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The current standard treatment for newly diagnosed glioblastoma patients is surgical resection followed by concurrent chemoradiotherapy with temozolomide. When progression is suspected during the treatment protocol, surgical resection is considered. Focal tumor cells can be found within extensive radiation necrosis specimens, and whether to categorize this finding as tumor progression or radiation necrosis is debatable. From June 2006 to June 2016, 115 patients were diagnosed as glioblastoma and 93 of them completed their concurrent chemoradiotherapy. During follow up, 31 patients underwent surgery due to radiologic progression. While 23 patients were diagnosed as recurrent glioblastoma, 8 patients’ specimen showed extensive radiation necrosis with a few tumor cells. Four patients who showed 1p19q codeletion positive and 4 patients who did not have available study results were excluded from the study according to the recent change in CNS tumor diagnosis from the 2016 WHO classification. Among the 6 patients in the mixed pathology group, 5 of them were discontinued from the primary treatment. Overall survival (OS) and survival after radiologic progression (SARP) was measured, and analyzed using the Kaplan-Meier method. Comparing the recurrence group and the mixed pathology group, MGMT methylation PCR results showed positive findings in 6/17 (35.3%) and 4/6 (66.7%), respectively. Although this finding suggests superior outcome on the mixed pathology group, the mean OS was 25.86 (SD 3.15, 95% CI 19.70-32.02) and 25.20 (SD 5.34, 95% CI 14.74-35.66) for recurrence and mixed pathology groups, respectively, with no statistical significance (p=0.875). The mean SARP was 9.63 (SD 1.06, 95% CI 7.56-11.7) and 13.20 (SD 2.05, 95% CI 9.19-17.22) for recurrence and mixed pathology groups. The survival curve showed superior outcome in the mixed pathology group, but failed to obtain statistical significance (p=0.110). The tendency of longer SARP in the mixed pathology group suggests the possibility of a better prognosis group within the previously known recurrence cases. The decision of treatment failure may have been premature in selected patients, and further study is warranted in order to define the exact patient group.

Objectives Expression of insulin-like growth factor 1 receptor (IGF-1R) in non-small cell lung cancer (NSCLC) is associated with poor prognosis. The IGF-1R pathway activates downstream targets that bypass dependency in signals from the epidermal growth factor receptor (EGFR), which mediates resistance to EGFR tyrosine kinase inhibitors (TKIs). The aim of the present study was to determine the predictive role of IGF-1R expression in the response to EGFR-TKIs of NSCLC patients harboring activating EGFR mutations. Materials and methods We retrospectively studied 62 NSCLC patients who had activating EGFR mutations and received TKIs. Protein expression of IGF-1R, vascular endothelial growth factor (VEGF), and human epidermal growth factor receptor 2 (HER2) were measured by immunohistochemical staining. Univariate and multivariate analyses were performed to identify predictive factors associated with the responses to EGFR-TKIs. The relationship of progression-free survival (PFS) with IGF-1R expression and the presence of diabetes mellitus (DM) were examined. Results Of 62 EGFR mutation positive patients, 26 expressed IGF-1R, and 13 had DM. In the multivariate analysis, young age, squamous cell carcinoma, and IGF-1R expression were independently associated with a shorter PFS after treatment with EGFR-TKIs. Patients expressing IGF-1R showed a significantly shorter PFS in response to EGFR-TKIs compared with those lacking IGF-1R expression (9.1 vs. 20.1 months, p =0.005). The 13 patients with DM were more likely to express IGF-1R ( p =0.001) and had shorter PFS times when treated with first-line EGFR-TKIs (7.6 vs. 18.6 months, p =0.005), compared with those without DM. Conclusion IGF-1R expression was a negative predictive factor for a response to EGFR-TKIs in NSCLC patients harboring activating EGFR mutations. Moreover, patients with DM highly expressed IGF-1R in tumor tissues, which was associated with a poor response to first-line TKI therapy. Further studies aimed at overcoming EGFR-TKI resistance will need to also address IGF-1R pathways.

The purpose of this study was to determine the role of lymph node micrometastasis in oral and oropharyngeal cancers.We investigated the presence of micrometastases by cytokeratin immunohistochemical staining in 54 patients with node-negative oral and oropharyngeal carcinomas.The positive rate of cytokeratin expression was 13.0% (7 of 54 patients). The incidence of micrometastasis was significantly higher in patients with more invasive tumors (p.001) and larger tumor size (p = .034). The 5-year disease-specific (DS) survival rate significantly correlated with micrometastasis, margin involvement, and depth of invasion in the univariate analyses. Multivariate Cox regression analysis confirmed a significant association between the 5-year DS survival rate and micrometastasis (hazard ratio [HR] = 7.89; 95% confidence interval [CI] = 1.09-57.14; p = .041) and margin involvement (HR = 11.68; 95% CI = 1.22-111.75; p = .033).Micrometastasis was significantly correlated with the depth of invasion and tumor size in oral and oropharyngeal cancers. Furthermore, micrometastasis was associated with adverse outcomes. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1777-E1782, 2016.

BACKGROUND AIM: We evaluated the efficacy and toxicities of three induction chemotherapy regimens in locally advanced head and neck cancer and assessed the clinical significance of human papillomavirus (HPV) in induction chemotherapy.Fifty-two patients were retrospectively evaluated; 12 patients received 5-fluorouracil-plus-cisplatin (FP); 24 patients received docetaxel-plus-cisplatin (DP); 16 patients received docetaxel, cisplatin, and 5-fluorouracil (TPF).The TPF regimen showed a trend towards a higher overall response rate and pathological complete response and led to a significantly higher rate of metabolic complete response. Patients with HPV-positive tumors exhibited a significantly higher pathological complete response rate than those with HPV-negative tumors. In univariate analysis, the prognostic factors significantly affecting progression-free survival were lymph node stage, and metabolic and pathological complete response.TPF induction chemotherapy tended to improve clinical outcome, with manageable toxicity. Pathological complete response was positively correlated with HPV positivity.

Median (18)F-FDG PET/CT maximum standardized uptake values (SUV max) cut-off values of 7.9 or greater were associated with high-risk human papillomavirus (HPV) negativity in patients with hypopharyngeal squamous cell carcinoma (HPSCC). Furthermore, median (18)F-FDG PET/CT SUV max cut-off values of 7.9 or greater and high-risk HPV negativity were associated with adverse outcomes.We studied the association and the potential prognostic significance of (18)F-FDG PET/CT and high-risk HPV status in HPSCC.The medical records of 45 patients who underwent (18)F-FDG PET/CT for HPSCC before surgery were reviewed. High-risk HPV in situ hybridization was performed to detect HPV infection.The median SUV max was 9.91 ± 4.91 (range 1.9-22.1) and the positive rate of high-risk HPV in situ hybridization was 11% (5 of 45). The SUV max values of negativity for the high-risk HPV subtypes (10.47 ± 4.87) and positivity (5.48 ± 2.45) were found to be significantly different (p = 0.030). The SUV max cut-off value for differentiating negativity for the high-risk HPV subtypes from positivity was 7.9, with a sensitivity of 65% and a specificity of 80%. The 5-year disease-specific survival rate (DSSR) in our cohort was 57%. Patients with an SUV max value higher than 7.9 (p = 0.005) and high-risk HPV negativity (p = 0.047) had decreased 5-year DSSR.

Histologic tumor grading requires assessments on a continuum of morphologic alterations for which objective measuring tools may not be as easily developed as for laboratory tests. As a consequence, some subjectivity cannot be avoided, and issues such as inter-observer variability and lack of reproducibility are frequently identified as limits to the prognostic and predictive values of grading[1-5]. Various methods have been suggested to resolve these issues, employing not only conventional semi-quantitative sche mes but also relatively new approaches such as entropy- based texture analysis and fractal dimension analysis[6-12]. Although the specific criteria used for tumor grading vary by type of cancer, the strategy behind histologic grading is based primarily on the degree of tumor differentiation or the extent to which a tumor resembles the normal tissue counterpart. In this study, we hypothesized that the amount of histologic disorderliness in the arrangement of tumor cells may be quantified by adopting the concept of entropy, and that the quantified measurements would correlate with degree of differentiation. Here, by modifying the statistical thermodynamic definition of entropy that is often taken to be a measure of disorderliness in a physical system, we develop a novel mathematical formula to compute the relative degree of histologic disorderliness of tumor cells. We then apply the formula to colorectal adenocarcinomas with varying degrees of differentiation and determine whether disorderliness is a useful feature for grading cancer.

Magnetic susceptibility (MS) measurements were carried out for 1,120 samples in the Middle Proterozoic to Early Tertiary granitoids so far recognized in South Korea, and the lateral and spatial variation of their magnetic susceptibility, i.e., content of magnetite, is studied. The Middle Proterozoic two mica granitoids related to cassiterite (Sn) deposits in northeastern part of the Sobaegsan Massif show very low MS (less than 0.3 A- 10-3 SI unit), and the Permo-Triassic tonalitic to granodioritic and monzonitic rocks which are barren in mineralization, distributed in the middle part of South Korea also show low MS (less than 1 A- 10-3 SI unit). On the contrary the Late Triassic to Jurassic granitoids (= Daebo granitoids) which were evolved from tonalite through granodiorite to granite, and are most widely distributed in South Korea, show a wide variation on MS. Particularly in the Andong, Igsan, Gimcheon and Geochang areas, the granitoids which are barren in mineralization, are characterized by high MS (more than 10 A- 10-3 SI unit). The Chuncheon, Jecheon, Namyang and Geumsan plutons related to molybdenite (Mo) and/or wolframite or scheelite (W), and fluorite (F) mineralizations show a little high MS (more than 3 A- 10-3 SI unit). However, more than 60% of the Daebo granitoids show low MS (less than 3 A- 10-3 SI unit) and the rest show a little high MS (more than 3 A- 10-3 SI unit). Heterogeneous distribution of magnetite content in the Daebo granitoids is considered to reflect heterogeneity of redox state of the source materials for these granitoids. The Cretaceous to Early Tertiary granitoids (= Bulgugsa granitoids) in the Gyeongsang Basin had been generally evolved in the order of tonalite, diorite, granodiorite, granite and alkali-feldspar granites, which are closely related to base metal ore deposits, and mostly show higher MS (more than 3 A- 10-3 SI unit) than other granitoids mentioned above, although some exceptions are recognized in highly evolved alkali-feldspar granites (SiO2 > 76%). In contrast, as most of the highly oxidized or evolved Cretaceous granitoids distributed in areas other than the Gyeongsang Basin show lower MS than those of the Gyeongsang Basin, and appear to be magnetite free, ilmenite-series granites, but they might be hematite bearing magnetite-series granitoids. Highly oxidized nature of the Bulgugsa granitoids may be due to high Fe2O3/FeO ratio of the source materials and also high level intrusion style of the granitic magma activities. Most of the granitic rocks of the Middle Proterozoic, Permo-Triassic and more than 60% of the Late Triassic to Jurassic (Daebo granitoids) belong to ilmenite–series, however less than 40% of the Daebo granitoids and most Cretaceous ones are magnetite–series. Thus, the granitic magma intruded in Korean Peninsula became oxidized while the intrusive ages become younger.

HLA expression is altered in a large variety of human cancers. We performed immunohistochemical staining on tissues from normal, preinvasive, invasive and metastatic cervical cancer tissues using anti-HLA class I or class II antibody. In tissues from normal squamous epithelium, carcinoma in situ (CIS) and microinvasive carcinoma (MIC), the expressions of HLA-B, C heavy chains and class II heavy chain were significantly decreased as disease progressed. When the expression patterns were compared between primary and metastatic squamous cell carcinoma (SCC) lesions, statistically significant down-regulation of HLA class I and class II antigen in metastatic lesions was observed. The rates of HLA-B, C heavy chains and class II heavy chain expressions were all significantly down-regulated compared to the down-regulation rate of class I beta2-microglobulin (beta2m) in invasive squamous lesions, and the expressions of class II heavy chain in metastatic lesions was decreased further than that in primary lesions. Unlike SCC, the degree of HLA class I and class II loss was not evident as disease progressed in early stage of adenocarcinoma. In invasive adenocarcinoma lesions, only the expression of HLA-B, C heavy chains was decreased and no differences were seen in HLA-B, C heavy chain expression patterns between primary and metastatic lesions. These results suggest that alterations of HLA class I and II expressions seem to occur at a particular step in cervical cancer development and depend on tissue types: when the tumor becomes invasive and starts to metastasize.

We report a 46-year-old woman with primary biliary cirrhosis (PBC) presenting with Sjögren’s syndrome and systemic mononuclear inflammatory vasculopathy. Biopsy specimens of sural nerve showed findings consistent with vasculitic neuropathy. Perivascular inflammatory mononuclear cell infiltration was observed on muscle biopsy specimen. The findings of abdominal computed tomography and brain magnetic resonance imaging were suggestive of vasculitis. Clinical manifestations and radiologic findings were improved after high dose prednisolone therapy.

A case of intestinal angiocentric T/NK-cell lymphoma in a 58-year-old man is reported. The patient presented initially with panperitonitis because of perforation of sigmoid colon diverticulum. He underwent segmentectomy of involved bowel. Histologically, the intestinal wall showed diffuse infiltration of medium or large size lymphoma cells with angiocentric growth and necrosis. The lymphoma cells were CD56+, CD45RO+, CD3+, CD4-, CD8-, CD20-, and CD30- in paraffin sections with germline configuration of TCR-gamma gene, consistent with T/NK-cell lymphoma. Further staging revealed splenomegaly. Intestinal angiocentric T/NK cell lymphoma represents a distinct etiology of diverticulum with perforation.

Human malignant gliomas are highly vascularized and aggressive tumors. Angiogenesis inhibitors have been shown to induce regression of a variety of primary and metastatic tumors in vivo. However, their usefulness in treating brain tumors is not well understood. Angiostatin, a multiple kringle (1–4 of 5)–containing fragment of plasminogen, is one of the highly effective natural cryptic angiogenesis inhibitors. In our study, the therapeutic efficacy of non-glycosylated and small molecular size recombinant kringles 1–3 (rPK1–3) was examined in the treatment of brain tumors generated by stereotactic intracerebral implantation of U-87 human glioma cells in nude mice. Mice bearing tumors 7 days post-implant were treated daily with rPK1–3 (100 mg/kg) s.c. for 21 days. Treated animals showed suppressed brain tumor growth by greater than 71.2% along with a 3-fold increase of apoptotic index and suppressed vascularization by 78.9%, without any observable signs of toxicity. Analysis of bFGF and VEGF expression in the tumors of treated animals using immuno-histochemical methods showed near complete absence of growth factors. Our results indicate that the non-glycosylated, small molecular size rPK1–3 is an efficient tumoristatic agent for the treatment of intracranial human glioma xenografts in mice and might provide new strategies for the treatment of brain tumors. Int. J. Cancer 82:694–699, 1999. © 1999 Wiley-Liss, Inc.

Intraspinal bronchogenic cysts are rare congenital cystic lesions. In all the reported cases, the cysts have been located in the cervical, upper thoracic or thoracolumbar segments. We report the case of an intraspinal bronchogenic cyst in the sacral location. We present the case of a 5-month-old female with a skin dimple in the midline over the sacral vertebra. Magnetic resonance image of the lumbar and sacral vertebra revealed a dermal sinus tract and an epidural cystic mass at the S2 level. The patient underwent the removal of the dermal sinus tract and the cyst. The cystic mass was shown to be connected to the subarachnoid space through a slender pedicle from the dura. The cyst was diagnosed to be a bronchogenic cyst based on the results of the histopathological examination. We conclude that intraspinal bronchogenic cysts may appear in the sacral location.

Two different distributions of declinations with dual polarities are found in the Tertiary rocks of the Yeonil Basin and Yangnam Basin along the Yangsan Fault in the southeastern part of the Korean Peninsula. These are northward declinations in the Middle Miocene Yeonil Group and strong eastward declinations in the Early Miocene Yangbuk Group and in the Eocene Volcanic Rocks. This is interpreted by invoking (1) the Yangsan Fault as a dextral wrench fault system by spreading in the Uleung Basin of the East Sea (Sea of Japan), and (2) a clockwise vertical rotation caused by the movement of the fault at around 17.3 Ma just prior to the sedimentation of the Yeonil Group. The timing of the deflection found in Korea is distinguished from that in southeastern and northwestern Japan at around 15 Ma. Two stages of spreading are thus constrained in the East Sea area: parallel at 23–15 Ma and pivotal at around 15 Ma. Crustal thinning also occurred. A reliable pole position (84.9°N, 292.6°E, d p / d m =3.3°/4.8°) for the Miocene (about 15 Ma) in Korea is obtained from the Yeonil Group.

A 13-year-old girl presented with multiple skin abscesses. She was diagnosed as having juvenile dermatomyositis (DM) at the age of 7 years. She had suffered from recurrent skin infections, atypical pruritic dermatitis and pneumonia since the age of 8 years. Bacteriologic and fungal cultures for skin abscesses and oral mucosa were positive S. aureus and C. albicans, respectively. Chemotactic defect in peripheral blood neutrophils was observed. The level of serum IgE was markedly elevated, and anti-S.aureus specific IgE was found. A diagnosis of hyperimmunoglobulin E-recurrent infection syndrome (HIE) was made and she was successfully treated with surgical drainage and antibiotics. To our knowledge, this is the first case report of HIE in a patient with juvenile dermatomyositis.

Background. Most patients with a preoperative diagnosis of thyroid follicular neoplasm (FN) undergo diagnostic surgery to determine whether the nodule is benign or malignant. Point mutations atNRAScodon 61 are the most common mutations observed in FN. However, the clinical significance ofNRASmutation remains unclear.Methods. From 2012 to 2013, 123 consecutive patients undergoing thyroidectomy for FN were evaluated prospectively. Molecular analyses forNRAScodon 61 were performed with pyrosequencing.Results. The overall malignancy rate in FN was 48.8% (60/123). Of 123 FNs, 33 (26.8%) were positive for theNRASmutation. The sensitivity, specificity, positive predictive value, and negative predictive value of aNRASmutation-positive FN specimen to predict malignancy were 37%, 83%, 67%, and 58%, respectively. Patients with aNRAS-positive FN had a higher malignancy rate in additional thyroid nodules beyond the FN than patients with a NRAS-negative FN. The overall malignancy rate of patients with a NRAS-positive FN was significantly higher than that of patients with a NRAS-negative FN (79% versus 52%;P= 0.008).Conclusions. Determining NRAS mutation status in FN helps to improve the accuracy of thyroid cancer diagnosis and to predict cancer risk in accompanying thyroid nodules.

Seven paleomagnetic poles are obtained from Early Ordovician, Late Carboniferous, Permo-Triassic, Jurassic, Early Cretaceous, Miocene and Quaternary rocks in Korea. These poles define the apparent polar wander path for the southern part of Korean Peninsula. The comparisons of APWPs from the North China Block, Yangtze Block and Korea reveals that the East Asia is comprised of two blocks, the North Sino-Korean and South Sino-Korean, which were parts of Gondwana during the Paleozoic time. The North Sino-Korean Block was migrated northwards in Late Permian and accreted with Laurasia in Triassic time. During Middle–Late Triassic time, the North Sino-Korean Block collided with the South Sino-Korean, and subsequently divided into two. The western part of the North Sino-Korean Block suffered counter-clockwise rotation, while the eastern part rotated clockwise until Jurassic time. Complicated shear senses of the Early Mesozoic fault systems in East Asia are well matched by this scenario.

Histopathological grading of papillary urothelial tumors (PUTs) of the urinary bladder is subjective and poorly reproducible. We investigated the relationship between the expression of frequently deregulated microRNAs (miRNAs) as well as their target genes (ZEB1/ZEB2) and bladder cancer histopathological grade in an attempt to find a miRNA that might allow more reliable grading of PUTs. We measured the expression levels of four miRNAs (miR-145, miR-205, miR-125b, and miR-200c) in 120 formalin-fixed, paraffin-embedded bladder tumor tissue samples using real-time PCR assays. ZEB1 and ZEB2 expression was assessed in the same bladder tissues by immunohistochemistry. MiR-205 distinguished low-grade papillary urothelial carcinoma (LG) from high-grade papillary urothelial carcinoma (HG), and miR-145 distinguished HG from infiltrating carcinoma (CA) with an area under the receiver operator characteristic curve (AUC) of 0.992 and 0.997, respectively (sensitivity/specificity of 95.8/96.7 % and 100/91.7 %, respectively; p < 0.05). The expression level of miR-125b was significantly lower in LG than in PUNLMP, with an AUC value of 0.870 (93.3 % sensitivity and 84.2 % specificity; p < 0.05). ZEB1 immunoreactivity was more frequently detected in HG than in LG (57 % vs 13 %, p < 0.01) and in HG than in CA (57 % vs 17 %, p < 0.01). ZEB2 immunoreactivity was more frequent in CA than in HG (83 % vs 54 %, p < 0.05). ZEB1/ZEB2 and miRNAs expression seems to reliably distinguish between different grades of PUTs of the urinary bladder. They might well serve as useful complementary diagnostic biomarkers for grading of papillary urothelial tumors.

Intracranial ependymal cysts are rare, congenital, benign lesions. These commonly occur in the supratentorial regions and usually generate no symptoms. The cerebellopontine angle (CPA) is an extremely rare site for ependymal cysts. Furthermore, there are no previous reports of CPA ependymal cysts related to syncope. We report a case of ependymal cyst in the left CPA with syncope. The patient underwent a cardiologic evaluation for syncope after admission, but there were no definite cardiologic abnormal findings. He underwent fenestration into the subarachnoid space, and the pathologic diagnosis revealed an ependymal cyst. We analyzed this case with review of other literatures.

Background: Clamydophila psittaci (C. psittaci) has been proposed as an etiologic factor for extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) in the ocular region. However, previous studies showed varied association rates ranging 0% to 87%, not constant even in the series of same geographical areas, which suggest that there could be some technical variance in detecting methods for C. psittaci. The authors validated five sets of primers for detecting C. psittaci DNA and investigated its association with ocular MALT lymphomagenesis. Material and Methods: Five sets of PCR primers including 4 previously reported and one newly designed were evaluated with positive control C. psittaci DNA (acquired from Korea Centers for Disease Control and Prevention). One hundred fifty cases of confirmed ocular MALT lymphomas were collected from pathology archives of our institutes from 2008 to 2014, and entered into this study. DNA was extracted from archival paraffin block sections with Qiagen DNA extraction kits. Quality of DNA was assessed with NanoDrop and beta-globin PCR. Standard PCR was performed together with negative (H2O and tonsil DNA) and positive control C. psittaci DNA. Results: In all five primer sets for C. psittaci DNA, each PCR product showed clear positive band and negative with appropriate positive and negative controls, respectively. All 150 ocular MALT lymphoma cases showed positive for Beta-globin DNA control, but negative for C. psittaci DNA in any of PCR product with five primer sets. Conclusion: These results suggest that possibility of the pathogenetic role of C. psittaci in ocular MALT lymphoma would have been overestimated so far, at least in Korean people. Disclosures No relevant conflicts of interest to declare.

Objective To determine whether invasion of the pharyngeal constrictor muscle in early squamous cell carcinoma of the tonsil is correlated with lymph node metastasis. Design Retrospective analysis of medical records and pathology specimens. Setting Tertiary care referral center. Patients Forty-eight patients who were diagnosed as having T2 squamous cell carcinoma of the tonsil and who underwent surgery. They were divided into 2 groups: an invasive group with invasion of the pharyngeal constrictor muscle and a noninvasive group without invasion of the pharyngeal constrictor muscle. Main Outcome Measures Comparison of regional metastasis, 5-year locoregional recurrence, and 5-year disease-specific survival between the 2 groups. Results Invasion of the pharyngeal constrictor muscle was found in 36 patients (75%) with T2 squamous cell carcinoma of the tonsil. The rate of lymph node metastasis, the mean (SD) number of positive nodes, and the mean (SD) lymph node density were 81%, 5.47 (9.27), and 0.15 (0.22) in the invasive group, respectively, and 50%, 1.33 (1.72), and 0.04 (0.04) in the noninvasive group, respectively (P = .04, P = .02, and P = .01, respectively). Five-year locoregional recurrence was significantly correlated with invasion of the pharyngeal constrictor muscle (P = .05) and with multiple lymph node metastasis (≥5 nodes) (P = .04) in the univariate analyses. No factor was correlated with 5-year locoregional recurrence in the multivariate analysis. Five-year disease-specific survival was significantly correlated with multiple lymph node metastasis (≥5 nodes) in the univariate analyses (P = .009). Five-year disease-specific survival was not significantly correlated with any clinicopathological factor in the multivariate analysis. Conclusion Higher risk for multiple lymph node metastasis and 5-year locoregional recurrence seems to be predicted in patients with extratonsillar invasion of the pharyngeal constrictor muscle, even in early squamous cell carcinoma of the tonsil.

Syndecan-1 (SDC1) is reported to modulate several key processes of tumorigenesis and to show variable expression in many cancers. The cause of these variations in expression is not known to date. In this study, we compared SDC1 status with clinicopathologic parameters to evaluate the prognostic implications of SDC1 status on squamous cell carcinoma (SCC) of the tonsil. In 56 cases of tonsillar SCC, we screened SDC1 expression using immunohistochemistry and analyzed the relationships between SDC1 expression and clinicopathological parameters. To identify the cause of the changes in SDC1 expression seen in tumors, we measured the gene dosage of SDC1 in tumor cells using fluorescent in situ hybridization. SDC1 expression was found in cancer cells in 36 cases (64.3 %) of tonsillar SCC. It was associated with lymph node metastasis (p = 0.010) and a positive surgical resection margin (p = 0.014). On the other hand, it was not significantly correlated with sex, age, smoking status, degree of differentiation, T stage, or distant metastasis. We could not find any copy-number variation of SDC1 in the cases showing increased SDC1 immunopositivity. In addition, strong SDC1 expression in the tumor cells predicted a shorter overall survival (p = 0.020, log-rank). We showed that SDC1 expression is associated with N stage and the status of resection margin involvement in SCC of the tonsil. With respect to survival, there were unfavorable outcomes in cases with SDC1 positivity. More studies are needed to better understand the role of SDC1 in the progression and invasiveness of tonsillar SCC.

Background/Aims: A single gene mutation alone cannot explain the poor prognosis of colorectal cancer. This study aimed to establish a correlation between the expression of six proteins and the prognosis of colorectal cancer patients. Methods: Tissue samples were collected from 266 patients who underwent surgery for colorectal cancer at our institu- tion from January 2006 to December 2007. The expression of six proteins were determined using immunohistochemi- cal staining of specimens. Results: Cathepsin D, p53, COX- 2, epidermal growth factor receptor, c-erbB-2, and Ki-67 expression were detected in 38.7%, 60.9%, 37.6%, 35.7%, 30.1%, and 74.4% of the samples, respectively. The expres- sion of cathepsin D was significantly correlated with reduced cancer-free survival (p=0.036) and colorectal cancer-specific survival (p=0.003), but the other expression levels were not. In a multivariate analysis, cathepsin D expression was found to be an independent prognostic factor for poorer colorectal cancer-specific survival (hazard ratio, 8.55; 95% confidence interval, 1.07 to 68.49). Furthermore, patients with tumors expressing four or more of the proteins had a significantly decreased cancer-free survival rate (p=0.006) and colorectal cancer-specific survival rate (p=0.002). Conclusions: Pa- tients with cathepsin D positivity had a poorer outcome than patients who were cathepsin D-negative. Thus, cathepsin D may provide an indicator for appropriate intensive follow-up and adjuvant chemotherapy. (GutLiver�2014;8:13-23)

Klinefelter’s syndrome, which is characterized by small testes, gynecomastia, hypogonadism, and infertility, is the most common cause of primary testicular failure, and commonly has an XXY karyotype. Deep vein thrombosis and thomboembolic events are a rare occurrence in these patients. Although the exact mechanism is not completely understood, it is thought that increased thromboembolic risk in hypogonadic men can be explained by hypofibrinolysis resulting from androgen deficiency. We present the case of a 48-year-old man with Klinefelter’s syndrome who experienced recurrent episodes of deep venous thrombosis and pulmonary embolism while undergoing therapeutic anticoagulation. Our report discusses this association and management of the prothrombotic state in patients with Klinefelter’s syndrome.

Background Palonosetron is a new potent 5-hydroxytryptamine 3 antagonist. Although this drug is thought to be more effective in patients receiving opioid-based patient-controlled analgesia (PCA), clinical data are lacking. This study compared the effects of i.v. ondansetron and palonosetron administered at the end of surgery in preventing postoperative nausea and vomiting (PONV) in high-risk patients receiving i.v. PCA after thyroidectomy. Methods A total of 100 female non-smoking subjects were randomly assigned into a palonosetron group or an ondansetron group. Ondansetron was given as an 8 mg bolus and 16 mg was added to the i.v. PCA mixture. In the palonosetron group, 0.075 mg was injected as a bolus only. Fentanyl-based PCA was provided for 24 h after operation. The incidence of nausea and vomiting, severity of nausea, requirement for rescue anti-emetics, and adverse effects were evaluated during 0–2 and 2–24 h. Results The incidence of PONV during the 24 h postoperative period was lower in the palonosetron group than in the ondansetron group (42% vs 62%, P=0.045). No differences were observed between the groups during the first 2 h. However, the incidence of nausea and vomiting and nausea severity were significantly lower in the palonosetron group than in the ondansetron group during 2–24 h. The only difference in the use of rescue anti-emetics was at 2–24 h (10% with palonosetron compared with 28% with ondansetron, P=0.02). Conclusions Palonosetron is more effective than ondansetron for high-risk patients receiving fentanyl-based PCA after thyroidectomy, especially 2–24 h after surgery.

We have determined O(6)-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status by methylation-specific polymerase chain reaction (MSP) in 22 paraffin-embedded specimens of glioblastoma multiforme. A MGMT methylation-specific high resolution melting (HRM) assay was performed to compare the methylation levels of the tumorous and non-tumorous portions of each sample, which were selectively collected using a microdissection technique. MGMT methylation was detected in 10 patients using MSP, while 8 patients had both methylated and unmethylated MGMT promoters. HRM assays showed that there was no difference in the level of methylation between tumorous and non-tumorous portions of each sample. In patients with MSP-positive tumors, the overall survival (median, 22 months) was longer as compared to those with MSP-negative tumors (median, 14 months). A correlation between the methylation status of the MGMT promoter and MGMT protein expression was observed in 12 samples. This study demonstrates that MGMT methylation is not restricted to glioblastoma cells. Additionally, methylation-specific HRM is a feasible approach that can be readily applied to the methylation analysis of MGMT. A further study will be needed to determine the dynamic change of MGMT methylation in the tumor environment.

Background and Objectives This study evaluated several tumor angiogenesis-related markers to examine their expression pattern and relation to clinicopathologic implications of nasopharyngeal carcinoma. Methods Paraffin sections from 69 nasopharyngeal carcinomas obtained before radiotherapy were prepared. The expression of vascular endothelial growth factor (VEGF), cyclooxygenase-2 (Cox-2), C-erbB2, and epidermal growth factor receptor (EGFR) were investigated by immunohistochemistry and then correlated with various clinicopathologic parameters. Results VEGF was inversely correlated with C-erbB2 (P = 0.036). In survival analysis, high mitosis (≥5/10 high power field) was significantly associated with worse relapse-free survival in univariate analysis (P = 0.048) but not in multivariate analysis (P = 0.153). High stage, high mitotic rate, absence of VEGF, and presence of Cox-2 were associated with worse survival in both univariate analysis (P = 0.002, P = 0.038, P = 0.044, and P = 0.028, respectively) and multivariate analysis (P = 0.007, P = 0.036, P = 0.047, and P = 0.004, respectively). Conclusions Absence of VEGF is a useful indicator of poor prognosis in addition to Cox-2 expression, high stage, and high mitosis. J. Surg. Oncol. 2011;103:46–52. © 2010 Wiley-Liss, Inc.

Background Cell transdifferentiation is characterized by loss of some phenotypes along with acquisition of new phenotypes in differentiated cells. The differentiated state of a given cell is not irreversible. It depends on the up- and downregulation exerted by specific molecules. Results We report here that HCCR-1, previously shown to play an oncogenic role in human cancers, induces epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) in human and mouse, respectively. The stem cell factor receptor CD117/c-Kit was induced in this transdifferentiated (EMT) sarcoma tissues. This MET occurring in HCCR-1 transfected cells is reminiscent of the transdifferentiation process during nephrogenesis. Indeed, expression of HCCR-1 was observed during the embryonic development of the kidney. This suggests that HCCR-1 might be involved in the transdifferentiation process of cancer stem cell. Conclusions Therefore, we propose that HCCR-1 may be a regulatory factor that stimulates morphogenesis of epithelia or mesenchyme during neoplastic transformation.

Stem cells are characterized by self renewal and multipotent differentiation.We report the effects of intracavernosal transplant of human umbilical cord blood stem cells on diabetic erectile dysfunction.Seven type 2 diabetics who had failed to achieve an erection for at least 6 months despite medications, and who are currently awaiting penile prostheses, participated. All laboratory results were normal, except for impotence and diabetes mellitus. A total of 1.5 x 10(7) human umbilical cord blood stem cells were infused into the corpus cavernosum. No immunosuppressive measures were taken in any of the patients. International index of erectile function-5, SEP, GAQ, erection diary, blood glucose diary, and medication dosage were followed for 9 months.The mean age was 69.5 years (range, 57-87 years). Morning erections were regained in 3 participants within 1 month, and for all except 1 by the third month, and maintained for more than 6 months. Rigidity increased as the result of stem cell therapy alone, but was insufficient for penetration. With the addition of PDE5 inhibitor before coitus, 2 achieved penetration and experienced orgasm, and maintained for more than 6 months; however, 1 participant could not achieved penetration at ninth month. All but 1 reported increased desire. During follow-up, 2 returned for prosthesis, 4 returned to a nonerectile condition at 9 months, and 1 maintained erection sufficient for coitus with medication until the 11th month. Blood glucose levels decreased by 2 weeks, and medication dosages were reduced in all but 1 subject for 4 to 7 months. Glycosylated hemoglobin levels improved after treatment for up to 3 to 4 months.Human umbilical cord blood stem cell therapy has positive effects on erectile dysfunction and diabetes mellitus. Stem cells and unknown humoral factors of human umbilical cord blood stem cells mediate mechanism may contribute to these positive effects.

Papillary thyroid carcinoma with nodular fasciitis-like stroma (PTC-NFS) is an extremely rare variant of papillary thyroid carcinoma characterized by prominent stromal cell proliferation. To our knowledge, sonographic findings of PTS-NFS have not been reported. Here, we report a case of PTC-NFS that presented as a homogenous and hypoechoic mass in the peripheral portion of the left thyroid gland on sonography in a 35-year-old pregnant woman.

Despite remarkable progress in understanding and treating gastrointestinal stromal tumors (GISTs) during the past two decades, the pathological characteristics of GISTs have not been made clear yet. Furthermore, concrete diagnostic criteria of malignant GISTs are still uncertain. We collected pathology reports of 1,227 GISTs from 38 hospitals in Korea between 2003 and 2004 and evaluated the efficacy of the NIH and AFIP classification schemes as well as the prognostic factors among pathologic findings. The incidence of GISTs in Korea is about 1.6 to 2.2 patients per 100,000. Extra-gastrointestinal GISTs (10.1%) are more common in Korea than in Western countries. In univariate analysis, gender, age, tumor location, size, mitosis, tumor necrosis, vascular and mucosal invasions, histologic type, CD34 and s-100 protein expression, and classifications by the NIH and AFIP criteria were found to be significantly correlated with patient's survival. However, the primary tumor location, stage and classification of the AFIP criteria were prognostically significant in predicting patient's survival in multivariate analysis. The GIST classification based on original tumor location, size, and mitosis is more efficient than the NIH criteria in predicting patient's survival, but the mechanism still needs to be clarified through future studies.

Infantile hemangioendothelioma is the most common benign mesenchymal tumor of the liver presenting during the first 6 months of life. Serum alpha fetoprotein is an important tumor marker for hepatoblastoma, hepatocellular carcinoma, and germ cell tumors. However, it is rarely elevated in patients with hepatic infantile hemangioendothelioma. In such cases, surgery may be done to rule out malignancies when alpha fetoprotein levels are high. The etiology of the elevated alpha fetoprotein level has not yet been elucidated. We report 2 cases of solitary hepatic infantile hemangioendothelioma and demonstrate immunohistochemically that hepatocytes near or entrapped within the tumor were the source of the increased serum levels of alpha fetoprotein explaining the unusual clinical presentation.

The proliferative capacity of tumor cells is a characteristic feature in the whole growing tumors. Many pathologists and clinicians have used the estimation of cell proliferation for prognostic information. Minichromosome maintenance protein 3 (MCM3) is known to have a role on the initiation and regulation of DNA replication during cell cycle. The aim of this study was to evaluate the potential applicability of one of the MCM proteins, MCM3, as a proliferation marker in papillary thyroid carcinoma (PTC) with correlation to clinicopathological parameters. We performed the immunohistochemical analysis for MCM3 and Ki-67 in 60 cases of PTC and Western blot analysis for MCM3 expression in 6 PTCs and normal thyroid tissues. The comparison of MCM3 labeling index (LI) to tumor size ( P = 0.031) and extrathyroidal extension ( P = 0.037) was statistically significant while that of Ki-67 LI to them was not. Moreover, a significant association was not observed between MCM3 and Ki-67, but the MCM3 LI was considerably higher. Western blot analyses revealed that the MCM3 protein expression levels were overexpressed in all PTCs. On the contrary, the levels of MCM3 were very low or absent in all normal thyroid tissues. Our results indicate that MCM3 may be a more reliable proliferation marker than Ki-67 in accessing the growth of tumor and evaluating tumor aggressiveness of PTC.

Rectal enema used for diagnostic and therapeutic purposes infrequently causes colitis. In medical practice, enemas are known to incidentally bring about colitis by mechanical, thermal, or direct chemical injuries. Coffee enema is told to ameliorate the constipation in alternative medicine. We hereby report a case of acute colitis resulting from coffee enema, which was presented with severe abdominal pain and hematochezia.

Background and Objectives: Self renewal, homing or migration and multipotent differentiation are characteristics of stem cell. We studied the effect of stem cell treatments on diabetes complicated with impotencies using human umbilical cord blood stem cells (hUCBSCs). Methods and Results: The patients who had no erection more than 6 months, were not responded to any medication more than 6 months and were waiting penile prosthesis due to type 2 diabetics were participated and number was 5. All had normal laboratory findings except diabetes mellitus related one. Prepared hUCBSCs were ABO, HLA-AB, DR and sex identical to each patient. Total 1.5×10 7 hUCBSCs were infused into both corpus cavernosa. Immune suppression was not done. The blood glucose, medication dose and erection diary were recorded and followed for 9 months. Mean age of participants were 61 (57∼66). The blood glucose dropped from second week, and insulin or hypoglycemic agent doses were reduced in all patients for 6∼7 months. The level of glycosylated hemoglobin was improved from post-treatment for 3∼4 months. The libido was improved and morning erection was regained from 3 weeks. During the follow-up, one patient turned out for prosthesis, two patients were returned to non-erection state at 8 and 9 months and two patients maintained erections with medication. Conclusions: The hUCBSCs has positive effect on blood glucose and erectile dysfunction, although it is not sufficient. We suppose that the stem cell effects might be caused by combination of unknown humoral factors from hUCBSCs and hUCBSCs

Background This study evaluates several tumor-related markers to examine the expression pattern of markers according to the invasiveness and histopathologic differentiation of squamous cell carcinoma and basal cell carcinoma. Methods Ninety-four cases of squamous cell carcinoma and 108 cases of basal cell carcinoma using tissue array in order to determine correlations between the expression of Ki-67, p53, EGFR, CD44v6, MMP-1 and MMP-3, invasiveness and histologic differentiation. In order to determine invasiveness, we measured the depth of invasion in resected tissues. Results The depth of invasion showed a correlation with CD44v6 expression of tumor cell in both squamous cell carcinoma and basal cell carcinoma (P = 0.009, P = 0.036, respectively) and with the MMP-1 expression of stromal cell in squamous cell carcinoma (P = 0.010). The differentiation of squamous cell carcinoma was correlated with Ki-67 index. The loss of palisading arrangement in basal cell carcinoma was correlated with the MMP-1 expression of stromal cells (P = 0.045). Conclusions CD44v6 and MMP-1, expressed in tumor cells and stromal cells respectively, are significant markers associated with the invasiveness of tumors in squamous cell carcinoma and basal cell carcinoma of the skin and that it will be helpful to evaluate the invasiveness by measuring the expression of these markers. J. Surg. Oncol. 2008;97:615–620. © 2008 Wiley-Liss, Inc.

Alterations in beta-catenin degradation cause it to accumulate to immunohistochemically detectable levels in the nuclei of tumor cells. Although it has been shown that nuclear beta-catenin immunostaining is useful for the diagnosis of some mesenchymal tumors, there is little known about beta-catenin expression in endometrial stromal tumors. In this study, nuclear beta-catenin immunoreactivity was evaluated in normal endometrium and endometrial mesenchymal tumors and then compared with that of CD10. The endometrial mesenchymal tumors evaluated included endometrial stromal nodules (n=2), low-grade endometrial stromal sarcomas (n=12), undifferentiated endometrial sarcomas (n=8) and uterine cellular leiomyomata (n=9). In addition, direct DNA sequencing of beta-catenin exon 3 was conducted in 15 endometrial stromal tumors. Normal endometrial stromal cells showed strong cytoplasmic reactivity for CD10 but no detectable reactivity for beta-catenin. Nuclear beta-catenin immunoreactivity was detected in 11 low-grade endometrial stromal sarcomas (92%) and 6 undifferentiated endometrial sarcomas (75%). Ten low-grade endometrial stromal sarcomas (83%) and six undifferentiated endometrial sarcomas (75%) were positive for CD10. Eight low-grade endometrial stromal sarcomas (67%) exhibited diffuse, strong nuclear immunoreactivity with beta-catenin, whereas only four cases (33%) expressed diffuse, strong immunoreactivity with CD10. All nine cases of uterine cellular leiomyomata were completely negative for both CD10 and beta-catenin. beta-catenin mutations were rare in endometrial stromal tumors. Taken together, these results indicate that nuclear beta-catenin immunostaining can serve as a sensitive immunohistochemical marker for the diagnosis of endometrial stromal tumors and is useful for differentiating low-grade endometrial stromal sarcomas from uterine cellular leiomyomata.

Oncogene HCCR-1 functions as a negative regulator of the p53 and contributes to tumorigenesis of various human tissues. HCCR transgenic mice developed breast cancers but it is unknown how HCCR-1 contributes to human tumorigenesis. This study identified a HCCR-1-binding protein 1 (HCCRBP-1) as an HCCR binding partner by performing yeast two hybrid screening. Their endogenous interaction was further confirmed by coimmunoprecipitation experiments. These two proteins colocalized in the mitochondria. HCCRBP-1 was overexpressed in various human tumors. In addition, HCCRBP-1 alone converted NIH/3T3 cells into tumor cells in combination with no other oncogenes. HCCRBP-1 induced tumorigenesis by markedly activating PKC activities but decreasing the pro-apoptotic PKC alpha and PKC delta isoform levels. We observed that p53 stabilization also occurred with functional impairment in HCCRBP-1-transfected 293 cells, as indicated by defective induction of p21, MDM2 and bax. Indeed, HCCRBP-1 decreased p21 promoter activity probably via p53 stabilization leading to the defective function. These results indicate that HCCRBP-1 oncogene induces p53 stabilization and thereby contributes to tumorigenesis.

We analyzed the clinical efficacy and toxicity of concurrent therapy as a first line modality for malignant glioma patients. From 1998 to 2004, 39 patients, 22 with glioblastoma (GM), nine with anaplastic astrocytoma (AA), 7 with anaplastic oligodendroglioma (AO) and 1 with anaplastic oligodendro-astrocytoma (AOA) were enrolled in this study. The median age was 46.2 years (range 8-67). Both external involved field radiotherapy and chemotherapy, composed of CCNU (75-110 mg/m(2)), procarbazine (60 mg/m(2)) and vincristine (1.4 mg/m(2)), were started simultaneously two weeks after surgery. The median progression-free survival time for the GM, AA, and AO patients was 6, 26, and 31 months, respectively. The median survival of the patients with GM and AA was 27 and 41 months. The two-year survival rate of the GM and AA patients was 50.4 and 66.7%, respectively. Grade III/IV hematological toxicity was reduced from 25.6 to 13% after reduction of the dose of CCNU (75 mg/m(2)). Radiation necrosis was confirmed by pathologic examination in four patients (10.3%). The median interval from the completion of radiotherapy to the diagnosis of necrosis was 19 weeks. Modified concurrent chemoradiotherapy may be a feasible option for treating malignant glioma with acceptable toxicity.

Mitochondrial microsatellite instability (mtMSI) and mutations of mitochondrial DNA has been reported in cancer epithelia of carcinomas. However, mtMSI in cancer stroma has not yet been identified in human cancers. In this study, we attempted to determine if mtMSI occurs in the cancer stroma of sporadic colorectal cancers, and if the stromal mtMSI has any correlations with stromal nuclear MSI (nMSI) and cancer epithelial mtMSI. Nine microsatellite sequences within the D-loop and 5 coding genes for mtMSI, and 9 microsatellites for nMSI were analyzed in the microdissected cancer epithelia and adjacent stromas of 48 sporadic colorectal cancers. Overall, 23 somatic mitochondrial DNA alterations were detected in 15 cancer epithelia (31.2%) and 5 stromas (10.4%). The mutations consisted of 19 D-loop mtMSI alterations, and 1 missense and 3 framshift mutations of repeat sequences within the coding genes. All of the 5 stromal genetic alterations showed D-loop mtMSI. In regards to other MSI status, the stromal mtMSI had no association with stromal nMSI or epithelial mtMSI, either. These findings indicate that in addition to the cancer epithelia the cancer stroma harbor mtMSI, and suggest a possible role of stromal mtMSI in the pathogenesis of colorectal cancers. Furthermore, the data suggest that stromal mtMSI may occur independently of stromal nMSI and epithelial mtMSI in sporadic colorectal cancers.

Correlation of disease phenotype with protein profile (proteotype) is a significant challenge for biomedical research. The main obstacles have been the need to insure sufficient quantities of pure protein sample, the reproducibility of protein display, and rapid and accurate protein identification. We present a modified approach that combines enhanced detection sensitivity with tissue microdissection from frozen primary renal cancer tissues of different histological subtypes, followed by 2D gel analysis and protein identification with MALDI mass spectrometry. We obtained reliable and highly consistent results in phenotypically similar tumors of each individual subtype by performing strict morphological control of the analyzed tumor cells without physical or chemical alteration of the frozen tissue samples. By application of non-oxidizing silver staining, proteins were resolved and identified with high levels of specificity and sensitivity. This new combination of techniques allows not only for sensitive identification of specific protein patterns that correspond to a histological tumor phenotype, but also for identification of specific disease-associated protein targets.

Correlation of disease phenotype with protein profile (proteotype) is a significant challenge for biomedical research. The main obstacles have been the need to insure sufficient quantities of pure protein sample, the reproducibility of protein display, and rapid and accurate protein identification. We present a modified approach that combines enhanced detection sensitivity with tissue microdissection from frozen primary renal cancer tissues of different histological subtypes, followed by 2D gel analysis and protein identification with MALDI mass spectrometry. We obtained reliable and highly consistent results in phenotypically similar tumors of each individual subtype by performing strict morphological control of the analyzed tumor cells without physical or chemical alteration of the frozen tissue samples. By application of non-oxidizing silver staining, proteins were resolved and identified with high levels of specificity and sensitivity. This new combination of techniques allows not only for sensitive identification of specific protein patterns that correspond to a histological tumor phenotype, but also for identification of specific disease-associated protein targets.

Purpose: HCCR oncoprotein is reported to be related to tumorigenesis, including breast cancer, functioning as a negative regulator of p53. Mice transgenic for HCCR developed breast cancers. The objective of this study was to validate the HCCR oncoprotein as a candidate biomarker for breast cancer. Experimental Design: HCCR expression in breast cancer cells was analyzed by quantitative PCR, ELISA, immunohistochemistry, Western blotting, fluorescence-activated cell sorting, and confocal microscopy. Epitope areas were determined using mass spectrometry through the analysis of time-dependent tryptic fragment patterns of HCCR. HCCR expression profiles in breast cancer patient sera were analyzed, and correlations with clinicopathologic data and carbohydrate antigen 15-3 (CA15-3) levels were determined. Results: HCCR was up-regulated in breast cancer cells and tissues. The epitope regions of HCCR recognized by monoclonal antibody (BCS-1) were HFWTPK and QQTDFLDIYHAFR. According to fluorescence-activated cell sorting and confocal microscopic analysis, BCS-1 was bound to HCCR antigen on the cell surface. Serum HCCR concentrations were measured using ELISA from 299 subjects, including 129 patients with breast cancer, 24 patients with benign breast disease, and 158 normal volunteers, and comparisons were made to CA15-3. Serologic studies revealed an 86.8% sensitivity for HCCR in breast cancer, which was higher than 21.0% for CA15-3. Eighty-six of 98 (87.8%) patients with breast cancers that were negative for CA15-3 were positive for HCCR-1. A positive response rate of 83.3% was identified even at early stages for pathologic factors in breast cancer. Conclusions: The HCCR assay has an advantage over CA15-3 in diagnosing breast cancer and detecting early stages of the disease.

Object.Von Hippel—Lindau (VHL) disease is characterized by multiple tumors in specific organs. The cell of origin and the reason for the particular organ distribution of the tumors remains unknown. Endolymphatic sac tumor (ELST) is one of the lesions associated with VHL disease. Data from previous studies of VHL disease—associated hemangioblastomas (HBs) and renal cell carcinomas (RCCs) have indicated thatVHLgene deficiency causes coexpression of erythropoietin (Epo) and its receptor (Epo-R), which facilitates tumor growth.Methods.The authors studied ELSTs from five patients with VHL germline mutations. Analysis of the five ELST samples revealed loss of the wild-type allele, consistent with Knudson's two-hit hypothesis for tumorigenesis. All five ELST specimens were characterized microscopically and by immunohistochemical analysis. Coexpression of Epo and Epo-R was found in all five tumors on immunohistochemical studies and confirmed through reverse transcription—polymerase chain reaction and Western blot analysis.Conclusions.Expression of Epo appears to be a result ofVHLgene deficiency, whereas the simultaneous coexpression of Epo-R may reflect a developmental mechanism of tumorigenesis. Coexpression of Epo and Epo-R in ELSTs together with the morphological and genetic similarities of these lesions with other VHL disease—associated tumors indicates that VHL disease—associated tumors in different organs share common pathogenetic pathways.