Expression of phosphoprotein enriched in astrocytes 15 kDa (PEA-15) in astrocytic tumors: a novel approach of correlating malignancy grade and prognosis

Phosphoprotein enriched in astrocytes 15 kDa (PEA-15) is a multifunctional protein that was first identified in brain astrocytes and that has subsequently been shown to be expressed in different tissues. Despite its many important roles, the clinical significance of PEA-15 expression levels in astrocytic tumors has yet to be properly defined. We studied the PEA-15 expression pattern of 65 patients [diagnosed according to World Health Organization (WHO) criteria] with diffuse astrocytoma (WHO grade II), anaplastic astrocytoma (grade III), and glioblastoma (grade IV). PEA-15 expression levels were immunohistochemically measured and categorized as no, low, or high expression. All tumors expressed PEA-15 in our study. Twenty-three (35.4%) and 42 (64.6%) tumors expressed low and high PEA-15 levels, respectively. In grade II astrocytoma (diffuse astrocytoma) and grade III astrocytoma (anaplastic astrocytoma), 100% and 88.9% of patients expressed high PEA-15 levels, respectively, while a smaller number (50%) of patients with grade IV astrocytoma (glioblastoma) expressed high PEA-15 levels. PEA-15 expression level was inversely associated with WHO grade (P = 0.0006). Next, we evaluated prognosis and PEA-15 expression levels in 43 patients with high-grade astrocytomas based on the following parameters: age, gender, WHO grade, surgical resection extent, MIB-1 labeling index (LI), and PEA-15 expression level. Multivariable analyses revealed that high PEA-15 expression level displayed a significant correlation with longer overall survival (OS) in high-grade astrocytomas (P = 0.0024). Patients with total resection survived significantly longer (P = 0.0044) than those with lower resection extent, while patients with MIB-1 labeling index ≤25% indicated significant (P = 0.0434) correlation with OS as well. In conclusion, PEA-15 expression level was inversely associated with WHO grade and may serve as an important prognostic factor for high-grade astrocytomas.     

Radiation-induced glioblastoma occurring 35 years after radiation therapy for medulloblastoma: case report

A 41-year-old man was admitted in June 2007 with a 1-month history of headache and cerebellar ataxia. At the age of 5 years, in May 1971, he had presented with headache, vomiting, and gait disturbance. Cerebral angiographical study demonstrated vascular shift caused by a mass lesion in the cerebellar vermis. He had immediately undergone partial removal. Histological diagnosis was medulloblastoma (MB). Postoperatively he received a total of 40 Gy radiation to the whole brain and 30.5 Gy to the spine without chemotherapy. He was again seen 35 years later with a radiation-induced glioblastoma (GB) that arose in the region of the original MB. The tumor was surgically removed, and he received radiotherapy and chemotherapy with ACNU, procarbazine, and vincristine. Postoperative irradiation reduced the size of the second tumor.     

Development of a combined real time monitoring and integration analysis system for volatile organic compounds (VOCs)

A combined integration analysis and real time monitoring (Peak Capture System) system was developed for volatile organic compounds (VOCs). Individual integration analysis and real time monitoring can be used to qualitatively and quantitatively analyze VOCs in the atmosphere and in indoor environments and determine the variation in total VOC (TVOC) concentration with time, respectively. In the Peak Capture System, real time monitoring was used to predict future elevations in the TVOC concentration (peak), and this was used an indicator of when to collect (capture) ambient air samples for integration analysis. This enabled qualitative and quantitative analysis of VOCs when the TVOC concentration was high. We developed an algorithm to predict variation in the TVOC concentration, and constructed an automatic system to initiate air sampling for integration analysis. With the system, auto-sampling and analysis of VOCs in a conventional house were conducted. In comparison with background concentrations, the results of peak analysis enabled identification of compounds whose concentration rose. This also enabled an evaluation of possible VOC emission sources.     

Chromoendoscopy of gastric adenoma using an acetic acid indigocarmine mixture

AIM:To investigate the usefulness of chromoendoscopy,using an acetic acid indigocarmine mixture(AIM),for gastric adenoma diagnosed by forceps biopsy.METHODS:A total of 54 lesions in 45 patients diagnosed as gastric adenoma by forceps biopsy were prospectively enrolled in this study and treated by endoscopic submucosal dissection(ESD)between January 2011 and January 2012.AIM-chromoendoscopy(AIMCE)was performed followed by ESD.AIM solution was sprinkled and images were recorded every 30 s for 3min.Clinical characteristics such as tumor size(<2cm,≥2 cm),surface color in white light endoscopy(WLE)(whitish,normochromic or reddish),macroscopic appearance(flat or elevated,depressed),and reddish change in AIM-CE were selected as valuables.RESULTS:En bloc resection was achieved in all 54 cases,with curative resection of fifty two lesions(96.3%).Twenty three lesions(42.6%)were diagnosed as welldifferentiated adenocarcinoma and the remaining 31lesions(57.4%)were gastric adenoma.All adenocarcinoma lesions were well-differentiated tubular adenocarcinomas and were restricted within the mucosal layer.The sensitivity of reddish color change in AIM-CE is significantly higher than that in WLE(vs tumor size≥2 cm,P=0.016,vs normochromic or reddish surface color,P=0.046,vs depressed macroscopic type,P=0.0030).On the other hand,no significant differences were found in the specificity and accuracy.In univariate analysis,normochromic or reddish surface color in WLE(OR=3.7,95%CI:1.2-12,P=0.022)and reddish change in AIM-CE(OR=14,95%CI:3.8-70,P<0.001)were significantly related to diagnosis of early gastric cancer(EGC).In multivariate analysis,only reddish change in AIM-CE(OR=11,95%CI:2.3-66,P=0.0022)was a significant factor associated with diagnosis of EGC.CONCLUSION:AIM-CE may have potential for screening EGC in patients initially diagnosed as gastric adenoma by forceps biopsy.     

Novel orally bioavailable EZH1/2 dual inhibitors with greater antitumor efficacy than an EZH2 selective inhibitor

Polycomb repressive complex 2 (PRC2) methylates histone H3 lysine 27 and represses gene expression to regulate cell proliferation and differentiation. Enhancer of zeste homolog 2 (EZH2) or its close homolog EZH1 functions as a catalytic subunit of PRC2, so there are two PRC2 complexes containing either EZH2 or EZH1. Tumorigenic functions of EZH2 and its synthetic lethality with some subunits of SWItch/Sucrose Non‐Fermentable (SWI/SNF) chromatin remodeling complexes have been observed. However, little is known about the function of EZH1 in tumorigenesis. Herein, we developed novel, orally bioavailable EZH1/2 dual inhibitors that strongly and selectively inhibited methyltransferase activity of both EZH2 and EZH1. EZH1/2 dual inhibitors suppressed trimethylation of histone H3 lysine 27 in cells more than EZH2 selective inhibitors. They also showed greater antitumor efficacy than EZH2 selective inhibitor in vitro and in vivo against diffuse large B‐cell lymphoma cells harboring gain‐of‐function mutation in EZH2. A hematological cancer panel assay indicated that EZH1/2 dual inhibitor has efficacy against some lymphomas, multiple myeloma, and leukemia with fusion genes such as MLL‐AF9, MLL‐AF4, and AML1‐ETO. A solid cancer panel assay demonstrated that some cancer cell lines are sensitive to EZH1/2 dual inhibitor in vitro and in vivo. No clear correlation was detected between sensitivity to EZH1/2 dual inhibitor and SWI/SNF mutations, with a few exceptions. Severe toxicity was not seen in rats treated with EZH1/2 dual inhibitor for 14 days at drug levels higher than those used in the antitumor study. Our results indicate the possibility of EZH1/2 dual inhibitors for clinical applications.     

Overexpression of leucine‐rich α2‐glycoprotein‐1 is a prognostic marker and enhances tumor migration in gastric cancer

Gastric cancer is one of the most common malignant tumors. Although improvement in chemotherapy has been achieved, the clinical prognosis of advanced gastric cancer remains poor. Therefore, it is increasingly important to predict the prognosis and determine whether patients should or should not receive neoadjuvant or adjuvant chemotherapy. Leucine‐rich α2‐glycoprotein‐1 (LRG1) is overexpressed during inflammation and is associated with various malignancies. In this study, we assessed LRG1 expression in cancer specimens and in the sera of patients with cancer to clarify the usefulness of LRG1 as a biomarker in gastric cancer. This study enrolled 239 (for immunohistochemical staining; IHC) and 184 (for ELISA) patients with gastric cancer. Results of IHC showed that LRG1 expression was significantly associated with histological type, lymphatic and venous invasion, tumor and node factors, and disease stage. Overall survival was significantly worse in the high LRG1 expression group than in the low LRG1 group (P = 0.0003). Cox multivariate analysis of overall survival revealed that LRG1 expression was an independent prognostic factor (P = 0.0258). Serum LRG1 was significantly higher in gastric cancer patients than in healthy volunteers, and increased as the pathological stage progressed. Furthermore, a significant correlation was revealed between serum LRG1 level and LRG1 expression with IHC (P < 0.0001). Inhibition of LRG1 significantly decreased cell proliferation in vitro (migratory and invasive capacity of gastric cancer cells). These results suggest that LRG1 expression in tumors and serum may be a useful prognostic marker in gastric cancer patients.     

Hepatosplenic Hodgkin lymphoma without lymphadenopathy following reversible methotrexate-associated lymphoproliferative disorder

Lymphoproliferative disorders (LPDs) occur more frequently in rheumatoid arthritis (RA) patients treated with immunosuppressive agents than in the non-RA population. However, the various forms of disease progression have not yet been elucidated in detail. We encountered a case of Epstein–Barr virus (EBV)-positive atypical polymorphous LPD in the cervical and intraabdominal lymph nodes with hepatosplenomegaly in an 88-year-old female with RA who had taken infliximab and methotrexate (MTX) for six years. Although spontaneous remission occurred following the withdrawal of infliximab and MTX, reversible LPD evolved into hepatosplenic Hodgkin lymphoma without lymphadenopathy presenting as a cholestatic febrile illness. Our findings suggest that the recurrent lesions of MTX-associated LPDs may not always coincide with the primary lesion and may present unexplained findings based on various extranodal diseases.     

Validation study of a health risk appraisal model and endoscopic screening for early esophageal cancer in men in specialized hospitals

Background

This study was designed to validate a health-risk appraisal (HRA) model for identifying Japanese men in specialized hospitals who were at high risk for esophageal cancer on the basis of their past and present facial flushing reactions after drinking alcohol, drinking and smoking status, and intake of vegetables and fruit.

Methods

We prospectively studied men 50 years or older with no history of head and neck cancer or esophageal cancer who presented at Kitasato University Hospital to undergo endoscopic examination from January 2011 to March 2013. The subjects responded to an HRA questionnaire before examination.

Results

Among the 164 patients enrolled, 157 were eligible for analysis. The median HRA score was 3 in patients aged 70–90 years and 6 in those aged 50 to 69 years. Early esophageal cancer was diagnosed on endoscopic examination in 3 subjects (1.9%, 3/157). Among 70 patients 70–90 years of age, 18 (25.7%, 18/70) had an HRA score of 7 or higher, and early esophageal cancer was detected in 2 (11.1%, 2/18) of these patients. Early esophageal cancer was not detected in 87 patients 50–69 years of age. Early esophageal cancer was detected in a 70-year-old patient with an HRA score of 2 who had no history of drinking alcohol or smoking.

Conclusions

Our results suggest that an HRA questionnaire is useful for identifying persons 70 years or older who are at high risk for alcohol-related esophageal cancer in specialized hospitals.