High prevalence of TP53 mutations is associated with poor survival and an EMT signature in gliosarcoma patients

Gliosarcoma (GS) is a rare variant (2%) of glioblastoma (GBM) that poses clinical genomic challenges because of its poor prognosis and limited genomic information. To gain a comprehensive view of the genomic alterations in GS and to understand the molecular etiology of GS, we applied whole-exome sequencing analyses for 28 GS cases (6 blood-matched fresh-frozen tissues for the discovery set, 22 formalin-fixed paraffin-embedded tissues for the validation set) and copy-number variation microarrays for 5 blood-matched fresh-frozen tissues. TP53 mutations were more prevalent in the GS cases (20/28, 70%) compared to the GBM cases (29/90, 32%), and the GS patients with TP53 mutations showed a significantly shorter survival (multivariate Cox analysis, hazard ratio=23.9, 95% confidence interval, 2.87–199.63, P=0.003). A pathway analysis showed recurrent alterations in MAPK signaling (EGFR, RASGRF2 and TP53), phosphatidylinositol/calcium signaling (CACNA1s, PLCs and ITPRs) and focal adhesion/tight junction (PTEN and PAK3) pathways. Genomic profiling of the matched recurrent GS cases detected the occurrence of TP53 mutations in two recurrent GS cases, which suggests that TP53 mutations play a role in treatment resistance. Functionally, we found that TP53 mutations are associated with the epithelial–mesenchymal transition (EMT) process of sarcomatous components of GS. We provide the first comprehensive genome-wide genetic alternation profiling of GS, which suggests novel prognostic subgroups in GS patients based on their TP53 mutation status and provides new insight in the pathogenesis and targeted treatment of GS.

Preliminary Study on Neurodevelopmental Outcome and Placental Pathology among Extremely Low Birth Weight Infants / 대한주산의학회잡지

PURPOSE: To investigate the relationship between placental pathology and neurodevelopmental outcomes among extremely low birth weight (ELBW) infants. METHODS: Pathology of placentas from ELBW infants born at a tertiary neonatal intensive care unit from January 2007 to December 2012 were reviewed and placental histology was grouped into 3 categories by a designated pathologist: acute chorioamnionitis (ACA), maternal vascular underperfusion (MVU), and control group. Matched ELBW infants were tested for significant neurodevelopmental delays defined as mental developmental index (MDI) or psychomotor developmental index (PDI) <70, using Bayley Scales of Infant Development-II (BSID-II). RESULTS: The mean gestational age and birth weight of 175 infants were 27.1+/-2.5 weeks and 764.7+/-152.3 g respectively. Placental histology revealed MVU (48.0%), ACA (25.1%) and control (26.9%) in distribution. There were less significant patent ductus arteriosus in MVU group than in control group [adjusted odds ratio (OR)=0.331, P=0.011]. The frequencies of other neonatal diseases and mortality were similar in 3 groups. Sixty four of 175 infants were examined for BSID-II at mean corrected 19.9+/-3.2 months. MVU was associated with significant mental developmental delay (OR=5.185, P=0.036), but after adjustment for head circumference/weight at birth, the statistically significance of association disappeared (adjusted OR=4.391, P=0.075). ACA did not affect neonatal and neurodevelopmental outcomes. CONCLUSION: The result of placenta biopsy could be a useful tool in counseling parents for future neurodevelopmental outcome, however, further studies are required to define definitive association in between placenta biopsy and neurodevelopmental outcomes.

A case of primary hepatic actinomycosis: an enigmatic inflammatory lesion of the liver

Primary hepatic actinomycosis is one of the chronic abscess-forming infections of the liver. Accurate diagnosis is frequently delayed due to its indolent course and nonspecific clinical and radiological manifestations. We report a case of a 57-year-old man presenting with asymptomatic multiple hepatic masses on follow-up abdominal computed tomography performed 1 year after stomach cancer surgery. Although a percutaneous liver biopsy procedure was conducted twice in order to obtain confirmative pathology, only a nonspecific organizing abscess with plasma cell infiltration was revealed, without identification of any organism in the tissue cultures. Ultimately, actinomycosis was diagnosed following the detection of sulfur granules on open surgical biopsied tissue. This case suggests that primary hepatic actinomycosis should be considered as one of the possible causes for enigmatic inflammatory lesions of the liver.

Persistent Pulmonary Hypertension of the Newborn in a Preterm Infant Exposed to Methotrexate During the Early Gestational Period / 대한주산의학회잡지

Methotrexate (MTX) is used in the reproductive aged females for the management of medical conditions such as ectopic pregnancy, autoimmune diseases and malignancies. Because of its antimetabolite effect, exposure to MTX during the fetal period can cause multiple anomalies. The most common anomalies related to intrauterine MTX exposure include growth retardation, craniofacial dysmorphism, central nervous system anomalies, cardiac anomalies and skeletal defects. We report a premature baby boy born after 27(+5) weeks of gestation who presented intrauterine growth restriction, single umbilical artery, small chest and anomalies of rib and thoracic vertebra. His mother had received 50 mg of MTX for the treatment of misdiagnosed ectopic pregnancy at 5th week of gestation. During the hospitalization, he was ventilator dependent and pulmonary hypertension persisted despite medical treatment including nitric oxide and sildenafil. Open lung biopsy revealed nonspecific findings suggestive of lung hypoplasia. He died at 141 days after birth due to respiratory failure.

Enhanced Expression of Cell Adhesion Molecules in the Aorta of Diabetic Mice is Mediated by gp91phox-derived Superoxide

Endothelial activation and subsequent recruitment of inflammatory cells are important steps in atherogenesis. The increased levels of cell adhesion molecules (CAM) have been identified in diabetic vasculatures, but the underlying mechanisms remain unclear. To determine the relationship among vascular production of superoxide, expression of CAM and diabetes, superoxide generation and expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E- and P-selectin in the aorta from control (C57BL/6J) and diabetic mice (ob/ob) were measured. In situ staining for superoxide using dihydroethidium showed an increased superoxide production in diabetic aorta, accompanied with an enhanced NAD (P) H oxidase activity. Immunohistochemical analysis revealed that the endothelial expression of ICAM-1 (3.5+/-0.4) and VCAM-1 (3.8+/-0.3) in diabetic aorta was significantly higher than those in control aorta (0.9+/-0.5 and 1.6+/-0.3, respectively), accompanied with the enhanced expression of gp91phox, a membrane subunit of NAD (P) H oixdase. Furthermore, there was a strong positive correlation (r=0.89, P< 0.01 in ICAM-1 and r=0.88, P< 0.01 in VCAM-1) between ICAM-1/VCAM-1 expression and vascular production of superoxide. The present data indicate that the increased production of superoxide via NAD (P) H oxidase may explain the enhanced expression of CAM in diabetic vasculatures.

Canine Liver Transplantation without in Situ Portal Perfusion

BACKGROUND: Many liver transplant surgeons think that portal vein cold perfusion is essential during liver procurement. However, it may limit the perfusion to the pancreas and small intestine and may lengthen the procedure. If visceral arteries are not ligated, perfusates passing the spleen and the small intestine can eventually cool the liver. Aorta only perfusion is rapid and easy and can be performed with the better perfusion of the pancreas and small intestine than with conventional perfusion. However, it may delay the cooling of the liver. The purpose of this study was to evaluate the feasibility of aorta only perfusion compared with conventional perfusion as an alternative method for multiorgan procurement. METHODS: Male mongrel dogs of 16-18 kg were used. In the control group (n=5), standard multiorgan procurement method, including portal vein perfusion, was performed. In experimental group (n=4), aorta only perfusion without superior mesenteric artery ligation was performed. An isotonic citrate solution was used as a perfusate. In the control group, a total amount of 800 to 1000 ml of the perfusate was used to each portal vein and aorta perfusion. In the experimental group, 1500 to 2000 ml of the perfusate were infused only to aorta. After donor liver procurement, 200 to 300 ml of the perfusate was added to the portal vein and the hepatic artery at a ratio of 8:2. Core temperature changes of the liver during perfusion with preservation solution were checked at 5-second intervals. Standard orthotopic liver transplantation was performed. Wedge liver biopsies were performed after procurement and 1 hour after reperfusion. A liver function test was performed, and the hematologic features, and the coagulation profiles were measured preoperatively and one hour after reperfusion. In histologic examination, injuries of hepatic vessel endothelia and hepatocytes were evaluated semiquantitatively under light microscopic and electron microscopic exams. RESULTS: A comparion of the two groups showed no differences in operation time, anhepatic time, and ischemic time. The values of the leukocyte count, the hemoglobin, hematocrit, the prothrombin time,the partial thromboplastin time, the total protein/albumin, bilirubin, ALT/AST and alkaline phosphatase were not different between two groups. Falling of liver core temperature during perfusion was slightly delayed in experimental group. However the delayed time was less than 2 minutes until to reach the temperature of 10oC. The histological grading scores of hepatocytes and endothelial damage determined from light microscopic and electron microscopic examinations were not different from each other. CONCLUSIONS: There was no difference between aorta only perfusion group and portal vein perfusion group, including the severity of liver damages. Therefore, liver procurement without in situ portal perfusion may be a reasonable alternative to combined portal and aorta perfusion on the background of rapid procurement and benefit to the pancreas and small intestine procurement.

A Case of Neuroendocrine Carcinoma of the Thymus / 대한내과학회지

Neuroendocrine tumors originate from neuroendocrine cell, so called APUD (amine precursor uptake and decarboxylation). Most neuroendocrine tumors have typical histopathology, immunohistochemical findings, and can be diagnosed by specific electromicroscopic feature of dense core granules. Neuroendocrine tumors are a diverse group of neoplasms that include carcinoid tumors, islet cell tumors, neuroblastoma, and small cell carcinoma. Neuroendocrine carcinoma of thymus bears similarities to neuroendocrine carcinoma in other organs, but it is clinicopathologically distinct from other tumors of thymus. Rare reports have been seen about thymus neuroendocrine carcinoma. Authors experienced a case of neuroendocrine carcinoma of thymus which cannot be classified as carcinoid, atypical carcinoid, or small cell carcinoma. Herein, we report this case with a review of the literatures.

Optimal Number of Blood Cultures and Volume of Blood Needed to Detect Bacteremia in Children

PURPOSE: We compared pathogen recovery rates by obtaining two blood cultures instead of one blood culture containing 1ml and collecting a larger volume, 1 to 3ml. METHODS: Total of 750 blood specimens from 250 patients with fever, a temperature higher than 39degrees C and suspected bacteremia were obtained. Each patient had two samples of blood, A (1ml) and B (4ml), obtained at 30-minute interval from separate sites of extremities and B was divided into B1 (1ml) and B2 (3ml). Each sample was inoculated into aerobic culture media. Patients were excluded if two samples of blood were not obtained or if the isolate represented a contaminant. RESULTS: A pathogen was isolated in 19 (7.6%) of 250 patients and 37 (4.9%) of 750 specimens. In 7 patients, the pathogen was isolated with all the culture methods and in 12 patients, one or more of the cultures yielded no growth. The pathogen recovery rates were 53% (10/19) in A and B1, 89% (17/19) in B2 and 68% (13/19) in A+B1. No difference was detected between A or B1 and A+B1 (P>0.05) and the pathogen recovery rate for B2 was significantly greater than that for A or B1 (P<0.05), but no significant differences were found in pathogen recovery when B2 was compared with A+B1. CONCLUSION: Increasing volume of blood from 1 to 3ml inoculated into blood culture bottles improves detection of bacteremia in pediatric patients and spares patients the cost and pain of an additional venipuncture.

Optimal Number of Blood Cultures and Volume of Blood Needed to Detect Bacteremia in Children

PURPOSE: We compared pathogen recovery rates by obtaining two blood cultures instead of one blood culture containing 1ml and collecting a larger volume, 1 to 3ml. METHODS: Total of 750 blood specimens from 250 patients with fever, a temperature higher than 39degrees C and suspected bacteremia were obtained. Each patient had two samples of blood, A (1ml) and B (4ml), obtained at 30-minute interval from separate sites of extremities and B was divided into B1 (1ml) and B2 (3ml). Each sample was inoculated into aerobic culture media. Patients were excluded if two samples of blood were not obtained or if the isolate represented a contaminant. RESULTS: A pathogen was isolated in 19 (7.6%) of 250 patients and 37 (4.9%) of 750 specimens. In 7 patients, the pathogen was isolated with all the culture methods and in 12 patients, one or more of the cultures yielded no growth. The pathogen recovery rates were 53% (10/19) in A and B1, 89% (17/19) in B2 and 68% (13/19) in A+B1. No difference was detected between A or B1 and A+B1 (P>0.05) and the pathogen recovery rate for B2 was significantly greater than that for A or B1 (P<0.05), but no significant differences were found in pathogen recovery when B2 was compared with A+B1. CONCLUSION: Increasing volume of blood from 1 to 3ml inoculated into blood culture bottles improves detection of bacteremia in pediatric patients and spares patients the cost and pain of an additional venipuncture.

Initial Perfusion Solution for Donor hepatectomy in Canine Liver Transplantation: Ringers' Lactated Solution: UW Solution

The purposes of initial preservation solution are rapid cooling of the organ and washing out the intravascular components. After the introduction of University of Wisconsin (UW) solution, it has become the standard organ preservation solution in liver transplantation. However, due to several problems such as high viscosity and potassium concentration, let alone its cost, there has been several attempts to use UW solution in combination with other preservation solutions for initial perfusion of the graft during the organ harvest procedure. In order to evaluate the efficacy of Ringers' Lactated (RL) solution as an initial perfusion solution, we performed orthotopic hepatic allografts on dogs. In 4 dogs, UW solution was used as the initial perfusion solution and in the other 4, RL solution was used. After initial perfusion, UW solution was used successively for the preservation of the graft. All harvested grafts were stored in UW solution. Average cold ischemic time was 163.5 minutes for RL group and 159 minutes for UW group. The two groups were compared in terms of hematologic and biochemical markers before and after the transplantation. The extent of graft injury during cold ischemia and after reperfusion was also compared directly under light and electron microscope. There was no difference in cold and warm ischemic time, anhepatic time, and total operation time between the two groups. The groups did not differ in liver function test, complete blood count and coagulation profile. Histologic exams also showed similar changes between the two groups. In conclusion, RL solution can be used as the initial perfusion solution in hepatic transplantation.

Mucormycosis in Leukemic Children

PURPOSE: Mucormycosis is an opportunistic fungal infection caused by one of the ubiquitous fungi of the order Mucorales, occurring almost exclusively in immunocompromised hosts such as patients with diabetes, leukemia and lymphoma. Recently the incidence of mucormycosis is rising associated with the increasing predisposing factors such as cytotoxic drugs and immunosuppressive agents. Though mucormycosis is frequently fatal, there has been a dramatic improvement in outcome by early diagnosis and aggressive treatment. The aim of this study is to investigate the clinical characteristics of mucormycosis developed in leukemic children. METHODS: Clinical characteristics of mucormycosis was analyzed by retrospective review of 6 patients diagnosed as mucormycosis during chemotherapy of acute leukemia at the Seoul National University Children's Hospital from May 1990 to May 1995. Diagnosis was confirmed by the pathologic examination of the biopsy specimens from the involved site. RESULTS: 1) The age distribution ranged from 7 to 15 years. Three patients were male and 3 were female. 2) At the onset of mucormycosis all six patients were under the cytotoxic chemotherapy with resultant neutropenia. Four of 6 patients received large doses of corticosteroids and 2 of 6 patients were receiving broad-spectrum antibiotics intravenously. 3) Of the 6 cases of mucormycosis, 5 cases were of the type involving a particular body site(rhinocerebral in 3 patients, gastrointestinal in 1 and laryngeal in 1) and 1 case was of the disseminated type. In a case of rhinocerebral type, the orbit as well as paranasal sinuses were involved and in the case of disseminated type, the lung, skin and muscle were invaded by the fungi. 4) Except one case(gastrointestinal type) in which complete resection of lesion was possible, amphotericin B was administrated for at least two months in combination with rifampin. Surgical resection was done in 4 cases. In a case who expired during medical treatment and the other one who was almost cured with medical treatment alone, surgery was not done. 5) Of the 6 cases, mucormycosis was cured in 3 cases and recurred in 1 case despite initial improvement. Two cases expired -one who showed almost complete improvement but expired due to bacterial sepsis during the following chemotherapy, and the other who showed little improvement with persistent neutropenia and expired due to septic shock. CONCLUSIONS: In the immunocompromised patients including acute leukemia, mucormycosis should be considered as a possible complicating condition, and early diagnosis and aggressive treatment may improve the survival and outcome.

The Diagnostic Value of Liver Biopsy in Children with Fever of Unknown Origin and Hepatosplenomegaly

PURPOSE: Although many strides have been made in the radiological and laboratory diagnosis, the liver biopsy is still considered an important tool for the diagnosis of liver disease. We report our experience that histologic investigation of the liver was essential searching for the etiologic diagnosis in eight children with fever of unknowm origin and hepatosplenomegaly, who's diagnosis were not documented by other diagnostic studies. METHODS: Histologic investigation of the liver including Percutanous liver biopsy, open surgical biopsy, necropsy or autopsy was taken at Seoul national university of children's hospital between 1985 and 1995 in twelve children with fever of unknown origin and hepatosplenomegaly. We performed light and electron microscopic examination, culture and PCR of the tissue obtained by liver biopsy. RESULTS: 1) The etiologic diagnoses were possible by histologic investigation of the liver in 9 of 12 Cases; Nine cases were congenital tuberculosis, cryptococcosis, hepatic capillariasis, candidiasis, amoebiasis, neonatal herpes hepatitis, Escherichia. coli abscess and two cases of cytomegalovirus hepatitis. Three cases in which organisms could not be found in tissue obtained from biopsy were suspected clinically as liver abscess and parasite infestation. 2) Three cases were males and 6 were females, ranging in age from 1 days to 6 years; mean age 23.6 months. 3) Clinical manifestations were fever of unknown origin(9 Cases), hepatomegaly(9 Cases), splenomegaly(5 Cases), skin lesions(2 Cases) and jaundice(3 Cases). 4) Laboratory findings were increased AST/ALT(7 Cases), hyperbilirubinemia(3 Cases), leukocytosis(5 Cases), eosinophilia(2 Cases), increased CRP(9 Cases) and increased ESR(5 Cases). 5) In four children, there were underlying diseases which were acute lymphoblastic leukemia, acute myeloid leukemia and two cases of prematures. CONCLUSIONS: In children with fever of unknown origin and hepatosplenomegaly, we recommend liver biopsy for early diagnosis and apropriate management.

Chronological Relationships between the Irreversible Vasoconstriction by the Vasodilator and the Electron Microscopic Changes of the Arterial Wall in the Rabbit Chronic Vasospasm Model

One of the characteristics of the cerebral vasospasm is its irreversibility with the vasodilators. Under the hypothesis that the irreversibility with vasodilators might be caused by the structural change in the arterial wall, authors examined the chronological relationships between the irreversibility and the electron microscopic findings of the arterial wall in the rabbit chronic vasospasm model. The development of the vasospasm and the irreversibility of the vasospasm with the intra-arterial papaverine were defined angiographically. After the second angiography done in ont to 30 days after subarachnoid hemorrhage(SAH), eighteen rabbits were sacrificed, and the basilar artery was examined with electron microscope. Arterial narrowing was the severest one day after SAH(54.1% of the pre-SAH diameter), and was maintained up to 30 days after SAH. The irreversibility of the arterial constriction with the papaverine developed 5 days after SAH, which had a tendency to recover 6 to 9 days after SAH. However the irreversibility was noted again 16 days after SAH. Electron microscopy revealed the endothelial wrinkling, disorganization of muscle fiber, myonecrosis, thickening of smooth muscle fibers, and increase of connective tissue in the tunica media. These structural changes were severest one day after SAH, and gradually diminished up to 30 days after SAH. These data show that there are no chronological relationships between the irreversibility and the structural change per se. However the fact that the irreversibility developed during the reparative phase of the arterial wall injury by SAH suggests that the chronic vasospasm is not a primary event but a secondary phenomenon following an injury to the cerebral arterial wall.

Changes of intercellular adhesion molecule expression and cytogenetic abnormalities during the differentiation process in human neuroblastoma cell lines / 대한암학회지

No abstract available.