% confidence interval [CI]:1.10-2.16; p = 0.01). Later, we collected AMs from the tumor periphery and distant segments in 13 resected lungs by bronchoalveolar lavage (BAL) procedure and compared mRNA expression. AMs in the tumor periphery expressed significantly higher levels of IL-10 and CCL2 than those in the distant segment (p < 0.01 and p = 0.03, respectively). Additionally, IL-10 and CCL2 significantly induced the growth and migration of the PC9 cells in vitro. This study suggests that p-exAMs should be considered as a tumor-promoting component in the tumor microenvironment., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Introduction: This study aimed to clarify the correlation between the number of AMs and prognosis and to examine the gene expression of AMs in lung squamous cell carcinoma (SqCC)., Methods: We reviewed 124 stage I lung SqCC cases in our hospital and 139 stage I lung SqCC cases in The Cancer Genome Atlas (TCGA) cohort in this study. We counted the number of AMs in the peritumoral lung field (P-AMs) and in the lung field distant from the tumor (D-AMs). Moreover, we performed a novel ex vivo bronchoalveolar lavage fluid (BALF) analysis to select AMs from surgically resected lung SqCC cases and examined the expression of IL10, CCL2, IL6, TGFβ, and TNFα (n = 3)., Results: Patients with high P-AMs had significantly shorter overall survival (OS) (p < 0.01); however, patients with high D-AMs did not have significantly shorter OS. Moreover, in TCGA cohort, patients with high P-AMs had a significantly shorter OS (p < 0.01). In multivariate analysis, a higher number of P-AMs were an independent poor prognostic factor (p = 0.02). Ex vivo BALF analysis revealed that AMs collected from the tumor vicinity showed higher expression of IL10 and CCL2 than AMs from distant lung fields in all 3 cases (IL-10: 2.2-, 3.0-, and 10.0-fold; CCL-2: 3.0-, 3.1-, and 3.2-fold). Moreover, the addition of recombinant CCL2 significantly increased the proliferation of RERF-LC-AI, a lung SqCC cell line., Conclusion: The current results indicated the prognostic impact of the number of peritumoral AMs and suggested the importance of the peritumoral tumor microenvironment in lung SqCC progression., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Dirty necrosis (DN) is a form of tumor necrosis (TN) with prominent neutrophil infiltration and cell detritus in the necrotic foci. This study aimed to characterize the clinicopathological features of DN in metastatic lung cancers of the colon and rectum (MLCRs). A total of 227 patients who underwent pulmonary metastasectomy and complete resection for MLCR were included in this study. TN was evaluated using digitally scanned resection specimens. These slides were immunostained for biomarkers of NETosis (citrullinated histone H3 [citH3] and myeloperoxidase [MPO]), and the area positive for citH3 and MPO was further quantified. TN was observed in 216 cases (95.2%), and 54 (25.0%) of these cases had DN. The presence of TN was not associated with a worse prognosis; however, patients with DN had a significantly shorter overall survival than those without DN (p < 0.01). Furthermore, the presence of DN was a poor prognostic factor in both the univariate and multivariate analyses. Immunohistochemical analysis revealed that the percentage of citH3-positive and MPO-positive areas in the DN-positive cases was significantly higher than that in the DN-negative cases (p < 0.01 and p < 0.01, respectively). In surgically resected MLCR, DN is the characteristic TN subtype associated with poor prognosis and neutrophil extracellular traps (NETs)., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Although the opportunity to treat subcentimeter lung cancers has increased, the optimal surgical methods remain unclear. We performed a retrospective study to examine the clinical outcome of subcentimeter lung cancers., Patients and Methods: In total, 118 patients who underwent curative resection for subcentimeter lung cancer from January 2005 to December 2013 were analyzed. Multivariate Cox proportional hazards models were used to calculate the hazard ratio to identify independent predictors of recurrence-free survival (RFS) and overall survival (OS)., Results: Anatomical resections were performed for 64 patients (59 lobectomies and 5 segmentectomies) and wedge resections for 54 patients. Recurrence developed in six patients who had consolidation-predominant tumors (consolidation/tumor [C/T] ratio of >0.5) and underwent wedge resections. The first recurrence patterns were regional recurrences in three patients, both regional and distant in one, and distant in two. Seventeen patients died of other causes. The multivariate analysis revealed that the C/T ratio was the independent predictor of RFS ( p  = 0.008) and OS ( p  = 0.011)., Conclusion: Patients with subcentimeter lung cancer rarely developed recurrence. The C/T ratio was the independent prognostic factor, and all relapsed patients received wedge resections. Even for subcentimeter lung cancers, we should select the extent of pulmonary resection after thoroughly considering whether wedge resection (less invasiveness) is a reasonable alternative to anatomical resection (superior oncologic efficacy) considering the C/T ratio of the lesion., Competing Interests: None declared., (Thieme. All rights reserved.)

Purpose: Intratumoral macrophages are reportedly involved in tumor progression in non-small cell lung cancer; however, little is known about the prognostic impact and function of alveolar macrophages (AMs). This study aims to investigate the prognostic impact of the number of peri-tumoral AMs in patients with stage I lung adenocarcinoma., Methods: We investigated 514 patients with pathological stage I lung adenocarcinoma who underwent complete resection with lobectomy or pneumonectomy. The numbers of peri-tumoral AMs were counted, and patients were classified into two groups based on the number of peri-tumoral AMs. Using the Cancer Genome Atlas (TCGA) database of stage I lung adenocarcinoma, we compared gene expression profiles of high and low peri-tumoral AM contents., Results: The median number of peri-tumoral AMs per alveolar space was 15.5. Patients with a high peri-tumoral AM content had significantly shorter disease-free survival and overall survival than patients with a low peri-tumoral AM content (both p < 0.01). In the multivariate analyses, a higher number of peri-tumoral AMs were an independent prognostic factor (p = 0.02). The analysis of TCGA database revealed that patients with a high peri-tumoral AM content had shorter disease-free survival than those with a low peri-tumoral AM content (p = 0.04). Gene expression analysis of TCGA stage I lung adenocarcinoma revealed enrichment of biological processes, such as chemotaxis and epithelial proliferation, in patients with a high peri-tumoral AM content., Conclusion: The number of peri-tumoral AMs had a strong impact on disease-free survival in patients with stage I lung adenocarcinoma., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Tertiary lymphoid structures (TLS) are observed in several cancers and are associated with favorable prognosis. This study aimed to examine the clinicopathological, genetic, and gene expression profiles of lung adenocarcinoma patients with TLS., Methods: A total of 112 patients with pathological stage IB lung adenocarcinoma who underwent complete resection between 2011 and 2015 were enrolled in this study. We investigated whether TLS correlated with prognosis and programmed death-ligand 1 (PD-L1) expression. Furthermore, the correlation of TLS with tumor mutation burden (TMB) and genetic mutations was evaluated in patients for whom whole-exon sequencing data were available. In addition, using the Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) dataset, gene expression analysis according to the TLS status was performed., Results: Among the 112 patients, 49 were TLS-positive (TLS+). TLS+ correlated with longer recurrence-free survival (RFS) than TLS-negative cases (TLS-) (hazard ratio [HR], 0.47; 95 % confidence interval [CI]: 0.23-0.88, p = 0.02). In the multivariate analysis, TLS was a better independent prognostic factor for RFS (HR 0.37, 95 %CI 0.18-0.72, p < 0.01). PD-L1 expression was not significantly different between TLS+ and TLS- patients (p = 0.54). TMB in TLS+ was similar to that in TLS- patients (p = 0.39); however, it tended to be lower than that in TLS- especially among smokers (p = 0.07). In gene expression analysis, RNA expression of chemokines related to lymph node formation, such as CXCL13, CCL19 and CCL21, was significantly higher, and biological processes such as positive regulation of humoral immune response and regulation of antigen receptor-mediated signaling pathway were enhanced in TLS+., Conclusions: TLS was a favorable prognostic factor and was not associated with PD-L1 expression in patients with lung adenocarcainoma. Moreover, gene expression analysis indicated that TLS is a site for the generation and regulation of antitumor immune responses., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Positron emission tomography is a useful technique for diagnosing lymph node (LN) metastasis. This study aimed to elucidate the association between fluorodeoxyglucose accumulation and the microenvironment in metastatic LNs in lung adenocarcinoma. We retrospectively analyzed 62 patients with surgically resected pathological N2 lung adenocarcinoma who underwent preoperative PET. The maximum standardized uptake value (SUV max ) in the metastatic LNs was measured. Lymph node specimens were immunohistochemically analyzed for CD8 + , FoxP3 + , and CD79a + lymphocytes, CD204 + tumor-associated macrophages (TAMs), and alpha-smooth muscle actin-positive cancer-associated fibroblasts (αSMA + CAFs). We compared the clinicopathologic and immunohistochemical characteristics between two groups with high and low LN SUV max . Using novel 3D hybrid spheroid models, we investigated the change in invasiveness of cancer cells in the presence of CAFs. In the multivariate analyses, LN SUV max was an independent prognostic factor. The overall survival in the LN SUV max high group was significantly worse than in the low group (P = .034). In the LN SUV max high group, metastatic cancer cell invasion of extranodal tissue was more frequent (P = .005) and the number of CD204 + TAMs and αSMA + CAFs in metastatic LNs was significantly higher than in the low group (P < .001 and P = .002, respectively). Hybrid spheroid models revealed that cancer cells coexisting with CAFs were more invasive than those without CAFs. Our results indicated a strong association between LN SUV max and poor prognosis in patients with N2 lung adenocarcinoma. Moreover, LN SUV max was suggested to be associated with the presence of tumor-promoting stromal cells in metastatic LNs., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Extratumoral lymphatic permeation (ly-ext) has been reported as an independent poor prognostic factor for lung adenocarcinoma, but whether or not the number of ly-ext foci is associated with prognosis and its relationship to the immune microenvironment is unclear. We counted the number of ly-ext foci on pathological slides from patients with completely resected lung adenocarcinoma with ly-ext, and divided them into two groups: a group with a high number of ly-ext foci (ly-ext high) and one with a low number of ly-ext foci (ly-ext low). Among the patients with ly-ext, only a high number of ly-ext foci was an independent poor prognostic factor. The 3-year recurrence-free survival (RFS) rate of the ly-ext high group was significantly lower than that of the ly-ext low group (14.7% vs. 50.0%, P < 0.01). Then, we analyzed the immune microenvironment of pT1 lung adenocarcinoma with ly-ext (13 cases of ly-ext high and 11 cases of ly-ext low tumor) by immunohistochemistry using antibodies for stem cell markers (aldehyde dehydrogenase 1 A1 and CD44), tumor-promoting mucin (MUC1), tumor-infiltrating lymphocytes (CD4, CD8, FOXP3, and CD79a), and tumor-associated macrophages (CD204). The number of CD8+ TILs within the primary lesion was significantly lower and the number of FOXP3+ TILs within the primary lesion was significantly higher in the ly-ext high group (P < 0.05 and P < 0.01, respectively). Our results indicated that a high number of ly-ext foci was an independent poor prognostic factor. Moreover, tumors with high numbers of ly-ext foci had a more immunosuppressive microenvironment., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Purpose: Lymph node involvement is one of the important prognostic factors of patients with lung adenocarcinoma. In the tumor, node, and metastasis classification, lymph node involvement is categorized only according to the anatomical station and not the involvement pattern. The aim of this study was to investigate which morphological pattern of lymph node involvement affects the prognosis of patients with surgically resected lung adenocarcinoma., Methods: We retrospectively reviewed 168 consecutive patients who underwent surgical resection for primary lung adenocarcinoma with lymph node involvement. The morphological patterns of lymph node involvement (tumor area, number of metastatic lymph nodes, presence of necrosis, and extranodal extension) were histologically examined. The relationships between the patterns of lymph node involvement, clinicopathological features, and survival of patients were analyzed., Results: Eighty patients had N1 disease, and 88 patients had N2 disease. Univariate analysis revealed that invasive size, history of adjuvant chemotherapy, and presence of extranodal extension were significant prognostic factors in N1 patients, and vascular invasion, pleural invasion, presence of epidermal growth factor receptor mutation, history of adjuvant chemotherapy, and presence of extranodal extension were significant prognostic factors in N2 patients. In a bivariate analysis including other clinicopathological factors and patterns of lymph node involvement, the presence of extranodal extension was significantly associated with poor 3-year overall and recurrence-free survival of both N1 and N2 patients., Conclusions: In patients who underwent surgical resection for lung adenocarcinoma with lymph node involvement, the extranodal extension was the most important prognostic factor among morphological lymph node involvement patterns., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Lung cancer is one of the most aggressive tumour types. Targeted therapies stratified by oncogenic drivers have substantially improved therapeutic outcomes in patients with non-small-cell lung cancer (NSCLC) 1 . However, such oncogenic drivers are not found in 25-40% of cases of lung adenocarcinoma, the most common histological subtype of NSCLC 2 . Here we identify a novel fusion transcript of CLIP1 and LTK using whole-transcriptome sequencing in a multi-institutional genome screening platform (LC-SCRUM-Asia, UMIN000036871). The CLIP1-LTK fusion was present in 0.4% of NSCLCs and was mutually exclusive with other known oncogenic drivers. We show that kinase activity of the CLIP1-LTK fusion protein is constitutively activated and has transformation potential. Treatment of Ba/F3 cells expressing CLIP1-LTK with lorlatinib, an ALK inhibitor, inhibited CLIP1-LTK kinase activity, suppressed proliferation and induced apoptosis. One patient with NSCLC harbouring the CLIP1-LTK fusion showed a good clinical response to lorlatinib treatment. To our knowledge, this is the first description of LTK alterations with oncogenic activity in cancers. These results identify the CLIP1-LTK fusion as a target in NSCLC that could be treated with lorlatinib., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Objectives: The purpose of this study was to investigate the clinicopathological, gene expression and genetic features of stage I lung adenocarcinoma with necrosis., Methods: We retrospectively reviewed 521 cases with pathologic stage I lung adenocarcinoma resected by lobectomy and lymph node dissection. We calculated the ratio of tumor necrotic area by digital image analysis and investigated the relationship between tumor necrosis and prognosis. Furthermore, we analyzed the differentially expressed genes between cases with and without necrosis using The Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) dataset. Using whole exon sequencing data (n = 97), we examined whether tumor necrosis correlates with single nucleotide variants (SNVs) and driver mutations., Results: Eighty four (16%) cases of the study cohort had tumor necrosis. The presence of necrosis significantly correlated with poorer prognosis (5-year overall survival: 91.9% vs. 75.4%, p < 0.001; 5-year recurrence-free survival: 86.0% vs. 59.0%, p < 0.001); however, the ratio of necrotic area did not correlate with prognosis. In multivariable analysis, invasive component size, vascular invasion, and tumor necrosis were independently associated with a higher risk of recurrence (hazard ratio, 1.652; 95% confidence interval, 1.033-2.641; p = 0.036). Gene expression analysis of TCGA stage I lung adenocarcinoma revealed enrichment of biological processes, such as cell cycle and response to hypoxia, in cases with necrosis. The cases with tumor necrosis had more SNVs than those without tumor necrosis (p = 0.027), especially in smokers., Conclusion: Stage I lung adenocarcinoma with tumor necrosis has worse prognosis than that without, and has distinctclinicopathological features in terms of gene expression and genetic features., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: Tumor necrosis is a negative prognostic factor in various cancers. High-grade neuroendocrine carcinomas (HGNEC) of the lung, such as small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC), commonly have histopathological features of tumor necrosis. However, the prognostic value of tumor necrosis remains unknown., Materials and Methods: A total of 81 patients with HGNEC (SCLC, n = 42; LCNEC, n = 39) who underwent complete resection were enrolled. The proportion of necrosis in the tumor tissues was quantified using digital image analysis. We analyzed the relationship between the proportion of necrosis, clinicopathological factors, and prognosis. Moreover, we examined the correlation between genomic alterations and proportion of necrosis., Results: The median proportion of necrosis was 10.6 % (range, 0-62.8 %). The proportion of necrosis was not significantly different between SCLC (median, 5.1 %; range, 0-62.8 %) and LCNEC (median: 14.2 %; range, 0-59.3 %) (p =  0.14). The cumulative incidence of recurrence (CIR) and lung cancer-specific cumulative incidence of death (LC-CID) were significantly higher in patients with 10 % or higher necrosis (necrosis ≥ 10 %) than in those with less than 10 % (necrosis < 10 %) (hazard ratio [HR], 2.94; 95 % confidence interval [CI], 1.30-6.64, and HR, 2.87; 95 % CI, 1.13-7.29, respectively). In the bivariate analysis, necrosis ≥ 10 % was independently associated with higher CIR and tended to be associated with higher LC-CID. The frequency of genomic alterations in the PI3K/AKT/mTOR pathway, MYC family, MAPK/ERK pathway, and major RTK signaling pathways were not different between the necrosis ≥ 10 % and necrosis < 10 % groups for both SCLC and LCNEC., Conclusion: High proportion of tumor necrosis (≥ 10 %) had a negative prognostic value in surgically resected HGNEC., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: In primary lung cancer surgery, intraoperative pleural lavage cytology (PLC) has been identified as a prognostic marker. However, there have been no reports on PLC for pulmonary metastasectomies. Therefore, the impact of PLC status for patients undergoing pulmonary metastasectomy remains unknown. We aimed to know the incidence and prognostic impact of positive PLC findings in pulmonary metastasectomies., Methods: We retrospectively reviewed patients undergoing pulmonary metastasectomies between January 2013 and December 2018. One hundred and eighty-nine PLC procedures in 159 patients undergoing pulmonary metastasectomy were analyzed. Follow-up information was available in 107 patients who underwent 132 procedure, and they were investigated for pleural recurrence-free probability (PRFP) and overall survival (OS) after pulmonary metastasectomy., Results: The type of primary lesion was colorectal cancer (101/189, 53%), urothelial/kidney cancer (17/189, 9%), skeletal/soft tissue tumor (18/189, 10%), hepatobiliary/pancreatic cancer (19/189, 10%), uterine/ovarian cancer (14/189, 7%), otorhinolaryngological cancer (11/189, 6%), and other minor lesions (9/189, 5%). Nine PLC-positive metastasectomies were revealed (9/189, 4.8%). They consisted of six metastasectomies from pancreatic cancer, two from osteosarcoma, and one from tongue cancer. Significant predictors for PLC status was type of primary tumor (P < 0.001). PRFP and OS rate of PLC-positive group were significantly lower than PLC-negative (P < 0.001, respectively)., Conclusion: PLC-positive results were rarely seen in pulmonary metastasectomies. PLC status was associated with the incidence of ipsilateral pleural recurrence and survival after metastasectomy. Cytologic examination of PLC should be considered in patients undergoing pulmonary metastasectomy.

Background: Cancer tissue is composed of both a cancer cell component and a stromal component. The aim of this study was to investigate if the component ratio predicts a prognosis for lung squamous cell carcinoma (SqCC) patients by using a machine learning method., Methods: A total of 135 peripheral SqCC cases (tumor size: 3-5 cm) were enrolled in this study. The areas of the cancer cell component, the necrotic component, and the stromal component were accurately measured via a machine learning method. Each case was divided into the following three subtypes: 1) predominant cancer cell, 2) predominant necrosis, and 3) predominant stroma. The study examined if a particular subtype had prognostic significance., Results: The number of cases per subtype of predominant cancer cell, predominant necrosis, and predominant stroma was 59, 6, and 70, respectively. Patients with the predominant stroma subtype had a significantly shorter recurrence free survival (RFS) than did those with the predominant cancer cell subtype (5-yr RFS: 42.3 % vs. 84.3 %,p < 0.01). Also, in pathological stage I patients, the 5-year RFS rate for the predominant stroma subtype was significantly shorter (5-yr RFS: 64.3 % vs. 88.4 %, p < 0.01). In the multivariate analysis of p-stage I patients, the predominant stroma subtype was confirmed to be an independent prognostic factor for RFS (p < 0.01)., Conclusion: Using machine learning, the study confirmed that the predominant stroma subtype was an independent factor for RFS, suggesting that the ratio of the stromal component correlates with the malignant potential of SqCC., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Malignant mesothelioma (MM) is a fatal tumor, and the absence of a specific diagnostic marker and/or a pathogenic molecule-targeting drug is a major issue for its pathological diagnosis and for targeting therapy. The molecular target of MM has not been elucidated because of unknown survival, death, and cytotoxic signals in MM. HEG homolog 1 (HEG1) is a mucin-like membrane protein that contains epidermal growth factor-like domains, and it plays an important role in cancers through aberrant signaling, including that during cell adhesion, as well as through protection from invasion of tumor cells. HEG1 expression supports the survival and proliferation of MM cells. In this study, functional analysis of HEG1 and microRNAs using MM cell lines (H226, MESO4, H2052) was performed. The MTS assay revealed that cell proliferation was significantly reduced upon transient transfection with microRNA-23b (miR-23b) inhibitor and/or HEG1 siRNA. The Annexin V assay revealed that apoptosis was induced upon suppression of miR-23b and/or HEG1. Western blotting showed that the autophagy-related protein LC3-II was induced upon suppression of miR-23b and/or HEG1. These results revealed that miR-23b contributes to HEG1-dependent cell proliferation through evasion of cytotoxicity induced by apoptosis and autophagy in MM cells. HEG1-dependent/mediated miR-23b signaling may therefore be a potential target for MM diagnosis and therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background/aim: Although the histological grading systems (Grading) with respect to lung adenocarcinoma are defined using architectural approaches in the eighth cancer Tumor, Node, and Metastasis (TNM) Classification, the prognostic value of the architectural subtypes in advanced stages of the disease remains unclear. We aimed to assess which Grading was more suitable as a prognostic factor: i) (conventional) Grading based on differentiation or ii) (new) Grading based on architectural subtypes., Patients and Methods: We analyzed the outcomes and Gradings of resected 449 patients with adenocarcinoma using receiver operating characteristic (ROC) curves., Results: The tumor histological grade of 147 out of 449 patients changed using the results from the revised Grading. In these 147 patients, ROC curves showed that the area under the curve was 0.710 using the conventional Grading and 0.567 using the new Grading., Conclusion: The conventional Grading might be more suitable for lung adenocarcinoma recurrence compared to the new Grading., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Abnormality of genes including 9p21 is known in malignant mesothelioma and we have examined the frequency of gene deletion and amplification using the fluorescence in situ hybridization (FISH) method. We formerly reported that abnormality of the genes was more common in the sarcomatoid type than epithelioid type. In this study, we compared the clinicopathological factors including nuclear grade (NG) and genomic abnormality in epithelioid malignant pleural mesothelioma (MPM)., Methods: Using paraffin-embedded tissues of 31 epithelioid MPMs, we investigated the presence of gene abnormalities in the genes 9p21, 1p36, 14q32, 22q12, 5p15, 6p, 8q24, and 7p12 by the FISH method, and compared the results with NG, clinical stage, and prognosis., Results: In the higher NG group of epithelioid MPM, more gene amplifications [in particular 5p15 and 8q24(MYC)] were observed, and clinical stage was more advanced. Cases with the amplification of 7p12(EGFR) tended to exhibit a worse prognosis. The significant correlation between histological differentiation and clinical features such as prognosis was not confirmed., Conclusions: NG status in epithelioid MPM may be related to gene alteration and clinical features.

Our aim was to determine whether or not non-small-cell lung cancer is squamous cell carcinoma (SQCC); even in small samples, it is essential in view of the side effects attendant on new therapeutics. Lung adenocarcinoma (ADC) with the EML4-ALK fusion gene has been described as demonstrating mucinous cribriform/acinar growth and signet-ring cells, sometimes partially simulating SQCC. We investigated the relation among morphology, anaplastic lymphoma kinase (ALK) rearrangement, and immunophenotype in 321 ADCs by tissue microarray using SQCC markers cytokeratin (CK)5/6, CK14, desmocollin-3, desmoglein-3, p40, p63 versus ADC markers thyroid transcription factor (TTF)-1 and napsin A. Unlike 312 ALK-negative ADCs, 9 ALK-positive cases were negative for 4 SQCC markers. Only 1 ALK-positive ADC showing assertive morphology was positive for CK5/6 and p63 as well as for TTF-1 and napsin A. Coexpression of TTF-1/p40 was not observed, unlike that of TTF-1/p63 reported previously. There was no statistically significant difference between ALK-negative and ALK-positive ADC by immunohistochemical profiling.