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Background Periampullary cancers (PAC) including pancreatic, ampulla of Vater (AOV), and common bile duct (CBD) cancers are highly aggressive with a lack of useful prognostic markers beyond T stage. However, T staging can be biased due to the anatomic complexity of this region. Recently, several markers related to cancer stem cells and epithelial-mesenchymal transition (EMT) such as octamer transcription factor-4 (Oct4) and fibroblast growth factor receptor 1 (FGFR1) respectively, have been proposed as new promising markers in other solid cancers. The aim of this study was to assess the expression and prognostic significance of stem cell/EMT markers in PACs. Methods Formalin-fixed, paraffin-embedded tissues of surgically excised PACs from the laboratory archives from 1998 to 2014 were evaluated by immunohistochemical staining for stem cell/EMT markers using tissue microarray. The clinicopathologic parameters were documented and statistically analyzed with the immunohistochemical findings. Survival and recurrence data were collected and analyzed. Results A total of 126 PAC cases were evaluated. The average age was 63 years, with 76 male and 50 female patient samples. Age less than 74 years, AOV cancers, lower T & N stage, lower tumor size, no lymphatic, vascular, perineural invasion and histologic well differentiation, intestinal type, no fibrosis, severe inflammation were significantly associated with the better overall survival High expression levels of FGFR1 as well as CK20, CDX2, and VEGF were significantly related to better overall survival, while other stem cell markers were not related. Similar findings were observed for tumor recurrence using disease-free survival. Conclusions In addition to other clinicopathologic parameters, severe fibrosis was related to frequent tumor recurrence, and high FGFR1 expression was associated with better overall survival. Histologic changes such as extensive fibrosis need to be investigated further in relation to EMT of PACs.

Kikuchi-Fujimoto disease (KFD) is a rare benign lymphadenitis that mainly involves cervical lymph nodes of young Asian women with unknown etiology. Recently, we experienced a case of KFD found with Torque teno virus/Torque teno-like mini virus (TTV/TTMV) from a 26-year-old woman. TTV/TTMV is a genus of Circoviridae that causes necrotizing lymphadenitis in pigs, which shares the key histologic finding of KFD. The purpose of this study is to investigate the pathogenic role of TTV/TTMV in KFD by quantitative polymerase chain reaction (qPCR) analysis.We performed two-step qPCR specific to TTV/TTMV with formalin-fixed paraffin-embedded tissue of sequentially selected 100 KFD patients and 50 randomly selected, matched normal controls. Consequent direct sequencing was done for confirmation with PCR products.PCR amplification of TTV and TTMV was found in a significantly higher proportion in KFDs than normal controls (TTV, 85% vs. 18%, p0.000; TTMV, 91% vs. 24%, p0.000). After the sequencing, KFD samples showed more sequence matching than control samples for TTMV (94% vs. 30%, p0.000).This finding strongly suggests the possible implication of TTV/TTMV in the pathogenesis of KFD. Animal or in vivo experimental design should be followed in the future.Key Points• Kikuchi-Fujimoto disease (KFD) is rare and its etiology is still unclear.• Torque teno/Torque teno-like minivirus (TTV/TTMV) is a recently introduced virus in the Circoviridae family that causes necrotizing lymphadenitis in pigs, histologically similar to KFD.• We discovered the significantly increased TTV/TTMV viral loads in the KFD patients than normal controls, which implicates TTV/TTMV in the pathogenesis of KFD.

Context Mullerian-inhibiting substance/anti-Mullerian hormone (MIS/AMH) is produced in the ovarian granulosa cells, and it is believed to inhibit ovarian folliculogenesis and steroidogenesis in women of reproductive age. Objective To investigate the expression of MIS/AMH type II receptor (MISRII/AMHRII) that binds MIS/AMH in the ovaries of reproductive-age women; to identify the exact targets of MIS/AMH. Design Laboratory study using human ovarian tissue. Setting University hospital. Patients Tissue samples from 25 patients who had undergone ovarian surgery. Interventions The segregation of ovarian granulosa and theca cells by laser microdissection was followed by RT-PCR, analyzing MISRII/AMHRII mRNA expression. Afterward, in situ hybridization and immunohistochemistry were performed to determine the localization of MISRII/AMHRII mRNA and protein expression. Main outcome measures MISRII/AMHRII mRNA expression by RT-PCR, in situ hybridization, and immunohistochemistry. Results MISRII/AMHRII were expressed in granulosa and theca cells of preantral and antral follicles. The granulosa cells showed stronger MISRII/AMHRII expression than theca cells. MISRII/AMHRII mRNA staining of granulosa and theca cells in large antral follicles, early atretic follicles, and corpus luteum waned but were still detected weakly, showing higher expression in theca cells than in granulosa cells. However, MISRII/AMHRII protein in the granulosa layer of the atretic follicle and corpus luteum could not be assessed. Conclusions As MISRII/AMHRII is expressed in both granulosa and theca cells, this indicates that MIS/AMH, produced in the granulosa cells, is active in the theca cells as well. MIS/AMH is most likely actively involved not only in the autocrine and endocrine processes but also in the paracrine processes involving theca cells.

Background: The objective of this study was to investigate the expression of human papilloma virus (HPV) L1 capsid protein in abnormal cervical cytology with HPV16 infection and analyze its association with cervical histopathology in Korean women. Material and Methods: We performed immunocytochemistry for HPV L1 in 475 abnormal cervical cytology samples from patients with HPV16 infections using the Cytoactiv® HPV L1 screening set. We investigated the expression of HPV L1 in cervical cytology samples and compared it with the results of histopathological examination of surgical specimens. Results: Of a total of 475 cases, 188 (39.6%) were immunocytochemically positive and 287 (60.4%) negative for HPV L1. The immunocytochemical expression rates of HPV L1 in atypical squamous cells of unknown significance (ASCUS), low-grade squamous intraepithelial lesions (LSIL), high-grade squamous intraepithelial lesions (HSIL), and cancer were 21.8%, 59.7%, 19.1%, and 0.0%, respectively. LSIL exhibited the highest rate of HPV L1 positivity. Of a total of 475 cases, the multiple-type HPV infection rate, including HPV16, in HPV L1-negative cytology samples was 27.5%, which was significantly higher than that in HPV L1-positive cytology samples (p = 0.037). The absence of HPV L1 expression in ASCUS and LSIL was significantly associated with high-grade (≥cervical intraepithelial neoplasia [CIN] 2) than low-grade (≤CIN1) histopathology diagnoses (p < 0.05), but was not significantly different between HPV16 single and multiple-type HPV infections (p > 0.05). On the other hand, among 188 HPV L1-positive cases, 30.6% of multiple-type HPV infections showed high-grade histopathology diagnoses (≥CIN3), significantly higher than the percentage of HPV16 single infections (8.6%) (p = 0.0004) Conclusions: Our study demonstrates that the expression of HPV L1 is low in advanced dysplasia. Furthermore, the absence of HPV L1 in HPV16-positive low-grade cytology (i.e., ASCUS and LSIL) is strongly associated with high-grade histopathology diagnoses. The multiplicity of HPV infections may have an important role in high-grade histopathology diagnoses (≥CIN3) in HPV L1-positive cases.

The follicular variant of papillary thyroid carcinoma (FVPTC) presents distinct histologic subtypes and molecular genotyping. The preoperative diagnosis of FVPTC through fine-needle aspiration cytology (FNAC) is challenging.We reviewed 59 archival thyroid FNAC specimens of surgically confirmed FVPTC according to histologic subtype: encapsulated FVPTC (n = 30) and infiltrative FVPTC (n = 29). Galectin-3 immunostaining and molecular analyses for BRAF and three RAS genes (NRAS, HRAS, and KRAS) were performed.FNAC diagnoses of FVPTC included benign (5%), atypia of undetermined significance (19%), follicular neoplasm/suspicious for follicular neoplasm (14%), suspicious for PTC (29%), and PTC (34%). Galectin-3 immunostaining was positive in 50% of FNAC specimens. A BRAF mutation was found only in 14 (24%) tumors with the FNAC diagnosis of PTC or suspicious for PTC: 13 cases with the usual c.1799TA (p.V600E) mutation and 1 case with a 3 base-pair deletion (c.1799_1801delTGA), resulting in a deletion of lysine at codon 601 and a deletion c.1799_1801delTGA that results in a valine-to-glutamate substitution at codon 600 (p.V600_K601E) while preserving the reading frame. A BRAF K601E mutation was not found. RAS mutations were observed in 18 (33%) tumors (NRAS, 22%; HRAS, 6%; KRAS, 6%). Mutations of the three RAS genes were detected in codon 61 but not in codons 12 and 13. There was a decreasing trend of RAS mutation rates associated with an increasing risk of malignancy in the FNAC diagnostic categories. The triage efficacy of FNAC to make a recommendation for surgery was 73% for encapsulated tumors and 79% for infiltrative tumors. Addition of galectin-3 or the BRAF test to FNAC showed no significant improvement in the triage efficacy. However, RAS mutations significantly improved the triage efficacy of FNAC. There was no significant difference in the triage efficacy of FNAC, galectin-3 expression, and the prevalence of somatic mutations between encapsulated and infiltrative tumors.Thyroid FNAC has a low sensitivity for the detection of FVPTC regardless of histologic subtype. Encapsulated FVPTC and infiltrative FVPTC have similar molecular profiles and rates of galectin-3 expression. RAS mutational analysis is more useful than BRAF testing to improve the triage efficacy of FNAC for FVPTC.

Objective We report a case of intramural florid cystic endosalpingiosis in the lower uterine segment of the uterus. Case report A 43-year-old female presented with vaginal bleeding. Abdominal computed tomography suggested a leiomyoma with cystic degeneration. A total hysterectomy revealed a 4.0 cm × 3.8 cm cystic mass in the lower uterine segment. The cystic space microscopically was lined with a single layer or stratified layer of ciliated columnar cells that resembled tubal epithelium without cytologic atypia. The glandular spaces were surrounded by normal myometrium with no evidence of periglandular endometrial stroma, which was consistent with the diagnosis of florid cystic endosalpingiosis. Conclusion Florid cystic endosalpingiosis involving the uterus is a rare and clinically unexpected finding; however, it should be considered in the differential diagnosis of a uterine mass.

Cancer stem cells are thought to be responsible for tumor recurrence and resistance in glioblastomas. An isocitrate dehydrogenase1 (IDH1) mutation, affecting codon132 of the isocitrate dehydrogenase1 gene, has prognostic significance in glioblastomas. We investigated whether stem cell marker expression [CD133, CD34, and vascular endothelial growth factor (VEGF)] and IDH1 mutation correlate with clinical factors and prognosis in glioblastoma. CD133, CD34, and VEGF expression was evaluated by immunohistochemistry in 67 cases of glioblastoma identified between 2005 and 2012. IDH1 mutation was assessed by immunohistochemistry, peptide-nucleic-acid mediated PCR clamping, and direct gene sequencing. Diffuse CD133 expression was detected in 12 (17.9 %) cases and was associated with poor overall survival (OS) (P = 0.010) and progression-free survival (P = 0.017). CD34 and VEGF expression were not associated with prognosis in these samples. IDH1 mutation was detected in ten (14.9 %) cases. Eight were clinically secondary tumors and two were primary tumors (P

Meningiomas are slow-growing neoplasms that recur locally. Their morphologic grading does not always correlate with patient outcome. We evaluated the status of several immunohistochemical markers with histopathologic parameters in various grades of meningioma.Eighty-eight meningioma specimens were examined immunohistochemically to determine the status of Ki-67, cyclin D1, epidermal growth factor receptor (EGFR), cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), and bcl-2. Several clinical and pathological parameters were investigated.Forty-nine Grade I, 33 Grade II, and 6 Grade III meningiomas were observed. VEGF and Ki-67 expression was correlated with higher tumor grade. The association between grade and other immunohistochemical markers expression was not significant. A correlation was observed between COX-2 expression and invasiveness to the brain or adjacent soft tissue. Tumor recurrence was correlated with brain or adjacent soft tissue invasion. We also observed a relationship between VEGF level and COX-2 expression, and they were both correlated with necrosis.Immunohistochemical evaluation of VEGF, COX-2, and Ki-67 expression can provide information regarding the behavior of meningiomas, particularly for cases in which histological grading is not straightforward.

Perivascular epithelioid cell tumor (PEComa) is a rare collection of tumors arising in a wide array of anatomic locations. It is characterized by the presence of a peculiar population of myomelanocytic marker-positive perivascular epithelioid cells, and is commonly detected in the uterus. The colorectal area is an uncommon site for primary PEComa. In this study, we describe a 17-year-old patient presenting with a rectal polyp. Histologically, the tumor consisted of sheets of round to polygonal epithelioid cells with clear and granular cytoplasm, and a prominent capillary network. Some of the tumor cells were positive for Fontana-Masson staining. Immunohistochemically, the tumor cells were positive for HMB-45, and were negative for cytokeratin, vimentin, S-100 protein, actin, desmin, EMA, CD34, and c-kit. After finding melanosomes or premelanosomes at the ultrastructural level, the diagnosis of PEComa was made. Although PEComa arising within the intestinal tract is unusual and clinically unexpected, PEComa should be considered in the differential diagnosis of rectal polypoid lesions.

Objectives: The trefoil factor family (TFF) is composed of three thermostable, and protease-resistant proteins, named TFF1, TFF2 and TFF3, and plays a role in gastrointestinal mucosal defence and repair. Recently, TFFs have been found to be related to the development of various types of cancer. This study assessed the relationship between the expression of TFF1 and TFF3 and the clinicopathological parameters in gastric carcinoma (GC). Materials and Methods: The expression of TFF1 and TFF3 was analyzed by immunohistochemistry in 292 GCs and 20 normal gastric tissues. Results: All normal gastric tissues expressed TFF1, but 53.8% of GCs showed reduced TFF1 expression. However, TFF3 was not detected in normal gastric tissues and 44.2% of GCs showed a high level of expression. Highly expressed TFF3 was significantly correlated with lymph node metastasis, lymphatic invasion, vein invasion, and advanced stage. The overall survival was shorter in patients with high expression of TFF3 than in those with low expression of TFF3 in 292 GCs and in 125 early GCs (EGCs). Moreover, in patients with EGCs, high expression of TFF3, associated with reduced expression of TFF1, was determined as an independent poor prognostic marker. Conclusions: Reduced expression of TFF1 and increased expression of TFF3 may play a role in the carcinogenesis of gastric cancer. Furthermore, high expression of TFF3 with reduced expression of TFF1 may be a marker of poor prognosis for patients with EGC.

We investigated the relationship between frequently deregulated microRNAs (miRNAs) and enodometrial pathology in an attempt to find the most dependable miRNA or combination of miRNAs to identify normal, hyperplastic and malignant endometrial tissues. We also investigated the association between those miRNAs and PTEN status. We measured the expression of six miRNAs (miR-21, 182, 183, 200a, 200c and 205) in 75 formalin-fixed, paraffin-embedded normal, hyperplastic, and malignant endometrial tissue blocks using Taqman-based real-time PCR assays. PTEN loss of expression was assessed in the same endometrial tissues by immunohistochemistry. Expression of five miRNAs (miR-182, 183, 200a, 200c and 205) was significantly higher in endometrial carcinoma (CA) when compared with complex atypical hyperplasia (CAH), simple hyperplasia (SH) and normal endometrial tissue (P

The American Joint Committee on Cancer has proposed the tumor, node, metastasis (TNM) staging system to overcome the limitations of the Ann Arbor staging system for ocular adnexal lymphoma. We performed this study to evaluate the feasibility of the TNM staging system for ocular adnexal extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (OAML). The data form 66 total eyes from 54 patients with biopsy-confirmed OAML according to World Health Organization classification were retrospectively analyzed. Using the TNM staging system, we reclassified all patients into two categories: (1) T1N0M0 stage group (n = 26), for patients with lymphoma involving only the conjunctiva; and (2) above T1N0M0 or bT1N0M0 stage group (n = 28), for patients with lymphoma extending to the orbit, eyelid, or adjacent structures, and/or bilateral OAML. After a 24-month median follow-up period for all patients, the T1N0M0 group revealed higher progression-free survival (PFS) than the above T1N0M0 or the bT1N0M0 group (P = 0.041). In a separate analysis of only 50 patients categorized as Ann Arbor stage IE, the T1N0M0 group demonstrated higher PFS (100%) than the above T1N0M0 or the bT1N0M0 group (84.7%; P = 0.067). Our data show that the poor prognostic group classified as Ann Arbor stage IE can be further distinguished by using the TNM staging system. Thus, further studies to develop treatment strategies for reducing relapse after treatment for OAML should use the TNM staging system.

While fine-needle aspiration cytology (FNAC) using conventional smear has been widely accepted as the primary diagnostic tool for thyroid lesions, liquid-based preparations (LBPs) are increasingly replacing it. A new automated LBP method, EASYPREP(®) (EP), was recently introduced and has shown relevant diagnostic efficacy in gynecologic samples. We compared the diagnostic utility of EP and SurePath(®) (SP), a more widely established LBP method, in thyroid FNAC.Under the ultrasonographic guidance, 253 thyroid FNAC samples were collected by sample-splitting manner. Three pathologists made cytologic diagnoses of EP and SP according to the Bethesda system independently and compared the cytomorphologic parameters. Cytohistologic correlation was performed in 30 resected cases.Fifteen (5.9%) and 21 (8.3%) samples were unsatisfactory in SP and EP, respectively, owing to the unequal sample-splitting. Cytologic diagnoses of SP and EP were consistent in 228 cases (90.1%), and inconsistent in remainder mostly owing to the unequal distribution of pathognomic cells. While cytomorphologic parameters were not significantly different between two methods, EP showed less three-dimensional configuration in benign lesions. Cytohistologic correlation showed no significant differences in sensitivity (100% vs. 95.5%) and specificity (100% vs. 100%) between SP and EP. Labor time for processing 48 cases was 42% shorter with EP than with SP (28 min vs. 48 min).The diagnostic utility of EP in thyroid FNAC was comparable to that of SP. EP allowed better visibility owing to better fragmentation of follicular clusters. The automated system of EP has the advantages of a shorter labor time for batch processing. Diagn. Cytopathol. 2016;44:283-290. © 2016 Wiley Periodicals, Inc.

Transforming acidic coiled-coil containing protein 3 (TACC3) is known to be involved in the control of normal cell growth and differentiation and in mechanisms of unregulated growth leading to tumorigenesis. The aim of the present paper was to determine the rate of TACC3 expression in a non-small cell lung cancer (NSCLC) collection and to clarify its correlation with clinicopathological parameters. A total of 163 NSCLC were analyzed immunohistochemically using a polyclonal TACC3 antibody and monoclonal p53 and Ki-67 antibodies on NSCLC tissue microarrays. A high level of TACC3 expression was observed in 14.8% of cases, preferentially squamous cell carcinomas. Patients whose tumors had a high TACC3 expression had a significantly shorter median survival time. In the Cox regression-based multivariate analysis, TACC3 expression proved to be an independent prognostic parameter (P = 0.031). TACC3 expression was correlated with p53 expression, and patient whose tumors highly expressed TACC3 and p53 had a significantly poorer prognosis than patients whose tumors had low-level expression for both immunostainings (P = 0.006). It is suggested that increase in TACC3 may impart a proliferative advantage to NSCLC and contribute to tumor progression, and that TACC3 expression is a strong prognostic indicator of clinical outcome in NSCLC.

Chronic tubulointerstitial injury (CTI), commonly a sequel to chronic glomerulonephritis (CGN), is associated with the proliferation of new blood vessels. Angiogenesis is an essential process in chronic inflammation, and is controlled by a number of angiogenic factors including thymidine phosphorylase (TP). Knowledge of TP in renal disease is still rudimentary, and its role in CGN has not been explored. We analyzed the expression of TP by RTPCR, immunohistology and in situ hybridization in 20 human kidneys with CGN. To evaluate the degree of angiogenesis, we counted the microvessel density (MVD). MVD was significantly higher in all categories of CGN, between 19.7 ± 7.7 and 58.9 ± 7.5, compared to control value, 12.7 ± 5.0 (p< 0.05). MVD was increased in areas of abundant mononuclear cell infiltration with minimal interstitial fibrosis, and decreased or absent in areas of marked fibrosis. There was a significant correlation between MVD and interstitial fibrosis (p < 0.0001). TP mRNA was upregulated for all categories of CGN. TP was strongly expressed by mononuclear inflammatory cells and in most atrophic tubules. Each MVD and interstitial volume was significantly correlated with both the number of TP+ mononuclear cells and TP+ tubular cells, respectively (p < 0.0001). We have demonstrated an upregulation of TP and increase in MVD in areas of CTI in a variety of CGN. The up-regulation of TP may contribute to angiogenesis, which may play a critical role in the progression of interstitial fibrosis in CGN.

The initial aim of this study was to examine the expression profiles of P53 and its upstream genes, downstream genes, and cell cycle regulators to determine whether these markers are useful for making a differential diagnosis among the benign, borderline, and malignant ovarian epithelial tumors. Between borderline and malignant tumors, the increased expression levels of P53, Bax, Cyclin E, and cyclin-dependent kinase-2 as well as the decreased expression levels of growth arrest and DNA damage (GADD45) and murine double minute-2 (MDM2) were significantly associated with malignancy (P0.01, each). Using the receiver operating curve (ROC), the most reliable cutoff value of the added-up staining scores of those markers was 4.5 with 79% sensitivity and 89% specificity for malignancy. Between benign and borderline tumors, the P21 and Bax expression levels were significantly higher in borderline tumors, whereas the Bcl-2 expression level was much higher in benign tumors (P0.01, each). Using the ROC, the cutoff value of the added-up staining scores used to discriminate between the two groups was 2.5 with 70% sensitivity and 74% specificity for borderline tumors. Thus, for the differential diagnosis between borderline and malignant tumors, the cutoff value 4.5 of the cumulative staining scores can be used. However, the cutoff value 2.5 for discrimination between benign and borderline tumors may not be useful because of its relatively low sensitivity and specificity. In addition, the P53, GADD45, Cyclin E, and MDM2 expression levels in malignant ovarian tumors might be useful for determining the histologic grade and type.

Granulomas in gastric biopsy specimens are extremely rare, and in Western countries, more than half are associated with Crohn's disease. To evaluate the incidence and their etiology in a gastric carcinoma (and Helicobater pylori infection)-prevalent area, gastric mucosal biopsies were reviewed and their clinicopathologic findings were analyzed. The clinicopathologic diagnoses of the 18 patients with granulomatous gastritis were as follows: chronic gastritis with (n = 14) and without (n = 1) H. pylori infection; gastric adenocarcinomas (n = 2); and Crohn's disease (n = 1). Almost all cases of granulomatous gastritis in this study showed small erosions or ulcers on the endoscopic examinations. H. pylori were found to be one of the most common causes of granulomatous gastritis after excluding all other causes for the granulomas in this study. The granulomas were more frequently found in the antrum, superficially located, and were related to damage within a pit in which the H. pylori were commonly observed. These findings suggest that H. pylori can be causal in the pathogenesis of granulomatous gastritis.

Determining of HER-2/neu oncogene amplification has become clinically important for managing breast cancer. Fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC) are currently regarded as the standard methods. Chromogenic in situ hybridization (CISH) was investigated as a new modification with an accurate, sensitive technique. From 1998 to 2002, using CISH and IHC, the amplification and protein expression of the HER-2/neu oncogene were examined using paraffin sections in 130 breast carcinomas and to determine the prognostic role of HER-2/neu for outcome after a follow-up of 24- 64 months. Amplifications by CISH and overexpression by IHC were observed in 28 (22%) and 27 cases (20.8%), respectively. Of the 104 patients, 20 patients (19.2%) with amplification had a shorter disease-free interval (34.9 months vs. 38.0 months in controls) (p=0.372). 15 patients (14.4%) had a disease recurrence, but there is no significant difference between 3 patients amplifying the oncogene and 12 patients without oncogene (20.6 months vs. 19.6 months) (p=0.862). 6 patients (5.8%) of these died. CISH is a useful alternative, particularly for confirming the IHC results. There is no relationship between the early recurrence and the HER-2/neu positive group, but lymph node status was statistically significant.

The new BDProbeTec ET System (BDET; BD Biosciences, Sparks, MD) was compared with the Roche COBAS AMPLICOR System (CAS) and culture for Mycobacterium tuberculosis (MTB). A total of 253 specimens (152 respiratory and 101 pleural fluid specimens) collected from 240 patients were tested in parallel with the 3 assays. After resolving the discrepancies, the sensitivity, specificity, and positive and negative predictive values of the BDET for detecting MTB was 76.9%, 93.7%, 71.4%, and 95.2% for the respiratory specimens and 88.9%, 92.4%, 53.3%, and 98.8% for the pleural fluid specimens, respectively. The corresponding values of the CAS were 69.2%, 100%, 100%, and 94% for the respiratory specimens and 33.3%, 100%, 100%, and 93.9% for the pleural fluid specimens, respectively. No significant differences in sensitivities were observed between the results of both assays for the respiratory specimens. However, statistically significant differences in sensitivities were found between the BDET and CAS for the pleural fluid specimens (P = .02). Although the BDET was less specific than the CAS (P = .007), the BDET has an excellent sensitivity for detecting MTB in the pleural fluid specimens. Considering the low sensitivity of other available tests, the BDET can be a useful diagnostic tool for excluding MTB, particularly in the pleural fluid specimens.

Telomerase is an RNA-dependent DNA polymerase that synthesizes TTAGGG telomeric DNA onto chromosome ends to compensate for sequence loss during DNA replication. It has been detected in 85–90% of all primary human cancers, implicating that the telomerase seems to be reactivated in tumors and that such activity may play a role in the tumorigenic process. The purpose of this study was to evaluate telomerase activity, human telomerase RNA (hTR), and telomerase reverse transcriptase (TERT) in stomach cancer and to determine their potential relationships to clinicopathologic parameters. Frozen and corresponding methacarn-fixed paraffin-embedded tissue samples were obtained from 51 patients with gastric adenocarcinoma and analyzed for telomerase activity by using a TRAPeze ELISA kit. Tissue sections of all the samples were further investigated for hTR and TERT by in situ hybridization and a sensitive immunohistochemical technique, respectively. Telomerase activity was detected in 37 (73%) tumors. Telomerase positivity from methacarn-fixed paraffin blocks was found to be 35% of that from frozen tissues. hTR was overexpressed in 46 (90%) samples: 33/37 (89%) with and 13/14 (93%) without telomerase activation. Expression of TERT was demonstrated in 40 (78%) cases: 30/37 (81%) with and 10/14 (71%) without telomerase. Telomerase activity correlated well with depth of invasion (P = .037) and tumor differentiation (P = .022), whereas hTR significantly correlated with nodal metastasis (P = .047) and tumor size (P = .023). These data suggest that reactivated telomerase may play a significant role in the tumorigenesis of gastric cancer and may reflect, along with enhanced hTR, the malignant potential of the tumor. It is noteworthy that methacarn-fixed tissue cannot as yet substitute for the frozen section in the TRAP assay.

BACKGROUND: A new flow cytometric monocyte phagocytic assay (FMPA) was developed with 5-chloromethyl fluorescein diacetate (CMFDA)-labeled platelets for predicting the outcome of platelet transfusion. STUDY DESIGN AND METHODS: Twelve patients with a history of multiple platelet transfusions and 21 controls were enrolled in this study. Platelets labeled with CMFDA were incubated with patient serum and then incubated with monocytes. They were then analysed by flow cytometry. Monocytes that had phagocytized platelets (%) were detected as a CMFDA-positive platelet population with a CD14+ monocyte gate. The performance of FMPA was evaluated in 29 transfusions by 1- and 24-hour CCIs and platelet crossmatching. RESULTS: FMPA results were well correlated with 1-hour (r = −0.818, p = 0.001) and 24-hour (r = −0.782, p = 0.001) CCIs. In the group with high FMPA results (mean ± SD, 79.1 ± 7.3%), nine of 10 positive crossmatches revealed low CCIs, and six of seven negative crossmatches revealed high CCIs. The CCI predictability of crossmatching in the group with high FMPA results was high (88.2%). In the group with low FMPA results (mean ± SD, 34.6 ± 7.8%), all 12 transfusions revealed high CCIs even though in four transfusions there were positive results in both platelet antibody testing and platelet crossmatching. CONCLUSION: FMPA is designed with near in vivo conditions to measure an immune response to transfused platelets, including phagocytosis. This is a useful method for predicting the outcome of platelet transfusion.

Oncogenic osteomalacia is a rarely described clinical entity characterized by hypophosphatemia, phosphaturia, and a low concentration of 1,25-dihydroxyvitamin D 3 . It is most often associated with benign mesenchymal tumor and can be cured with surgical removal of the tumor. In this paper, we present a case of oncogenic osteomalacia caused by chondromyxoid fibroma in the soft tissue of the sole of the foot in a 56-year-old woman.

Various haematological and immunological studies on patients infected with Plasmodium vivax were undertaken, at diagnosis (day 0), after treatment with chloroquine but during primaquine treatment (day 10) and after all treatment (day 59), in South Korea (where there has been a recent and abrupt increase in the incidence of such infection). The main aims were to gain an understanding of the haemato-immunological alterations of this malarial infection, both before and after treatment, and to identify at least one useful marker for the diagnosis and post-treatment monitoring of P. vivax malaria. Thirty-eight patients with P. vivax malaria were compared with 20, apparently healthy controls. At diagnosis, the patients had lymphopenia, marked eosinopenia (the eosinophil count being correlated with the platelet count) and thrombopenia. Cells of most of the lymphocyte subsets investigated [i.e. CD3 + , CD8 + , CD19 + , CD56 + , CD3 - /CD56 + and CD8 + /CD56 + but not CD4 + , CD3 + /CD56 + or CD25 + ] were significantly less common among the lymphocytes of patients at diagnosis than among those of the controls. After initiating treatment, the numbers of CD19 + lymphocytes gradually increased (to normal values by day 59), whereas those of CD3 + /56 lymphocytes remained abnormally low throughout the follow-up period. The proportions of lymphocytes identified as CD4 + appeared to be unaffected by treatment. Although serum concentrations of IgE (and, to a lesser extent, IgM) were elevated in the patients at diagnosis, they were subnormal on day 10 post-treatment and normal at the day-59 follow-up. Serum concentrations of IgG and IgA in the patients were always found to be similar to those in the controls. At diagnosis the serum concentrations of complements C3 and C4 were significantly elevated in the patients. C3 remained at the same high concentration during follow-up but the concentration of C4, like that of IgE, was found to be subnormal on day 10 and normal 7 weeks later. The level of parasitaemia (%) was only found to be significantly correlated with haemoglobin concentration. The observation of eosinopenia with elevated IgE and C4 could be a useful indicator of P. vivax malaria, and treatment response could be followed by serial monitoring of serum concentrations of IgE and C4.

Liver dysfunction is a common problem in BMT recipients and it is important to determine the etiology in order to institute appropriate therapy. The purpose of this study was to evaluate the possible causes of liver dysfunction during the first post-transplant year in BMT recipients and to identify a possible relationship between pre-existing liver dysfunction and viral hepatitis with prognosis after BMT. We reviewed liver status before and after BMT in 130 consecutive patients at the Catholic Hematopoietic Stem Cell Transplantation Center. Liver dysfunction during the first post-transplant year occurred in 85 out of 101 (84.2%) allogeneic BMT recipients and 13 out of 29 (44.8%) autologous BMT recipients. In allogeneic BMT, GVHD and drug hepatotoxicity were major causes. In autologous BMT, drug hepatotoxicity was the most common cause. Eighteen out of 130 patients (13.8%) had abnormal liver function tests before BMT. These patients did not have an increased risk of post-transplant liver dysfunction, GVHD, and death compared to patients who had normal liver function tests prior to BMT. Nine patients were hepatitis B antigen positive and three patients were anti-HCV positive prior to BMT. There was no significant increase in the incidence of post-transplant liver dysfunction, GVHD, and death in these patients. Bone Marrow Transplantation (2000) 26, 193–197.

Objectives: Tumor hypoxia confers poor prognosis of a wide range of solid tumors due to increased malignancy, increased likelihood of metastasis and treatment resistance. The aim of this study was to assess the significance of the expression of HIF-1α and HIF-1α-inducible proteins in gastric cancer and their impact on prognosis. Materials and Methods: The expression of HIF-1α, GLUT-1, CA-9, and iNOS proteins was analyzed by immunohistochemistry in 193 gastric adenocarcinomas (GAs) and 20 normal gastric mucosa. Results: HIF-1α, GLUT-1, CA-9 and iNOS were expressed in 52.3%, 43.0%, 57.0%, and 43.0% of GAs, respectively, which are higher than the normal counterparts except for CA-9. HIF-1α expression was positively correlated with the expression of GLUT-1, CA-9 and iNOS. GLUT-1 expression was higher in the intestinal type (p = 0.012); however, iNOS expression was higher in the less-differentiated type and the diffuse type (p = 0.006, p = 0.032, respectively). The expression of HIF-1α and GLUT-1 was significantly correlated with lymph node metastasis (p = 0.009, p = 0.008, respectively), while the expression of GLUT-1 and iNOS was significantly correlated with the depth of invasion and advanced stage (p = 0.044, p = 0.004; p = 0.009, p = 0.008, respectively). Overall survival was shorter in patients with GLUT-1 expression than in those without GLUT-1 expression, which was statistically significant by univariate analysis (p = 0.042). On multivariate analysis, however, stage was determined as the only independent prognostic marker (p < 0.001). Conclusions: Our data suggest that overexpression of HIF-1α, GLUT-1, and iNOS may play an important role in gastric cancer progression. GLUT-1 is a potential candidate for predicting patient survival.

We studied 14 adult patients presenting with fever and cytopenia of the peripheral blood and histiocytic hyperplasia with hemophagocytosis (HHH) in the bone marrow regarding an association of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) by using in situ hybridization (ISH) and also evaluated the clinical and laboratory findings according to the encountered organisms. ISH using a CMV RNA probe demonstrated infected cells in 6 out of 14 cases (43%), and ISH using an EBV EBER RNA probe demonstrated infected nuclei in 5 out of the same 14 cases (36%) of HHH. No cases showed a positive reaction with both probes. Three cases showed a negative reaction with both probes. The mean age of all patients was 29 years; and that of the CMV-positive patients was 27 years and that of the EBV-positive patients was 36 years. Organomegaly was found in 3 out of 6 CMV-positive patients (1 hepatomegaly, 1 splenomegaly, 1 hepatosplenomegaly), and 4 out of 5 EBV-positive patients (lymphadenopathy in all 4 cases, hepatosplenomegaly in 2 cases). One of the CMV-positive case had acute myeloblastic leukemia, and 2 EBV-positive cases had underlying malignancy (1 Hodgkin's disease, 1 non-Hodgkin's lymphoma). Seven out of the 14 HHH cases (50%) died within several months after diagnosis. Nucleic acid hybridization methods can be used for the routine examination of the association of CMV or EBV.

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.

The tall cell variant (TCV) of papillary thyroid carcinoma (PTC) is the most common among the aggressive variants of the disease. We aimed to investigate the clinicopathologic characteristics of TCV, and evaluate the diagnostic efficacy of liquid-based cytology (LBC) in TCV detection compared with conventional smear in thyroid fine needle aspiration (FNA). A total of 266 consecutive patients (220 women and 46 men) with PTC were enrolled. We analyzed tumor characteristics according to histologic growth patterns as classic, classic PTC with tall cell features, and TCV. The cytomorphologic features of these subtypes were investigated according to the preparation methods of conventional smear and LBC. TCV and classic PTC with tall cell features comprised 4.9% and 6.0% of all tumors, respectively, and were significantly associated with older age at presentation, larger tumor size, high frequency of extrathyroid extension, and BRAF mutation in comparison with classic PTC. However, there was no statistically significant difference in clinicopathologic features between TCV and classic PTC with tall cell features. Tall cells were more easily detected by LBC than by conventional smear. The percentage of tall cells identified using LBC was well correlated with three histologic subtypes. Our results demonstrate that TCV is more common than previously recognized in Korea and any PTC containing tall cells may have identical biological behavior regardless of the precise proportions of tall cells. It is possible to make a preoperative diagnosis of TCV using LBC.

The BRAFV600E mutation has been reported to occur in 30% to 80% of papillary thyroid carcinomas (PTCs). Although direct sequencing is the method most commonly used to identify mutations, this technique is not sensitive enough to accurately detect low level mutation. To determine the optimal diagnostic method for detecting the BRAFV600E mutation in PTC, we compared the diagnostic efficacy of four representative detection methods in formalin-fixed paraffin-embedded thyroid tissues obtained from 40 patients diagnosed with PTC. To detect the BRAFV600E mutation, we amplified exon 15 of the BRAF gene and performed mutational analysis with direct sequencing, denaturing high-performance liquid chromatography (DHPLC), pyrosequencing and colorimetric assay. The BRAF mutation was detected in 33 cases (82.5%) by DHPLC, 23 cases (57.5%) by direct sequencing, 22 cases (55.0%) by pyrosequencing, and 37 cases (92.5%) by colorimetric assay. The sensitivity, negative predictive value and accuracy of DHPLC were 100%. The specificity and positive predictive values for DHPLC, direct sequencing and pyrosequencing were 100%, and for colorimetric assay they were 14.3% and 83.8%, respectively. The kappa value for DHPLC was a perfect 1.0, which was superior to the other methods. In conclusion, DHPLC is a sensitive, specific and accurate method for detecting the BRAFV600E mutation, especially low level mutation, in PTC.

This study aimed to analyze expression of Mullerian inhibiting substance type II receptor (MISRII) protein and mRNA in cervical neoplasia, to demonstrate the growth inhibition of cervical cancer cells by administration of highly purified recombinant human Mullerian inhibiting substance (MIS) and, furthermore, to evaluate the clinical significance of MIS as a biological modifier for MIS receptor expressing tumors. Reverse transcriptase polymerase chain reaction (RT-PCR) was used for MISRII mRNA expression, and in situ hybridization and immunohistochemistry were used to observe expression, location of MISRII mRNA and protein, respectively. To demonstrate the effect of MIS on the viability of cervical cancer cells, methyl thiazole tetrazolium (MTT) assay was performed. Flow cytometry was used to evaluate the cell cycle distribution after exposure to MIS in cervical cancer cells, and the annexin-V-FITC staining method was performed to demonstrate apoptosis by MIS in cervical cancer cells. Expression of MISRII protein and mRNA were observed in all normal cervical and cervical carcinoma tissues. There was no significant difference in expression of MISRII protein and MISRII mRNA between normal cervical and cervical carcinoma tissues. MTT assay showed negative correlation between MIS exposure time and the viability of cervical cells (P=0.008). The changes in cell cycle distribution after MIS exposure suggest that MIS plays an important role in inducing cellular apoptosis by causing arrest at the G1 phase and increasing cells at sub-G0G1 phase. Annexin-V-FITC staining methods showed that cellular apoptosis was, respectively, 10.44 and 12.89% after 24 and 48 h of MIS exposure in cervical carcinoma cells. There was a negative correlation between cellular survival and MIS exposure time. This study demonstrates that MISRII is present on normal cervical and cervical carcinoma tissues, and MIS shows receptor-mediated antiproliferative effect on cervical cells in vitro. These data suggest that MIS may be used as a biological modifier or therapeutic modulator on MISRII-expressing tumors in the future.

Fluorescence in situ hybridization (FISH) with chromosome-specific probes was used to study cytogenetic changes in five cases of leiomyosarcoma (LMS) and nine cases of uterine leiomyoma (LM). Biotinylated DNA probes for the centromeric regions of chromosomes 1, 6, 8, 9, 17, and 18, painting probes for chromosomes 1 and 22, and the cosmid probe for chromosome region 21q22.3 were used on nuclei isolated from paraffin blocks. Four of five LMS cases revealed major chromosomal aberrations, while the only case with minor clonal aberrations was subsequently found not to be a typical LMS. The most common numerical aberrations found in the LMS cases were extra copies of chromosome 8 (three of five cases), loss of chromosome 1 (three of five cases), and loss of chromosome 6 (two of five cases). One of two LMS cases studied with a chromosome 1 painting probe demonstrated translocations of chromosome 1. In contrast to LMS, only five of nine uterine LM cases had abnormal clones, and these were smaller than those in LMS. Two LM cases showed 9% tetrasomy 8 with 17 or 20% monosomy 6, and three other cases had monosomy 6 clones in 18-34% of cells. These results indicate that typical LMS is characterized by multiple chromosomal aberrations affecting most of the cells, whereas borderline LMS and LM have fewer affected chromosomes and less clonal involvement.

Background AIB1 (amplified in breast cancer I) is a member of the p160 steroid receptor coactivator family. AIB1 is frequently overexpressed in breast cancer and has functions that promote oncogenesis that are independent of estrogen receptor (ER) coactivation. We investigated prognostic significance of AIB1 and relationship between AIB1 and ER, progesterone receptor (PR), androgen receptor (AR), DAX-1, and HER2. Methods RNA in situ hybridization (ISH) and immunohistochemical (IHC) staining for AIB1, IHC staining for ER and the progesterone receptor (PR) and IHC staining and silver in situ hybridization (SISH) for HER2 were performed for 185 breast cancer cases. Results A high level of expression of AIB1 mRNA was observed in 60.0% of tumors. IHC analysis detected AIB1 positivity in 47.3% of tumors, which did not correlate with AIB1 mRNA expression (p = 0.24, r = 0.10). AIB1 protein expression correlated with AR and DAX-1 expression (p = 0.01, r = 0.22 and p = 0.02, r = 0.21, respectively) but not with ER or PR expression (p = 0.14, r = -0.13 and p = 0.16, r = -0.12, respectively). AIB1 protein expression correlated with the amplification of the HER2 gene (p = 0.03, r = 0.19). In contrast to AIB1 protein expression, AIB1 mRNA expression did not correlate with AR, DAX-1, ER, and PR expression, and the amplification of the HER2 gene (p > 0.05 for all). There were trends that strong AIB1 protein expression correlated with poorer disease free survival (p = 0.07). Strong AIB1 protein expression correlated with poorer overall survival (p = 0.04). Among the ER-negative subgroup, strong AIB1 protein expression correlated with poorer disease free survival and overall survival (p = 0.01 and p < 0.01, respectively). Conclusions Strong AIB1 protein expression was poor prognostic factor in breast cancer, especially in ER-negative breast cancers. Further investigation is essential to determine whether AIB1 might be effective therapeutic targets for ER-negative breast cancers.

Lymph node metastasis (LNM) is recognized as an important factor in the progression of tumor malignancy. It is required to discover molecular markers for the prediction of LNM in gastric cancers (GCs).An isotope coded affinity tag (ICAT) method and mass spectrometry were used for the quantitative profiling of LNM-related proteins. Western blot analysis of the identified proteins and immunohistochemistry on a tissue microarray comprising 120 GC cases were performed for validation.We identified 151 differentially expressed proteins (DEPs) with an abundance ratio greater than 1.5-fold. The proteins upregulated in LNM-negative GCs were largely populated with proteins related to cell death. Among the DEPs, galectin-2 was further tested because its expression level was significantly higher in LNM-negative GCs (~12-fold, p 0.0001) and its expression is known to be not ubiquitous but confined to the gastrointestinal tract. Immunohistochemical analysis revealed that low expression of galectin-2 was significantly associated with LNM (p = 0.031) and advanced clinical stage (p = 0.024). The association of low galectin-2 with LNM was found even in early GCs (p = 0.020).Our results show that proteomic analysis coupled with immunohistochemistry using tissue microarray is a useful tool for identifying LNM-associated proteins in GC. Also, loss of galectin-2 might play an important role in the aggressiveness of GC.

The calcium-binding protein S100A4 promotes tumor progression and metastasis. We investigated the expression of S100A4 in colorectal cancer and its clinicopathologic significance in colorectal cancer.A total of 526 colorectal cancer patients were examined for S100A4 protein by immunohistochemistry using tissue microarrays. S100A4 mRNA was subsequently investigated by in situ hybridization.S100A4 protein was expressed in various cell types including tumor cells, but S100A4 mRNA was only expressed in tumor cells. Cytoplasmic expression of S100A4 protein was seen in 127 (24.1%) of 526 tumors and significantly correlated with older age, depth of invasion, lymph node metastasis, and worse overall survival. Nuclear expression of S100A4 protein was observed in 136 (25.9%) tumors and significantly related to the depth of invasion, perineural invasion, and worse overall survival. However, there was no correlation between S100A4 mRNA expression and clinicopathological parameters. Upon multivariate analysis nuclear expression of S100A4 protein was found to be an independent prognostic factor of poor survival.Expression of S100A4 protein in colorectal cancers may indicate tumor progression and lymph node metastasis and can be useful for prediction of overall survival of patients with colorectal cancers.

Although thyroid transcription factor-1 (TTF-1) immunoreactivity is considered as a specific marker of lung and thyroid neoplasms, it may be positive in a proportion of extrapulmonary adenocarcinomas. This study examined the expression of TTF-1 in 555 colorectal adenocarcinomas using three commercial monoclonal antibodies: clone SPT24 (Novocastra) and 8G7G3/1 (Dako and Cell Marque), and compared the TTF-1 staining with other immunohistochemical markers, cytokeratin (CK) 7, CK 20, caudal-type homeobox transcription factor 2 (CDX2), and MUC2. The clinicopathological prognostic factors were compared with the TTF-1 expression status. Nuclear TTF-1 staining was detected in 24 cases (4.3%) with the SPT24 antibody and 18 cases (3.2%) with the 8G7G3/1 antibody. All cases positive for 8G7G3/1 were also positive for SPT24. CDX2 was expressed constantly in all 24 TTF-1-positive colorectal cancers, whereas CK7, CK20, and MUC2 were detected in 2 (8.3%), 23 (95.8%), and 8 (33.3%) cases, respectively. There was no correlation between TTF-1 expression and clinicopathological significance. To avoid potential pitfalls, TTF-1 should be interpreted in conjunction with the clinical setting, histological features, and the results of other markers, such as CK7, CK20, and CDX2. MUC2 can be used as supplementary information to confirm difficult cases.

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.

Interdigitating dendritic cell sarcoma (IDCS) is an extremely rare malignancy derived from antigen-presenting cells, with 55 cases reported thus far. A standard treatment modality is still being debated. This report describes a 56-year-old female who presented with right tonsillar enlargement and right submandibular swelling for 6 months. Treatment with empiric antibiotics did not result in improvement of her symptoms. Fine needle aspiration of the tonsil revealed no malignant cells. Tonsillectomy was eventually performed due to persistent symptoms. Based on microscopic findings, immunohistochemical stains, and review of the literature, the present case was finally diagnosed as IDCS of the tonsil with cervical lymph node involvement. The patient received four cycles of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy, and a clinically complete response was achieved followed by adjuvant radiation.

This study investigated the expression patterns of Mullerian inhibiting substance/anti-Mullerian hormone type II receptor (MIS/AMHRII) and mRNA in various types of ovarian neoplasia and evaluated the clinical significance of MIS/AMH as a biological response modifier for MIS/ AMHR-positive tumors. Reverse transcriptase polymerase chain reaction was used to detect MIS/AMHRII mRNA expression and in situ hybridization and immunohistochemistry were used to localize MIS/AMHRII mRNA and protein expression. The degree of expression was scored from 0 (no staining) to 3 (strong staining). There was no significant difference in expression intensity between MIS/ AMHRII protein and mRNA on all ovarian samples whether benign or malignant. MIS/AMHRII protein and mRNA were weakly expressed on 45.45% of benign ovarian tumors. In borderline tumors, expression rates of MIS/AMHRII protein and mRNA were 77.78% with score 1.22 and 55.56% with score 1, respectively. In malignant ovarian tumors, expression rates of MIS/AMHRII protein and mRNA were 70% with score 1.23 and 75% with score 1.43, respectively. Among malignant ovarian tumors, sex cord stromal tumors showed the highest expression rate and the strongest intensity of MIS/AMHRII protein and mRNA followed by germ cell tumor and epithelial ovarian tumor. Non-epithelial malignant tumors showed stronger expression than that of epithelial tumors (P

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.

Background : Atrophic gastritis is a well known risk factor for gastric adenocarcinoma. Its confirmatory diagnosis requires histology via endoscopy, which is an invasive method; therefore, periodic follow up evaluation as a screening method is difficult to perform. We evaluated the clinical utility of serum pepsinogens (PG) as a biomarker for screening of atrophic gastritis. Methods : The study population consisted of 130 selected dyspeptic patients (M:F=52:78; age, 16-105 yrs; mean age, 50.8 yrs) who had undergone a diagnostic endoscopy. The serum pepsinogen test was performed by a latex turbidimetric immunoassay method (HBI, Korea) using Toshiba200FR automatic analyzer. The PGI, II level and PGI:PGII ratio of non-atrophic gastritis group were compared with those of atrophic gastritis group, and a correlation with Helicobacter pylori infection was examined. Cut-off points for screening of atrophic gastritis were determined. Results : The mean serum concentration of PGI showed a decline from normal (60.7 ng/mL), nonatrophic gastritis (54.2 ng/mL), and atrophic gastritis (51.8 ng/mL) to gastric adenocarcinoma (32.6 ng/mL). The mean ratio of PGI:PGII was lower in atrophic gastritis (3.2) compared to non-atrophic gastritis (4.7) (P=0.021). In patients with H. pylori infection, the mean serum PGII level was higher and the PGI:PGII ratio was lower than those in patients without H. pylori infection, and the differences were statistically significant. For screening of atrophic gastritis, the best cut-off point of PGI:PGII ratio was 4, with a sensitivity of 82.6% and specificity of 91.7%. Conclusions : The serum pepsinogen test is a useful biomarker for screening of atrophic gastritis, a well-known precancerous lesion of gastric adenocarcinoma. Measuring both pepsinogen I and II concentrations simultaneously to obtain pepsinogen I/II ratio provides a clinically useful information for the detection of atrophic gastritis. (Korean J Lab Med 2008;28:201-6)

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.

The gastrointestinal (GI) tract is the major target site of the graft-versus-host disease (GVHD). Whether endoscopic findings can predict the histological diagnosis and degree of severity in GVHD remains controversial. We investigated the degree of correlation between endoscopic and histological findings, and evaluated the impact of endoscopic examination on clinical decision in GVHD management. This study was conducted as a retrospective single-center study. One hundred and one patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) and at the risk of GI GVHD were referred for endoscopic evaluation. Endoscopic images and histology were reviewed to diagnose and grade in a blind fashion, and the histological findings were used as the “gold standard” for diagnosis. Endoscopic findings revealed a significantly positive association with histological abnormalities of GVHD (odds ratio [OR] = 33.6, 95% CI 4.3–261.1), and the sensitivity and specificity were 98 and 44%, respectively. The kappa coefficient for agreement between the endoscopic and histological grading was 0.423 (p-value

Primary extranodal lymphomas of the central nervous system constitute 2% of all malignant lymphomas. The involvement of the peripheral nervous system is very rare. A solitary primary CD56-positive NK/T-cell lymphoma of the median nerve is described in a 70-year-old woman. On physical examination, a rubbery hard mass measuring 2.0 cm in diameter was palpated on the volar aspect of second to third finger of left hand. Excisional biopsy was performed. Under the fascia, a large fusiform tumor of the median nerve encapsulated with the epineurium was noted. Microscopically, the enlarged nerve showed extensive infiltration of atypical lymphoid cells. The lymphoid elements had abundant pale cytoplasm and large vesicular nuclei with peripheral prominent nuclei. The cells strongly expressed T-cell marker (UCHL-1) and natural killer cell marker (CD56). Gene rearrangement study showed rearrangement of T cell receptor (TCR-gamma).

The quantitative levels of intracellular cytokines IL-4, IL-10, and IFN-gamma (ie, the number of bound PE-conjugated antibody molecules/cell) of leukemic cells and bone marrow T cells (bmT cells) of acute leukemia patients were analyzed by flow cytometry. One hundred, thirty-one (95 AML, 25 ALL, 11 ABL) patients were studied. The leukemic cell IL-4 level was highest in the monocytic AML group (1735 +/- 1056) and lowest in the dysplastic AML group (960 +/- 545). The IFN-gamma level was highest in the acute promyelocytic leukemia (APL) group (495 +/- 159), and lowest in the ALL group (252 +/- 119). The IL-10 level was not significantly different among the diagnosis groups. In bmT cells, the IL-10 level was highest in the dysplastic AML group (972 +/- 1049) and lowest in the APL group (397 +/- 352). The leukemic cell cytokine levels were lowest and bmT cell cytokine levels were highest in the dysplastic AML group. There were no significant correlations of these cytokine levels with 2-yr survival rate, complete remission (CR) rate, or relapse rate. The cytokine levels of bmT cells at the time of CR became normal and were not different among the diagnosis groups. In summary, leukemic cell and bmT cell cytoplasmic expression profiles of IL-4, IL-10, and IFN-gamma are characteristic for each diagnostic group of acute leukemia patients and the profiles of bmT cells are normal at the time of CR.

Immunoglobulin A nephropathy (IgAN) is the most common form of immune complex-mediated glomerulonephritis worldwide. Although chronic renal failure develops in considerable numbers of IgAN patients, the exact etiology has not yet been clearly elucidated. To establish the urinary protein map of IgAN, we performed a urinary proteomic analysis. Thirteen patients with IgAN and 12 normal controls were recruited. Morning midstream spot urine samples were used with Centriprep ultrafiltration for concentration and desalting. 2-DE was performed and compared between IgAN and normal control, and urinary proteins were identified by MALDI-TOF MS. A large number of protein spots were identified in IgAN and normal control samples, with means of 311 spots and 174 spots, respectively. Approximately 216 protein spots were detected as differentially expressed in IgAN. Among these, 82 spots were over-expressed, and 134 spots were under-expressed compared to normal controls. A total of 84 differentially expressed spots, representing 59 different proteins, were finally identified in IgAN. We have established a urinary proteomic map of IgAN and this result helps in the identification. Further study is needed to determine the potential pathogenic role of these proteins.

p16(INK4A) and p57(KIP2) are inhibitors of cyclin-dependent kinases and their inactivation by methylation has been reported as a major tumorigenic mechanism in tumors. To examine whether methylation of p16(INK4A) and p57(KIP2) is involved in the development and progression of gastric MALT lymphomas, 24 gastric low-grade lymphomas of MALT, 11 diffuse large B-cell lymphomas, and 10 each case of gastric lymphoid follicles with and without Helicobacter pylori infection were studied. H. pylori infection was positive in 85.7% of the gastric lymphomas. In the gastric lymphoid follicles positive for H. pylori, methylation of p16(INK4A) was detected in 10% of cases, while methylation of p57(KIP2) was not detected. In low-grade MALT lymphomas, p16(INK4A) and p57(KIP2) were methylated in 41.7 and 29.2% of the cases, respectively. In diffuse large B-cell lymphomas, methylation of p16(INK4A) and p57(KIP2) was found in 72.7 and 36.4% of the cases, respectively. All but one case with p16(INK4A) and p57(KIP2) methylation was H. pylori positive and most of them were stage I. Our results indicate that methylation of p16(INK4A) followed by p57(KIP2) methylation involves during the tumorigenesis of gastric MALT lymphomas associated with H. pylori infection. As methylation of these two genes was more frequent in the higher grade (P

Context.—The traditional triple test for breast cancer diagnosis is physical examination, mammography, and aspiration cytology. However, the accuracy of mammography on young women with nonatrophied breasts is poor compared with that for women older than 50 years, and additional methods for diagnosis of breast cancer are needed. Objective.—To investigate whether carcinoembryonic antigen (CEA), CA 15-3, and CA 125 concentrations in breast aspiration fluid are useful as breast cancer biochemical markers and whether APC and cyclin D2 gene promoter hypermethylation could be regarded as a breast cancer molecular marker. Design.—CEA, CA 15-3, and CA 125 concentrations were measured, and methylation status of the APC gene promoter 1A and the promoter region of the cyclin D2 gene were analyzed using a methylation-specific polymerase chain reaction assay of ex vivo breast aspiration fluid obtained from 49 samples of excised breast tissue. Setting.—The specimens were collected during a 1-year period in the tertiary care teaching hospital in Seoul, Korea. Patients.—Forty-nine patients with breast masses were surgically treated. Thirty-four patients had breast cancer, and 15 had benign breast disease. Results.—Aspiration fluid CEA concentrations were significantly higher in breast cancer cases than in cases of benign breast disease (mean, 69.90 ng/mg protein vs 0.68 ng/mg protein, respectively; P < .001). At 90% specificity of the assay (CEA, 2.13 ng/mg protein), the corresponding sensitivity for breast cancer detection was 62%, according to the receiver operating characteristic curve drawn. The APC gene promoter 1A and the promoter region of the cyclin D2 gene were methylated in 42% (14/33) and 70% (23/33) of the breast cancer aspiration fluid samples, respectively. A cumulative incidence of methylation of these 2 genes was 85% (28/33). The APC and cyclin D2 gene promoters were both unmethylated in the aspiration fluids from 19 women with nonmalignant breast disease. Conclusions.—Breast aspiration fluid CEA concentration and the methylation of the APC gene promoter 1A and the promoter region of the cyclin D2 gene can be used as tumor markers to overcome some of the limitations of aspiration cytology. In combination with the mammogram and physical examination, assays for these markers could be used to help determine a definitive diagnosis when cytologic results are suspicious for malignancy.

The effectiveness of As2O3 treatment was studied in 3 carcinoma cell lines, LoVo, OVCAR-3, and PA-1, and in cancer cells obtained from ascites fluids of 8 patients with carcinomatosis peritonei. LoVo, OVCAR-3, and PA-1 cell lines, and cancer cells from the patients were cultured in As2O3 gradient media; As2O3 sensitivity was evaluated by trypan blue dye exclusion and by morphologic examination after Wright staining. PA-1 was the most sensitive cell line to As2O3; OVCAR-3 and LoVo were resistant to As2O3. Cancer cells from 2 of 8 patients were sensitive to As2O3. The in vivo tumoricidal effect of As2O3 (100 microg/day, i.p.) was studied in 30 BALB/c nude mice following i.p. implantation of PA-1 tumor cells. The 17 As2O3-injected mice died of extensive intratumoral hemorrhage, necrosis, and hemorrhagic ascites within 48 hr after initial treatment. In 10 As2O3-untreated tumor-bearing control mice, only focal intratumoral hemorrhage and necrosis were noted. In summary, solid tumor cell lines and cancer cells from patients showed various As2O3 sensitivities in vitro, and As2O3 had a marked tumoricidal effect on PA-1 cells in vivo. These results suggest that As2O3 treatment might possibly be beneficial in patients with carcinomatosis peritonei who are resistant to conventional therapy and whose tumors show in vitro sensitivity to As2O3. However, to minimize the life-threatening tumor lysis effect, it would be better to administer As2O3 after removal of the peritoneal tumor masses.

Although advances in imaging technology have allowed for earlier detection of disease, hepatocellular carcinoma is usually asymptomatic and discovered at an advanced stage with metastasis. The most common sites of metastasis include lung, peritoneum, adrenal gland, and bone, but rarely, the nasal cavity, orbit, gallbladder, and ovary can be metastatic sites. We experienced a case of metastatic hepatocellular carcinoma of the ovary in a living patient. The differential diagnosis includes hepatoid yolk sac tumor of the ovary, primary or metastatic hepatoid carcinoma and primary or metastatic oxyphil cell tumor of the ovary. To the best of our knowledge, there have been eight cases of metastatic hepatocellular carcinoma of the ovary in the English literature and only six cases discovered in living patients. This is the first report of a metastatic hepatocellular carcinoma of the ovary in Korea.