Norihiro Teramoto

Prospective study of thoracoscopic limited resection for ground-glass opacity selected by computed tomography

BACKGROUND With recent advances in low-dose helical computed tomography (CT), detection of ground-glass opacity (GGO) has increased. The aim of this study was to correlate high-resolution CT (HRCT) findings with pathologic features and to evaluate the efficacy of thoracoscopic limited resection for focal GGO, which were selected based on HRCT findings. METHODS Focal GGO lesions were classified into two subtypes based on HRCT findings: pure type and mixed type. Ninety-six patients with persistent GGO 2 cm or less in diameter underwent pulmonary resection from January 1997 to December 2001. Among these, thoracoscopic wedge resection was performed prospectively between June 2000 and December 2001 in 33 patients with pure GGO lesions that were 1 cm or less. RESULTS Thoracoscopic wedge resection was completed with complete safety. The histologic diagnoses of these 33 lesions were adenocarcinoma in 1, bronchioloalveolar carcinoma (BAC) in 23, and atypical adenomatous hyperplasia (AAH) in 9. No patients have had any evidence of tumor recurrence to date. Of the total 96 GGO lesions, 93.0% (53/57) of pure GGO 1 cm or less were BAC or AAH, whereas 38.5% (15/39) of pure GGO larger than 1 cm or mixed GGO were adenocarcinoma. CONCLUSIONS Pure GGO 1 cm or less was characteristic of noninvasive lesions. Thoracoscopic limited resection for small GGO lesions selected by HRCT was valid.

Reduction of Hematopoietic Cell-Specific Tyrosine Phosphatase SHP-1 Gene Expression in Natural Killer Cell Lymphoma and Various Types of Lymphomas/Leukemias: Combination Analysis with cDNA Expression Array and Tissue Microarray

To investigate the lymphomagenesis of NK/T lymphoma, we comprehensively and systematically analyzed the expression pattern of the human NK/T cell line (NK-YS) genome by cDNA expression array and tissue microarray. We detected significant changes in the gene expression of NK-YS cell line: an increase in 18 and a decrease in 20 genes compared to normal NK cells or peripheral blood mononuclear cells. Among these genes, we found a strong decrease in hematopoietic cell specific protein-tyrosine-phosphatase SH-PTP1 (SHP1) mRNA by cDNA expression array and reverse transcriptase-polymerase chain reaction. Further analysis with standard immunohistochemistry and tissue microarray, which used 207 paraffin-embedded specimens of various kinds of malignant lymphomas, showed that 100% of NK/T lymphoma specimens and more than 95% of various types of malignant lymphoma were negative for SHP1 protein expression. On the other hand, SHP1 protein was strongly expressed in the mantle zone and interfollicular zone lymphocytes in reactive lymphoid hyperplasia specimens. In addition, various kinds of hematopoietic cell lines, particularly the highly aggressive lymphoma/leukemia lines, lacked SHP1 expression in vitro, suggesting that loss of SHP1 expression may be related to not only malignant transformation, but also tumor cell aggressiveness. SHP1 expression could not be induced in either of two NK/T cell lines by phorbol ester, suggesting that genetic impairment or modification with methylation of SHP1 DNA could be one of the critical events in the pathogenesis of NK/T lymphoma. This evidence strongly suggests that loss of SHP1 gene expression plays an important role in multistep tumorigenesis, possibly as an anti-oncogene in the wide range of lymphomas/leukemias as well as NK/T lymphomas.

Utility of Contrast-Enhanced FDG-PET/CT in the Clinical Management of Pancreatic Cancer: Impact on Diagnosis, Staging, Evaluation of Treatment Response, and Detection of Recurrence

Objectives Fluorodeoxyglucose (FDG)–positron emission tomography/contrast-enhanced computed tomography (PET/CE-CT) involving whole-body scanning first by non–CE-CT and FDG-PET followed by CE-CT has been used for detailed examination of pancreatic lesions. We evaluated PET/CE-CT images with regard to differential diagnosis, staging, treatment response, and postoperative recurrence in pancreatic cancer. Methods Positron emission tomography/CE-CT was conducted in 108 patients with pancreatic cancer and in 41 patients with other pancreatic tumor diseases. Results The maximum standardized uptake value (SUVmax) overlapped in benign and malignant cases, suggesting that differential diagnosis of pancreatic tumors based on the SUVmax is difficult. In the evaluation of staging in 31 resectable pancreatic cancer by PET/CE-CT, the diagnostic accuracy rate was more than 80% for most factors concerning local invasion and 94% for distant metastasis but only 42% for lymph node metastasis. Significant positive correlations were found between the SUVmax and tumor size/markers, suggesting that SUVmax may be a useful indicator for the treatment response. Regarding the diagnosis of the postoperative recurrence, PET/CE-CT correctly detected local recurrence in all the 11 cases of recurrence, whereas abdominal CE-CT detected only 7 of 11 cases, suggesting that PET/CE-CT is superior in this context. Conclusions Positron emission tomography/CE-CT is useful for the clinical management of pancreatic cancer.

EBV-expressing AGS gastric carcinoma cell sublines present increased motility and invasiveness.

Tumor invasion marks a critical point in cancer progression; it is a harbinger of morbidity and mortality. Thus, the cellular events that enable the invasive phenotype are under intense investigation. Epstein‐Barr virus (EBV) is associated with a number of cancers, including Burkitt lymphoma (BL) and nasopharyngeal carcinoma (NPC) and is suspected to contribute to their tumorigenesis. On average, 8% of gastric carcinomas have been shown to carry this virus. To explore whether the presence of EBV in gastric carcinoma contributes to tumor progression in this predominantly invasive carcinoma, we examined a panel of 2 in vitro EBV‐infected human gastric cancer cell line sublines and their mock‐infected AGS parental control line. We found EBV infection caused a marked increase in transmigration of a Matrigel barrier (415% and 303%, p < 0.05, for the 2 infected lines). This correlated with increased motility of these sublines (233% and 140%, p < 0.05). As this pattern of increased motility leading to a more pronounced enhancement of invasion has been noted in other tumor cells, we explored the roles of autocrine signaling pathways previously implicated in carcinoma motility and invasion. Inhibitors to the epidermal growth factor receptor (EGFR) (PD153035), phospholipase C (PLC) (U73122), extracellular‐signal regulated kinase (ERK)/mitogen‐activated protein kinase (MAPK) (PD089035) and PI‐3 kinase (Wortmannin) were not informative. These data suggest that EBV increases migration of AGS cells by a mechanism independent of these autocrine growth factor‐induced pathways. Instead, we found that the EBV‐infected cells presented increased focal adhesion kinase (FAK) phosphorylation. These findings suggest a role for integrin‐mediated signaling in promoting EBV‐associated invasiveness.

Clonal analysis by polymerase chain reaction of B-cell lymphoma with late relapse: A report of five cases

Little is known about the clonal heterogeneity of non‐Hodgkins lymphoma between presentation and relapse, although several such reports have been published on acute lymphoblastic leukemia.

An Animal Model for Human EBV-Associated Hemophagocytic Syndrome: Herpesvirus Papio Frequently Induces Fatal Lymphoproliferative Disorders with Hemophagocytic Syndrome in Rabbits

Epstein-Barr virus-associated hemophagocytic syndrome (EBV-AHS) is often associated with fatal infectious mononucleosis. However, the animal model for EBV-AHS has not been developed. We reported the first animal model for EBV-AHS using rabbits infected with EBV-related herpesvirus of baboon (HVP). Eleven of 13 (85%) rabbits inoculated intravenously with HVP-producing cells developed fatal lymphoproliferative disorders (LPD) between 22 and 105 days after inoculation. LPD was also accompanied by hemophagocytic syndrome (HPS) in nine of these 11 rabbits. The peroral spray of cell-free HVP induced the virus infection with increased anti-EBV-viral capsid antigen-IgG titers in three of five rabbits, and two of these three infected rabbits died of LPD with HPS. Autopsy revealed hepatosplenomegaly and swollen lymph nodes. Atypical lymphoid T cells expressing EBV-encoded small RNA-1 infiltrated diffusely in many organs, frequently involving the lymph nodes, spleen, and liver. Hemophagocytic histiocytosis was observed in the lymph nodes, spleen, bone marrow, and thymus. HVP-DNA was detected in the tissues and peripheral blood from the infected rabbits by polymerase chain reaction or Southern blot analysis. Reverse transcriptase-polymerase chain reaction revealed both HVP-EBNA1 and HVP-EBNA2 transcripts, suggesting latency type III infection. These data indicate that the high rate of rabbit LPD with HPS induction is caused by HVP. This system is useful for studying the pathogenesis, prevention, and treatment of human EBV-AHS.

Epstein‐Barr virus infection in the neoplastic and nonneoplastic cells of lymphoid malignancies

The Epstein‐Barr virus (EBV) has been frequently detected in lymphoid malignancies. However, EBV infection in the nonneoplastic cells of lymphoid malignancies has not been extensively studied.

Mixed Duct-Acinar-Islet Cell Tumor of the Pancreas: Report of a Case

Abstract A 72-year-old Japanese woman presented at our hospital complaining of altered consciousness on arising every morning. The laboratory findings showed hypoglycemia and hyperinsulinemia. Abdominal ultrasonography revealed a tumor in the body of the pancreas. With a diagnosis of insulinoma, a surgical excision of the tumor was performed. A light microscopic examination and an immunohistochemical study revealed the tumor to consist of duct, acinar, and islet cell components. Mixed tumors of the pancreas are rare, and their clinical features and pathogenesis remain unclear. A further accumulation of clinical cases as well as a large number of histopathological studies on these rare mixed tumors is needed.

Epstein-Barr virus infection to Epstein-Barr virus-negative nasopharyngeal carcinoma cell line TW03 enhances its tumorigenicity.

Almost all nasopharyngeal carcinomas (NPCs) are infected by Epstein-Barr virus (EBV), but most ex vivo NPC cells lose EBV genomes during passages. In this study, an EBV-negative NPC cell line, TW03, established from EBV-carrying NPC was reinfected with EBV by cocultivation with irradiated Akata cells carrying recombinant EBV containing a neomycin-resistant gene. The reinfected EBV (+) TW03 cells expressed EBERs and EBNA1, but not EBNA2, lytic proteins (ZEBRA and EA-D), or LMP1. They had an epithelial appearance similar to that of EBV (−) TW03 cells. The doubling times of EBV (+) and EBV (−) TW03 cells were almost identical. However, the EBV (+) TW03 cells formed larger colonies with ragged contours in anchorage-independent cultures. An in vitro invasion assay showed that EBV (+) TW03 cells had a higher invasive activity than EBV (−) TW03 cells (p < 0.01). Both EBV (−) and EBV (+) TW03 cells formed poorly differentiated squamous cell carcinomas in SCID and nude mice. EBV (+) TW03 cells showed a higher tumorigenicity to nude mice (12 of 13) than EBV (−) TW03 cells (1 of 9) (p < 0.001). In the severe combined immunodeficiency (SCID) tumors of EBV (+) TW03 cells, not all of the tumor cells were EBER-1 positive. EBER-1 was more frequently detected in the peripheral regions and daughter nodules of the tumors than in the central areas. The microdissection polymerase chain reaction showed that the EBER-1-negative TW03 cells in the EBV (+) TW03 SCID tumors lost EBV genomes. EBER-1-negative cells showed as high a rate of Ki-67 positivity as EBER-1-positive cells, indicating that the former were proliferating rather than dead or dying. In horny pearls, keratinizing cells were ZEBRA-positive and EBER-negative. Loss of EBV genomes was not associated with squamous differentiation. These data indicated that reinfection of EBV promotes the tumorigenicity of EBV (−) TW03 cells by enhancing the invading activity.

Usefulness of liquid-based cytology in hormone receptor analysis of breast cancer specimens

Immunohistochemical (IHC) analysis of the hormone receptor (HR) in breast cancer cytology is an important issue nowadays. Several studies have shown discrepancy in the HR status between the primary tumor and metastases. Cytology can be used for patients with metastatic disease. Although cytological assessment of HR is an excellent method, it has not been routinely used because of the difficulty in consistently preparing multiple good quality slides. Liquid-based cytology (LBC) preparation is considered as the key to resolving the aforementioned problem; however, few studies have reported the HR assessment in breast cancer using LBC. Therefore, the HR status of LBC slides from 82 breast cancers was compared with that of the corresponding surgical specimens. The HR assay in both the LBC slides and surgical specimens was conducted by IHC using an autostainer. For the IHC staining, the protocol recommended by the manufacturer for paraffin-embedded sections was used for both the cytology and histology specimens. The HR results of the cytology agreed with those of the histology in 80 of the 82 cases (accuracy rate, 98%) for estrogen receptor, and in 78 of the 82 cases (accuracy rate, 95%) for progesterone receptor. The overall accuracy of the HR status on the cytology and the histology was 99% in 81 of the 82 cases. In conclusion, in HR analysis of breast cancers, LBC followed by IHC using an autostainer was useful for the standard processing of cytological specimens and showed a good correlation with the results of analysis on the histology specimens.