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Aims: Programmed death‐ligand 1 (PD‐L1) expression is a predictive biomarker for adjuvant immunotherapy and has been linked to poor differentiation in lung adenocarcinoma. However, its prevalence and prognostic role in the context of the novel histologic grade has not been evaluated. Methods: We analysed a cohort of 1233 patients with resected lung adenocarcinoma where PD‐L1 immunohistochemistry (22C3 assay) was reflexively tested. Tumour PD‐L1 expression was correlated with the new standardized International Association for the Study of Lung Cancer (IASLC) histologic grading system (G1, G2, and G3). Clinicopathologic features including patient outcome were analysed. Results: PD‐L1 was positive (≥1%) in 7.0%, 23.5%, and 63.0% of G1, G2, and G3 tumours, respectively. PD‐L1 positivity was significantly associated with male sex, smoking, and less sublobar resection among patients with G2 tumours, but this association was less pronounced in those with G3 tumours. PD‐L1 was an independent risk factor for recurrence (adjusted hazard ratio [HR] = 3.25, 95% confidence intervals [CI] = 1.93–5.48, P < 0.001) and death (adjusted HR = 2.69, 95% CI = 1.13–6.40, P = 0.026) in the G2 group, but not in the G3 group (adjusted HR for recurrence = 0.94, 95% CI = 0.64–1.40, P = 0.778). Conclusion: PD‐L1 expression differs substantially across IASLC grades and identifies aggressive tumours within the G2 subgroup. This knowledge may be used for both prognostication and designing future studies on adjuvant immunotherapy. [ABSTRACT FROM AUTHOR]

Aims: The prognostic role of EGFR mutations remains controversial. We aimed to evaluate the prognostic role of EGFR mutation in consideration of the IASLC histological grade in patients with resected early‐stage lung adenocarcinoma. Methods and results: A total of 3297 patients with stages I–IIA resected lung adenocarcinoma who had had EGFR mutation tests between January 2014 and December 2019 at the Samsung Medical Center, Seoul, Korea were included. Recurrence‐free survival (RFS) was compared by EGFR mutation status (EGFR‐M+ versus EGFR‐WT) and IASLC histological grade (G1, G2 and G3). Cox proportional hazards models were used to estimate the adjusted HRs (aHRs) and 95% confidence intervals (CIs). Results: Compared to the EGFR‐WT group, the EGFR‐M+ group had a significantly lower proportion of G3 tumour (16 versus 33%, P < 0.001). During a median follow‐up of 41.4 months, 376 patients experienced recurrence. After adjusting for histological grade, the aHR for recurrence comparing the EGFR‐M+ to the EGFR‐WT was 1.30 (95% CI = 1.04–1.62, P = 0.022). The EGFR‐M+ group had a significantly lower 5‐year RFS than the EGFR‐WT group among G3 patients (58.4 versus 71.5%, P < 0.001), but not among G1 and G2 patients. Conclusions: EGFR mutation status was associated with a risk of recurrence after consideration of the IASLC histological grading, especially in G3 tumours. The results of this study would be useful for developing a new staging system and identifying a subset of patients who may benefit from adjuvant targeted therapy. [ABSTRACT FROM AUTHOR]

Background: The current standard treatment for patients with inoperable, locally advanced esophageal squamous cell carcinoma (ESCC) is definitive concurrent chemoradiotherapy (CCRT). Methods: Patients with locally advanced ESCC received 2 cycles of 5‐fluorouracil, cisplatin, durvalumab, and tremelimumab every 3 weeks with concurrent radiation therapy (60.2 or 64.5 grays). After completing CCRT plus immunotherapy, patients received 2 cycles of consolidative durvalumab and tremelimumab followed by durvalumab monotherapy every 4 weeks for 2 years after enrollment. Their survival outcomes were compared with those from a propensity score‐matched historical control group that had received CCRT alone. Results: In total, 40 patients were enrolled and analyzed. The 24‐month progression‐free survival (PFS) and overall survival rates were 57.5% and 75%, respectively. Compared with the historical control group (n = 75), the study population had significantly longer PFS (hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.28‐0.97; P =.040) and overall survival (HR, 0.49; 95% CI, 0.25‐0.98; P =.043). In the study population, patients who had PD‐L1–positive tumors (n = 28) had significantly longer PFS (HR, 0.20; 95% CI, 0.07‐0.54; P <.001) and overall survival (HR, 0.16; 95% CI, 0.05‐0.56; P =.001) compared with those who had PD‐L1–negative tumors (n = 11). However, there was no difference in survival outcomes according to PD‐L1 status in the historical control group, indicating a strong interaction between PD‐L1–positive status and survival outcomes in the treatment groups (PFS, P for interaction =.003; overall survival, P for interaction =.002). Conclusions: Durvalumab and tremelimumab with definitive CCRT had promising efficacy in patients with locally advanced ESCC. In addition, PD‐L1 expression had strong predictive value in the study population. The clinical efficacy of durvalumab and tremelimumab with definitive chemoradiotherapy was studied in patients who had inoperable esophageal squamous cell carcinoma. Significantly longer progression‐free and overall survival were observed compared with a propensity scored‐matched historical control group, and PD‐L1 expression seemed to have a strong predictive role in patients who had positive PD‐L1 combined proportion scores. [ABSTRACT FROM AUTHOR]

Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions are emerging tissue‐agnostic drug targets in malignancies including colorectal carcinomas (CRCs), but their detailed landscape in the context of various colorectal carcinogenesis pathways remains to be investigated. In this study, pan‐tropomyosin receptor kinase (TRK) protein expression was assessed by immunohistochemistry (IHC) in retrospectively collected colorectal epithelial tumor tissues, including 441 CRCs [133 microsatellite instability‐high (MSI‐high) and 308 microsatellite stable (MSS)] and 595 premalignant colorectal lesions (330 serrated lesions and 265 conventional adenomas). TRK‐positive cases were then subjected to next‐generation sequencing and/or fluorescence in situ hybridization to confirm NTRK rearrangements. TRK IHC positivity was not observed in any of the MSS CRCs, conventional adenomas, traditional serrated adenomas, or hyperplastic polyps, whereas TRK positivity was observed in 11 of 58 (19%) MLH1‐methylated MSI‐high CRCs, 4 of 23 (17%) sessile serrated lesions with dysplasia (SSLDs), and 5 of 132 (4%) sessile serrated lesions (SSLs). The 11 TRK‐positive MSI‐high CRCs commonly harbored CpG island methylator phenotype‐high (CIMP‐high), MLH1 methylation, BRAF/KRAS wild‐type, and NTRK1 or NTRK3 fusion (TPM3–NTRK1, TPR–NTRK1, LMNA–NTRK1, SFPQ–NTRK1, ETV6–NTRK3, or EML4–NTRK3). Both NTRK1 or NTRK3 rearrangement and BRAF/KRAS wild‐type were detected in all nine TRK‐positive SSL(D)s, seven of which demonstrated MSS and/or CIMP‐low. TRK expression was selectively observed in distorted serrated crypts within SSLs and was occasionally localized at the base of serrated crypts. NTRK fusions were detected only in SSLs of patients aged ≥50 years, whereas BRAF mutation was found in younger age‐onset SSLs. In conclusion, NTRK‐rearranged colorectal tumors develop exclusively through the serrated neoplasia pathway and can be initiated from non‐dysplastic SSLs without BRAF/KRAS mutations prior to full occurrence of MSI‐high/CIMP‐high. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Because of the growing number of actionable biomarkers in non–small cell lung cancer (NSCLC), sufficient tissue availability for testing is becoming a greater challenge. Liquid biopsy offers a potential solution by complementing standard tissue‐based methods. In this study, the authors analyzed the concordance of actionable genomic alterations sequenced from circulating tumor DNA (ctDNA; Guardant360) and tissue (Oncomine Focus Assay). Methods: From September 2015 to May 2018, 421 paired plasma and tissue samples from patients with advanced NSCLC who had previously undergone tissue testing by standard methods were collected. Both types of samples were available for 287 patients (262 in cohort 1 [treatment‐naive] and 25 in cohort 2 [treatment failure]), and only 1 sample type was available for 134 patients (50 in cohort 3 [plasma only] and 84 in cohort 4 [tissue only]). Results: In cohort 1, 198 samples (77.6%) showed concordance between tissue and plasma next‐generation sequencing (NGS). Among the discordant cases, plasma testing detected additional genomic alterations in 11 patients (4.2%). In 50 patients without tissue‐based NGS results (cohort 3), the ctDNA‐based test detected genomic alterations in 20 samples (40.0%). The median allele frequency (AF) of mutations identified with ctDNA‐based NGS (0.74%) was lower than that identified with the tissue‐based NGS test (13.90%). Clinical responses to matched targeted therapy occurred, regardless of the ctDNA AF. Upfront ctDNA‐based testing identified 60.4% of patients with genomic alterations. In addition, ctDNA‐based testing uncovered 12.0% more actionable alterations when it was performed after tissue‐based NGS testing. Conclusions: The results indicate that a ctDNA‐based test identifies additional patients with actionable genomic alterations and could, therefore, be used to complement traditional tissue‐based testing for NSCLC. Lay Summary: Circulating tumor DNA (ctDNA)–based next‐generation sequencing (NGS) testing is becoming essential as the number of actionable genomic biomarker increases for the treatment selection of non–small cell lung cancer.This study demonstrates the additive value of ctDNA‐based testing in addition to tissue‐based NGS and standard of care–based biomarker testing for detecting additional patients with actionable genomic alterations.Clinical responses have also been observed in patients with a low allele frequency detected by ctDNA‐based NGS testing. The results of this study support the benefit of circulating tumor DNA–based next‐generation sequencing (NGS) when it is used along with the tissue‐based standard of care and NGS to prevent undergenotyping in patients with non–small cell lung cancer at the time of the initial diagnosis and during later disease progression. [ABSTRACT FROM AUTHOR]

Background: Nuclear protein in testis (NUT) carcinoma is a rare tumor associated with NUT rearrangement that can present as poorly differentiated to undifferentiated carcinoma, with or without abrupt squamous differentiation. It is often misdiagnosed as poorly differentiated carcinoma or undifferentiated carcinoma if NUT is not suspected. In this study, we retrospectively analyzed pulmonary NUT carcinoma cases diagnosed with NUT immunohistochemical staining and discuss the differential diagnosis to provide information for this rare and aggressive entity. Methods: Cases, diagnosed as "NUT carcinoma" in lung pleura and "metastatic NUT carcinoma from the lung" in lymph nodes were diagnosed between 2017 and 2019 at the Samsung Medical Center (SMC). Clinical features such as age, sex, treatment and follow‐up period, and pathological reports were obtained by reviewing patients' electronic medical records. Results: A total of 10 NUT carcinoma cases were found in the SMC pathology database. Seven patients were men and six were non‐smokers. Tumor cells showed various cellular features such as round, squamoid, and spindle. Some cases had initially been misdiagnosed as spindle cell neoplasm, round cell sarcoma, squamous cell carcinoma and small cell carcinoma. All cases showed diffuse strong nuclear expression of NUT immunohistochemical staining, and some were positive for p63 staining and negative for CD56 staining. Conclusions: NUT carcinoma is often misdiagnosed because of its various morphologies. It is important to consider NUT as one of the differential diagnoses when encountering lung biopsy with undifferentiated morphology. Key points: Due to various morphological features, NUT carcinoma can be misdiagnosedIt is important to consider NUT carcinoma when diagnosing a poorly differentiated or undifferentiated tumor [ABSTRACT FROM AUTHOR]

Background and Aim: Knowledge of lymph node metastasis (LNM) status is crucial to determine whether patients with superficial esophageal squamous cell carcinoma (ESCC) can be cured with endoscopic resection alone, without the need for additional esophagectomy. The present study aimed to identify predictive factors and develop a prediction model for LNM in patients with superficial ESCC. Methods: Clinicopathologic data from 501 patients with superficial ESCC treated with radical esophagectomy were reviewed. Stepwise logistic regression analysis determined the predictors of LNM. Using these predictors, a nomogram for predicting the risk of LNM was constructed and internally validated using a bootstrap resampling method. Results: LNM rates of tumors invading the lamina propria, muscularis mucosa, and SM1 layers were 3.7%, 15.5%, and 40.7%, respectively. Deep tumor invasion depth, moderately or poorly differentiated histology, and lymphovascular invasion were independent predictors of LNM. ESCC with muscularis mucosa and SM1 invasion had odds ratios of 3.635 and 11.834, respectively, compared with that for ESCC confined to the lamina propria. Large tumor size (>2.0 cm) and presence of tumor budding showed borderline significance for LNM prediction. These five variables were incorporated into a nomogram. A constructed nomogram showed good calibration and good discrimination with an area under the receiver‐operating characteristic curve (area under the curve [AUC]) of 0.812. After bootstrapping, AUC was 0.811. Conclusions: We developed a nomogram that can facilitate individualized prediction of risk of LNM in patients with superficial ESCC. This model can aid in decision‐making for the need for additional esophagectomy after endoscopic resection for superficial ESCC. [ABSTRACT FROM AUTHOR]

Well‐differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) are the most common types of liposarcoma. Although WDLPS and DDLPS patients receive intensive treatment including radical surgery and systemic therapy, their overall 5‐year survival rates are 90% and 30%, respectively, indicating that DDLPS is clinically more aggressive. We examined whether adipogenic stimulation induces adipogenesis in human WDLPS/DDLPS cells by using dexamethasone, indomethacin, insulin, and 3‐isobutyl‐1‐methylxanthine (IBMX), all putative medications or drugs. Functional in vitro experiments showed that treatment with these four compounds induced adipogenic potency by transcriptional and translational upregulation of genes related to the maintenance of stemness and adipogenic differentiation. Using in vivo xenograft models, we found that the induction of stemness and adipogenesis inhibited the tumorigenic potency of DDLPS. This study suggests a potential application of drug repositioning in which adipogenesis‐inducing compounds could be used to treat DDLPS patients in a clinical setting. [ABSTRACT FROM AUTHOR]

The roles of miRNAs in lung cancer have not yet been explored systematically at the genome scale despite their important regulatory functions. Here, we report an integrative analysis of miRNA and mRNA sequencing data for matched tumor–normal samples from 109 Korean female patients with non‐small‐cell lung adenocarcinoma (LUAD). We produced miRNA sequencing (miRNA‐Seq) and RNA‐Seq data for 48 patients and RNA‐Seq data for 61 additional patients. Subsequent differential expression analysis with stringent criteria yielded 44 miRNAs and 2322 genes. Integrative gene set analysis of the differentially expressed miRNAs and genes using miRNA–target information revealed several regulatory processes related to the cell cycle that were targeted by tumor suppressor miRNAs (TSmiR). We performed colony formation assays in A549 and NCI‐H460 cell lines to test the tumor‐suppressive activity of downregulated miRNAs in cancer and identified 7 novel TSmiRs (miR‐144‐5p, miR‐218‐1‐3p, miR‐223‐3p, miR‐27a‐5p, miR‐30a‐3p, miR‐30c‐2‐3p, miR‐338‐5p). Two miRNAs, miR‐30a‐3p and miR‐30c‐2‐3p, showed differential survival characteristics in the Tumor Cancer Genome Atlas (TCGA) LUAD patient cohort indicating their prognostic value. Finally, we identified a network cluster of miRNAs and target genes that could be responsible for cell cycle regulation. Our study not only provides a dataset of miRNA as well as mRNA sequencing from the matched tumor–normal samples, but also reports several novel TSmiRs that could potentially be developed into prognostic biomarkers or therapeutic RNA drugs. [ABSTRACT FROM AUTHOR]

Abstract: Aim: The purpose of this study was to evaluate the efficacy of en bloc nephrectomy for perirenal retroperitoneal sarcoma (RPS) with respect to postoperative kidney function and oncological benefits. Methods: We performed a comparative study of 114 patients undergoing surgery for primary RPS, classifying cases as nephrectomy (NPX, n = 65) versus no nephrectomy (no‐NPX, n = 49). The Δ and % change between preoperative and postoperative estimated glomerulus filtration rate (eGFR) were analyzed to compare renal function changes after surgery. Kaplan–Meier analysis was performed to verify the incidence of local relapse between the two groups. Results: During a median follow‐up of 29 months, median postoperative GFR of 65 patients in the NPX group decreased to 73.5% of preoperative eGFR. Although 38 patients (58%) in the NPX group experienced a progression in chronic kidney disease stage after nephrectomy, no patients progressed to end‐stage renal disease (ESRD). In French Federation of Cancer Centers Sarcoma grade 2, the NPX group had statistically significant local control benefits, compared with the no‐NPX group (P = 0.048). Conclusions: Residual renal function after en bloc nephrectomy was stabilized without progression to ESRD. Moreover, en bloc nephrectomy for perirenal RPS might secure a complete resection margin for local tumor control. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study is to analyze the clinical impact of radical nephrectomy on retroperitoneal liposarcoma near the kidney. Methods: Data of patients who underwent surgery for unilateral primary retroperitoneal liposarcoma near the kidney were retrospectively collected. Patients were divided into four groups according to whether they underwent nephrectomy and combined resection of other organs. Kaplan-Meier survival analysis was used to estimate disease-free survival and overall survival. Multivariable Cox analysis was used to analyze factors related to disease-free survival and overall survival. Results: Nephrectomy (HR = 0.260, CI = 0.078-0.873, p = 0.029) had a beneficial effect on disease-free survival, while interaction model of nephrectomy*other organ resection (HR = 4.655, CI = 1.767-12.263, p = 0.002) showed poor disease-free survival. Other organ resection was not related to disease-free survival (HR = 1.543, CI = 0.146-16.251, p = 0.718). Operation method ( p = 0.007) and FNCLCC grade ( p < 0.001; G2, HR = 1.833, CI = 0.684-4.915, p = 0.228; G3, HR = 9.190, CI = 3.351-25.199, p < 0.001) were significant factors for disease-free survival. While combined organ resection without nephrectomy group (HR = 1.604, CI = 0.167-15.370, p = 0.682) and radical nephrectomy with combined organ resection group (HR = 1.309, CI = 0.448-3.825, p = 0.622) did not show significant difference in disease-free survival from the mass excision only group, radical nephrectomy without combined organ resection group (HR = 0.279, CI = 0.078-0.991, p = 0.048) showed superior disease-free survival. Conclusions: Radical nephrectomy of unilateral primary retroperitoneal liposarcoma near the kidney has a beneficial effect on disease-free survival. [ABSTRACT FROM AUTHOR]

Most anaplastic lymphoma kinase ( ALK)-rearranged non-small cell lung cancers (NSCLCs) show good clinical response to ALK inhibitors. However, some ALK-rearranged NSCLC patients show various primary responses with unknown reasons. Previous studies focused on the clinical aspects of ALK fusions in small cohorts, or were conducted in vitro and/or in vivo to investigate the function of ALK. One of the suggested theories describes how echinoderm microtubule-associated protein-like 4 ( EML4) -ALK variants play a role towards different sensitivities in ALK inhibitors. Until now, there has been no integrated comprehensive study that dissects ALK at the molecular level in a large scale. Here, we report the largest extensive molecular analysis of 158 ALK-rearranged NSCLCs and have investigated these findings in a cell line construct experiment. We discovered that NSCLCs with EML4-ALK short forms (variant 3/others) had more advanced stage and frequent metastases than cases with the long forms (variant 1/others) ( p = 0.057, p < 0.05). In vitro experiments revealed that EML4-ALK short forms show lower sensitivity to ALK inhibitors than do long forms. Clinical analysis also showed a trend for the short forms showing worse PFS. Interestingly, we found that breakpoints of ALK are evenly distributed mainly in intron 19 and almost all of them undergo a non-homologous end-joining repair to generate ALK fusions. We also discovered four novel somatic ALK mutations in NSCLC (T1151R, R1192P, A1280V, and L1535Q) that confer primary resistance; all of them showed strong resistance to ALK inhibitors, as G1202R does. Through targeted deep sequencing, we discovered three novel ALK fusion partners ( GCC2, LMO7, and PHACTR1), and different ALK fusion partners showed different intracellular localization. With our findings that the EML4-ALK variants, new ALK somatic mutations, and novel ALK-fusion partners may affect sensitivity to ALK inhibitors, we stress the importance of targeted therapy to take the ALK molecular profiling into consideration. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is pathologically classified as non-small-cell lung cancer (NSCLC), but its clinical behavior is more aggressive than other types of NSCLC. Accordingly, the optimal treatment strategy for LCNEC, including the indication of adjuvant treatment, remains controversial. Methods: A retrospective review of 139 patients who underwent curative-intent surgery for LCNEC was performed to investigate clinicopathologic features and survival outcomes and to evaluate whether adjuvant treatment affected survival outcomes. Results: The mean patient age was 64 years (126 men, 90.6%). Operative procedures included 111 lobectomies (79.8%), 12 pneumonectomies (8.6%), and 2 sublobar resections. Pathologic stage was IA in 31 (22%), IB in 36 (26%), IIA in 34 (24%), IIB in 9 (6%), IIIA in 19 (14%), IIIB in 2 (1.4%), and IV in 4 patients (2.9%). Postoperatively, 50 patients (36%) received adjuvant treatment. The median follow-up duration was 33 months. The 5-year overall survival (OS) rate was 53%, and 5-year disease-free survival (DFS) rate was 39%. In patients with pathologic stage I, there was no significant difference in either OS or DFS according to the addition of adjuvant treatment. However, in patients with pathologic stage II or higher, patients who underwent adjuvant treatment showed significantly better OS ( p = 0.023) and DFS ( p = 0.038). Conclusions: Our findings showed that patients who underwent curative-intent surgery for LCNEC benefitted from the use of adjuvant treatment especially in pathologic stage II or higher. [ABSTRACT FROM AUTHOR]

Background: Fibroblast growth factor receptor 1 (FGFR1) amplification is a potential driving oncogene in squamous cell cancer (SCC) of the lung. The current phase 2 study evaluated the efficacy and tolerability of dovitinib, an FGFR inhibitor, in patients with advanced SCC of the lung.Methods: Patients with pretreated advanced SCC of the lung whose tumors demonstrated FGFR1 amplification of > 5 copies by fluorescence in situ hybridization were enrolled. Dovitinib at a dose of 500 mg was administered orally, once daily, on days 1 to 5 of every week, followed by 2 days off. The primary endpoint was overall response. Secondary endpoints were progression-free survival, overall survival, and toxicity.Results: All 26 patients were men with a median age of 68 years (range, 52-80 years). The majority of patients were ever-smokers. The median duration of dovitinib administration (28 days per cycle) was 2.5 months (range, 0.7-8.6 months). The overall response rate was 11.5% (95% confidence interval [95% CI], 0.8%-23.8%) and the disease control rate was 50% (95% CI, 30.8%-69.2%), with 3 patients achieving partial responses. Response durations for the patients with partial responses were ≥4.5 months, ≥ 5.1 months, and 6.1 months, respectively. After a median follow-up of 15.7 months (range, 1.2-25.6 months), the median overall survival was 5.0 months (95% CI, 3.6-6.4 months) and the median progression-free survival was 2.9 months (95% CI, 1.5-4.3 months). The most common grade 3 or higher adverse events were fatigue (19.2%), anorexia (11.5%), and hyponatremia (11.5%) (event severity was graded based on National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]).Conclusions: Treatment with dovitinib demonstrated modest efficacy in patients with advanced SCC with FGFR1 amplification. Further studies to evaluate other biomarkers correlated with the efficacy of dovitinib in patients with SCC are warranted. Cancer 2016;122:3024-3031. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Aim To investigate the effects of Tubastatin A, a selective histone deacetylase-6 inhibitor, on synovial inflammation and joint destruction in a collagen antibody-induced arthritis ( CAIA) mouse model. Methods Collagen antibody-induced arthritis mice were given daily intraperitoneal injections of various concentrations of Tubastatin A (0, 10, 50, 100 mg/kg). The clinical score and paw thickness were measured. Mice were sacrificed on day 15, and the expression of tumor necrosis factor ( TNF)-α, interleukin ( IL)-1 and IL-6 in the serum were analyzed using enyme-linked immunosorbent assay ( ELISA). Two pathologists independently measured the synovitis score. Micro-computed tomography ( CT) scans of the joints were performed to quantify joint destruction. The expression of IL-6 from human fibroblast-like synoviocytes ( FLSs) after incubation with various doses of Tubastatin A (0, 0.75, 1.5, 3 μmol/L) was measured using ELISA. Results The clinical arthritis score was significantly attenuated and paw thickness was lower in the group treated with 100 mg/kg Tubastatin A compared with those treated with vehicle alone. The synovitis score was significantly reduced in the 100 mg/kg Tubastatin A-treated group compared with the control group. Micro- CT showed that quantitative measures of joint destruction were significantly attenuated in the 100 mg/kg Tubastatin A-treated group compared with the control. The expression of IL-6 in the sera was lower in the mice treated with Tubastatin A compared with the control. The expression of IL-6 in human FLSs decreased dose-dependently after incubation with Tubastatin A without affecting cell viability. Conclusions Tubastatin A successfully ameliorated synovial inflammation and protected against joint destruction in CAIA mice, at least in part, by modulating IL-6 expression. [ABSTRACT FROM AUTHOR]

Background Sarcomatoid carcinoma of the upper aerodigestive tract, a variant of squamous cell carcinoma, is a rare biphasic tumor consisting of epithelial and mesenchymal components. Methods and Results We report a case of 34-year-old woman with a relapsed refractory sarcomatoid carcinoma in the maxillary sinus. Because anaplastic lymphoma kinase (ALK) translocation is common in sarcoma, ALK fluorescence in situ hybridization (FISH) was performed and the result was positive. After crizotinib was administered, clinical improvement and stable disease lasted for 4 months. To identify the incidence of ALK rearrangement in this disease entity, ALK FISH was performed on tumor samples of 10 patients. Among them, 2 patients were positive. Conclusion To the best of our knowledge, this is the first case report demonstrating the clinical benefit of crizotinib in sarcomatoid carcinoma of the head and neck with ALK translocation. Our results suggest that the ALK FISH test may be suitable and encouraged for patients with sarcomatoid carcinoma of the head and neck. © 2015 Wiley Periodicals, Inc. Head Neck 37: E66-E69, 2015 [ABSTRACT FROM AUTHOR]

MET, a cell surface receptor for hepatocyte growth factor, is involved in the development of triple-negative/basal-like breast cancer (TNBC/BLBC). However, its utility as a therapeutic target in this subtype of breast cancer is poorly understood. To evaluate MET fully as a potential therapeutic target for TNBC/BLBC, we investigated the relationship between MET expression and clinical outcomes of patients with breast cancer and the functional effect of MET inhibition. Using automated immunohistochemistry (Ventana), we analyzed MET expression in 924 breast cancer patients with relevant clinicopathologic parameters. BLBC showed the strongest relationship with MET expression (57.5%, p < 0.001). High expression of MET in breast cancer resulted in poor overall survival ( p = 0.001) and disease-free survival (DFS, p = 0.010). MET expression was relatively high in TNBC cell lines, and the silencing of MET via small interfering RNA reduced cell proliferation and migration. We observed reduced TNBC cell viability after treatment with the MET inhibitor PHA-665752. In the most drug-resistant cell line, MDA-MB-468, which showed elevated epidermal growth factor receptor (EGFR) expression, silencing of EGFR resulted in increased sensitivity to PHA-665752 treatment. We confirmed that PHA-665752 synergizes with the EGFR inhibitor erlotinib to decrease the viability of MDA-MB-468 cells. TNBC patients coexpressing MET and EGFR showed significantly worse DFS than that in patients expressing EGFR alone ( p = 0.021). Our findings strongly suggest that MET may be a therapeutic target in TNBC and that the combined therapy targeting MET and EGFR may be beneficial for the treatment of TNBC/BLBC patients. [ABSTRACT FROM AUTHOR]

Epithelioid hemangioendothelioma ( EHE) is a rare vascular neoplasm that has the ability to recur locally and metastasize. Thus, it is important to distinguish this tumor from other epithelioid vascular neoplasms. A 47-year-old man presented to our hospital with a pelvic mass with severe ischialgia and weight loss. Surgical resection was performed, and the mass was found to have dark red multiloculated cysts with hemorrhage and calcification. The histopathologic examination showed a central sclerotic, hypocellular zone and a peripheral cellular zone. Only the peripheral portion of the wall revealed nested tumor cells in light blue myxoid stroma. These tumors are typically composed of short strands or cords of bland epithelioid cells with occasional intracytoplasmic lumens embedded in a myxohyalinized stroma. The tumor cells were positive for CD31 and CD34 and negative for factor VIII-related antigen, CK ( AE1/AE3) and S-100. The tumor nuclei showed distinct break-apart signals with individual green and/or red signals, indicating the presence of CAMTA1 rearrangement. In this study, we report a case of EHE that was difficult to diagnose based on histology alone. Therefore, we also performed fluorescence in situ hybridization, and found that the tumor harbored a CAMTA1 gene rearrangement, which confirmed the diagnosis. [ABSTRACT FROM AUTHOR]

Backgroud Procurement of tumor tissue is mandatory for a mutation analysis in patients with non-small cell lung cancer. The purpose of this study was to evaluate the usefulness of bronchoscopic biopsy and endobronchial ultrasound-guided transbronchial needle aspiration ( EBUS-TBNA) biopsy for detecting epidermal growth factor receptor ( EGFR) and KRAS mutations in routine practice. Methods Tumor DNA was extracted from formalin-fixed paraffin-embedded tissues, and amplifications of exons 18-21 of EGFR and codons 12, 13 and 61 of KRAS were performed using polymerase chain reaction ( PCR). PCR products were subjected to direct sequencing in both directions. Results Of 211 consecutive specimens, 201 (95.3%) were available for EGFR mutation analysis, and 196 (92.9%) were adequate for KRAS mutation analysis. EGFR and KRAS mutations were detected in 14.9% and 5.4%, respectively. A median of 16 days was spent from biopsy to the final report for either EGFR or KRAS mutation status. The detection rates for both mutations were similar between bronchoscopic biopsy and EBUS-TBNA (P > 0.05). Female gender (53.3%), never smoker (63.3%), and adenocarcinoma (96.7%) were predominant in patients with EGFR mutations. Among patients with adenocarcinoma (n = 104), the frequencies of EGFR and KRAS mutations were 27.9% and 10.6%, respectively. Conclusions Small tissue samples obtained by bronchoscopic biopsy and EBUS-TBNA are sufficient for detecting EGFR and KRAS mutations in routine practice. Therefore, concurrent mutational analyses of small tissue samples should be considered at the time of initial diagnosis. [ABSTRACT FROM AUTHOR]

Most of the cancer xenograft models are derived from tumor cell lines, but they do not sufficiently represent clinical cancer characteristics. Our objective was to develop xenograft models of bladder cancer derived from human tumor tissue and characterize them molecularly as well as histologically. A total of 65 bladder cancer tissues were transplanted to immunodeficient mice. Passagable six cases with clinico-pathologically heterogeneous bladder cancer were selected and their tumor tissues were collected (012T, 025T, 033T, 043T, 048T, and 052T). Xenografts were removed and processed for the following analyses: (i) histologic examination, (ii) short tandem repeat (STR) genotyping, (iii) mutational analysis, and (iv) array-based comparative genomic hybridization (array-CGH). The original tumor tissues (P 0) and xenografts of passage 2 or higher (≥P2) were analyzed and compared. As a result, hematoxylin and eosin staining revealed the same histologic architecture and degree of differentiation in the primary and xenograft tumors in all six cases. Xenograft models 043T_P2 and 048T_P2 had completely identical STR profiles to the original samples for all STR loci. The other models had nearly identical STR profiles. On mutational analysis, four out of six xenografts had mutations identical to the original samples for TP53, HRAS, BRAF, and CTNNB1. Array-CGH analysis revealed that all six xenograft models had genomic alterations similar to the original tumor samples. In conclusion, our xenograft bladder cancer model derived from patient tumor tissue is expected to be useful for studying the heterogeneity of the tumor populations in bladder cancer and for evaluating new treatments. [ABSTRACT FROM AUTHOR]

Background The metastases, age at diagnosis, completeness of resection, invasion, size of the tumor (MACIS) scoring system was developed to predict disease-specific survival in patients with differentiated thyroid carcinoma (DTC), mainly for adults, with a cut-off score of 6. The purpose of this study was to evaluate its ability to predict prognosis of DTC in children and young adults. Methods The medical records of 66 children and young adult (<21 years old) patients with DTC were reviewed retrospectively. Receiver operating characteristic (ROC) analysis was performed to determine the cut-off for predicting poor prognosis. Results Extrathyroidal invasion and regional lymph node metastasis were noted in 64% each, and distant metastases were found in 8%. The optimal cut-off for the MACIS score for poor prognosis was 4 (93% sensitivity, 67% specificity). The overall 10-year recurrence-free survival was better in patients with MACIS score <4 than score ≥4 ( p < .05). Conclusion A MACIS score of more than 4 was associated with a poor prognosis in children and young adult patients with DTC. © 2011 Wiley Periodicals, Inc. Head Neck, 2012 [ABSTRACT FROM AUTHOR]

The prognostic significance of IDH1 mutations has been demonstrated in gliomas. It is unclear whether IDH1 mutation is also a prognostic factor in gliomatosis cerebri (GC). Primary GCs can be grouped into type 1 GCs, which have the classical diffuse growth pattern without mass formation, and type 2 GCs, which form neoplastic masses in addition to classic diffuse lesions. In this study, the prognostic relevance of IDH1/2 mutations in 74 GCs (43 type 1 and 31 type 2) was evaluated. We detected 33 (44.6%) IDH1 mutations, including R132H and R132S, by bidirectional Sanger sequencing. No mutations were detected in IDH2. The percentage of 2-year overall survival for wild-type IDH1 patients was 46 vs. 72% for patients with IDH1-mutated tumors. Mutations of IDH1 were strongly correlated with both increased overall survival (OS) and progression-free survival (PFS) in patients with type 2 GCs, and IDH1 mutations were also an independent prognostic factor predicting increased OS and PFS in type 2 GC patients in multivariate analysis. However, IDH1 mutations did not correlate with survival outcomes in patients with type 1 GCs. Finally, the subgroup of GC, which has IDH1 wild-type and additional solid component showed the worst prognosis. [ABSTRACT FROM AUTHOR]

Human papillomavirus (HPV) types 16 and 18 are the major etiologic factors in the development of cervical epithelial neoplasia. Our study was designed to validate antiviral short interfering RNA (siRNA) targeting the E6 and E7 oncogenes as a potential chemosensitizer of cisplatin ( cis-diaminedichloroplatinum II; CDDP) in cervical carcinoma. Specifically, the therapeutic efficacy of combination of CDDP and E6/E7-specific siRNA was assessed in an in vivo cervical cancer xenograft models. The combination of CDDP and E6/E7-specific siRNA had greater efficacy than the combination of CDDP and E6-specific siRNA especially in terms of inducing cellular senescence. Through in vitro and in vivo experiments, the mechanism of synergy between these two treatments was revealed, demonstrating that the combination of E6/E7-specific siRNA and CDDP therapy was significantly superior to either modality alone. In vitro, long-term exposure of HeLa cells to the combination of CDDP and E6/E7-specific siRNA induced apoptosis and cellular senescence. In vivo, E6/E7-specific siRNA potentiated the antitumor efficacy of CDDP via induction of apoptosis, senescence and antiangiogenesis. Our results suggest that E6/E7-specific siRNA may be an effective sensitizer of CDDP chemotherapy in cervical cancer. [ABSTRACT FROM AUTHOR]

Kim T, Jung E A, Song J Y, Roh J H, Choi J S, Kwon J E, Kang S Y, Cho E Y, Shin J H, Nam S-J, Yang J H & Choi Y-L (2012) Histopathology 60, 347-356 Prevalence of the CTNNB1 mutation genotype in surgically resected fibromatosis of the breast Aims: To investigate CTNNB1 mutation and β-catenin expression in resected breast fibromatosis and to identify potential molecular markers of fibromatosis of the breast. Methods and results: We selected 12 patients with fibromatosis of the breast who underwent surgical resection and were confirmed by histological examination. Ultrasonography findings for 10 patients were reviewed and only two cases were suspicious for fibromatosis on imaging. On core needle biopsy for pre-operative diagnoses, only three cases were histologically suspicious for fibromatosis. Mutations in exon 3 of CTNNB1 were detected by direct DNA sequencing in nine (75.0%) cases: all were c.121G>A (p.T41A), which was much more frequent in breast fibromatoses than in other soft tissue lesions. Nuclear β-catenin expression was observed in all cases and the level of expression was higher in cases with mutation. In eight of nine cases, the matched biopsy specimen showed the same CTNNB1 mutation status as the pre-operative specimen. Conclusions: In the majority of cases, clinical presentation and breast imaging are highly suspicious for carcinoma. Definitive pre-operative pathological diagnosis by core needle biopsy is difficult. CTNNB1 mutation and nuclear β-catenin expression are frequently detected in sporadic breast fibromatoses, suggesting their potential as a useful tool to distinguish breast fibromatoses from other neoplasms. [ABSTRACT FROM AUTHOR]

Sclerosing epithelioid fibrosarcoma (SEF) is a rare but distinct variant of fibrosarcoma. A 43-year-old man presented with a lesion in his back that had been present for three years but had recently increased in size. Magnetic resonance imaging (MRI) revealed a 6-cm sized ovoid mass showing low intensities on T1 and T2 weighted images. Histologically, the tumor was of moderate cellularity, and the cells were relatively uniform in size and shape. The cells were epithelioid, round, oval and polygonal with clear and slightly eosinophilic cytoplasm, forming nests, cords, or sheet-like patterns with a dense collagenous and hyalinized matrix. The tumor was positive for vimentin, but negative for smooth muscle actin, desmin, HMB45, and CD34. Although the tumor showed nuclear overexpression of beta-catenin protein, the CTNNB1 exon3 mutation was not detected. Fluorescent in situ hybridization for FUS using dual color break-apart probes showed rearrangement of the FUS. In accordance with previous studies, our case showed positive findings of FUS rearrangement, reinforcing the notion of a close relationship between low grade fibromyxoid sarcoma and SEF. [ABSTRACT FROM AUTHOR]

Major histocompatibility complex (MHC) class II surface levels on thymocytes increase after CD99 ligation. The functional implication of the up-regulated MHC class II was assessed by engaging MHC class II on CD99-ligated cells. MHC class II engagement down-modulated surface levels of T cell receptor and MHC molecules, and inhibited apoptosis of CD99-ligated thymocytes and CEM tumor cells, antagonistic effects on the previously reported CD99 functions. The results were reproducible regardless of the order of ligation of MHC class II and CD99. We suggest that signaling via MHC class II on CD99-engaged cells might be involved in the thymic maturation process by damping CD99 ligation effects. [Copyright &y& Elsevier]

We studied the role of lipid rafts and actin cytoskeleton in CD99-mediated signaling to elucidate the mechanism of protein transport upon CD99 engagement. CD99 engagement in Jurkat cells elicited the exocytic transport of GM1 as well as several surface molecules closely related with CD99 functions. In addition, CD99 molecules were rapidly incorporated into lipid rafts and appeared to rearrange the actin cytoskeleton upon CD99 stimulation. Association of CD99 with actin cytoskeleton was inhibited by methyl-β-cyclodextrin, while CD99-mediated GM1 clustering was inhibited by cytochalasin D. Therefore, we suggest that CD99 may play a role in the vesicular transport of transmembrane proteins and lipid rafts from the intracellular location to the cell surface, possibly by effecting actin cytoskeleton reorganization. [Copyright &y& Elsevier]

Although non-functional islet cell tumor (NFICT) and solid and papillary neoplasm (SPN) share similar clinical and pathological features, the outcome of each is different. Because NFICT often follow a malignant course and SPN are usually benign, the correct differential diagnosis is very important. We investigated the clinical and pathological findings in 10 cases of NFICT and 12 cases of SPN, including immunohistochemical analysis for chromogranin, vimentin, neuron-specific enolase, somatostatin, alpha-1-antitrypsin, estrogen receptor, progesterone receptor, CD99, p21 and Ki-67. The current study shows that chromogranin is the most valuable marker in differentiating between the tumors (P < 0.01). In contrast to previous reports stating that SPN express the progesterone and/or estrogen receptors, which are absent in other pancreatic tumors, our results show that one-third of SPN were positive for the progesterone receptor. Downregulation of p21 was found more frequently in NFICT (40%) than SPN (17%). The mean value of the Ki-67 proliferation index for NFICT (2.77% ± 2.53%) was significantly higher than that for SPN (0.94% ± 0.89%; P = 0.043). These results are consistent with NFICT having more malignant behavior than SPN. [ABSTRACT FROM AUTHOR]