A gene expression profile related to immune dampening in the tumor microenvironment is associated with poor prognosis in gastric adenocarcinoma

Background

The TNM Classification of Malignant Tumours (TNM) staging system is the primary means of determining a prognosis for gastric adenocarcinoma (GC). However, tumor behavior in the individual patient is unpredictable and in spite of treatment advances, a classification of 'advanced stage' still portends a poor prognosis. Thus, further insights from molecular analyses are needed for better prognostic stratification and determination of new therapeutic targets.

Methods

A total of fifty-one fresh frozen tumor samples from patients with histopathologically confirmed diagnoses of GC, submitted to surgery with curative intent, were included in the study. Total RNA was extracted from an initial group of fifteen samples matched for known prognostic factors, categorized into two subgroups, according to patient overall survival: poor (<24 months) or favorable (at or above 24 months), and hybridized to Affymetrix Genechip human genome U133 plus 2.0 for genes associated with prognosis selection. Thirteen genes were selected for qPCR validation using those initial fifteen samples plus additional thirty-six samples.

Results

A total of 108 genes were associated with poor prognosis, independent of tumor staging. Using systems biology, we suggest that this panel reflects the dampening of immune/inflammatory response in the tumor microenvironment level and a shift to Th2/M2 activity. A gene trio (OLR1, CXCL11 and ADAMDEC1) was identified as an independent marker of prognosis, being the last two markers validated in an independent patient cohort.

Conclusions

We determined a panel of three genes with prognostic value in gastric cancer, which should be further investigated. A gene expression profile suggestive of a dysfunctional inflammatory response was associated with unfavorable prognosis.     

The pathological implications of heart transplantation: Experience with 50 cases in a single center

Heart transplantation started in Japan in 1999. Since then, 50 transplants have been performed at our center. We performed histopathological analyses of the 50 explanted hearts and the post‐transplant biopsy specimens. The median age of recipients was 39 years. The primary diseases before transplant were idiopathic dilated cardiomyopathy in 33 patients (66%), hypertrophic cardiomyopathy in seven (14%), restrictive cardiomyopathy in one, arrhythmogenic right ventricular cardiomyopathy in one, and secondary cardiomyopathy in eight (16%). Before transplantation, 47 patients (94%) had left ventricular assist devices. No severe cardiovascular failure due to allograft rejection occurred. The post‐transplant survival rate was 97.6% at 1 year and 93.1% at 10 years. One recipient was lost to sepsis from myelodysplastic syndrome in the fourth year, one died of multiple organ failure and peritonitis 8 months after transplant. Another patient died of recurrent post‐transplant lymphoproliferative disorders (PTLD). Mild cardiac dysfunction occurred in seven recipients in the early postoperative period. Moderate acute cellular rejection occurred in six patients (12%), and antibody‐mediated rejection occurred in three (6%). The number of heart transplants performed in Japan is very small. However, the outstanding 10‐year survival rate is due to donor evaluation and post‐transplant care resulting in low grade rejection. Pathological evaluation has also greatly contributed to the results.     

Thrombus-related focal in-stent restenosis after everolimus-eluting stent implantation

A 60-year-old man who had received repeated angioplasty for silent ischemia was suspected to have restenosis based on radioisotope imaging (exercise-RI) findings 6 months after everolimus-eluting stent (EES) implantation (3.5 × 28, 3.5 × 28, 3.0 × 18 mm). The stents had been implanted for chronic total occlusion of the right coronary artery (RCA), and the patient was on continuous dual antiplatelet therapy. Diagnostic angiography demonstrated in-stent restenosis in the proximal RCA, which was treated by optical coherence tomography (OCT)-guided cutting balloon angioplasty with distal protection. OCT findings of the stenotic segment before angioplasty showed that the lesion had complex features. The lesion was successfully dilated, and whitish material obtained by a distal protection device was composed of fibrin thrombi with neutrophils and small pieces of mature fibrocellular neointima. The mechanisms and patterns of restenosis after EES placement have not been well clarified. This case may reflect a restenosis pattern (i.e., asymptomatic, focal, and thrombi-related) in the era of the newer generation of drug-eluting stents.     

Pulmonary hypertension due to tumor emboli: A report of three autopsy cases with morphological correlations to radiological findings

Three cases of pulmonary hypertension caused by tumor emboli to the lungs are described. Two of the three cases had a clinical diagnosis of pulmonary thromboembolism until surgical embolectomy, and the other had a diagnosis of primary pulmonary hypertension. Autopsy disclosed chondrosarcoma, choriocarcinoma and gastric cancer as the primary tumors, respectively. Pulmonary vascular obstruction due to tumor embolism leading to pulmonary hypertension is a previously rare clinical entity, and obstructed pulmonary vessels are believed to tend to be small vessels. We compared the autopsy and radiological findings and concluded that pulmonary tumor embolism involved not only the small peripheral arteries but also the segmental and/or lobar arteries.     

Expression of matrix Gla protein and osteonectin mRNA by human aortic smooth muscle cells.

BACKGROUND: Recent data indicate that matrix proteins such as matrix Gla protein (MGP) and osteonectin (ON) influence not only mineralization of vasculature but smooth muscle cell (SMC) differentiation. METHODS: We examined whether MGP and ON are expressed by human aortic SMCs in vivo using Northern blotting, in situ hybridization and immunohistochemistry. RESULTS: MGP and ON mRNAs were strongly expressed in the aorta without atherosclerosis from newborn and four young subjects up to 10 years old. In the aorta from 15 adult cases, MGP and ON mRNAs were decreased as atherosclerosis developed. We determined cell type and distribution of the MGP- and ON mRNA-expressing cells by in situ hybridization and immunohistochemistry. In the aorta obtained from newborn and young subjects, SMCs in the media and thin intima expressed MGP mRNA and, to a lesser extent, ON mRNA. In the adult aorta with fibrous thickening, MGP mRNA was expressed by intimal SMCs and subpopulation of medial SMCs. Osteonectin mRNA was expressed mainly by intimal SMCs and few medial SMCs. Double immunohistochemical staining revealed that both MGP- and ON protein-expressing cells were positive for anti-alpha-smooth muscle actin antibody, aortic SMCs. CONCLUSIONS: These results suggested that MGP and ON expression by aortic SMCs might be regulated by the degree of atherosclerosis and SMC differentiation in human aorta.