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Using a machine learning method, we investigated the intrinsic and extrinsic transcriptional profiles that affect the clinical response to PD-1 inhibitors in 57 patients with non-small cell lung cancer (NSCLC). Among the top 100 genes associated with the responsiveness to PD-1 inhibitors, the proportion of intrinsic genes in lung adenocarcinoma (LUAD) (69%) was higher than in NSCLC overall (36%) and lung squamous cell carcinoma (LUSC) (33%). The intrinsic gene signature of LUAD (mean area under the ROC curve (AUC) = 0.957 and mean accuracy = 0.9) had higher predictive power than either the intrinsic gene signature of NSCLC or LUSC or the extrinsic gene signature of NSCLC, LUAD, or LUSC. The high intrinsic gene signature group had a high overall survival rate in LUAD (p = 0.034). When we performed a pathway enrichment analysis, the cell cycle and cellular senescence pathways were related to the upregulation of intrinsic genes in LUAD. The intrinsic signature of LUAD also showed a positive correlation with other immune checkpoint targets, including CD274, LAG3, and PDCD1LG2 (Spearman correlation coefficient > 0.25). PD-1 inhibitor-related intrinsic gene patterns differed significantly between LUAD and LUSC and may be a particularly useful biomarker in LUAD.

We explored the prediction of programmed cell death ligand 1 (PD-L1) expression level in non-small cell lung cancer using a machine learning approach with positron emission tomography/computed tomography (PET/CT)-based radiomics.A total of 312 patients (189 adenocarcinomas, 123 squamous cell carcinomas) who underwent F-18 fluorodeoxyglucose PET/CT were retrospectively analysed. Imaging biomarkers with 46 CT and 48 PET radiomic features were extracted from segmented tumours on PET and CT images using the LIFEx package. Radiomic features were ranked, and the top five best feature subsets were selected using the Gini index based on associations with PD-L1 expression in at least 50% of tumour cells. The areas under the receiver operating characteristic curves (AUCs) of binary classifications afforded by several machine learning algorithms (random forest, neural network, Naïve Bayes, logistic regression, adaptive boosting, stochastic gradient descent, support vector machine) were compared. The model performances were tested by 10-fold cross validation.We developed and validated a PET/CT-based radiomic model predicting PD-L1 expression levels in lung cancer. Long run high grey-level emphasis, homogeneity, mean Hounsfield unit, long run emphasis from CT, and maximum standardised uptake value from PET were the five best feature subsets for positive PD-L1 expression. The Naïve Bayes model (AUC=0.712), with a sensitivity of 75.3% and specificity of 58.2%, outperformed all other classifiers. It was followed by the neural network model (AUC=0.711), random forest (AUC=0.700), logistic regression (AUC=0.673) and adaptive boosting (AUC=0.604).PET/CT-based radiomic features may help clinicians identify tumours with positive PD-L1 expression in a non-invasive manner using machine learning algorithms.

Background To systematically assess the consistency of recommendations regarding diagnosis and treatment of non-small cell lung cancer (NSCLC) in clinical practice guidelines (CPGs). Methods We systematically searched relevant literature databases and websites to identify CPGs related to NSCLC. We extracted the general characteristics of the included guidelines and their recommendations and descriptively compared and analyzed the consistency of recommendations across the guidelines. Results A total of 28 NSCLC guidelines were retrieved. The recommendations covered mainly diagnosis and treatment. The recommendations in the guidelines differed substantially in various topics, such as the application of positron emission tomography (PET) and the classification of stage III. Fourteen guidelines divided stage III into two types: operable and inoperable; and the remaining 14 guidelines into three sub-stages IIIA, IIIB and IIIC. Recommendations regarding the treatment in stage III were relatively inconsistent. In driver gene (EGFR, ALK, ROS1) positive patients, targeted therapy was the most common recommendation for first-line treatment, but recommendations regarding second-line treatment varied according to the site of the mutation. In driver gene negative patients, immunotherapy was the most frequently recommended option as both first- and second-line treatment, followed by chemotherapy. Discussion A number of countries are devoting themselves to develop NSCLC guidelines and the process of updating guidelines is accelerating, yet recommendations between guidelines are not consistent. We adopted a systematic review method to systematically search and analyze the NSCLC guidelines worldwide. We objectively reviewed the differences in recommendations for NSCLC diagnosis and treatment between the guidelines. Inconsistency of recommendations across guidelines can result from multiple potential reasons. Such as, the guidelines developed time, different countries and regions and many more. Poor consistency across CPGs can confuse the guideline users, and we therefore advocate paying more attention to examining the controversies and updating guidelines timely to improve the consistency among CPGs. Our study had also several limitations, we limited the search to CPGs published in Chinese or English, the interpretation of recommendations is inherently subjective, we did not evaluate the details of the clinical content of the CPG recommendations. Our research presents the current status of NSCLC guidelines worldwide and give the opportunity to pay more attention to the existing gaps. Further investigations should determine the reasons for inconsistency, the implications for recommendation development, and the role of synthesis across recommendations for optimal guidance of clinical care treatment. With the continuous revision and update of the guidelines, we are confident that future guidelines will be formulated with higher quality to form clear, definite and consistent recommendations for NSCLC diagnosis and treatment.

Background Lung adenocarcinoma (LUAD) with brain metastasis (BM) occurs frequently and has a poor prognosis. In this study, we aimed to assess the correlation between gene expression signatures and the development of BM after surgical resection of LUAD. Methods We analyzed the immune-related gene expression profiles of 72 LUADs with and without BM after surgery and verified them using NanoString method and immunohistochemistry (IHC). We matched the Tumor, Node, Metastasis (TNM) stage in the groups with and without BM to minimize the effect of TNM stage. Pathway enrichment studies were also performed. Results In the NanoString results, we identified 11 upregulated immune-related gene signature that correlated specifically with BM in the discovery and validation sets [area under the curve (AUC) =0.750 and 0.787, respectively]. The discovery set achieved 94% sensitivity and 62% specificity and the validation set displayed 100% sensitivity and 50% specificity. Eight out of the 11 genes were verified by IHC and had profiles similar to the gene expression profile results (AUC =0.844 for the discovery set and AUC =0.795 for the validation set). Subgroup analysis revealed that 11 immune-related gene signature enabled prediction of BM at all TNM stages. There were no differences in the 11 immune-related gene expression signatures between the primary LUAD samples and the matched brain samples. Pathway enrichment analysis revealed that the cytokine-cytokine receptor interaction pathway was closely correlated with BM. Conclusions The 11 identified immune-related gene expression signatures may be potentially clinically useful predictors for BM and can provide patient-specific treatment options.

Extranodal marginal zone lymphoma of mucosa‐associated lymphoid tissue (MALT) in the thymus is a rare disease. Furthermore, amyloid deposition in thymic MALT lymphoma has not been previously described. Here, we report a case of a 35‐year‐old man with thymic MALT lymphoma with amyloid deposition and myasthenia gravis. Chest computed tomography revealed an anterior mediastinal mass with internal cystic component and extensive calcification. Total thymectomy was performed and histopathologic findings were compatible with a diffuse amyloid deposition in extranodal marginal zone MALT lymphoma. The results indicate that thymic MALT lymphoma should be considered as a possible diagnosis in patients with a solid and cystic thymic mass and autoimmune disease, including myasthenia gravis.

Simple Summary It is important to be able to predict brain metastasis in lung adenocarcinoma patients; however, research in this area is still lacking. Much of the previous work on tumor microenvironments in lung adenocarcinoma with brain metastasis concerns the tumor immune microenvironment. The importance of the tumor nonimmune microenvironment (extracellular matrix (ECM), epithelial–mesenchymal transition (EMT) feature, and angiogenesis) has been overlooked with regard to brain metastasis. We evaluated tumor nonimmune-microenvironment-related gene expression signatures that could predict brain metastasis after the surgical resection of lung adenocarcinoma using a machine learning approach. We identified a tumor nonimmune-microenvironment-related 17-gene expression signature, and this signature showed high brain metastasis predictive power in four machine learning classifiers. The immunohistochemical expression of the top three genes of the 17-gene expression signature yielded similar results to NanoString tests. Our tumor nonimmune-microenvironment-related gene expression signatures are important biological markers that can predict brain metastasis and provide patient-specific treatment options. Abstract Using a machine learning approach with a gene expression profile, we discovered a tumor nonimmune-microenvironment-related gene expression signature, including extracellular matrix (ECM) remodeling, epithelial–mesenchymal transition (EMT), and angiogenesis, that could predict brain metastasis (BM) after the surgical resection of 64 lung adenocarcinomas (LUAD). Gene expression profiling identified a tumor nonimmune-microenvironment-related 17-gene expression signature that significantly correlated with BM. Of the 17 genes, 11 were ECM-remodeling-related genes. The 17-gene expression signature showed high BM predictive power in four machine learning classifiers (areas under the receiver operating characteristic curve = 0.845 for naïve Bayes, 0.849 for support vector machine, 0.858 for random forest, and 0.839 for neural network). Subgroup analysis revealed that the BM predictive power of the 17-gene signature was higher in the early-stage LUAD than in the late-stage LUAD. Pathway enrichment analysis showed that the upregulated differentially expressed genes were mainly enriched in the ECM–receptor interaction pathway. The immunohistochemical expression of the top three genes of the 17-gene expression signature yielded similar results to NanoString tests. The tumor nonimmune-microenvironment-related gene expression signatures found in this study are important biological markers that can predict BM and provide patient-specific treatment options.

Purpose We sought to distinguish lung adenocarcinoma (ADC) from squamous cell carcinoma using a machine-learning algorithm with PET-based radiomic features. Methods A total of 396 patients with 210 ADCs and 186 squamous cell carcinomas who underwent FDG PET/CT prior to treatment were retrospectively analyzed. Four clinical features (age, sex, tumor size, and smoking status) and 40 radiomic features were investigated in terms of lung ADC subtype prediction. Radiomic features were extracted from the PET images of segmented tumors using the LIFEx package. The clinical and radiomic features were ranked, and a subset of useful features was selected based on Gini coefficient scores in terms of associations with histological class. The areas under the receiver operating characteristic curves (AUCs) of classifications afforded by several machine-learning algorithms (random forest, neural network, naive Bayes, logistic regression, and a support vector machine) were compared and validated via random sampling. Results We developed and validated a PET-based radiomic model predicting the histological subtypes of lung cancer. Sex, SUVmax, gray-level zone length nonuniformity, gray-level nonuniformity for zone, and total lesion glycolysis were the 5 best predictors of lung ADC. The logistic regression model outperformed all other classifiers (AUC = 0.859, accuracy = 0.769, F1 score = 0.774, precision = 0.804, recall = 0.746) followed by the neural network model (AUC = 0.854, accuracy = 0.772, F1 score = 0.777, precision = 0.807, recall = 0.750). Conclusions A machine-learning approach successfully identified the histological subtypes of lung cancer. A PET-based radiomic features may help clinicians improve the histopathologic diagnosis in a noninvasive manner.

Objectives Therapies that target programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) have shown promising efficacy in non-small-cell lung cancer (NSCLC). Hypoxia-related genes are also important regulators of PD-L1, and the role of PD-L1 in NSCLC is still not clear. The objective of this study was to investigate PD-L1 expression and its correlation with hypoxic-inducible factor 1α (HIF1A), vascular endothelial growth factor A (VEGFA), glucose transporter 1 (GLUT1), and carbonic anhydrase 9 (CAIX) expression in NSCLC patients. The association between PD-L1 expression and survival was also determined. Materials and methods PD-L1/protein expression was evaluated in 295 resected NSCLCs and its correlation with HIF1A, VEGFA, GLUT1, CAIX expression and survival was determined based on immunohistochemical and RNA sequencing data obtained from The Cancer Genome Atlas (TCGA) database. Results PD-L1 protein expression was significantly correlated with HIF1A, VEGFA, GLUT1, and CAIX expression only in adenocarcinoma when a 10% or a 50% cut-off was used. PD-L1 mRNA expression was also significantly correlated with HIF1A, VEGFA, GLUT1, and CAIX expression in adenocarcinoma. Univariate analysis revealed that HIF1A expression was associated with poor recurrence-free survival (RFS), and GLUT1 was associated with poor overall survival (OS) and RFS. GLUT1 was an independent prognostic factor for OS in multivariate analysis of immunohistochemical and TCGA data (p = 0.024 and 0.029, respectively). Patients with low expression of both PD-L1 and GLUT1 had longer OS than other patterns in immunohistochemical and TCGA data (p = 0.003 and 0.051, respectively). Conclusions PD-L1 protein and mRNA expression were correlated with HIF1A, VEGFA, GLUT1, and CAIX expression in adenocarcinoma alone. Low expression of GLUT1 and low expression of both PD-L1 and GLUT1 were associated with improved prognosis. Our findings support the rationale for co-targeting hypoxia-related genes and PD-L1 in cancer therapy. Expression of hypoxia-related genes may be helpful in selecting patients appropriate for PD-L1 therapy.

High expression of glucose transporter family members, which augment glucose uptake and glycolytic flux, has been shown to play a pivotal role in the proliferation and survival of tumor cells, contributing to the energy supply, biosynthesis and homeostasis of cancer cells. Among the many members, solute carrier family 2 member 1 (SLC2A1) encodes a glucose transporter, GLUT1, that is critical in the metabolism of glucose, which is an energy source for cell growth that contributes to cancer progression and development. The aim of this study was to analyze the survival and genetic changes/immune profiles in patients with gastric cancer with high SLC2A1 expression and to provide treatment for improving prognosis. This study investigated the clinicopathologic parameters, the proportion of immune cells and gene sets affecting SLC2A1 expression in 279 and 415 patients with gastric cancer from the Eulji Hospital cohort and The Cancer Genome Atlas, respectively. We assessed the response to conventional chemotherapy drugs, including fluorouracil, a compound of fluoropyrimidine S-1, oxaliplatin, and all−trans−retinoic acid (ATRA), in gastric cancer cell lines with high SLC2A1 expression. High SLC2A1 expression was associated with poor prognosis, cancer cell proliferation, decreased immune cells, including CD8 T cells and B cells, and a low prognostic nutrition index, representing body nutrition-related status. In pathway network analysis, SLC2A1 was indirectly linked to the retinoic signaling pathway and negatively regulated immune cells/receptors. In the drug response analysis, the drug ATRA inhibited gastric cancer cell lines with high SLC2A1 expression. Treatment involving the use of SLC2A1 could contribute to better clinical management/research for patients with gastric cancer.

The purpose of this study was to investigate the expression of PD-L1, cancer stem cells (CSC) markers (CD44, NANOG, and ALDH1) and epithelial-mesenchymal transition (EMT) markers and to evaluate their correlation and prognostic significance in non-small cell lung cancer (NSCLC) patients. PD-L1 protein expression was evaluated in resected 277 NSCLC cases and its correlation with CSC and EMT marker expression and survival was determined based on immunohistochemical (IHC) analysis. mRNA expression obtained from The Cancer Genome Atlas and the Kaplan-Meier plotter database were compared with the IHC results. PD-L1 expression was negatively correlated with ALDH1 expression in adenocarcinoma by IHC and mRNA expression. PD-L1 expression was also associated with mesenchymal phenotype (vimentin and TWIST) adenocarcinoma by IHC and mRNA expression. PD-L1 expression was associated with poor prognosis in adenocarcinoma by IHC. However, NANOG or ALDH1 expression measured by IHC and mRNA expression was correlated with a favourable prognosis in adenocarcinoma. Epithelial marker p120-catenin detected by IHC and mRNA expression was associated with a favourable prognosis in adenocarcinoma, however mesenchymal marker TWIST was associated with a worse prognosis. Patients with low PD-L1 and high ALDH1 expression showed more favourable prognoses than adenocarcinoma patients with other expression patterns. In multivariate analysis, ALDH1 detected by IHC and mRNA expression was an independent favourable prognostic marker for adenocarcinoma. Our study results support the hypothesis that PD-L1 interacts with CSC and EMT features and that PD-L1, ALDH1, and the mesenchymal phenotype may serve as tandem markers as prognostic factor in NSCLC.

Emerging data indicate that interferon‐induced transmembrane protein 1 (IFITM1) plays an important role in many cancers. However, it remains unclear whether IFITM1 is functionally indispensable in nonsmall cell lung cancer (NSCLC). Here, using NSCLC cell lines and patient‐derived samples, we show that IFITM1 is essentially required for the progression of NSCLC in vitro and in vivo. Specifically, IFITM1 depletion resulted in a significant reduction in sphere formation, migration, and invasion of NSCLC cells in vitro; these events were inversely correlated with the ectopic expression of IFITM1. In addition, tumor development was significantly impaired in the absence of IFITM1 in vivo. Mechanistically, epidermal growth factor receptor/sex‐determining region Y‐box 2 (EGFR/SOX2) signaling axis was compromised in the absence of IFITM1, and the ectopic expression of SOX2 partially rescued the defects caused by IFITM1 depletion. More importantly, using 226 patient‐derived samples, we demonstrate that a high level of IFITM1 expression is associated with a poor overall survival (OS) rate in adenocarcinoma but not in squamous cell carcinoma. Collectively, these data suggest that IFITM1 is a poor prognostic marker of adenocarcinoma and an attractive target to develop novel therapeutics for NSCLC., What's new? Interferon response genes play key roles in pathogen defense but emerging evidence also link them with cancer. The authors report that interferon‐induced transmembrane protein 1 (IFITM1) critically regulates epidermal growth factor receptor‐mediated signaling in nonsmall lung cancer models and is associated with a poor prognosis of patients with adenocarcinoma. This expands the function of this innate defense factor and might lead to improved clinical management of individuals afflicted with lung cancer.

We explored the relationship between preoperative 18F-FDG-PET parameters, tumor necrosis, and microvessel density (MVD) in patients with pulmonary adenocarcinomas. A total of 164 patients, who underwent surgical resection for lung adenocarcinoma, were reviewed retrospectively. The maximum standardized uptake value (SUVmax), peak SUV corrected for lean body mass (SULpeak), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) values were measured by preoperative 18F-FDG-PET. The extent of tumor necrosis was examined and CD31 expression was evaluated to count the MVD. The SUVmax, SULpeak, MTV, and TLG levels were significantly lower in patients exhibiting no necrosis compared to those with necrosis. When we divided the patients into two groups based on high vs. low PET parameter values, elevated SUVmax, SULpeak, MTV, and TLG values were significantly more associated with partial or diffuse necrosis than were lower values (p

Exon 19 deletion and L858R mutation in exon 21 of the epidermal growth factor receptor (EGFR) are both common mutations that predict a good response to EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC). However, the existence of clinically significant difference in sensitivity to EGFR tyrosine kinase inhibitors among different EGFR mutation subtypes is still a matter of debate.The outcome of 60 EGFR mutation-positive advanced NSCLC patients who received first-line gefitinib therapy (250 mg/d) was retrospectively analyzed according to EGFR mutation subtypes.The median progression-free survival (PFS) and overall survival (OS) after the initiation of gefitinib therapy for all patients was 11 and 26 months, respectively. Univariate analysis showed that patients with exon 19 deletion (n=28) had significantly longer median PFS (20 vs. 8 mo, P=0.004) and OS (36 vs. 22 mo, P=0.001) compared with those with L858R mutation (n=25) and uncommon or dual mutations (n=7). Multivariate analysis revealed that exon 19 deletion (P=0.007) was an independent prognostic factor of favorable PFS, with an independent association with poor PFS of male sex (P=0.049). Exon 19 deletion was also independently associated with favorable OS (P0.0001), whereas male sex (P=0.004) and primary metastatic disease (P=0.032) were independent prognostic factors of poor OS.The EGFR exon 19 deletion was associated with favorable PFS and OS in patients receiving first-line gefitinib treatment. The EGFR mutation subtype should be considered when making treatment decision or designing clinical trials for chemotherapy-naive, EGFR mutation-positive advanced NSCLC patients.

Pulmonary nodular lymphoid hyperplasia is a reactive lymphoproliferative disease. It is very rare, which means that many aspects of the disease are unknown or have not been proven. Pulmonary nodular lymphoid hyperplasia can be symptomatic or asymptomatic, progressive or not, and solitary or multiple, and a surgical approach is the current treatment of choice. We present a case of pulmonary nodular lymphoid hyperplasia that was visualized as multiple ground glass opacities on a computed tomography (CT) scan, and observed for 1 year because the patient was pregnant. Over this period, the number and extent of the opacities progressed, but no symptoms were reported. A surgical biopsy was done and some remaining lesions regressed on follow-up CT scans, while others progressed, without any appearance of symptoms.

Epstein-Barr virus (EBV) is a significant contributor to the development of classical Hodgkin's lymphoma (cHL). Recent studies have documented associations between angiogenesis and EBV-associated malignancies. No study has yet examined the associations among, and prognostic implications of, EBV infection, vascular endothelial growth factor (VEGF) expression, and microvessel density (MVD) in cHL patients. Diagnostic tissues from 135 cHL patients treated with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) were retrospectively evaluated by in situ hybridization of EBV-encoded small RNA (EBER) and immunohistochemical staining for VEGF and CD31 (a measure of MVD). EBER and VEGF expression were positively correlated (P = 0.038). The mean MVD value of EBER-positive tumors was significantly higher than that of EBER-negative tumors (P = 0.034). The mean MVD of tumors positive for both EBER and VEGF was significantly higher than that of tumors negative for both markers (P = 0.008). EBER-positive patients had a lower 5-year overall survival (OS) rate than EBER-negative patients (P = 0.046). A high MVD was also associated with a poorer OS (P = 0.01); multivariate analysis showed that this was a significant and independent prognostic factor (P = 0.026). We found positive correlations between EBER and VEGF levels, and the MVD, indicating that EBV plays an important role in tumor angiogenesis. Targeting of both angiogenesis and EBV may be important when treating cHL patients who are EBER-positive and/or have a high MVD.

Background We evaluated glucose transporter type 1 (GLUT1) and carbonic anhydrase IX (CAIX) expression, together with volume-based 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) parameters, in non-small cell lung cancer (NSCLC) patients, and examined the prognostic significance of those parameters according to its histologic subtype. Method A total of 269 patients, who underwent surgical resection for NSCLC, were reviewed retrospectively. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) values were measured by preoperative 18 F-fluorodeoxyglucose positron emission tomography computed tomography. GLUT1 and CAIX expression was evaluated using immunohistochemical method. Results The mean MTV and TLG values were 30.0±57.1 and 165.4±361.3, respectively, and were significantly higher in patients with squamous cell carcinoma than with adenocarcinoma ( p =0.047 for MTV; p =0.042 for TLG). GLUT1 expression was identified in 99% of squamous cell carcinoma and 50% of adenocarcinoma patients. MTV and TLG values were significantly higher in GLUT1-positive than GLUT-negative adenocarcinomas; however, CAIX expression did not show this pattern. GLUT1-positive adenocarcinoma patients had a lower OS than GLUT1-negative patients ( p p =0.226). Patients with high MTV and TLG values showed lower OS rates than those with low MTV and TLG values. Multivariate analysis showed that GLUT1 positivity was an independent risk factor for a lower OS rate in lung adenocarcinoma patients (hazard ratio=2.574, p =0.016). GLUT1 expression was associated with micropapillary/solid histology, lymphovascular invasion, and advanced pTNM stage. Conclusions MTV and TLG values, and GLUT1 expression, significantly differed between patients with squamous cell carcinoma and adenocarcinoma. High GLUT1 expression levels were significantly associated with MTV and TLG values and adverse clinical outcomes in patients with adenocarcinoma.

Metastasis-associated in colon cancer-1 (MACC1), a newly identified oncogene, promotes tumor proliferation and invasion via the MET pathway. The purpose of this study is to determine the clinical significance of MACC1 and MET expression in the long-term survival and recurrence in a large cohort of gastric carcinoma patients following curative resection. We evaluated the prognostic value of MACC1 and MET expression using immunohistochemistry in 331 gastric adenocarcinoma patients. MACC1-positive patients had lower overall survival (OS) or event-free survival (EFS) rates than MACC1-negative patients (P=0.039 and P=0.044, respectively), while MET positivity itself was not associated with either OS or EFS. Multivariate analysis identified the expression level of MACC1 protein as an independent negative prognostic factor for OS or EFS (P=0.021 and P=0.016, respectively). This study suggests that MACC1 is an independent prognostic factor in gastric adenocarcinoma and that the prognostic impact of MACC1 may be associated with MACC1 partners other than MET.

Huntingtin-interacting protein 1-related protein (HIP1R) plays an important role in the regulation of programmed death-ligand 1 (PD-L1). The aim of this study was to investigate the expression of HIP1R and confirm its predictive or prognostic roles in anti-PD-1 therapy in nonsmall cell lung cancer (NSCLC) patients. HIP1R and PD-L1 immunohistochemical expression was examined in 52 refractory advanced NSCLC patients treated with anti-PD-1 inhibitors. We performed gene set enrichment analysis (GSEA) to detect HIP1R-specific gene sets. Patients in the PD-1 inhibitor responder group had lower HIP1R expression by univariate logistic regression analysis (odds ratio (OR) = 0.235, p = 0.015) and multivariate logistic regression analysis (OR = 0.209, p = 0.014). Patients with high HIP1R expression had poorer progression-free survival (PFS) than patients with low HIP1R expression in univariate analysis (p = 0.037) and multivariate Cox analysis (hazard ratio = 2.098, p = 0.019). The web-based mRNA dataset also showed that high HIP1R expression correlated with inferior overall survival in lung adenocarcinoma (p = 0.026). GSEA revealed that HIP1R levels correlate with a set of genes that reflect PD-L1-related immune pathways. HIP1R expression may be a promising predictor for determination of patient responses to anti-PD-1 treatment.

Malignant metastatic melanoma (MM) is the most lethal of all skin cancers, but detailed mechanisms for regulation of melanoma metastasis are not fully understood. Here, we demonstrated that developmentally regulated GTP-binding protein 2 (DRG2) is required for the growth of primary tumors and for metastasis. DRG2 expression was significantly increased in MM compared with primary melanoma (PM) and dysplastic nevi. A correlation between DRG2 expression and poor disease-specific survival in melanoma patients was also identified. Furthermore, inhibition of DRG2 suppressed the binding of Hypoxia-inducible factor 1α to the VEGF-A promoter region, expression of vascular endothelial growth factor (VEGF)-A, and formation of endothelial cell tubes. In experimental mice, DRG2 depletion inhibited the growth of PM and lung metastases and increased survival. These results identify DRG2 as a critical regulator of VEGF-A expression and of growth of PMs and lung metastases.

Cancer stem cells (CSC) and epithelial–mesenchymal transition (EMT) pathways are crucial for cancer progression. However, synergistic interactions between CSC and EMT are not clear in non-small cell lung cancer (NSCLC). The objective of this study was to investigate CSC markers such as CD44, NANOG, and ALDH1 expression and its correlation with EMT markers in NSCLC patients. Its association with survival was also determined. CD44, NANOG, and ALDH1 protein expression was evaluated in 267 resected NSCLC and its correlation with e-cadherin, β-catenin, p120 catenin, vimentin, SNAIL, and TWIST expressions was determined based on immunohistochemical and mRNA expression data from The Cancer Genome Atlas (TCGA) database. Survival analyses also were performed based on immunohistochemistry and mRNA expression data from Gene Expression Omnibus dataset. ALDH1 expression in lung adenocarcinoma was positively correlated with the epithelial-like phenotype, low vimentin and low TWIST in immunohistochemical and mRNA expression data. NANOG and ALDH1 expressions measured by immunohistochemical and mRNA expression profiling data of adenocarcinomas were associated with a favorable prognosis. ALDH1 was an independent favorable prognostic marker for overall survival or recurrence-free survival in adenocarcinoma (P = 0.026 and P = 0.033, respectively). The epithelial-like phenotype expressing P120-catenin and beta-catenin was associated with a favorable prognosis; however, the TWIST-expressing mesenchymal-like phenotype was correlated with an unfavorable prognosis. NANOG and ALDH1 protein or mRNA expression showed improved prognosis in adenocarcinoma alone. ALDH1 expression correlated with an epithelial-like phenotype.

Two pentose phosphate pathway-related proteins, NF-E2-related factor 2 (Nrf2)/ NAD(P)H dehydrogenase (Quinone) 1 (NQO1) regulate the expression of glucose metabolism and antioxidant genes. We evaluated the prognostic significance of NRF2, NQO1 and 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) parameter and their relationship with non-small cell lung cancer (NSCLC) histology. A total of 241 patients, who underwent surgical resection for NSCLC, were reviewed retrospectively. Preoperative 18F-FDG PET and immunohistochemical results of Nrf2 and NQO1 were evaluated. In SQCC, the maximum standardized uptake value (SUVmax) was significantly higher in NQO1-high than in NQO1-low expression (p=0.023). In adenocarcinoma, SUVmax was not correlated with NQO1 expression. Patients with a high NQO1 expression showed poor recurrence-free survival (RFS) and overall survival (OS) than patients with a low NQO1 expression in squamous cell carcinoma (SQCC) (p=0.002 and p=0.014, respectively). NQO1 expression was not associated with clinical outcome in adenocarcinoma. Nrf2 expression was not correlated with prognosis in two types of NSCLC. High SUVmax was associated with poor RFS (p=0.03) but is not related to poor OS (p=0.569) in SQCC. In multivariate analyses, NQO1 expression and SUVmax were not independent prognostic factors in SQCC. However, in multivariate analysis combining NQO1 and SUVmax values, both low SUVmax and low NQO1 was independent prognostic factor for RFS and OS (HR= 3.790, p = 0.033 and HR= 2.961, p = 0.045, respectively). In conclusion, both low SUVmax and low NQO1 was an independent prognostic factor in SQCC alone. The sample size was small but there was a positive correlation between NQO1 expression and SUVmax in SQCC.

Objective: EGFR genetic polymorphisms have been investigated for carcinogenesis in various tumors including lung cancer. We evaluated EGFR mutations in four exons, with an emphasis on the Q787Q EGFR polymorphism in non-small-cell lung cancer. Methods: To determine the presence of the Q787Q polymorphism in patients with lung cancer, we performed direct sequencing analyses of four exons for 83 squamous cell carcinomas and 80 adenocarcinomas untreated with EGFR tyrosine kinase inhibitors. Results: The Q787Q EGFR polymorphism was more frequently detected in squamous cell carcinoma patients than in adenocarcinoma patients (24 vs. 15.9%). The group of patients with the Q787Q EGFR polymorphism included more males and heavy smokers compared with other patient groups. The presence of the Q787Q EGFR polymorphism significantly and negatively affected the overall survival rate among patients with non-small-cell carcinoma (p = 0.011), particularly those with squamous cell carcinoma (p = 0.037). Among stage I and II squamous cell carcinoma patients, those with the Q787Q EGFR polymorphism had a poor prognosis (p = 0.032). Conclusions: The Q787Q EGFR polymorphism allows stratifying lung squamous cell carcinoma patients and could be an independent prognostic marker, particularly among those in stages I and II.

Summary The purpose of this study was to examine the prognostic significance of insulin-like growth factor-1 receptor (IGF-1R) expression alone and in relation to the expression of the MET- receptor and the MET-homologous receptor RON, in classical Hodgkin's lymphoma (cHL). Tumour samples from patients with cHL (n = 202; median age 37.5 years) were analysed retrospectively for IGF-R1, MET or RON expression by immunohistochemistry using tissue microarrays. The median follow-up time was 3.7 years (range, 0.1–20 years). Twenty-nine patients (14.3%) expressed IGF-1R protein in Hodgkin/Reed–Sternberg (HRS) cells, which was associated with a better overall survival (OS) (P = 0.036). IGF-1R expression was closely associated with MET receptor expression and low level of lactate dehydrogenase. In patients with cHL receiving doxorubicin, bleomycin, vinblastine and dacarbazine, those expressing IGF-1R showed a trend towards better OS and event-free survival than IGF-1R-negative patients (P = 0.129 and P = 0.115 respectively), but statistical significance was not reached. This study suggests that IGF-1R expression could be associated with better clinical outcome in cHL but is significantly associated with the expression of MET receptor.

Ovarian microcystic stromal tumor (MCST) is a very rare neoplasm; hence, its nomenclature was recently designated as "Distinctive morphologic and immunohistochemical features" in 2009. Its exact origin, etiological genetic alterations, and background are not yet clearly known. Familial adenomatous polyposis (FAP) is an autosomal dominant disease that leads to development of colorectal polyps via germ-line mutations of the APC gene on chromosome 5q21∼22. In this study, we report a 40-year-old female patient who had ovarian MCST and FAP. On sequencing the APC gene in ovarian MSCT, we detected a novel somatic mutation of the APC gene in exon 11, with a heterozygous deletion at nucleotide position c.1540delG (p.Ala514 Profs*9). Mutations of β-catenin (CTNNB1) and FOXL2 were not detected. Although one case demonstrating involvement of Wnt/β-catenin in ovarian MCST associated with FAP has been presented previously, no detailed information was provided. Thus, this is the ovarian MCST with a somatic mutation of APC in a patient with FAP.

Although genetic p53 aberrations are correlated with the prognosis of various types of cancer, their prognostic relevance is currently unclear in patients with gastrointestinal stromal tumors (GISTs) of the small intestine. Between 1994 and 2008, 113 patients with resected localized GISTs of the small intestine were included in this analysis. Patients who received pre- and/or postoperative chemotherapy were excluded. p53 overexpression was assessed by immunohistochemical staining and defined as expression in >10 % of tumor cells. p53 overexpression was identified in 38 patients (34 %) and was significantly associated with epithelioid histology (p = 0.040) and high cellularity (p = 0.004). Relapse-free survival (RFS) significantly differed according to p53 overexpression (5-year RFS rates, 57 vs. 78 %; p = 0.005). By multivariate analysis, which included tumor necrosis, tumor size, mitotic count, and primary genotype, p53 overexpression significantly affected RFS with a hazard ratio of 3.50 (95 % confidence interval 1.48–8.25; p = 0.004). p53 overexpression is an independent prognostic factor in patients with small intestinal GISTs. This suggests that p53 expression can be used to further stratify recurrence risk in patients with resected GISTs of the small intestine.

This study evaluated the effect of age and cell of origin on the prognostic significance of Ki-67 labeling index (Ki-67 LI) on overall survival (OS) of diffuse large B-cell lymphoma (DLBCL) in a cohort of 697 patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). Multivariate analysis revealed no prognostic significance of high Ki-67 LI (≥ 85%) for OS. However, on subgroup analysis, high Ki-67 LI was significantly associated with poor OS in late-elderly patients (aged ≥ 70 years) (p = 0.021) and non-germinal center B-cell-like (GCB) subtype (p = 0.015). In particular, high Ki-67 LI was associated with a poor prognosis in late-elderly patients with non-GCB subtype. No correlation was observed in young adults (aged < 60 years) or early-elderly (aged 60–70 years) patients or GCB subtype. The present study shows that high Ki-67 LI is a risk factor for poor OS in the late-elderly age group and non-GCB subtype in patients with DLBCL treated with R-CHOP.

Background/aim We evaluated the association between positron emission tomography (PET) textural features and glucose transporter 1 (GLUT1) expression level and further investigated the prognostic significance of textural features in lung adenocarcinoma. Patients and methods We evaluated 105 adenocarcinoma patients. We extracted texture-based PET parameters of primary tumors. Conventional PET parameters were also measured. The relationships between PET parameters and GLUT1 expression levels were evaluated. The association between PET parameters and overall survival (OS) was assessed using Cox's proportional hazard regression models. Results In terms of PET textural features, tumors expressing high levels of GLUT1 exhibited significantly lower coarseness, contrast, complexity, and strength, but significantly higher busyness. On univariate analysis, the metabolic tumor volume, total lesion glycolysis, contrast, busyness, complexity, and strength were significant predictors of OS. Multivariate analysis showed that lower complexity (HR=2.017, 95%CI=1.032-3.942, p=0.040) was independently associated with poorer survival. Conclusion PET textural features may aid risk stratification in lung adenocarcinoma patients.

Recent studies have indicated that the C-reactive protein (CRP)/albumin (CRP/Alb) ratio is associated with clinical outcomes in patients with various carcinomas. However, no studies have explored the association between the ratio of CRP/Alb and clinical outcome of inoperable patients with nonsmall cell lung cancers (NSCLCs). We examined the prognostic impact of CRP/Alb ratio on 165 stage IV NSCLC receiving palliative chemotherapy. The optimal cutoff level of CRP/Alb ratio was set at 0.195. The median follow-up time was 9 months (range, 1–74 months). On univariate analysis, high CRP/Alb ratio (≥0.195) was correlated (P

LGALS3, a member of the lectin family, has an important role in tumor progression through inhibition of apoptosis. LGALS3 shares several significant structural properties with BCL2. In this study, we examined the prognostic significance of LGALS3 and BCL2 in uniformly treated classical Hodgkin’s lymphoma. Diagnostic tissues from 110 patients with uniformly treated classical Hodgkin’s lymphoma were evaluated retrospectively by immunohistochemical analysis of LGALS3 and BCL2 expression. The median follow-up time was 6.2 years (range, 0.2–17.3 years). Twenty-seven patients (25%) expressed LGALS3 protein in Hodgkin/Reed–Sternberg cells, which was associated with poor overall survival and event-free survival (P=0.007 and P

Recent studies suggest that absolute lymphocyte count, absolute monocyte count and their ratio [lymphocyte/monocyte ratio (LMR)] at diagnosis may predict survival in classical Hodgkin lymphoma (cHL). Here, we investigated the prognostic significance of LMR in cHL patients in relation to age of patients. Subjects included 351 cHL patients (age range from 4 to 84 years, median age 34 years, sex ratio 1.58) who had been followed-up for a median period of 59 months (range, 0.1-245 months). The estimated 5-year overall survival (OS) rate was 86.8%. Subgroup analysis was performed according to patients' age; non-elderly group (

The aim of this study was to determine the predictive or prognostic impact of absolute neutrophil count/absolute lymphocyte count ratio (NLR) in breast cancer patients with estrogen receptor/progesterone receptor (ER/PR)-positive and human epidermal growth factor receptor 2 (HER2)-negative subtype who have received neoadjuvant chemotherapy (NAC). We performed retrospective analysis of 157 patients with primary breast cancer with ER/PR-positive and HER2-negative subtype who were treated with NAC, followed by definitive surgical resection. The median follow-up after surgery was 21 months (range, 1-108 months). On univariate analysis, high NLR (>2.25) correlated with poorer recurrence-free survival (RFS) and overall survival (OS) (P = 0.001 and P

Objectives A recent study suggested a prognostic role for the peripheral blood absolute lymphocyte/monocyte ratio (LMR) at diagnosis of diffuse large B-cell lymphoma (DLBCL). Here, we investigated the significance of LMR in DLBCL patients in relation to advanced age. Methods We examined the prognostic impact of LMR in 603 DLBCL treated with rituximab plus CHOP, using the receiver operating characteristic curve analysis for optimal cut-off values, and performed a subgroup analysis according to age. Results In elderly groups (age ≥ 70), absolute monocyte count was significantly increased, whereas LMR was significantly decreased compared to younger groups. Patients under 70 yr of age with LMR

Pseudomyxoma peritonei (PMP) cases can be classified into the prognosis-related subtypes of disseminated peritoneal adenomucinosis (DPAM) and peritoneal mucinous carcinomatosis (PMCA). To investigate the mechanisms of mucinous invasion and the differing prognoses of these two subtypes, we examined the expression levels of proteins involved in cellular adhesion and invasion, including E-cadherin, vimentin, β-catenin, and S100A4, in single isolated tumor cells (SICs) and cohesive cellular strips within mucin pools isolated from DPAM (n = 31) and PMCA (n = 21) patients. In both PMCA and DPAM cases, SICs showed a complete loss of E-cadherin expression, whereas cells in cohesive cellular clusters retained E-cadherin expression. The frequency of high numbers of SICs (>8) in PMCA cases was significantly greater than that in DPAM cases (86% and 26%, respectively) and was correlated with poor progression-free survival (P = 0.019) in a univariate analysis. In both PMP subtypes, strong vimentin expression was identified in most of the SICs but not the cohesive cellular strips. The relatively slow progression of DPAM may be attributable to the smaller number of SICs that lack E-cadherin expression and have increased vimentin expression, whereas the rapid progression of PMCA may be due to larger numbers of these SICs.

We evaluated the relationship between interferon-induced transmembrane protein 1 (IFITM1) expression, epithelial-mesenchymal transition (EMT) signature and angiogenesis in lung adenocarcinoma. Additionally, we examined prognostic significance of IFITM1 according to pTNM stage to confirm that IFITM1 can serve as a complement to the pTNM stage. A total of 141 lung adenocarcinoma specimens were evaluated retrospectively by immunohistochemical staining for IFITM1, EMT markers (e-cadherin, β-catenin, and vimentin), and CD31 to measure microvessel density. IFITM1was expressed in 46.8% of the specimens. IFITM1 expression was significantly correlated with increased microvessel density (P = 0.048). However, IFITM1 expression was not associated with three EMT markers. In a multivariate analysis, IFITM1 was an independent prognostic factor for overall survival in a multivariate analysis (hazard ratio: 2.59, P = 0.01). Online database with data from 720 lung adenocarcinoma patients also revealed a negative prognostic significance of IFITM1 (P 0.001). Furthermore, high IFITM1 expression was significantly correlated with decreased OS rates in each pTNM stage. IFITM1 is significantly correlated with angiogenesis and it may be used as a useful additional prognostic marker to aid pTNM classification.

CKLF-like MARVEL transmembrane domain containing 6 (CMTM6) plays a crucial role in the stability of the programmed death-ligand 1 (PD-L1). However, there has been no previous study of CMTM6 in non-small cell lung cancer (NSCLC) and its association with PD-L1 has not been confirmed. The aim of this study was to investigate the expression of CMTM6 and PD-L1 and to confirm their predictive roles for anti-PD-1 therapy in non-small cell lung cancer. CMTM6 and PD-L1 immunohistochemical expressions were evaluated in 35 advanced, treatment-refractory NSCLC patients who received PD-1 inhibitor therapy. The correlation between CMTM6 and PD-L1 expression was also determined based on immunohistochemistry and RNA-sequencing data obtained from The Cancer Genome Atlas (TCGA) database. CMTM6 expression was positively correlated with PD-L1 expression in immunohistochemical data (Pearson’s r = 0.342 and p = .044). A positive correlation was also identified in the mRNA expression data. Using receiver operating characteristic curves, the levels of CMTM6 and PD-L1 expression which provided the best distinguishing point between responder versus non-responder to PD-1 inhibitors were 70 and 75 H-scores, respectively. The patients in the PD-1 inhibitor responder group had higher CMTM6 expressions in univariate logistic regression analysis (odds ratio (OR) = 5.333, p = .037). However, PD-L1 expression was not associated with response to PD-1 inhibitor (p = .288). In multivariate analysis, CMTM6 was also found to be an independent predictor of the response to PD-1 inhibitors (OR = 6.226, p = .032). CMTM6 expression can be a promising predictor useful for therapeutic decision-making regarding PD-1 inhibitors.