Fumio Shimamoto

Aurora-B expression and its correlation with cell proliferation and metastasis in oral cancer

Aurora-B kinase is a chromosomal passenger protein and is essential for chromosome segregation and cytokinesis. Aurora-B overexpression in various cancer cells induces chromosomal number instability to produce multinuclearity and relates to metastasis. Here, we examined the expression of Aurora-B in oral squamous cell carcinoma (OSCC) to elucidate the relationship between Aurora-B expression and clinico-pathological findings by immunohistochemistry. Aurora-B expression was observed in normal oral squamous epithelia and OSCC cases, but the number of positive cells was significantly higher in OSCC than in normal squamous epithelium (p < 0.01). The labeling index of Aurora-B was significantly correlated with lymph node metastasis (p < 0.01) and histological grades of differentiation (p < 0.01). We also compared Aurora-B expression with Ki-67 expression and a positive correlation was found (p < 0.0001). Moreover, Aurora-B expression is significantly more frequent in multinuclear tumor cells than in total tumor cells. In summary, we found that Aurora-B expression was well correlated with cell proliferation, induction of multinuclear cells, histological differentiation, and metastasis in OSCC. These findings suggest that Aurora-B may be involved in tumor progression and that Aurora-B can be a new diagnostic and therapeutic target for OSCC.

Lymphatic Vessel Density at the Site of Deepest Penetration as a Predictor of Lymph Node Metastasis in Submucosal Colorectal Cancer

PurposeLymph node metastasis is an important factor that influences curability after endoscopic treatment of submucosal colorectal cancer. This study was designed to determine the usefulness of identification of lymphatic vessels by immunohistochemistry in predicting lymph node metastasis of submucosal colorectal cancer.MethodsLymphatic involvement was assessed by hematoxylin and eosin staining and podoplanin immunostaining on samples resected from 268 patients with submucosal colorectal cancer. Lymphatic vessel density was estimated by two investigators by average count of three fields (×200) in the area of greatest number of podoplanin-positive capillaries at the site of deepest submucosal penetration. Relations with other clinicopathologic parameters also were investigated.ResultsLesions with high lymphatic vessel density (≥9 vessels per field) showed a significantly greater incidence of lymph node metastasis than did those with low lymphatic vessel density (<9 vessels per field; 23.3 vs. 8.4 percent). By multivariate analysis, lymphatic vessel density was determined to be an independent risk factor for lymph node metastasis of submucosal colorectal cancer (P = 0.0044). Lymphatic vessel density also correlated with tumor budding and the degree of inflammation at the invasive front.ConclusionsIdentification of lymphatic vessels by podoplanin immunostaining provides objective and accurate evaluation of lymphatic involvement. Lymphatic vessel density at the site of deepest penetration is a useful predictor of lymph node metastasis of submucosal colorectal cancer.

Telomere Shortening and Telomerase Expression during Multistage Carcinogenesis of Intraductal Papillary Mucinous Neoplasms of the Pancreas

Intraductal papillary mucinous neoplasm (IPMN) of the pancreas has been increasingly identified as a precursor to infiltrating ductal adenocarcinoma. Telomerase activation in response to telomere crisis followed by telomere shortening is thought to be a crucial event in the development of most human cancers. The aim of this study was to determine when this event occurs in the context of histologically defined IPMN progression. We analyzed telomerase expression in 68 IPMN samples and assessed telomere length by quantitative fluorescence in situ hybridization in samples taken from 17 sequential IPMN patients that included 37 individual loci. Samples from pancreatic ductal adenocarcinomas (PDACs, n = 15) and chronic pancreatitis patients (n = 10) were also examined. Telomeres were significantly shortened in 36 (97.3%) of 37 IPMN loci, with average telomere length decreasing with IPMN progression. Notably, even adenoma IPMNs demonstrated a 50% reduction of telomere length in 7 of 14 foci examined. Marked telomere shortening was observed from the in situ IPMN carcinoma stage (P < 0.001; vs borderline IPMNs) through the invasive stage, although telomerase had been activated, indicating that telomeres had shortened to a critical length by this histological grade. Up-regulated human telomerase reverse transcriptase expression was detectable and increased gradually with cancer development and was primarily observed at the borderline IPMN stage and then in more advanced histopathologies. Progressive telomere shortening predominantly occurs during early IPMNs carcinogenesis before telomerase activation and progression from borderline to carcinoma in situ IPMNs is the critical stage of IPMNs carcinogenesis at which telomere dysfunction occurs.

Predicting the absence of lymph node metastasis of submucosal invasive gastric cancer: Expansion of the criteria for curative endoscopic resection

Abstract Objective. The conditions upon which endoscopic resection (ER) can be considered curative for submucosal invasive gastric cancer remain controversial; thus, unnecessary surgery is sometimes performed after ER. Our purpose is to evaluate the significance of several clinicopathological factors for predicting the absence of lymph node (LN) metastasis of submucosal invasive gastric cancer and thus determining cases in which ER can be considered curative. Patients and methods. The study group comprised 220 patients with submucosal invasive gastric cancer that was resected surgically or endoscopically. Patients treated by ER underwent additional surgical resection. The presence of LN metastasis was evaluated in all patients, retrospectively. Results. LN metastasis was detected in 37 (16.8%) of the 220 patients. Independent risk factors for LN metastasis were width of submucosal invasion >6000 μm, lymphatic involvement, undifferentiated type at the deepest invasive portion, depth of submucosal invasion >1000 μm, and tumor diameter >30 mm. The group of 36 patients with submucosal invasion to a depth of ≤1000 μm, tumor diameter ≤30 mm, differentiated type as the dominant histologic type, and absence of vessel involvement was entirely free of LN metastasis (95% confidence interval, 0–8.0%). Conclusions. Taken together, the five independent risk factors may allow expansion of the criteria for determining whether ER for submucosal invasive gastric cancer has been curative.

Is It Possible to Discriminate Between Neoplastic and Nonneoplastic Lesions in Ulcerative Colitis by Magnifying Colonoscopy

Background:Colitis-associated cancer/dysplasia is an intestinal tract condition that can affect the life expectancy of patients with ulcerative colitis. It is often difficult to detect neoplastic lesions. This study evaluated whether any endoscopic features are effective for distinguishing colitis-associated cancer/dysplasia from nonneoplastic lesions in patients with ulcerative colitis. Methods:The study involved 52 patients with 61 lesions treated at Hiroshima University Hospital between September 1999 and May 2012: 10 patients with 11 dysplastic lesions, 5 patients with 5 intramucosal carcinomas, 3 patients with 3 submucosal carcinomas, and 34 patients with 42 nonneoplastic lesions. All patients had undergone targeted biopsy. Endoscopic findings were compared between patients with biopsy-determined neoplasia and those with biopsy-determined nonneoplasia. Multivariate regression analysis was performed to identify magnifying chromocolonoscopy features predictive of neoplasia. Results:No significant difference was found in conventional endoscopy features between the neoplastic and nonneoplastic lesions. Under magnifying chromocolonoscopy, the pit density of the neoplastic lesions was found to be significantly greater than that of the nonneoplastic lesions (89% [17/19] versus 60% [25/42], respectively). Pit margins were more frequently irregular in the neoplastic lesions than in the nonneoplastic lesions (63% [12/19] versus 33% [14/42], respectively). Conclusions:In differentiating between colitis-associated neoplastic and nonneoplastic lesions, focus should be on the high residual density of pits and irregular pit margins observed under magnifying chromocolonoscopy.

The Detergent-Soluble Cytoplasmic Pool of Survivin Suppresses Anoikis and Its Expression Is Associated with Metastatic Disease of Human Colon Cancer

Survivin is a component of the chromosomal passenger complex (CPC) that is essential for accurate chromosome segregation. Interfering with the function of Survivin in mitosis leads to chromosome segregation errors and defective cytokinesis. Survivin contains a Baculovirus IAP Repeat (BIR) and therefore was originally classified as inhibitor of apopotosis protein (IAP), yet its role in apoptosis after cellular stress remains largely unknown. We demonstrate here, that Survivin predominantly suppresses anoikis, a form of programmed cell death induced by loss of cellular adhesion to extracellular matrix. Interestingly, cells ectopically overexpressing EGFP-Survivin showed after loss of cell-matrix-interaction a decreased expression of IκB-α. Subsequent subcellular protein fractionation and immunoprecipitation experiments revealed that XIAP interacts with detergent-soluble Survivin which is known to cooperatively activate NF-κB signaling. Examination of the expression levels of detergent soluble Survivin in colorectal cancer cell lines and in colorectal cancerous tissues revealed that detergent soluble cytoplasmic Survivin levels correlated inversely with anoikis susceptibility in colorectal cancer. Therefore, the detergent soluble cytoplasmic Survivin might be a promising predictive biomarker for lymph node and distant metastases of colorectal cancer. We conclude that an anti-apoptotic function of detergent-soluble Survivin in interphase cells experiencing anoikis is mediated at least via XIAP/IκB-α/NF-κB signaling.

Expression of olfactomedin 4 and claudin‐18 in serrated neoplasia of the colorectum: a characteristic pattern is associated with sessile serrated lesion

Olfactomedin 4 is a useful marker for stem cells in the intestine and is an independent prognostic molecule for survival in patients with colorectal cancer (CRC). Claudin‐18, a component of tight junctions, correlates with poor survival in patients with CRC and is associated with the gastric phenotype. We investigated the possible usefulness of these molecules in serrated neoplasia of the colorectum.

Clinical features of pharyngeal intraepithelial neoplasias and outcomes of treatment by endoscopic submucosal dissection

BACKGROUND Endoscopic detection of superficial squamous epithelial lesions of the pharynx has increased. OBJECTIVE To clarify the association between macroscopic and histologic characteristics of intraepithelial pharyngeal neoplasias, and to evaluate the effectiveness of endoscopic submucosal dissection (ESD) for their treatment. DESIGN Retrospective analysis of the features of high-grade dysplasia or carcinoma in situ (HGD/CIS) versus low-grade dysplasia (LGD) and of ESD-based outcomes. SETTING Endoscopy department at a university hospital. PATIENTS Fifty-one patients with 66 lesions treated by ESD from November 2007 to March 2011. RESULTS Primary hypopharyngeal lesions were significantly more frequent in HGD/CIS than in LGD (54.1% vs 20.7%, P = .011), and oropharyngeal lesions were significantly less frequent in HGD/CIS (45.9% vs 79.3%, P = .011). HGD/CIS lesions were significantly larger than LGD lesions (median 8 mm vs 4 mm, P < .01). Morphologically, type 0-IIa was significantly more frequent in HGD/CIS lesions than in LGD lesions (37.8% vs 3.4%, P < .001), and type 0-IIb was significantly less frequent in HGD/CIS lesions (59.5% vs 96.6%, P < .001). The type IV intraepithelial papillary capillary loop pattern was significantly less frequent in HGD/CIS lesions than in LGD lesions (27.0% vs 55.2%, P = .025), and type V-2 was significantly more frequent in HGD/CIS lesions (18.9% vs 0%, P = .015). The en bloc resection rate was 97%. No serious complications occurred. There were no recurrent or metachronous tumors in the 41 patients followed for more than 1 year (median follow-up 27 months). LIMITATIONS Retrospective design and single-center study. CONCLUSIONS HGD/CIS and LGD differ in various clinical features. ESD appears to be an effective treatment for pharyngeal intraepithelial neoplasias.

Human Telomerase Reverse Transcriptase, p53 and Ki-67 Expression and Apoptosis in Colorectal Serrated Adenoma

Background: Serrated adenoma (SA) has recently been proposed as a distinct histological lesion of the colorectum. However, no definite histopathologic criteria for SA have been established, and its histogenesis and natural history remain unclear. Methods: We analysed 25 hyperplastic polyps (HPs), 26 low-grade SAs (LG-SAs), 32 high-grade SAs (HG-SAs), 18 low-grade tubular adenomas (LG-TAs), 16 high-grade TAs (HG-TAs) and 20 carcinoma in situ (CIS). To clarify molecular features of SA, we used in situ hybridization to examine the expression of human telomerase reverse transcriptase (hTERT), immunohistochemistry to examine the expressions of p53 and Ki-67, and in situ DNA nick end labeling to detect apoptotic cells. Results: The incidence of hTERT expression was 1 (4.0%) of 25 for HP, 12 (46.2%) of 26 for LG-SA, 18 (56.3%) of 32 for HG-SA, 6 (33.3%) of 18 for LG-TA, 7 (43.8%) of 16 for HG-TA, 12 (80.0%) of 15 for CIS, respectively. The incidence of hTERT expression in SA was significantly higher than that in HP. Seventeen (29%) of the 58 SAs were regarded as positive for p53 protein, but none of the HPs showed p53 immunoreactivity. Ki-67 labeling index in SA, TA and CIS was significantly higher than that in HP. The apoptototic index was not significantly different between HP, SA, TA and CIS. In HG-SA, the incidence of hTERT expression in p53-positive lesions was significantly higher than that in p53- negative lesions. Conclusions: These results suggest that hTERT and p53 expression increase in the early stages of carcinogenesis in SA and that SA has a malignant transformation similar to that of TA. It may be useful to investigate hTERT and p53 expression for differential diagnosis of SA from HP.

Diagnostic performance of Japan NBI Expert Team classification for differentiation among noninvasive, superficially invasive, and deeply invasive colorectal neoplasia

BACKGROUNDS AND AIMS The Japan NBI Expert Team (JNET) classification is the first universal narrow-band imaging magnifying endoscopic classification of colorectal tumors. Considering each type in this classification, the diagnostic ability of Type 2B is the weakest. Generally, clinical behavior is believed to be different in each gross type of colorectal tumor. We evaluated the differences in the diagnostic performance of JNET classification for each gross type (polypoid and superficial) and examined whether the diagnostic performance of Type 2B could be improved by subtyping. METHODS We analyzed 2933 consecutive cases of colorectal lesions, including 136 hyperplastic polyps/sessile serrated polyps, 1926 low-grade dysplasias (LGDs), 571 high-grade dysplasias (HGDs), and 300 submucosal (SM) carcinomas. We classified lesions as polypoid and superficial type and compared the diagnostic performance of the classification system in each type. Additionally, we subtyped Type 2B into 2B-low and 2B-high based on the level of irregularity in surface and vessel patterns, and we evaluated the relationship between the subtypes and histology, as analyzed separately for polypoid and superficial types. We also estimated interobserver and intraobserver variability. RESULTS The diagnostic performance of JNET classification did not differ significantly between polypoid and superficial lesions. Ninety-nine percent of Type 2B-low lesions were LGDs, HGDs, or superficial submucosal invasive (SM-s) carcinomas. In contrast, 60% of Type 2B-high lesions were deep submucosal invasive (SM-d) carcinomas. The results were not different between each gross type. Interobserver and intraobserver agreements for Type 2B subtyping were good, with kappa values of .743 and .786, respectively. CONCLUSIONS Type 2B subtyping may be useful for identifying lesions that are appropriate for endoscopic resection. JNET classification and Type 2B sub classification are useful criteria, regardless of gross type.