PLEKHA5 regulates the survival and peritoneal dissemination of diffuse-type gastric carcinoma cells with Met gene amplification.

Met gene amplification has been found in a subset of malignant carcinomas, including diffuse-type gastric carcinoma (DGC), which has a poor prognosis owing to rapid infiltrative invasion and frequent peritoneal dissemination. Met is considered a promising therapeutic target for DGC. However, DGC cells with Met gene amplification eventually acquire resistance to Met inhibitors. Therefore, identification of alternate targets that mediate Met signaling and confer malignant phenotypes is critical. In this study, we conducted a phosphoproteomic analysis of DGC cells possessing Met gene amplification and identified Pleckstrin Homology Domain Containing A5 (PLEKHA5) as a protein that is tyrosine-phosphorylated downstream of Met. Knockdown of PLEKHA5 selectively suppressed the growth of DGC cells with Met gene amplification by inducing apoptosis, even though they had acquired resistance to Met inhibitors. Moreover, PLEKHA5 silencing abrogated the malignant phenotypes of Met-addicted DGC cells, including peritoneal dissemination in vivo. Mechanistically, PLEKHA5 knockdown dysregulates glycolytic metabolism, leading to activation of the JNK pathway that promotes apoptosis. These results indicate that PLEKHA5 is a novel downstream effector of amplified Met and is required for the malignant progression of Met-addicted DGC.

Biochemical and Clinical Predictive Approach and Time Point Analysis of Hepatobiliary Phase Liver Enhancement on Gd-EOB-DTPA-enhanced MR Images: A Multicenter Study.

Purpose To identify biochemical factors associated with liver enhancement over time on gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance (MR) images and predict the optimal time point of the hepatobiliary phase in various clinical settings. Materials and Methods This study was approved by the institutional review boards, and written informed consent was obtained from the 1903 patients enrolled. Simple and multiple logistic regression analyses were performed to investigate the biochemical factors associated with liver-to-spleen contrast (LSC) of at least 1.5 in the hepatobiliary phase. Changes in LSC and lesion-to-liver contrast (LLC) of lesions over time (at 5, 10, 15, and 20 minutes) were investigated with a linear mixed-effects model in patients and lesions. For LSC, the optimal cutoff value was determined with receiver operating characteristic analysis of the most significant variable. Differences in LSC and LLC were analyzed in various clinical settings. Results Ultimately, 1870 patients were evaluated, as 33 were excluded according to study criteria. Prothrombin (PT) activity, total bilirubin level (P = .020), and total cholesterol level (P = .005) were significantly associated with LSC of at least 1.5 at 20 minutes, and PT activity was identified as the most significant factor (odds ratio, 1.271; 95% confidence interval: 1.109, 1.455; P = .001). LSC of at least 1.5 at 20 minutes with PT activity of at least 86.9% and less than 86.9% occurred in 555 of 626 patients (88.6%) and 388 of 575 patients (67.5%), respectively. Satisfactory liver enhancement at 20 minutes was significantly more likely to be achieved by patients with hepatitis B virus than by those with hepatitis C virus (P < .001) and by patients with metastasis than by those with hepatocellular carcinoma (P < .001). No significant difference in LLC was observed in patients examined at 1.5 and 3.0 T (P = .133). Conclusion Hepatic enhancement is significantly associated with PT activity, total bilirubin level, and total cholesterol level. PT activity of at least 86.9% could be used to shorten examination times at Gd-EOB-DTPA-enhanced MR imaging. © RSNA, 2016 Online supplemental material is available for this article.

Mucinous Balls Tangled With Mesothelial Cells and MUC2-Positive Cancer Cells in the Ascites of Pseudomyxoma Peritonei.

Pseudomyxoma peritonei (PMP) is characterized by extensive mucinous ascites following rupture of mucinous neoplasms of an intra-abdominal origin, and contain secreted gel-forming mucins such as MUC2 and MUC5AC. We encountered a 66-year-old Japanese man complaining of abdominal distension. Ascites at the site was gelatinous upon gross examination, and needle aspirate smears showed histiocytes and many mucinous balls wrapped in spindle cells, which were positive for vimentin, pan-cytokeratin, and podoplanin. The cell block showed several adenocarcinoma clusters, which were positive for MUC2, MUC5AC, CK20, and CDX-2, and negative for CK7. From these findings, a diagnosis of PMP arising from colon cancer was indicated. Cytoreductive surgery was performed, and the cystic diverticulum was found to be infiltrated by tumor cells in the sigmoid colon that caused PMP. Mucinous balls surrounded by mesothelial cells and MUC2-positive adenocarcinoma cells are useful clues in the diagnosis of PMP. Diagn. Cytopathol. 2016;44:628-631. © 2016 Wiley Periodicals, Inc.

Is cardiac and hepatic iron status assessed by MRI T2* associated with left ventricular function in patients with idiopathic cardiomyopathy?

Excess accumulation of iron in the heart is known to aggravate cardiac function in some cases of genetic and acquired iron overload. We investigated the possible association between cardiac function and iron content in the heart and liver, estimated non-invasively by T2 star (T2*)-weighted magnetic resonance (MR) imaging among patients with cardiomyopathy. MR images were acquired on a 3.0 T MR imaging system using an 8-channel phased-array cardiac coil. Average T2* values of the heart were estimated at regions of interest that were located on short axis mid-ventricular slices positioned at the cardiac septum. In total, 82 patients were enrolled: 48 patients with dilated cardiomyopathy (DCM), 16 patients with hypertrophic cardiomyopathy (HCM), and 18 patients without apparent cardiovascular abnormalities. Cardiac T2* values were lower in the DCM group (median 18.6 ms) than in the HCM (22.0 ms) and control (21.4 ms) groups, although hepatic T2* values did not differ significantly across the groups. Among the whole population, the highest cardiac T2* tertile (≥21.2 ms) was significantly negatively associated with a low left ventricular ejection fraction (LVEF) of <50 %, and this association retained statistical significance after adjustment for sex, age, renal function, hemoglobin and hepatic T2*. Among DCM patients, both hemoglobin and cardiac T2* were selected as parameters that were, respectively, negatively and positively, associated with LVEF (P < 0.05). DCM patients with lower cardiac T2*, and thus higher iron content, were found to have lower LVEF. The possibility that cardiac iron overload may have a role in reducing the systolic cardiac function in DCM patients who do not have systemic iron overload requires further investigation in the future.

Cytokeratin-positive rib osteosarcoma metastasizing to the small intestine.

Osteosarcoma (OS) is a malignant tumor in which osteoid or bone is produced directly by tumor cells. Some OS cells are positive for cytokeratin (CK) and epithelial membrane antigen by immunohistochemistry (IHC) and this may lead to a misdiagnosis of metastatic carcinoma, particularly when the tumor location is unusual. On the other hand, gastrointestinal metastasis of OS is rare. We present the case of a 67-year-old Japanese man with a small intestinal intussusception due to metastasis of a CK-positive rib OS. The tumor cells were positive for CK, osteopontin and osteonectin by IHC and a diagnosis of a CK-positive chest wall OS metastasizing to the small intestine was considered. Osteoid or bone formation was histologically absent and therefore chest wall OS had to be differentially diagnosed from metastatic carcinoma of unknown origin. A postmortem histological analysis confirmed a rib OS. Awareness of CK-positive OS is important for making a correct diagnosis and for disease management and an immunohistochemical analysis of the tumor for expression of osteopontin and osteonectin may be used to support the diagnosis. In addition, this case shows that rib OS can metastasize to the gastrointestinal tract, albeit rarely, which may induce an intestinal intussusception.

Pulmonary tumor thrombotic microangiopathy caused by gastric cancer.

Pulmonary tumor thrombotic microangiopathy (PTTM) is a fatal cancer-related pulmonary complication with rapidly progressing dyspnea, and occasionally induces sudden death. Here, we describe a postmortem-diagnosed PTTM case caused by gastric cancer, with the complaint of progressing dyspnea for 5 days.He did not have any abdominal symptoms or cancer history. PTTM should be considered in patients with rapidly worsening respiratory conditions, even if there is no cancer history.