Hoon-Kyu Oh

Clinico-pathologic Parameters for Prediction of Microsatellite Instability in Colorectal Cancer

Purpose Although the incidence of microsatellite instability (MSI) accounts for 10-15% of cases of colorectal cancer, its clinical application for all colorectal cancers has widened. We attempted to identify clinical and pathological parameters that may be helpful in selection of patients with MSI-high (MSI-H). Materials and Methods A total of 120 resected colorectal cancers were enrolled retrospectively for this MSI study. Polymerase chain reaction (PCR) and denaturing high performance liquid chromatography and/or real time PCR methods with five markers and immunohistochemistry (IHC) for MLH1 and MSH2 were performed for analysis of cancer and blood specimens. Clinico-pathologic parameters, including IHC, were investigated in order to determine their usefulness as predictive factors of MSI. Results Among 120 cases of colorectal cancer, MSI was observed in 15 cases (12.5%), including 11 cases of MSI-H and four cases of MSI-low. Patients with MSI were younger, less than 50 years old, had a family history of cancer, Rt. sided colon cancer and/or synchronous multiple colorectal cancer, mucinous histologic type, and serum carcinoembryonic antigen group in the normal range. Results of multivariate analysis showed Bethesda guidelines, Rt. sided and/or synchronous multiple colorectal cancer, and negative expression of IHC for MLH1, which was consistently associated with MSI-H. MSI-H colorectal tumors have met at least one of these three parameters and their sensitivity and specificity were 100% and 72.5%, respectively. Conclusion Bethesda guidelines, tumor location, and negative expression of MLH1 protein are important parameters for selection of patients with colorectal cancers for MSI testing. MSI testing is recommended for patients showing any of these three parameters.

Tumor initiation inhibition through inhibition COX-1 activity of a traditional Korean herbal prescription, Geiji-Bokryung-Hwan, in human hepatocarcinoma cells.

Some Korean and oriental herbal prescriptions used for a syndrome expressed as chest paralysis and heartache are thought to be effective for angina pectoris. We investigated the effects of an oriental medicinal prescription, Geiji-Bokryung-Hwan (GBH) consisting of herbs of Cinnamomi Ramulus, Poria Cocos Hoelen (Pachymae Fungus), Moutan Cortex Radicis, Paeoniae Radix, and Persicae Semen, on growth-inhibitory activity and cancer chemopreventive activity in assays representing three major stages of carcinogenesis. The GBH was found to act as an potent inhibitor of cyclooxygenase (COX)-1 only but not as COX-2 inhibitor. Furthermore, the extract mediated anti-inflammatory effects and inhibited COX-associated hydroperoxidase functions (antipromotion activity). Inhibitory effect of the GBH on the growth of cancer cell lines such as HepG2 cell and Hep3B cell was shown. These data suggest that GBH extracts merit investigation as a potential cancer chemopreventive agent in humans, especially in hepatological cancers.

Effect of age and stage of endometriosis on ovarian follicular loss during laparoscopic cystectomy for endometrioma

To identify the risk factors associated with inadvertent follicular loss during laparoscopic cystectomy for endometrioma.

Correlation of hypoxia inducible transcription factor in breast cancer and SUVmax of F-18 FDG PET/CT

BACKGROUND Tumor hypoxia induces the expression of several genes via the hypoxia-inducible transcription factor-1 alpha (HIF-1a). It is associated with the prognosis of several cancers. We studied the immunohistochemical expression of HIF-1a in patients with invasive ductal cancer (IDC) of the breast and the possible correlation with the maximum standardized uptake value of the primary tumor (pSUVmax) as well as other biological parameters. Prognostic significance of pSUVmax and expression of HIF-1a for the prediction of progression-free survival (PFS) was also assessed. MATERIAL AND METHODS Two-hundred seven female patients with IDC who underwent pretreatment fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT) were enrolled. The pSUVmax was compared with clinicopathological parameters including estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), axillary lymph node (LN) metastasis, stage and HIF-1a expression. The prognostic value of pSUVmax for PFS was assessed using the Kaplan-Meier method. RESULTS pSUVmax was significantly higher in patients with HIF-1a expression ≥ 2 compared to patients with HIF-1a expression < 2 (5.2 ± 4.5 vs. 3.7 ± 3.1, p = 0.008). pSUVmax was also significantly higher in higher stage (p < 0.000001), ER-negative tumors (p < 0.0001), PR-negative tumors (p = 0.0011) and positive LN metastasis (p = 0.0013). pSUVmax was significantly higher in patients with progression compared to patients who were disease-free (6.8 ± 4.4 vs. 4.1 ± 3.7, p = 0.0005). A receiver-operating characteristic curve demonstrated a pSUVmax of 6.51 to be the optimal cutoff for predicting PFS (sensitivity: 53.6%, specificity: 86.0%). Patients with high pSUVmax (> 6.5) had significantly shorter PFS compared to patients with low pSUVmax (p < 0.0001). CONCLUSIONS pSUVmax on pretreatment F-18 FDG PET/ CT reflect expression of HIF-1a and can be used as a good surrogate marker for the prediction of progression in patients with IDC. The amount of FDG uptake is determined by the presence of glucose metabolism and hypoxia in breast cancer cell.

Inhibitory Effects of Type IV Collagenase by Disulfiram

기질의 침윤과 전이를 특징으로 하는 악성종양 세포는 세포외 기질이나 기저막에 의존적으로 작용한다. 세포외 기질을 분해하는 효소인 matrix metalloproteinase (MMP) 계들의 발현 및 활성증가는 대부분의 악성종양세포에서 전이와 침윤를 촉진시킨다. MMP family 가운데 특히 type Ⅳ collagenase 활성을 지닌 MMP-2와 MMP-9은 세포외기질의 중요한 구성분인 collagen, fibronectin을 분해하는 특성을 가지며 암 전이를 용이하게 하는 주요한 효소로 잘 알려져 있다. 본 연구에서는 항암후보물질인 disulfiram이 골 육종(U2OS), 신장암 (Caki-1) 및 자궁암 (Caski) 세포에서 MMP-2와 MMP-9의 효소활성 및 발현억제에 대해 조사하였다. MTT assay를 이용하여 disulfiram에 대한 암세포 viability 실험에서는 disulfiram이 암세포의 viability를 저해하였다. 또한 zymography, western blot 및 RT-PCR 등을 이용한 type Ⅳ collagenase의 활성 및 발현 실험에서 disulfiram은 type Ⅳ collagenase의 활성을 비롯하여 단백질 및 mRNA 발현을 억제시키는 것을 확인하였다. 따라서 disulfiram이 MMP-2와 MMP-9의 활성 및 발현 억제 기전을 통하여 골 육종, 신장암 및 자궁경부암 세포의 작용을 억제한다는 연구 결과는 disulfiram이 각종 악성종양의 침윤과 전이를 억제 또는 방지하기 위한 치료물질로서 임상에서 활용할 수 있는 가능성을 보여준다.

Breast Carcinoma with Choriocarcinomatous Features: A Case Report

Nongestational choriocarcinoma differentiation is extremely rare in breast neoplasms. It is characterized by tumor cells similar to chorionic trophoblastic cells, which react with human placental lactogen and human chorionic gonadotropin (hCG). A 56-year-old woman presented with a palpable right breast mass without past history of trophoblastic tumors. An F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) scan revealed one focus with low accumulation of FDG in the right breast (maximum standardized uptake value, 1.98). The patient underwent a right mastectomy and biopsy of sentinel nodes. Microscopically, the tumor was a typical invasive ductal carcinoma with multiple foci of choriocarcinoma features. Immunohistochemistry showed that the tumor cells resembling choriocarcinoma were positive for hCG antibody, but negative for HER2/neu, estrogen receptor, and progesterone receptor. A pathologic diagnosis of breast carcinoma with choriocarcinomatous features was made. To our knowledge, this is the first report of invasive carcinoma with choriocarcinomatous features and an unusual finding of low accumulation in an F-18 FDG PET/CT scan in Korea.

Abstract P2-06-05: Association of promoter methylation status of the FHIT gene and Fhit expression with HER2/neu status in breast cancer

Purpose: Aberrant DNA methylation has been recognized to contribute to breast carcinogenesis, and promoter hypermethylation of many tumor suppressor genes has been correlated with decreased gene expression. The fragile histidine triad (FHIT) gene is a putative tumor suppressor gene in breast and other cancers, and loss of Fhit expression has been observed in breast cancers. The aim of this study was to evaluate the association between methylation of the FHIT gene and its expression in breast cancer, and to investigate whether methylation and expression of the FHIT gene would correlate with clinicopathological characteristics in relation to human epidermal growth factor receptor 2 (HER2) status. Methods: Pyrosequencing of bisulfite treated DNA was performed to study the methylation status of the FHIT gene in 60 breast cancer samples from Korean women obtained at Daegu Catholic University Hospital. We examined the expression of FHIT using tissue microarrays by immunohistochemical staining. Association between the methylation status of the FHIT gene and its expression was analyzed, and the relationship between the FHIT expression and the clinicopathological characteristics of the patients was evaluated. Results: FHIT methylation was detected in 96.7% and positive expression rate of Fhit was 87.3% of the patients. The mean methylation level of the FHIT gene was associated with intratumoral inflammation. Methylation level of the FHIT gene had no significant differences according to molecular subtypes. Loss of Fhit expression was associated with large tumor size, basal-like subtype and positive expression of EGFR. In HER2-negative breast cancers, loss of Fhit expression was significantly associated with tumor size, estrogen receptor status and Ki-67 proliferation index. There was no significant correlation between methylation of the FHIT gene and its expression in this study. Conslusion: Our study revealed that loss of Fhit expression in breast cancer is associated with poor prognostic features, although there is no significance association between the FHIT gene methylation and Fhit expression. We found that in HER2-negatvie breast cancers, loss of Fhit expression was associated with poor prognostic features. These results support the possibility of potential complementation between HER2 and the Fhit pathway. The clinical significance of our findings needs to be further evaluated in larger cohorts with longer follow-up. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-06-05.

Ovarian mixed germ cell tumor in a patient with 45,X/46,X,+mar mosaic Turner's syndrome

We report a case that mixed germ cell tumor developed in an 18-year-old girl with 45,X/46,X,+mar mosaic Turner`s syndrome. Molecular biological studies showed that the patient`s DNA contained a fragment of Y chromosome. The patient underwent an operation and chemotherapy, and until now there is no evidence of recurrence. A presence of Y chromosome component should be evaluated in case a marker chromosome is found in a woman with Turner`s syndrome.

Comparison of Synchrotron Images of DCIS of the Breast with Their Pathologic Findings.

Background : Synchrotron radiation x-ray imaging have opened a new door to explore breast tissue below the micron scale providing detailed internal structures of the samples with a great magnification and an excellent resolution. Using phase contrast technique, we got monochromated synchrotron images of DCIS (Ductal Carcinoma In Situ) of the breast tissue section. To figure out relation with their optical microscopic features, we compared the synchrotron images of the DCIS with their histopathologic findings of the same stained section.Material and Methods : A x-ray microscope was installed on 1B2 beamline of Pohang Light Source, a third generation synchrotron radiation facility with operating energy of 2.5 GeV in Pohang, Korea. The x-ray energy was set at 11.1 keV, and the x-ray beam was monochromatized by a W/B4C monochromator. Zernike phase-shifter was adapted for phase contrast x-ray microscopy. Formalin-fixed 5µm-thick breast tissue sample was attached onto the Kapton film, and positioned 25 m away from the beam source. The synchrotron image of sample was converted into a visual image on the CsI(TI) scintillation crystal, and this visual image was captured by a full frame CCD camera. After scanning, we patched these images one and another to show the large area of the tissue section. For the comparative analysis with their synchrotron image, synchrotron-scanned breast tissue sections were stained, and the histopathologic findings of the samples were captured by image analyzer. The magnifying power of this microscope was 100x.Results: The monochromated x-ray microscopic images of DCIS of the breast tissue were obtained with a good resolution. These images revealed various structures of DCIS lesion with a good contrast and high visibility by phase contrast technique. They include prominent and intact periductal basement membrane - a hallmark of DCIS lesion, and stippled fine microcalcifications which were indistinct in the histologic section, and a shadow of intense peritumoral inflammatory cell infiltration. But the minute changes of each cancer cell showing the features of cancer tissue such as, cellular differentiation and nuclear grade, were not identified well.Discussion: The x-ray microscopic imaging of DCIS of the breast tissue section with synchrotron radiation showed a good correspondence with the histopathologic findings of their stained tissue sections. And the synchrotron image of DCIS had some unique radiologic features differentiating from histopathogic findings. Therefore the synchrotron images of the DCIS lesion appear to have a new possibility of use for the clinical and research purposes in near future. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5015.