Downregulation of PRRX1 Confers Cancer Stem Cell-Like Properties and Predicts Poor Prognosis in Hepatocellular Carcinoma.

BACKGROUND: Downregulation of paired related homeobox 1 (PRRX1) is associated with the acquisition of cancer stem cell (CSC)-like properties and poor prognosis in cancers. The purpose of this study is to clarify the role of PRRX1 expression in predicting prognosis and mediating CSC-like properties in hepatocellular carcinoma (HCC). METHODS: The association between PRRX1 expression and overall survival (OS) of patients with HCC was analyzed in three independent datasets: 62 resected primary cases, 242 cases from GSE14520, and 162 cases from The Cancer Genome Atlas (TCGA). A cell line expressing PRRX1 (HuH7) was established for the functional analyses. The ability to form spheres, the expression levels of the hepatic CSC surface markers (CD13, CD133, and EpCAM), in vitro chemosensitivity to 5-fluorouracil (FU), and radiosensitivity were evaluated. RESULTS: Univariate and multivariate analyses showed that the 5-year OS of the low PRRX1 expression group was significantly poorer than that of the high PRRX1 expression group (P = 0.024 and P = 0.045, respectively). Consistent with this, the low PRRX1 expression group in GSE14520 and TCGA datasets showed significantly shorter OS (P = 0.027 and P = 0.010, respectively). Gene set enrichment analysis on GSE14520 and TCGA datasets indicated that downregulation of PRRX1 was correlated with the stemness signature. The number of spheres and the expression levels of CSC markers were significantly decreased when PRRX1 was expressed. Moreover, PRRX1 impaired resistance to 5-FU and radiation. CONCLUSIONS: Downregulation of PRRX1 expression contributes to the poor prognosis of patients with HCC through acquisition of CSC-like properties.

[Remote radiation planning support system].

We constructed a remote radiation planning support system between Kyushu University Hospital (KUH) in Fukuoka and Kyushu University Beppu Hospital (KBH) in Oita. Between two institutions, radiology information system for radiotherapy division (RT-RIS) and radiation planning system (RTPS) were connected by virtual private network (VPN). This system enables the radiation oncologists at KUH to perform radiotherapy planning for the patients at KBH. The detail of the remote radiation planning support system in our institutions is as follows: The radiation oncologist at KBH performs radiotherapy planning and the data of the patients are sent anonymously to the radiation oncologists at KUH. The radiation oncologists at KUH receive the patient's data, access to RTPS at KBH, verify or change the radiation planning at KBH: Radiation therapy is performed at KBH according to the confirmed plan by the radiation oncologists at KUH. Our remote radiation planning system is useful for providing radiation therapy with safety and accuracy.

Portal Vein Stenting for Jejunal Variceal Bleeding after Recurrence of Pancreatic Adenocarcinoma: A Case Report and Review of the Literature.

A 73-year-old woman with portal vein stenosis caused by tumor recurrence after pancreatoduodenectomy was treated with stent placement without embolization of the jejunal varix. Anticoagulation therapy using heparin followed by rivaroxaban was administered after the procedure. She continued to receive systemic chemotherapy as an outpatient. Neither restenosis nor stent thrombosis was observed after 7 months. Based on the presented case and literature review, portal vein stenting is an effective treatment option for jejunal variceal bleeding caused by malignant portal venous stricture after pancreaticoduodenectomy. Antithrombotic therapy following portal venous stenting is required to prevent stent thrombosis in the majority of cases, although it has a risk of inducing recurrent variceal bleeding. Adjunctive jejunal variceal embolization can possibly be omitted in selected cases to obtain sufficient portal-SMV flow reconstruction.

Radiology- and gene-based risk stratification in small renal cell carcinoma: A preliminary study.

PURPOSE: Most small renal cell carcinomas (small RCCs) will remain indolent after detection, but some stage I RCCs still metastasize. There are no risk-stratification imaging factors that could be used to identify poor-prognosis patients based on genomic profiling. Here, we evaluated the relationships between imaging parameters and RNA expressions in small RCC and attempted to identify imaging factors that could be used as effective biomarkers. METHODS: We acquired biopsy specimens of 18 clear cell carcinomas that had undergone perfusion CT (pCT) and MRI between April 2018 and March 2019. We performed RNA sequencing, assessed RNA expressions, and calculated each tumor's cell-cycle progression (CCP) score, which has prognostic value in predicting metastatic progression. We classified the tumors into two groups: clear cell type A (ccA) and type B (ccB). CcA has better survival compared to ccB. We evaluated the following characteristics of each tumor: tumor size, presence of pseudocapsule, and fat. We used the pCT and MRI to measure each tumor's volume transfer constant (Ktrans), rate constant (Kep), extracellular extravascular volume fraction (VE), fractional plasma volume (VP), and apparent diffusion coefficient (ADC). The correlations between these small RCC imaging parameters and the tumor size and RNA expressions were determined. RESULTS: The tumor size was significantly correlated with Kep and inversely correlated with VE, VP, ADC, and hallmark angiogenesis. The CCP score was significantly inversely correlated with Ktrans and Kep. The ccA tumors tended to show a pseudocapsule on MRI. CONCLUSION: Tumor size was correlated with low perfusion, but not with prognostic factors based on genomic profiling. Imaging parameters (e.g., Ktrans and Kep) and tumor characteristics (e.g., pseudocapsule) may enable gene-based risk stratification in small RCC.

MUTYH-null mice are susceptible to spontaneous and oxidative stress induced intestinal tumorigenesis.

MUTYH is a mammalian DNA glycosylase that initiates base excision repair by excising adenine opposite 8-oxoguanine and 2-hydroxyadenine opposite guanine, thereby preventing G:C to T:A transversion caused by oxidative stress. Recently, biallelic germ-line mutations of MUTYH have been found in patients predisposed to a recessive form of hereditary multiple colorectal adenoma and carcinoma with an increased incidence of G:C to T:A somatic mutations in the APC gene. In the present study, a systematic histologic examination revealed that more spontaneous tumors had developed in MUTYH-null mice (72 of 121; 59.5%) than in the wild type (38 of 109; 34.9%). The increased incidence of intestinal tumors in MUTYH-null mice (11 tumors in 10 of 121 mice) was statistically significant compared with the wild type (no intestinal tumors in 109 mice). Two adenomas and seven adenocarcinomas were observed in the small intestines, and two adenomas but no carcinomas were found in the colons. In MUTYH-null mice treated with KBrO(3), the occurrence of small intestinal tumors dramatically increased. The mean number of polyps induced in the small intestines of these mice was 61.88 (males, 72.75; females, 51.00), whereas it was 0.85 (males, 0.50; females, 1.00) in wild-type mice. The tumors developed predominantly in the duodenum and in the upper region of the (jejunum) small intestines. We conclude that MUTYH suppresses spontaneous tumorigenesis in mammals, thus providing experimental evidence for the association between biallelic germ-line MUTYH mutations and a recessive form of human hereditary colorectal adenoma and carcinoma.

Spontaneous internal oblique hematoma successfully treated by transcatheter arterial embolization.

Abdominal wall hematoma is an uncommon cause of acute abdominal pain. We report a case of internal oblique hematoma caused by rupture of the subcostal artery in a 57-year-old woman. Ultrasonography (US) showed a hypoechoic mass in the right lateral abdominal wall. Contrast-enhanced computed tomography (CT) showed a large soft tissue mass with extravasation of contrast medium located in the right internal oblique muscle. Angiography showed contrast extravasation from the subcostal artery, and transcatheter arterial embolization was performed successfully.

Cytolytic Activity (CYT) Score Is a Prognostic Biomarker Reflecting Host Immune Status in Hepatocellular Carcinoma (HCC).

BACKGROUND/AIM: The cytolytic activity (CYT) score is a new index of cancer immunity calculated from the mRNA expression levels of GZMA and PRF1. We assessed the clinical significance of the CYT score in HCC. MATERIALS AND METHODS: The calculated CYT scores of peripheral blood cells (GSE24759), cell lines (CCLE) and HCC tissues (TCGA, GSE14520 and Kyushu cohorts) were assessed. Then, immunohistochemical analysis (IHC) of GZMA and PRF1 was performed. RESULTS: The CYT scores of HCC tissues were lower than those of non-cancerous tissues. The 5-year recurrence-free survival of patients with low CYT scores was significantly shorter than that of patients with high CYT scores. Multivariate analysis indicated that the CYT score was an independent prognostic factor for RFS in TCGA and GSE14520 cohorts. CONCLUSION: CYT score could be a useful prognostic biomarker in HCC, possibly through reflecting the host immune status.

MTH1, an oxidized purine nucleoside triphosphatase, prevents the cytotoxicity and neurotoxicity of oxidized purine nucleotides.

In human and rodent cells, MTH1, an oxidized purine nucleoside triphosphatase, efficiently hydrolyzes oxidized dGTP, GTP, dATP and ATP such as 2'-deoxy-8-oxoguanosine triphosphate (8-oxo-dGTP) and 2'-deoxy-2-hydroxyadenosine triphosphate (2-OH-dATP) in nucleotide pools, thus avoiding their incorporation into DNA or RNA. MTH1 is expressed in postmitotic neurons as well as in proliferative tissues, and it is localized both in the mitochondria and nucleus, thus suggesting that MTH1 plays an important role in the prevention of the mutagenicity and cytotoxicity of such oxidized purines as 8-oxoG which are known to accumulate in the cellular genome. Our recent studies with MTH1-deficient mice or cells revealed that MTH1 efficiently minimizes accumulation of 8-oxoG in both nuclear and mitochondrial DNA in the mouse brain as well as in cultured cells, thus contributing to the protection of the brain from oxidative stress.

Decreased Expression of Fructose-1,6-bisphosphatase Associates with Glucose Metabolism and Tumor Progression in Hepatocellular Carcinoma.

Fructose-1,6-bisphosphatase (FBP1), the rate-limiting enzyme in gluconeogenesis, is reduced in expression in certain cancers where it has been hypothesized to act as a tumor suppressor, including in hepatocellular carcinoma (HCC). Here, we report functional evidence supporting this hypothesis, providing a preclinical rationale to develop FBP1 as a therapeutic target for HCC treatment. Three independent cohorts totaling 594 cases of HCC were analyzed to address clinical significance. Lower FBP1 expression associated with advanced tumor stage, poor overall survival, and higher tumor recurrence rates. In HCC cell lines, where endogenous FBP1 expression is low, engineering its ectopic overexpression inhibited tumor growth and intracellular glucose uptake by reducing aerobic glycolysis. In patient specimens, promoter methylation and copy-number loss of FBP1 were independently associated with decreased FBP1 expression. Similarly, FBP1 downregulation in HCC cell lines was also associated with copy-number loss. HCC specimens exhibiting low expression of FBP1 had a highly malignant phenotype, including large tumor size, poor differentiation, impaired gluconeogenesis, and enhanced aerobic glycolysis. The effects of FBP1 expression on prognosis and glucose metabolism were confirmed by gene set enrichment analysis. Overall, our findings established that FBP1 downregulation in HCC contributed to tumor progression and poor prognosis by altering glucose metabolism, and they rationalize further study of FBP1 as a prognostic biomarker and therapeutic target in HCC patients. Cancer Res; 76(11); 3265-76. ©2016 AACR.

A case of gastric plexiform fibromyxoma: radiological and pathological findings.

Plexiform fibromyxoma is a relatively new pathological category that consists of a rare group of non-gastrointestinal stromal tumors with a peculiar plexiform growth pattern. We report a case of gastric plexiform fibromyxoma in a 60-year-old man. Gastroscopic examination revealed a gastric submucosal tumor in the antrum. Magnetic resonance imaging (MRI) showed a nodule with distinct signal hyperintensity on T2-weighted images, with strong enhancement peripherally in the early phase to the entire lesion in the delayed phase. Endoscopic ultrasound-guided fine-needle aspiration cytology was performed, and the cytological diagnosis was spindle cell tumor, so partial gastrectomy was performed under a preoperative diagnosis of GIST. The resected tumor demonstrated plexiform architecture, myxoid stroma, prominent vasculature, and spindle cells, reflecting the characteristic findings on MRI. This is the first report to describe radiological findings for gastric plexiform fibromyxoma.

Mutagenesis and carcinogenesis caused by the oxidation of nucleic acids.

Genomes and their precursor nucleotides are highly exposed to reactive oxygen species, which are generated both as byproducts of oxygen respiration or molecular executors in the host defense, and by environmental exposure to ionizing radiation and chemicals. To counteract such oxidative damage in nucleic acids, mammalian cells are equipped with three distinct enzymes. MTH1 protein hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxo-2'-deoxyguanosine triphosphate and 2-hydroxy-2'-deoxyadenosine triphosphate (2-OH-dATP), to the corresponding monophosphates. We observed increased susceptibility to spontaneous carcinogenesis in MTH1-null mice, which exhibit an increased occurrence of A:T-->C:G and G:C-->T:A transversion mutations. 8-Oxoguanine (8-oxoG) DNA glycosylase, encoded by the OGG1 gene, and adenine DNA glycosylase, encoded by the MUTYH gene, are responsible for the suppression of G:C to T:A transversions caused by the accumulation of 8-oxoG in the genome. Deficiency of these enzymes leads to increased tumorigenesis in the lung and intestinal tract in mice, respectively. MUTYH deficiency may also increase G:C to T:A transversions through the misincorporation of 2-OH-dATP, especially in the intestinal tract, since MUTYH can excise 2-hydroxyadenine opposite guanine in genomic DNA and the repair activity is selectively impaired by a mutation found in patients with autosomal recessive colorectal adenomatous polyposis.