Expression of Organic Anion Transporting Polypeptides in an H-Ras 12V Transgenic Mouse Model of Spontaneous Hepatocellular Carcinoma

Purpose@#Expression of organic anion transporting polypeptides (OATPs) 1B1/1B3 in hepatocellular carcinoma (HCC) induces a paradoxical enhancement of gadoxetic acid on liver magnetic resonance imaging (MRI). We examined the expression profile of OATPs with regard to tumor differentiation in a genetically modified H-Ras 12V mouse model of spontaneous HCC that undergoes multistep hepatocarcinogenesis with minimal inter-individual variation. @*Materials and Methods@#Tumor nodules were harvested from transgenic H-Ras 12V mice. Hematoxylin and eosin-stained slides were examined for tumor differentiation and high-grade pathological components (tumor necrosis, thickened trabeculae, or vascular invasion). Immunohistochemistry of OATP 1B1/1B3 was performed, and OATP expression was assessed. @*Results@#We examined well-differentiated HCCs (n=59) in which high-grade pathological components were absent (n=49) or present (n=10). Among the well-differentiated HCCs without high-grade pathological components (n=49), OATP expression was negative, weak positive, and moderate positive in 23, 17, and nine cases, respectively. Among the well-differentiated HCCs with highgrade pathological components (n=10), OATP expression was negative, weak positive, and moderate positive in one, two, and seven cases, respectively. The ratio of positive OATP 1B1/1B3 expressing tumors was higher in HCCs with high-grade pathological components than in those without high-grade pathological components (p=0.004). @*Conclusion@#Our findings support those of previous clinical studies that have reported the frequent appearance of gadoxetic acidenhanced MRI in moderately differentiated HCC.

Expression of Organic Anion Transporting Polypeptides in an H-Ras 12V Transgenic Mouse Model of Spontaneous Hepatocellular Carcinoma

Purpose@#Expression of organic anion transporting polypeptides (OATPs) 1B1/1B3 in hepatocellular carcinoma (HCC) induces a paradoxical enhancement of gadoxetic acid on liver magnetic resonance imaging (MRI). We examined the expression profile of OATPs with regard to tumor differentiation in a genetically modified H-Ras 12V mouse model of spontaneous HCC that undergoes multistep hepatocarcinogenesis with minimal inter-individual variation. @*Materials and Methods@#Tumor nodules were harvested from transgenic H-Ras 12V mice. Hematoxylin and eosin-stained slides were examined for tumor differentiation and high-grade pathological components (tumor necrosis, thickened trabeculae, or vascular invasion). Immunohistochemistry of OATP 1B1/1B3 was performed, and OATP expression was assessed. @*Results@#We examined well-differentiated HCCs (n=59) in which high-grade pathological components were absent (n=49) or present (n=10). Among the well-differentiated HCCs without high-grade pathological components (n=49), OATP expression was negative, weak positive, and moderate positive in 23, 17, and nine cases, respectively. Among the well-differentiated HCCs with highgrade pathological components (n=10), OATP expression was negative, weak positive, and moderate positive in one, two, and seven cases, respectively. The ratio of positive OATP 1B1/1B3 expressing tumors was higher in HCCs with high-grade pathological components than in those without high-grade pathological components (p=0.004). @*Conclusion@#Our findings support those of previous clinical studies that have reported the frequent appearance of gadoxetic acidenhanced MRI in moderately differentiated HCC.

Yonsei Criteria, a Potential Linkage to Intratumoral Foxp3⁺/CD8⁺ Ratio for the Prediction of Oncologic Outcomes in Resected Left-Sided Pancreatic Cancer

PURPOSE: This study sought to investigate associations among Yonsei criteria (tumor confined to the pancreas, intact fascia layer between the distal pancreas and the left adrenal gland and kidney, and tumor located more than 1–2 cm from the celiac axis) and tumor infiltrating lymphocytes in pancreatic cancer.MATERIALS AND METHODS: Patients who underwent curative distal pancreatectomy due to left-sided pancreatic cancer from January 2000 to December 2011 were enrolled. Follow-up was completed September 30, 2015.RESULTS: Fifty patients were enrolled. Having ≥ two metastatic lymph nodes (LNs, p=0.002), intraoperative transfusion (p=0.011), low levels of tumor infiltrating CD8⁺ T-cells (p=0.001), and a high Foxp3⁺/CD8⁺ ratio (p=0.009) were independent risk factors for disease-free survival. Not satisfying the Yonsei criteria (p=0.021), having ≥ two metastatic LNs (p=0.032), low levels of tumor infiltrating CD8⁺ T-cells (p=0.040) and a high Foxp3⁺/CD8⁺ ratio (p=0.032) were associated with unfavorable overall survival. High levels of CA19-9 and not satisfying the Yonsei criteria were significantly associated with a high Foxp3⁺/CD8⁺ ratio [Exp(β)=3.558; 95% confidence inverval: 1.000–12.658; p=0.050].CONCLUSION: Yonsei criteria may be clinically detectable biologic marker with which to predict immunologic status and survival in pancreatic cancer patients.

Pathological Classification of Focal Cortical Dysplasia (FCD) : Personal Comments for Well Understanding FCD Classification

In 2011, the International League against Epilepsy (ILAE) proposed a first international consensus of the classification of focal cortical dysplasia (FCD). This FCD classification had been widely used in worldwide. In this review paper, the authors would like to give helpful comments for better understanding of the current FCD classification. Especially, the basic concepts of FCD type I, such as “radial”, “tangential” and “microcolumn” will be discussed with figures. In addition, the limitations, genetic progress and prospect of FCD will be suggested.

Effects of Oxytocin on Cell Proliferation in a Corticotroph Adenoma Cell Line

BACKGROUND: Oxytocin (OXT) has been reported to act as a growth regulator in various tumor cells. However, there is a paucity of data on the influence of OXT on cell proliferation of corticotroph adenomas. This study aimed to examine whether OXT affects cell growth in pituitary tumor cell lines (AtT20 and GH3 cells) with a focus on corticotroph adenoma cells. METHODS: Reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay were conducted with AtT20 cells to confirm the effects of OXT on hormonal activity; flow cytometry was used to assess changes in the cell cycle after OXT treatment. Moreover, the impact of OXT on proliferating cell nuclear antigen (PCNA), nuclear factor κB, and mitogen-activated protein kinase signaling pathway was analyzed by Western blot. RESULTS: OXT treatment of 50 nM changed the gene expression of OXT receptor and pro-opiomelanocortin within a short time. In addition, OXT significantly reduced adrenocorticotropic hormone secretion within 1 hour. S and G2/M populations of AtT20 cells treated with OXT for 24 hours were significantly decreased compared to the control. Furthermore, OXT treatment decreased the protein levels of PCNA and phosphorylated extracellular-signal-regulated kinase (P-ERK) in AtT20 cells. CONCLUSION: Although the cytotoxic effect of OXT in AtT20 cells was not definite, OXT may blunt cell proliferation of corticotroph adenomas by altering the cell cycle or reducing PCNA and P-ERK levels. Further research is required to investigate the role of OXT as a potential therapeutic target in corticotroph adenomas.

Pathological Classification of Focal Cortical Dysplasia (FCD) : Personal Comments for Well Understanding FCD Classification

In 2011, the International League against Epilepsy (ILAE) proposed a first international consensus of the classification of focal cortical dysplasia (FCD). This FCD classification had been widely used in worldwide. In this review paper, the authors would like to give helpful comments for better understanding of the current FCD classification. Especially, the basic concepts of FCD type I, such as “radial”, “tangential” and “microcolumn” will be discussed with figures. In addition, the limitations, genetic progress and prospect of FCD will be suggested.

The Effect of Mental Rotation on Surgical Pathological Diagnosis

PURPOSE: Pathological diagnosis involves very delicate and complex consequent processing that is conducted by a pathologist. The recognition of false patterns might be an important cause of misdiagnosis in the field of surgical pathology. In this study, we evaluated the influence of visual and cognitive bias in surgical pathologic diagnosis, focusing on the influence of “mental rotation.” MATERIALS AND METHODS: We designed three sets of the same images of uterine cervix biopsied specimens (original, left to right mirror images, and 180-degree rotated images), and recruited 32 pathologists to diagnose the 3 set items individually. RESULTS: First, the items found to be adequate for analysis by classical test theory, Generalizability theory, and item response theory. The results showed statistically no differences in difficulty, discrimination indices, and response duration time between the image sets. CONCLUSION: Mental rotation did not influence the pathologists' diagnosis in practice. Interestingly, outliers were more frequent in rotated image sets, suggesting that the mental rotation process may influence the pathological diagnoses of a few individual pathologists.

Poorly Differentiated Thyroid Carcinoma with Gross Internal Jugular Vein Invasion and Multiple Lung Metastases / 대한갑상선학회지

A rare case of poorly differentiated thyroid carcinoma (PDTC) with gross intraluminal invasion to the internal jugular vein whose clinical manifestation was multiple lung metastases is described. A 66-year-old man was referred to the outpatient clinic of the Department of Internal Medicine, hemato-oncology subdivision for multiple lung nodules found by his regular health check-up. These lung nodules showed variable sizes with irregular shapes, and typical distributions throughout the parenchyma, which were consistent with metastatic nodules. Ultrasonography revealed a 4.5 cm sized hypoechoic mass with irregular shape in his left thyroid lobe and a huge thrombus in the left internal jugular vein. PDTCs associated with gross intraluminal invasion to the great cervical vein and multiple lung nodules as their first clinical manifestation are extremely rare. We would emphasize the importance of preoperative detailed evaluation of the disseminated disease by ultrasonography in suspected patients.

Omega-3 polyunsaturated fatty acid and ursodeoxycholic acid have an additive effect in attenuating diet-induced nonalcoholic steatohepatitis in mice

Nonalcoholic steatohepatitis (NASH) can progress into liver cirrhosis; however, no definite treatment is available. Omega-3 polyunsaturated fatty acid (omega-3) has been reported to alleviate experimental NASH, although its beneficial effect was not evident when tested clinically. Thus, this study aimed to investigate the additive effect of omega-3 and ursodeoxycholic acid (UDCA) on diet-induced NASH in mice. C57BL/6 mice were given a high-fat diet (HFD) for 24 weeks, at which point the mice were divided into three groups and fed HFD alone, HFD with omega-3 or HFD with omega-3 in combination with UDCA for another 24 weeks. Feeding mice an HFD and administering omega-3 improved histologically assessed liver fibrosis, and UDCA in combination with omega-3 further attenuated this disease. The assessment of collagen alpha1(I) expression agreed with the histological evaluation. Omega-3 in combination with UDCA resulted in a significant attenuation of inflammation whereas administering omega-3 alone failed to improve histologically assessed liver inflammation. Quantitative analysis of tumor necrosis factor alpha showed an additive effect of omega-3 and UDCA on liver inflammation. HFD-induced hepatic triglyceride accumulation was attenuated by omega-3 and adding UDCA accentuated this effect. In accordance with this result, the expression of sterol regulatory binding protein-1c decreased after omega-3 administration and adding UDCA further diminished SREBP-1c expression. The expression of inducible nitric oxide synthase (iNOS), which may reflect oxidative stress-induced tissue damage, was suppressed by omega-3 administration and adding UDCA further attenuated iNOS expression. These results demonstrated an additive effect of omega-3 and UDCA for alleviating fibrosis, inflammation and steatosis in diet-induced NASH.

Perfusion Parameters of Dynamic Contrast-Enhanced Magnetic Resonance Imaging in Patients with Rectal Cancer: Correlation with Microvascular Density and Vascular Endothelial Growth Factor Expression

OBJECTIVE: To determine whether quantitative perfusion parameters of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) correlate with immunohistochemical markers of angiogenesis in rectal cancer. MATERIALS AND METHODS: Preoperative DCE-MRI was performed in 63 patients with rectal adenocarcinoma. Transendothelial volume transfer (Ktrans) and fractional volume of the extravascular-extracellular space (Ve) were measured by Interactive Data Language software in rectal cancer. After surgery, microvessel density (MVD) and vascular endothelial growth factor (VEGF) expression scores were determined using immunohistochemical staining of rectal cancer specimens. Perfusion parameters (Ktrans, Ve) of DCE-MRI in rectal cancer were found to be correlated with MVD and VEGF expression scores by Spearman's rank coefficient analysis. T stage and N stage (negative or positive) were correlated with perfusion parameters and MVD. RESULTS: Significant correlation was not found between any DCE-MRI perfusion parameters and MVD (rs = -0.056 and p = 0.662 for Ktrans; rs = -0.103 and p = 0.416 for Ve), or between any DCE-MRI perfusion parameters and the VEGF expression score (rs = -0.042, p = 0.741 for Ktrans ; r = 0.086, p = 0.497 for Ve) in rectal cancer. TN stage showed no significant correlation with perfusion parameters or MVD (p > 0.05 for all). CONCLUSION: DCE-MRI perfusion parameters, Ktrans and Ve, correlated poorly with MVD and VEGF expression scores in rectal cancer, suggesting that these parameters do not simply denote static histological vascular properties.

Mini-review: Eosinophils, a Useful Diagnostic Clue in Surgical Neuropathology / 고신대학교의과대학학술지

Eosinophils are one of the polymorphonuclear granulocytes derived from bone marrow stem cells, and they contain many small cytoplasmic granules that stain bright red with eosin or brick-red with Romanowsky staining. Eosinophilic infiltration is also present in various human central nervous system (CNS) diseases such as parasitic infection, transverse myelitis, vasculitis, Langerhans cell histiocytosis, glioblastoma and etc... Due to the morphologic and functional characteristics, the presence of eosinophils in certain lesions may provide useful diagnostic clues in the right clinical setting. Consideration of this finding may facilitate the diagnosis of CNS pathologic lesions, especially in a small specimen such as a stereotactic biopsy.

Co-expression patterns of Notch1, Snail, and p53 in grade III hepatocellular carcinoma with postoperative recurrence: a preliminary study / 대한간학회지

BACKGROUND/AIMS: We aimed to determine the association between the co-expression patterns of Notch1, Snail, and p53 proteins (NSP) and the postoperative prognosis of hepatocellular carcinoma (HCC). METHODS: The immunoblot data for molecular expression (147 HCC/corresponding non-HCC tissues and 15 dysplastic nodules) and the sequencing data for p53 mutations (110 HCCs) were obtained from our previous study. Data analyses were restricted to cases with HCC differentiation grade III (n=47), due to its high p53 mutation rate. RESULTS: Nineteen of the 47 patients (40.4%) -comprising 12 in the liver and 7 in distant organs-had relapsed at 1-2 years after surgery. There was no relationship between p53 mutation and postoperative recurrence in the grade III HCCs. Seven (87.5%) of the eight relapsed cases with Notch1, Snail, and p53 (wild) co-expression experienced recurrence only within the liver, and all tumors were smaller than 5 cm in diameter. Extrahepatic relapse occurred mostly in HCC patients with tumors larger than 5 cm in diameter, without any deviation in the NSP pattern. CONCLUSIONS: The results of this preliminary study suggest that the co-expression of Notch1, Snail, and p53 (wild) is not inferior to the patterns with p53 mutation as an indicator of postoperative recurrence of grade III HCC.

CpG Island Methylation According to the Histologic Patterns of Early Gastric Adenocarcinoma

BACKGROUND: Although the importance of aberrant DNA methylation in the development of gastric adenocarcinoma has been described, the mechanism of pathogenesis has not been revealed yet. We quantitatively analyzed methylation of four CpG islands and one repetitive DNA element, according to the histologic features of adenocarcinoma with precursor lesions. METHODS: We divided the cases as adenocarcinoma with intestinal type precursors (type A, n=19 cases) and adenocarcinoma with diffuse type precursors (type B, n=19 cases). We micro-dissected tumor cells and matched non-neoplastic gastric mucosa from the hematoxylin and eosin-stained slides. RESULTS: A total of 20 CpG sites of long interspersed nucleotide element-1 (LINE1), RAR-related orphan receptor alpha (RORA), Kruppel-like factor 7 (KLF7), mutL homolog 1 (MLH1), MINT25, and CD133 were analyzed. Methylation was determined by bisulfate-pyro-sequencing, and hypomethylation of LINE1 and CD133 was noted in the tumors, compared to the levels in the non-neoplastic gastric mucosa (p=0.014 and p=0.015, respectively). A statistically different methylation pattern of CpG sites at CD133 and KLF7 was noted only in type B lesions, compared to that in matched non-neoplastic gastric mucosa (p=0.027 and p=0.043, respectively). CONCLUSIONS: Given that aberrant methylation occurs in a relatively early phase of carcinogenesis, different patterns of methylation may determine the carcinoma phenotype. However, further large-scale study is required to clarify the significance of this difference.

Value of Additional Immunocytochemical Stain for Cytokeratin in the Diagnosis of Leptomeningeal Involvement of Metastatic Carcinoma

BACKGROUND: The purpose of this study was to describe potential pitfalls in the diagnosis of metastatic adenocarcinoma in cerebrospinal fluid (CSF) and to suggest additional work in association with cytokeratin immunocytochemistry for the proper diagnosis, especially in the specimens with low cellularity. METHODS: We collected 267 cytologic specimens of CSF from patients, who were diagnosed over a 9-month period. Each of the individual samples were divided into half the sample size and processed via both, ThinPrep (TP) with Papanicolau stain and cytocentrifugation-based preparation (cytospin, CP) with immunocytochemical stain for cytokeratin. RESULTS: Amongst the 267 cases, 45 cases from 22 patients were diagnosed to be positive for metastasis adenocarcinoma in CSF. TP with Papanicolau stain showed satisfactory cytomorphology when compared with specimen of CP preparation and cytokeratin immunocytochemical staining. All the TP processed cases belonged to satisfactory/superior categories based on the assessment of technical artifact, which potentially helps in decreasing diagnositc errors. However, in 10 out of 45 cases, diagnostic atypical cells were present only in one of the two slides. CONCLUSIONS: Immunocytochemical stain for cytokeratin along with TP processed specimen helps in decreasing potential diagnostic errors in the cytological diagnosis of metastatic carcinoma in CSF specimen.

Concordant or Discordant? Imaging-Pathology Correlation in a Sonography-Guided Core Needle Biopsy of a Breast Lesion

An imaging-guided core needle biopsy has been proven to be reliable and accurate for the diagnosis of both benign and malignant diseases of the breast, and has replaced surgical biopsy. However, the possibility of a false-negative biopsy still remains. Imaging-pathology correlation is of critical importance in imaging-guided breast biopsies to detect such a possible sampling error and avoid a delay in diagnosis. We will review five possible categories and corresponding management after performing an imaging-pathology correlation in a sonography-guided core needle biopsy of a breast lesion, as well as illustrate the selected images for each category in conjunction with the pathologic finding. Radiologists should be familiar with the imaging features of various breast pathologies and be able to appropriately correlate imaging findings with pathologic results after a core needle biopsy.

A Case of Prothionamide Induced Hepatitis on Patient with Multi-Drug Resistant Pulmonary Tuberculosis / 결핵및호흡기질환

The prevalence of multi-drug resistant tuberculosis (MDR-TB), which is resistant to isoniazid and rifampin, has been increasing in Korea. And the side effects of 2nd line anti-tuberculosis medications, including drug-induced hepatitis, are well known. Although prothionamide (PTH) is one of the most useful anti-TB medications and although TB medication-induced acute hepatitis is a severe complication, there are only a few published case reports about prothionamide induced hepatitis. In this case report, a 22 year old male was diagnosed with pulmonary MDR-TB and was administered 2nd line anti-TB mediations, including PTH. Afterwards, he had a spiking fever and his liver enzymes were more than 5 times greater than the upper limit of the normal range. He was then diagnosed with drug-induced hepatitis by liver biopsy. His symptoms and liver enzyme elevation were improved after stopping PTH. Accordingly, we report this case of an association between PTH and acute hepatitis.

Novel Sunitinib Strategy in Metastatic Renal Cell Carcinoma on Hemodialysis: Intermittent Dose of Sunitinib after Hemodialysis / Journal of the Korean Cancer Association, 대한암학회지

The proper dose and schedule of sunitinib have yet to be established for patients with metastatic renal cell carcinoma (RCC) on hemodialysis. We reviewed two patients with metastatic RCC on hemodialysis who had been treated with sunitinib in Yonsei Cancer Center, Yonsei University College of Medicine. Fifty milligrams of sunitinib was administered intermittently after each hemodialysis session (3 or 4 times a week). Overall responses were partial response in both cases. Progression-free survivals were 16 and 6 months, respectively, at the time of reporting (April 2010). Both subjects tolerated the treatment.

A case of nephrogenic systemic fibrosis after gadolinium-based contrast agent injection / 대한내과학회지

Nephrogenic systemic fibrosis is a rare multisystemic disorder mainly affecting the skin and joints in patients with underlying renal insufficiency exposed to gadolinium-based contrast. We report a patient who had renal insufficiency caused by multiple myeloma and developed nephrogenic systemic fibrosis after exposure to gadolinium-based contrast for the first time in Korea.

Validation of Gene Expression Changes of Osteopontin and MMP-1 in Primary and Metastatic Colorectal Carcinomas

BACKGROUND: Metastasis is one of the most important characteristics of cancer in terms of its impact on patient survival. Unfortunately, identification of altered genes during tumor metastasis is limited. METHODS: Using high-throughput microarrays containing 19K spotted human oligonucleotides, gene expression of primary and matched metastatic colon cancer were compared in previous study. Although DNA microarray analysis did not demonstrate complete classification of primary and metastatic carcinoma, 80 differentially expressed genes were identified. Among these, expression of osteopontin, matrix metalloproteinase-1 (MMP-1) and serpin A1 was assessed using immunohistochemistry in a validation set containing 43 pairs from tissue microarrays. RESULTS: The expression of osteopontin was significantly higher in metastatic carcinoma than in primary carcinoma, as indicated by mRNA expression. The expression of MMP-1 was significantly lower in metastatic carcinoma. Expression of serpin A1 was not correlated with the microarray results. CONCLUSIONS: Osteopontin and MMP-1 expression successfully classified primary and metastatic colorectal carcinomas and further studies on their clinical application is encouraged.

Thymolipoma in a 13-year-old Korean girl / 소아과

Thymolipoma is a rare benign tumor of anterior mediastinum. Most patients are asymptomatic with incidental finding of the tumor during a diagnostic workup of other medical problems. We present a case of 13-year-old girl with anterior mediastinal thymolipoma, surgically removed after an incidental diagnosis.