Nobuyuki Yanagisawa

High expression of L-type amino acid transporter 1 (LAT1) predicts poor prognosis in pancreatic ductal adenocarcinomas

Background and aims Molecular target therapy against L-type amino acid transporter 1 (LAT1) is unique and expected to be developed soon. LAT1 expression was investigated in pancreatic cancer as a prognostic predictor. Methods Surgically resected pancreatic ductal adenocarcinomas (PDAC, n=66) were investigated using immunohistochemistry. For reference, intraductal papillary mucinous carcinomas (IPMC, including intraductal papillary mucinous neoplasm (IPMN) with high-grade dysplasia or with an associated invasive carcinoma, n=13) and adenomas (IPMA, including IPMN with low- and intermediate-grade dysplasia, n=5) were also examined. Results LAT1 expression scores increased from PDAC to IPMA to IPMC. Kaplan–Meier analysis showed significant differences between LAT1-high and -low scores in PDAC. Even in each Ki-67-labelling index (LI) low and high PDAC group (cut off 40%), high LAT1 expression could also predict poor prognosis. Multivariable analysis showed that LAT1 expression, Ki-67 LI, tumour differentiation and size were individual prognostic factors. Conclusions LAT1 aberrant overexpression in PDAC predicts poor prognosis, independent of Ki-67 LI, and offers a potential target for future anticancer therapy with its inhibitors.

Significant correlations of E-cadherin, catenin, and CD44 variant form expression with carcinoma cell differentiation and prognosis of extrahepatic bile duct carcinomas

To clarify the relation between alteration of expression of cell adhesion molecules and progression of extrahepatic bile duct carcinomas. 55 cases were immunohistochemically examined for E-cadherin, alpha-catenin, beta-catenin, and CD44, with additional reverse transcription-polymerase chain reaction and Southern blotting hybridization (RT-PCR/SBH) assays. Levels of E-cadherin, alpha-catenin, and beta-catenin proteins were lower in carcinomas than in normal mucosa, while CD44 variants 3 and 6 were upregulated. Well-differentiated carcinoma showed higher expression of E-cadherin and alpha-catenin than moderately to poorly differentiated types. Macroscopically papillary lesions had higher expression of E-cadherin than their nonpapillary counterparts. RT-PCR/SBH for CD44 revealed the CD44 variant form to be more prevalent in carcinoma than in normal mucosa, correlating with the immunohistochemical results, and with more exon variety. The Cox proportional hazards test identified histologic type and E-cadherin expression as prognostic factors. Among the examined molecules, E-cadherin was especially related to papillary mass formation and a good prognosis.

Unique and selective expression of L-amino acid transporter 1 in human tissue as well as being an aspect of oncofetal protein.

Dysregulated expression of L-type amino acid transporter 1 (LAT1), which transports large neutral amino acids, is a characteristic of various human cancers and possibly offers a molecular target for chemotherapy. LAT2, in contrast, shows lower expression in neoplasms. LAT1 is presumed to be a biomarker of many cancers, suggesting a kind of oncoprotein. However, no precise analysis of LAT1 and LAT2 expression has been performed in systemic normal tissues. To see characteristics of LAT1 and LAT2, immunohistochemical expression of LAT1 and LAT2 was assessed and compared in normal human systemic organs and tissues from 3 adults, 3 children and 3 fetuses in the present study. Cardiac muscles, hepatocytes, thymic epithelial cells and primitive neuroectodermal cells in fetus were positive with LAT1, whereas no expression was found in the respective adult tissues, indicating an aspect of oncofetal protein. In adult tissues, LAT1 was found to be expressed proximal to proliferative zones in gastrointestinal mucosa by double immunostaining of LAT1 and Ki-67. Testicular Sertoli cells, ovarian follicular cells, and pancreatic islet cells showed strong expression. Although the systemic capillary endothelium did not express LAT1, but did express LAT2, capillaries corresponding to the blood-brain, blood-follicle, and blood-retinal barriers demonstrated strong LAT1 immunoreactions. In conclusion, LAT1 was expressed in gonad tissues and several kinds of cells having special functions, as well as being discovered to be an aspect of oncofetal protein. In addition, ubiquitous LAT2 expression was confirmed immunohistochemically in systemic tissues, indicating constitutional function.

Reclassification of the current tumor, node, metastasis staging in pT3 renal cell carcinoma

Objectives:  Although the tumor, node, metastasis (TNM) staging classification of renal cell carcinoma (RCC) was last modified in 2002, pT3 staging has continued to be debated. It has been suggested that direct adrenal gland involvement and pT3b with pT3a should be reclassified. This study accordingly explores reclassification of the current 2002 TNM staging in pT3 RCCs.

Computer simulated additional deep apical biopsy enhances cancer detection in palpably benign prostate gland

Objectives: The objective of this study was to use computer simulation to investigate the optimal biopsy scheme for enhancing the detection of cancer in palpably benign prostate glands.

High expression of L-type amino acid transporter 1 as a prognostic marker in bile duct adenocarcinomas

Oncocytic L‐type amino acid transporter (LAT) 1 may be a prognostic indicator and target of new molecular therapeutic agents against malignancies. To investigate whether LAT1 expression influence the outcomes of patients with bile duct cancer, the expression of LAT1, LAT2, CD98, and Ki‐67 was investigated immunohistochemically in 134 surgically resected bile duct adenocarcinomas, including 84 distal extrahepatic bile duct adenocarcinomas, 21 hilar cholangiocarcinomas, 15 intrahepatic cholangiocarcinomas, and 14 ampullary adenocarcinomas. LAT1 expression was weakly correlated with CD98 expression and Ki‐67 labeling index (LI). Kaplan–Meier analysis showed a significant difference in prognosis between patients with bile duct adenocarcinomas having LAT1‐high and ‐low scores, whereas LAT2 and CD98 expression and Ki‐67 LI were not predictive of poor prognosis. Prognosis tended to be worse in patients having tumors with LAT1‐high/LAT2‐low than LAT1‐low/LAT2‐high scores (P = 0.0686). Multivariable analyses revealed that LAT1 expression, surgical margin, pT stage were independent prognostic factors. In conclusion, aberrant overexpression of LAT1 in bile duct adenocarcinoma predicts poor prognosis, suggesting that LAT1 may be a potential target of anticancer therapy.

Tumor budding, myofibroblast proliferation, and fibrosis in obstructing colon carcinoma: the roles of Hsp47 and basic fibroblast growth factor.

This study was designed to assess the mechanism of obstruction in obstructing colorectal carcinomas. Thirty-five cases of obstructing colorectal carcinoma and 34 cases of non-obstructing carcinoma were studied. The lesions were immunohistochemically analyzed using antibodies for pan-cytokeratin, α-smooth muscle actin, matrix metalloproteinase-7, 47-kDa heat shock protein (Hsp47), basic fibroblast growth factor (bFGF), myeloperoxidase, and CD68. Compared with non-obstructing cases, obstructing carcinoma cases included lesions of poorer differentiation. A higher value of tumor budding was observed in obstructing than in non-obstructing carcinoma. A higher number of α-smooth muscle actin-positive myofibroblasts, a higher expression of Hsp47 in stromal spindle cells, and a higher expression of bFGF in inflammatory cells were also significant in obstructing carcinoma. Therefore, obstructing colon carcinomas were characterized by poorer differentiation of cancer cells, a high level of tumor budding, and stromal myofibroblast proliferation resulting in fibrosis. Correlative Hsp47 expression in fibroblasts with bFGF in inflammatory cells may contribute to stromal fibrosis.

Primary squamous cell carcinoma of the seminal vesicle

A 69-year-old man with primary squamous cell carcinoma of the seminal vesicle was successfully treated. The patient presented with complaints of gross hematuria and difficulty in urination. Transrectal ultrasonography revealed a cystic mass behind the bladder, and solid tumorous lesions were visualized in the cyst wall by magnetic resonance imaging. The cystic mass was surgically excised and was verified as the enlarged seminal vesicle with concomitant squamous cell carcinoma. The histopathologic diagnosis was squamous cell carcinoma in the seminal vesicle. Postoperatively, 50 Gy of external beam radiation was targeted to the whole pelvic cavity, and the patient was alive without recurrence 2.5 years after surgery. No other neoplasm was discovered in the body.

Squamous cell carcinoma arising from a seminal vesicular cyst: Possible relationship between chronic inflammation and tumor development

A case of squamous cell carcinoma arising within an acquired seminal vesicular cyst is described. A 61‐year‐old man was hospitalized because of hemospermia and dysuria. Under the diagnosis of a left seminal vesicular cyst, surgical resection was performed. Pathological examination revealed squamous cell carcinoma within a seminal vesicular cyst, along with squamous metaplastic foci and severe chronic inflammation. Cell proliferation, determined with reference to MIB‐1 labeling indices, showed a stepwise increase from normal columnar epithelium, through squamous metaplasia, to squamous cell carcinoma. Sporadic p53 protein accumulation without evident gene mutations was also apparent in both the carcinoma and squamous metaplastic lesions. We therefore concluded that the squamous cell carcinoma might have developed from squamous metaplastic foci associated with chronic inflammatory stimulation, within a seminal vesicular cyst.

L-type amino acid transporter 1 (LAT1) expression in lymph node metastasis of gastric carcinoma: Its correlation with size of metastatic lesion and Ki-67 labeling

L-Type amino acid transporter 1 (LAT1) is one of the major amino acid transporters. High levels of LAT1 expression have been reported in various tumors, which can act as a novel prognostic marker. Previously, we demonstrated that LAT1 is highly expressed in advanced gastric carcinoma with lymph node metastasis, and proposed that LAT1 is an independent prognostic factor in non-scirrhous gastric carcinoma. The aim of the present study was to investigate the relationship between LAT1 expression and the size of lymph node metastatic lesions in gastric carcinoma. LAT1 and Ki-67 expression was immunohistochemically analyzed in 64 cases of advanced gastric carcinoma with lymph node metastasis. LAT1 expression in the metastatic lymph nodes was correlated with that in the primary lesions. The high LAT1 expression group showed a larger size of metastatic lesion and a higher Ki-67 labeling index than the low LAT1 expression group. LAT1 expression had a weak association with Ki-67 labeling index and tumor diameter of lymph nodes. These results suggest that LAT1 expression is associated with disease progression in gastric carcinoma. We proposed that LAT1 could be a potential therapeutic target for gastric carcinoma cases with large lymph node metastasis.