Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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An 85-year-old man with a history of aortic dissection suddenly fainted, underwent cardiac heart arrest, and died. An autopsy was performed, but the cause of death was not grossly identified. Congo red staining detected amyloid deposits in systemic organs, including the heart, lungs, liver, and kidneys. Immunohistochemical (IHC) analysis revealed immunoglobulin (Ig) λ light chain (-λ) in systemic blood vessels and transthyretin (TTR) in the heart and lungs. Ig-λ was predominantly positive in the blood vessels of the lungs, while TTR was detected in the alveolar septum. In the heart, Ig-λ was positive in the endocardium and blood vessels, and TTR was positive in nodular deposits between cardiomyocytes. The concurrent deposition of Ig-λ and TTR in the heart was further substantiated by laser microdissection (LMD)-liquid chromatography-tandem mass spectrometry (LC-MS/MS) at each deposition site. Despite systemic deposition of Ig-λ, bone marrow biopsy findings were not diagnostic for multiple myeloma. In summary, we present an autopsy case of concurrent Ig-λ and TTR deposition as revealed by IHC and LC-MS/MS. When Congo red staining and IHC results are indeterminate due to the deposition of multiple amyloid proteins, LMD-LC-MS/MS is useful for determining the precursor protein.

DOI： 10.1111/pin.13179

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Language：Japanese   Publisher：日本医科大学医学会  

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Language：Japanese   Publisher：日本医科大学医学会  

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Language：Japanese   Publisher：日本医科大学医学会  

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Language：Japanese   Publisher：日本医科大学医学会  

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Language：Japanese   Publisher：(公社)日本臨床細胞学会  

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Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

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Histiocytic sarcoma is a relatively new disease category and the gastrointestinal origin is sporadic. We report a case of a 74-year-old woman who underwent chemotherapy and proximal gastrectomy for extremely rare, advanced gastric histiocytic sarcoma. The resected specimen was subjected to numerous immunostainings to meet the diagnostic criteria of histiocytic sarcoma and was positive for the histiocyte markers' cluster of differentiation 68 and lysozyme. The markers of Langerhans cells, follicular dendritic cells, and myelocyte were all negative. Six reports of surgical resection of histiocytic sarcoma originating in the stomach exist, including our case. We reviewed the clinical course and the histological and immunohistochemical diagnostic features of surgically resected gastric histiocytic sarcoma.

DOI： 10.1007/s12328-021-01438-y

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Publishing type：Research paper (scientific journal)  

Histiocytic sarcoma is a relatively new disease category and the gastrointestinal origin is sporadic. We report a case of a 74-year-old woman who underwent chemotherapy and proximal gastrectomy for extremely rare, advanced gastric histiocytic sarcoma. The resected specimen was subjected to numerous immunostainings to meet the diagnostic criteria of histiocytic sarcoma and was positive for the histiocyte markers’ cluster of differentiation 68 and lysozyme. The markers of Langerhans cells, follicular dendritic cells, and myelocyte were all negative. Six reports of surgical resection of histiocytic sarcoma originating in the stomach exist, including our case. We reviewed the clinical course and the histological and immunohistochemical diagnostic features of surgically resected gastric histiocytic sarcoma.

DOI： 10.1007/s12328-021-01438-y

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Publisher：株式会社医学書院  

DOI： 10.11477/mf.1411202765

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(株)医学書院  

症例は26歳女性で、右下顎骨腫瘍(骨形成線維腫)術後の血液検査でカルシウム(Ca)とi-PTHが高値を示した。頸部造影CTでは嚢胞変性を伴う左上副甲状腺の腫大(長径20mm大)を認めたが、MIBIシンチグラフィでは病変に一致した集積はなく、産婦人科で子宮ポリープを指摘された。hyperparathyroidism-jaw tumor syndrome(HPT-JT)による原発性副甲状腺機能亢進症と判断して左上副甲状腺腫摘出術を行い、病理検査の結果は副甲状腺腺腫の所見であり、術後は血中Ca、i-PTHが正常化した。後日、遺伝子検査でCDC73遺伝子(cell division cycle protein 73 homolog gene)に「c.238-8G>A」変異を認め、HPT-JTと診断された。家族性副甲状腺機能亢進症ではHPT-JTも念頭に置いた診療が必要である。

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(株)医学書院  

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Accurate pre-operative localization of nonpalpable lesions plays a pivotal role in guiding breast-conserving surgery (BCS). In this multicenter feasibility study, nonpalpable breast lesions were localized using a handheld magnetic probe (TAKUMI) and a magnetic marker (Guiding-Marker System®). The magnetic marker was preoperatively placed within the target lesion under ultrasound or stereo-guidance. Additionally, a dye was injected subcutaneously to indicate the extent of the tumor excision. Surgeons checked for the marker within the lesion using a magnetic probe. The magnetic probe could detect the guiding marker and accurately localize the target lesion intraoperatively. All patients with breast cancer underwent wide excision with a safety margin of ≥5 mm. The presence of the guiding-marker within the resected specimen was the primary outcome and the pathological margin status and re-excision rate were the secondary outcomes. Eighty-seven patients with nonpalpable lesions who underwent BCS, from January to March of 2019 and from January to July of 2020, were recruited. The magnetic marker was detected in all resected specimens. The surgical margin was positive only in 5/82 (6.1%) patients; these patients underwent re-excision. This feasibility study demonstrated that the magnetic guiding localization system is useful for the detection and excision of nonpalpable breast lesions.

DOI： 10.3390/cancers13122923

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BACKGROUND: Non-functioning parathyroid carcinoma is an extremely rare malignancy among endocrine tumors. We report a case in which non-functional oxyphilic parathyroid carcinoma was diagnosed from clinical symptoms and pathological diagnosis. CASE PRESENTATION: The patient was a 42-year-old man with no medical or family history of note. He had presented to a local hospital with a neck mass 2 months earlier. Medullary thyroid carcinoma was diagnosed and he was referred to our department. A 3.5-cm mass was observed in the left thyroid lobe. Laboratory data for thyroid functions, thyroglobulin, anti-thyroglobulin antibodies, anti-thyroid peroxidase antibodies, serum calcium, and parathyroid hormone (PTH) were all within normal ranges. Ultrasonography revealed a 40-mm irregular, hypoechoic mass throughout the left thyroid lobe. Follicular thyroid tumor was suspected from fine-needle aspiration cytology. Left lobectomy was performed. Pathological features revealed a thick fibrous capsule around the tumor, and a thick fibrous band was observed inside the tumor. Both capsular invasions and vascular invasions were observed. Tumor cells were eosinophilic and displayed solid growth. Immunohistochemically, tumor cells were negative for thyroid transcription factor-1, negative for thyroglobulin, negative for chromogranin A (positive for normal parathyroid tissue within the nodule), positive for PTH, and positive for parafibromin. Ki-67 labeling index was 10%. Based on these findings, non-functional oxyphilic parathyroid carcinoma was diagnosed. One and a half years postoperatively, calcium and PTH were within normal ranges, and he has shown no evidence of recurrence or metastasis. CONCLUSIONS: Non-functioning oxyphilic parathyroid carcinoma is an extremely rare malignancy, and definitive diagnosis is difficult to obtain preoperatively. Few reports have been made worldwide, and information on the long-term prognosis is scarce. Long-term surveillance by imaging is mandatory, since no indices that can be used as a marker for postoperative recurrence and metastasis have been identified.

DOI： 10.1186/s40792-021-01201-y

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Language：Japanese   Publisher：日本外科系連合学会  

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Language：Japanese   Publisher：日本外科系連合学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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BACKGROUND: A retrospective study of the real-world use of neoadjuvant endocrine therapy (NET) is important for standardizing its role in breast cancer care. MATERIALS AND METHODS: In a consecutive series of women with operable breast cancer who received NET for ≥28 days, NET objectives, NET outcomes, adjuvant chemotherapy use after NET, and survivals, were examined for the correlation with clinicopathological factors. RESULTS: NET objectives were for surgery extent reduction in 49 patients, surgery avoidance in 31, and treatment until scheduled surgery in 8. The mean duration of NET was 349.5 (range, 34-1923), 869.8 (range, 36-4859), and 55.8 (range, 39-113) days in the above cohorts (success: 79.6%, 64.5%, and 100%), respectively, with significant difference. In patients of the former two cohorts, better progression-free survival was significantly correlated with stage 0 or I, ductal carcinoma in situ or invasive ductal carcinoma, ≥71% estrogen receptor (ER) positivity, and the surgery extent reduction cohort than the other counterparts. Postoperative chemotherapy use was significantly correlated with lymph node metastasis, a high Ki67 labeling index, lymphovascular invasion, and a high Preoperative Endocrine Prognostic Index, at surgery after NET. Better recurrence-free survival after surgery was significantly correlated with high ER expression after NET and high PgR expression before and after NET. CONCLUSIONS: NET can help to reduce the surgery extent or to avoid surgery in women with breast cancer of early-stage, ductal carcinoma, or high ER expression. NET may also contribute to appropriate decision of postoperative systemic therapy to improve survivals.

DOI： 10.1272/jnms.JNMS.2021_88-603

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Language：Japanese   Publisher：(一社)日本病理学会  

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BACKGROUND: The caudal type homeobox 2 transcription factor (CDX2) is a specific and sensitive marker for intestinal carcinoma, but usually not expressed in breast cancer. In CDX2-positive metastatic cancer of occult primary, the origin is highly suspicious of an enteric carcinoma. CASE PRESENTATION: A 50-year-old woman complained of enlarged lymph nodes (LNs) in the right axilla. Mammography and ultrasonography scans showed no abnormal findings in her breasts. Core needle biopsy (CNB) revealed metastatic adenocarcinoma. Immunohistochemical staining was positive for CDX2 intensely. The primary tumor was suspicious of intestinal adenocarcinoma. A dynamic contrast-enhanced magnetic resonance imaging scan revealed an accentuated lesion which was detected using a second-look ultrasound, and diagnosed invasive ductal carcinoma by CNB. A partial mastectomy of the right breast with level I and II axillary LN dissection was performed. A few cells of primary cancer were expressed CDX2 and estrogen receptor. The final pathological diagnosis was T1bN3aM0 stage IIIC. The fluorescent double staining showed that CDX2 simultaneously expressed on the Ki67 positive cells of metastatic tumors. The adjuvant treatment included chemotherapy and radiation, followed by tamoxifen administration. The patient survived without any recurrences over the following 36 months. CONCLUSIONS: We report a rare case of CDX2-positive metastatic breast cancer in the axillary LNs. As some literatures reported vitamin D pathways induced cancer cell apoptosis and inhibition, these metastatic cells of our case might play the effort of autoregulation of inhibiting progression.

DOI： 10.1016/j.ctarc.2020.100300

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A 26-year-old woman visited our hospital to undergo an evaluation for primary hyperparathyroidism (PHPT). She had undergone surgery for a mandibular tumor three years prior. Her blood calcium level and intact parathyroid hormone (PTH) levels were high, and computed tomography revealed swelling of the upper parathyroid on her left side. She underwent sur¬gery for the parathyroid tumor, and subsequently, her blood calcium level and intact parathyroid hormone level became normal. Genetic analysis revealed a CDC73 mutation. Based on the PHPT. mandibular tumor, and genetic analysis, she was diagnosed with hyperparathyroidism-jaw tumor syndrome (HPT-JT).

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Language：Japanese   Publisher：(公社)日本臨床細胞学会  

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Language：Japanese   Publisher：(公社)日本臨床細胞学会  

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Background Breast cancer survival outcomes vary across different ethnic groups. We clarified the differences in clinicopathological and survival characteristics of breast cancer among Japanese, US residents with Japanese origin (USJ), and US residents with other origins (USO). Method Using Surveillance, Epidemiology, and End Results (SEER) 18 dataset and Japanese Breast Cancer Society (JBCS) registry, we included patients first diagnosed with breast cancer between 2004 and 2015. We categorized the patients into three groups based on the database and the recorded ethnicity: Japanese (all those from the JBCS registry), USJ (those from SEER with ethnicity: Japanese), and USO (those from SEER with ethnicity other than Japanese). Excluding patients diagnosed after 2012, stage 0, and 4 patients, we examined the overall survival (OS) and breast cancer-specific survival (BCSS) using the Kaplan-Meier method and Cox proportional hazards models, adjusting for age, sex, cancer stage, and hormone receptor (HR) status. Results We identified 7362 USJ, 701,751 USO, and 503,013 Japanese breast cancer patients. The proportion of HR-positive breast cancer was the highest among USJ (71%). OS was significantly longer among Japanese and USJ than USO (Hazard ratio 0.46; 95% Confidence Interval [CI] 0.45-0.47 for Japanese and 0.66 [95% CI 0.59-0.74] for USJ) after adjusting for baseline covariates. BCSS was also significantly higher in the two groups (HR 0.53 [95% CI 0.51-0.55] for Japanese and 0.53 [95% CI 0.52-0.74] for USJ). Conclusions In stage I-III breast cancer, Japanese and US residents with Japanese origin experienced significantly longer survival than US residents with non-Japanese origins.

DOI： 10.1007/s10549-020-05869-y

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Other Link： http://link.springer.com/article/10.1007/s10549-020-05869-y/fulltext.html

Language：Japanese   Publisher：(一社)日本内分泌外科学会  

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BACKGROUND: Programmed death-ligand 1 (PD-L1) expression on immune cells (ICs) is a predictive marker for PD-L1 checkpoint blockade in patients with triple-negative breast cancer (TNBC). However, the level of PD-L1 expression and the percentage of cells that are PD-L1+ are continuous variables not dichotomous variables for tumor-infiltrating lymphocytes (TILs) and other cells. METHODS: Multiplexed immunohistochemistry was applied to 31 archived surgical specimens from untreated TNBC patients. TIL levels were visually scored, and CD8+ T cells and PD-L1+ ICs were quantified using an automated multispectral imaging system. PD-L1 expression was assessed within a multiplexed context (CD8 combined spectral composite). RESULTS: The mean value of stromal TILs (i.e., the percentage of the stromal area with a dese mononuclear infiltrate) was 20%. The frequency of patients with PD-L1-positive tumor cells (TC) and ICs was 38.7% and 32.2%, respectively, with a significant association between them. TIL levels were correlated with CD8+ T cell infiltration in the stroma (Spearman r = 0.795, p < 0.0001). PD-L1 expression on IC was significantly associated with TIL levels (Spearman r = 0.790, p < 0.001) and infiltration of CD8+ T cells (Spearman r = 0.683, p < 0.0001). CONCLUSIONS: The level of PD-L1 on IC was correlated with the level of PD-L1 on TC as well as TIL levels and infiltration of CD8+ T cells. These results suggest that high PD-L1 on IC may reflect T cell-inflamed tumors with the amount of TILs present, including the CD8+ T cells required for anti-tumor responses.

DOI： 10.1007/s12282-020-01110-2

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There is no predictive biomarker for response to 5‑fluorouracil (5FU)‑based neoadjuvant chemotherapy (NAC) in rectal cancer. In the present study, we examined potential long non‑coding RNAs (lncRNAs) linked to the susceptibility to 5FU in cultured colorectal cancer cells, and in biopsy and resected tissues of 31 human rectal cancer cases treated with NAC. Candidate lncRNAs for the prediction of susceptibility to 5FU were investigated by comprehensive analysis of expression profiles of 84 lncRNAs in cultured cells using PCR array. Bioinformatic analysis identified H19 and urothelial cancer associated 1 (UCA1) as candidate biomarkers for 5FU susceptibility. Quantitative PCR of H19 and UCA1 in cultures of colorectal cancer cells demonstrated the notable variation in expression. The ratios of changes of H19 and UCA1 expression in response to 5FU were low in cells resistant to 5FU, whereas ratios were high in cells susceptible to 5FU. In 5FU‑susceptible cells, cell proliferation was inhibited by 5FU. Upregulation of H19 and UCA1 were associated with the reduction in target molecule expression, including retinoblastoma and p27kip1. In 31 cases of rectal cancer, H19 and UCA1 expression levels in biopsy and resected tissue were comparable. The ratios of H19 and UCA1 expression in resected tissue compared with biopsy samples were low in 17 cases, whereas the ratios were high in 14 cases; 11 of the 17 cases (65%) with low ratios exhibited poor response to NAC, whereas 4 of the 14 cases (29%) with high ratios showed poor response (P=0.045). The increase in H19 and UCA1 expression may represent the response to impaired cell cycle in cells susceptible to 5FU. Our results indicate that changes in H19 and UCA1 expression may be considered for predicting the susceptibility to 5FU‑based NAC in rectal cancer.

DOI： 10.3892/ijo.2019.4895

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Language：Japanese   Publisher：日本医科大学医学会  

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Language：English   Publisher：日本癌学会  

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Language：English   Publishing type：Research paper (scientific journal)  

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Language：English   Publisher：(一社)日本癌学会  

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Language：Japanese   Publisher：(一社)日本内分泌外科学会  

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Decreased cell adhesion has been reported as a significant negative prognostic factor of lung cancer. However, the molecular mechanisms responsible for the cell incohesiveness in lung cancer have not yet been elucidated in detail. We herein describe a rare histological variant of lung adenocarcinoma consisting almost entirely of individual cancer cells spreading in alveolar spaces in an incohesive pattern. A whole exome analysis of this case showed no genomic abnormalities in CDH1 or other genes encoding cell adhesion molecules. However, whole mRNA sequencing revealed that this case had an extremely high expression level of mucin 21 (MUC21), a mucin molecule that was previously shown to inhibit cell-cell and cell-matrix adhesion. The strong membranous expression of MUC21 was found on cancer cells using mAbs recognizing different O-glycosylated forms of MUC21. An immunohistochemical analysis of an unselected series of lung adenocarcinoma confirmed that the strong membranous expression of MUC21 correlated with incohesiveness. Thus, MUC21 could be a promising biomarker with potential diagnostic and therapeutic applications for lung adenocarcinoma showing cell incohesiveness.

DOI： 10.1111/cas.14129

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE PUBLICATIONS LTD  

Current immunohistochemistry methods for diagnosing abnormal cells, such as cancer cells, require multiple steps and can be relatively slow compared with intraoperative frozen hematoxylin and eosin staining, and are therefore rarely used for intraoperative examination. Thus, there is a need for novel rapid detection methods. We previously demonstrated that functionalized fluorescent ferrite beads (FF beads) magnetically promoted rapid immunoreactions. The aim of this study was to improve the magnetically promoted rapid immunoreaction method using antibody-coated FF beads and a magnet subjected to a magnetic field. Using frozen sections of xenograft samples of A431 human epidermoid cancer cells that express high levels of epidermal growth factor receptor (EGFR) and anti-EGFR antibody-coated FF beads, we reduced the magnetically promoted immunohistochemistry procedure to a 1-min reaction and 1-min wash. We also determined the optimum magnetic force for the antibody reaction (from 7.79 x 10(-15) N to 3.35 x 10(-15) N) and washing (4.78 x 10(-16) N), which are important steps in this technique. Furthermore, we stained paraffin-embedded tissue arrays and frozen sections of metastatic breast cancer lymph nodes with anti-pan-cytokeratin antibody-coated FF beads to validate the utility of this system in clinical specimens. Under optimal conditions, this ultra-rapid immunostaining method may provide an ancillary method for pathological diagnosis during surgery. (J Histochem Cytochem 58:XXX-XXX, 2010)

DOI： 10.1369/0022155419841023

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Toll‑like receptor 4 (TLR4), a key regulator of the innate immune system, is expressed not only in immune cells, but also in a number of cancer cells. A biological role for TLR4 in cutaneous squamous cell carcinoma (SCC), however, is unclear. In this study, we first examined TLR4 expression and localization in cases of SCC, actinic keratosis (AK) and Bowen's disease (BD) by immunohistochemistry. TLR4 expression was significantly higher in the SCC than in the AK or BD tissues. We then determined the TLR4 expression level in vivo, in 3 histological subtypes of SCC. TLR4 expression in poorly differentiated SCC was significantly lower compared with that of the moderately and well‑differentiated type. In addition, the CD44 immunoreactivity tended to be high in the cell membrane of poorly differentiated SCC. Of note, poorly differentiated SCC is a risk factor of unfavorable outcomes in affected patients. We then assessed the biological role of TLR4 in HSC‑1 and HSC‑5 SCC cells and HaCaT human keratinocytes. TLR4 knockdown by transfection with siRNA accelerated HSC‑1 and HaCaT cell migration and invasion compared to the control siRNA‑transfected cells. TLR4 knockdown resulted in an increased CD44 expression and in an enhanced filopodia protrusion formation, particularly in HSC‑1. On the whole, these results suggest that a reduced TLR4 expression enhances the malignant features in SCC cases and cultured SCC cell lines. TLR4 may thus play an anti‑tumor role in cutaneous SCC.

DOI： 10.3892/ijo.2019.4790

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Language：Japanese   Publisher：(公社)日本臨床細胞学会  

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Language：Japanese   Publisher：(一社)日本内分泌外科学会  

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BACKGROUND AND OBJECTIVES: Emerging evidence suggests that the presence of atypical mitoses is associated with poor prognosis in some types of cancer, but its clinical significance remains uncertain. Here, we investigated the occurrence of atypical mitoses in breast cancers. METHODS: Mitotic figures, including normal and atypical mitoses, were assessed in resected histological sections from 109 patients with invasive carcinoma of no special type (ICNST). Comparisons with clinicopathological features and biomarkers such as Ki67 and phosphohistone H3 (PHH3) were performed. RESULTS: The total number of mitotic figures, including atypical mitoses, was higher in situ and invasive ductal carcinoma components than in normal ducts. Morphological characteristics of atypical mitoses included multipolar, lagged, ring, asymmetrical mitoses, and anaphase bridge. Patients with higher total mitoses and PHH3, and the presence of atypical mitoses showed reduced overall survival (OS), compared to those with lower total mitoses and PHH3, and without atypical mitoses (P = 0.03, 0.02, and <0.001, respectively). In multivariate analysis, the presence of atypical mitoses alone attained significant correlation with shorter OS (P < 0.001). CONCLUSIONS: Atypical mitoses in routinely resected specimens have a robust prognostic value for ICNST of the breast, but its clinical utility remains to be validated in a multicenter large material.

DOI： 10.1002/jso.25152

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Background: Some patients with genetic defects develop Epstein-Barr virus (EBV)-associated lymphoproliferative disorder (LPD)/lymphoma as the main feature. Hypomophic mutations can cause different clinical and laboratory manifestations from null mutations in the same genes. Methods: We sought to describe the clinical and immunologic phenotype of a 21-month-old boy with EBV-associated LPD who was in good health until then. A genetic and immunologic analysis was performed. Results: Whole-exome sequencing identified a novel compound heterozygous mutation of ZAP70 c.703-1G>A and c.1674G>A. A small amount of the normal transcript was observed. Unlike ZAP70 deficiency, which has been previously described as severe combined immunodeficiency with nonfunctional CD4+ T cells and absent CD8+ T cells, the patient had slightly low numbers of CD8+ T cells and a small amount of functional T cells. EBV-specific CD8+ T cells and invariant natural killer T (iNKT) cells were absent. The T-cell receptor repertoire, determined using next generation sequencing, was significantly restricted. Conclusions: Our patient showed that a hypomorphic mutation of ZAP70 can lead to EBV-associated LPD and that EBV-specific CD8+ T cells and iNKT cells are critically involved in immune response against EBV infection.

DOI： 10.1093/infdis/jiy231

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W.B. Saunders  

Breast carcinoma with osteoclast-like giant cells (OGCs) is a rare disease characterized by the infiltration of OGCs in the tumor
however, cytological aspects of this tumor type remain elusive. We examined the cytological features in fine needle aspiration (FNA) biopsy smears obtained from 5 patients who were histologically diagnosed with breast carcinoma with OGCs. We compared FNA and clinicopathological findings with results from the published literature. Histological assessment of the resected samples showed that all tumors exhibited a histological grade 1 phenotype with a predominant cribriform architecture. Four patients were estrogen receptor positive, and 1 patient showed a triple negative phenotype. All patients survived without tumor recurrence. In the FNA smears, tumor cells were arranged in loosely cohesive clusters, characterized by varying degrees of OGCs infiltration and rare formation of solid tumor nests. Occasionally, 2- or 3-dimensional clusters of tumor cells were found, accompanied by OGCs at the peripheral regions. In all patients, tumor cells were small without severe nuclear atypia. None of the patients showed significant background necrosis. In summary, cytological features of breast carcinoma with OGCs are characterized by loose aggregates of low grade tumor cells, the presence of OGCs, and the absence of necrosis, all of which were consistent with features reported previously. This peculiar form of breast tumors should be included in the differential diagnosis, when physicians encounter FNA findings including low grade ductal carcinoma with the admixture of multinucleated giant cells or OGCs.

DOI： 10.1016/j.anndiagpath.2017.11.003

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier GmbH  

Breast carcinoma with osteoclast-like giant cells (OGCs) is a rare tumor
however, their clinicopathological aspects remain unclear. We described the clinicopathological characteristics of 8 patients with breast carcinoma with OGCs. Immuno-phenotypes of the OGCs were comparatively examined with that of foreign body giant cells (FBGCs) in 4 cases of granulomatous reaction (GR) without cancerous elements. In most cancers, tumors displayed cribriform and tubular growth patterns. Three cases showed moderate to high nuclear grade, while all the other tumors had low nuclear grade. Six patients were estrogen receptor (ER) positive, while triple negative phenotype was identified in 2 patients. During the follow-up period, 1 patient had local recurrence of the tumor, and all the patients remained alive. All OGCs and FBGCs expressed CD68, a pan-macrophage marker. OGCs in all the breast cancers showed moderate to high expression of CD163 — a marker of M2-macrophage with pro-tumoral function — whereas its expression in FBGCs was low to moderate (p = 0.04). CD86 — a marker of M1-macrophage with a tumoricidal activity — was positive in the OGCs of 3 breast cancers, and in the FBGCs of 3 GR cases (p = 0.15). The expression of CD163 was significantly higher than that of CD86 in the OGCs of breast cancer (p &lt
0.001), whereas they were comparable in the FBGCs of GR (p = 0.79). In summary, we found that breast carcinoma with OGCs mostly exhibited cribriform and tubular growth pattern, ER positivity, and predominantly possessed the M2-macrophage phenotype. However, the clinical significance of OGCs in breast cancer needs to be elucidated in further studies involving a larger number of cases.

DOI： 10.1016/j.prp.2017.11.002

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publisher：(一社)日本病理学会  

30代、女性。画像所見から平滑筋肉腫および腹腔内播種が疑われ、子宮、両側付属器、大網および腹膜結節切除術が施行された。子宮腔内には10cm大の黄色で弾性軟の隆起性病変がみられ、漿膜および付属器周囲には大小の黄色結節が多発しており、腹膜播種性平滑筋腫症も疑われた。組織学的には核の大小不同を伴う紡錘形細胞が増殖し、tongue-likeパターンもみられた。これらの細胞はCD10陽性であったが、約20%の細胞でdesminとcaldesmonが陽性で、平滑筋分化を伴う低悪性度子宮内膜間質肉腫と診断した。腹腔内の多発病変がある子宮内膜間質肉腫、および腹膜播種性平滑筋腫症の鑑別には、特徴的な組織像と発現マーカーに留意しながら診断すべきと考えられた。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing Ltd  

Aims: Solid variant of papillary thyroid carcinoma (SVPTC) is characterized by a solid component (SC) involving more than 50% of the tumour with the preservation of the classical cytological features of papillary thyroid carcinoma (PTC). However, the clinical significance of SC in PTC has been rarely examined. Herein, we investigated retrospectively the clinicopathological features of PTC with various degrees (10–85%) of SC (PTCSC). Methods and results: Patients with PTCSC (n = 27) were stratified into SC-major (SC &gt
50% of the tumour) and SC-minor (SC &lt
49%) groups. The clinicopathological parameters were compared to the well-differentiated PTC (WPTC) group (n = 47). Both SC-minor (n = 18) and SC-major (n = 9) groups had increased incidence of a large-sized tumour, extracapsular extension and a high recurrence rate, compared to WPTC. Disease-free survival (DFS) of both SC-minor and SC-major was shorter than that of WPTC (P = 0.035 and P = 0.016, respectively). Overall survival was similar among all the groups. Univariate analysis revealed that SC was associated significantly with a recurrence rate (P = 0.018). Using multivariate analysis, SC appeared to be associated with a recurrence rate with borderline significance (P = 0.055). Conclusions: Our findings indicate that the presence of SC in PTC, regardless of the proportion, is associated with adverse clinical parameters and a shorter DFS.

DOI： 10.1111/his.13132

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER GMBH, URBAN & FISCHER VERLAG  

Triple negative breast cancer (TNBC) has an aggressive phenotype and poor prognosis. Neoadjuvant chemotherapy (NAC) is often used to treat TNBC, but some patients are resistant to NAC. We postulated that a subpopulation of TNBC cells expressing IMP3, an oncofetal protein, could be resistant to NAC, contributing to the poor prognosis. We investigated immunohistochemical expression of IMP3 in 42 TNBC patients who underwent NAC in association with clinical outcomes. The patients were divided into IMP3 positive (+) (n=19) and negative (-) (n=23) groups. High Ki67 positivity was detected in 13 patients of the IMP3 + group and 8 cases in the IMP3 - group (p = 0.03). While 9 patients in the IMP3 - group (39%) were responders, the majority of the IMP3 + patients (84.2%) were non-responders (p = 0.01). In a Cox proportional hazard model, IMP3 expression was independently associated with poor NAC response and clinical outcomes (p = 0.03 and 0.046, respectively). The IMP3 + group showed a tendency toward shorter overall survival compared to the IMP3 - group with marginal significance (p = 0.07). These findings suggest that IMP3 + tumor cells contributed to the poor clinical outcomes by exerting a chemoresistance to NAC, and that IMP3 expression has prognostic value as a biomarker for chemosensitivity and overall survival in TNBC. (C) 2017 Elsevier GmbH. All rights reserved.

DOI： 10.1016/j.prp.2017.07.002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BioMed Central Ltd.  

Background: Signet ring cells (SRCs) often accompany gastrointestinal carcinoma, referred to as SRC carcinoma
however, breast cancers containing SRCs have not been well characterized, leaving the prognostic significance of SRCs undetermined. We have described clinicopathological characteristics of patients with breast cancer containing SRCs in relation to the expression levels of MUC1, MUC2, MUC4, MUC5AC, and MUC6. Methods: Twenty-two breast cancer cases with variable degrees of SRC population were retrospectively studied. Each case was categorized as high (&gt
31%) or low (&lt
30%) SRC tumor. The SRCs were morphologically classified into the intra-cytoplasmic lumen (ICL) type, or the non-ICL type. The expression levels of MUC1, MUC2, MUC4, MUC5AC and MUC6 were determined immunohistochemically. Depending on its subcellular localization, MUC1 was categorized as the luminal and cytoplasmic (LC) type, or the cytoplasmic with circumferential membranous accentuation (CM) type. These histological findings were compared with other clinicopathological parameters. Results: The series consisted of invasive ductal carcinoma (n=9), invasive lobular carcinoma (n=9), and mucinous carcinoma (n=4) cases. The SRC population accounted for 8-81% of the tumor cells. Eight cases had ICL type SRCs, and the remaining 14 had non-ICL type SRCs. Neither the high (n=12) and low (n=10) percentage of SRCs, nor the SRC types affected the clinicopathological parameters. In the low MUC1 group (n=11), larger tumors, higher nuclear grade, lymph node metastasis, and negativity for estrogen receptor was more frequently identified compared to the high MUC1 group (n=11
p=0.01, p=0.002, p=0.008, and p=0.02, respectively). The CM group (n=7) had more patients with large-sized tumors, lymph node metastasis, lymphovascular invasion, and higher Ki67 indices than the LC group (n=15
p=0.04, p=0.001, p=0.006, and p=0.03, respectively). The expression levels of MUC2, MUC4, MUC5AC, and MUC6 showed no clinicopathological significance. Two patients with low MUC1 expression and CM patterns had tumor recurrence, resulting in death, while all the other patients survived without recurrence. Conclusion: Our results demonstrate that in breast cancers containing SRCs, low MUC1 expression and/or its CM subcellular localization patterns are associated with unfavorable clinicopathological factors. The utility of MUC1 expression as a prognostic marker remains to be verified in future studies.

DOI： 10.1186/s13000-016-0584-1

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Objective: Mucinous carcinoma (MCA) may show neuroendocrine differentiation (ND), but the cytological features characteristic of ND remains elusive. We compared fine needle aspiration (FNA) findings of MCA between cases with high and low degrees of ND. Methods: Histological sections of 37 MCA cases were immunohistochemically evaluated for expression of chromogranin A and synaptophysin, and were graded as 0 to 3+ degrees of ND. They were divided into low ND (grade 0 and 1+) and high ND (grade 2+ and 3+) groups. Pre-operative FNA samples of each group were assessed for cytological features. Results: The mean age of the high ND group (n = 18) was higher than the low ND group (n = 19, P = 0.01). In FNA samples of the high ND group, 17 cases showed moderate to severe degrees of discohesiveness, but low ND cases mainly showed no or only mild discohesiveness (P &lt
0.001). Nine of the low ND cases displayed overlapped, cohesive cell clusters, whereas, in the high ND cases, the cells were arranged in a loose, flat and monolayered pattern (P = 0.045). Fourteen of the high ND cases had round nuclei, but oval nuclei were predominant in the low ND cases (P = 0.027). The nuclei were eccentrically located in 12 of the high ND cases but were centrally located in 14 of the low ND cases (P = 0.01). Conclusions: Mucinous carcinoma with high ND may be diagnosed by the presence of discohesiveness, a flat, monolayered pattern, and round or eccentrically located nuclei. Features of ND in carcinomas in other organs, such as intracytoplasmic granules and coarse chromatin, may not be reliable cytological features of ND in MCA. This study describes the detailed cytological features of the Mucinous carcinoma (MCA) of breast with neuroendocrine differentiation (ND) in 37 patients. The staining distribution of ND markers was semi-quantitatively graded as high and low ND groups. This was correlated with the clinical profile of these patients.

DOI： 10.1111/cyt.12298

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Language：English   Publisher：AMER ASSOC CANCER RESEARCH  

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A lack of consistent methods to evaluate Ki67 expression is problematic in terms of accurately predicting prognosis in breast cancer. Accordingly, this study aimed to identify the causes of discrepancies in Ki67 labeling index measurements by different observers under different conditions using breast cancer samples.
This Japanese study group compared and assessed immunohistochemical (IHC) analysis of the Ki67 labeling index when measured by different pathologists. Six pathologists (pathologists A-F) in Japan participated in this ring study. One hundred and ten surgical cases of estrogen receptor-positive and human epidermal growth factor receptor 2-negative invasive breast cancer treated in 2007 were identified from the breast cancer database of Tokai University Hospital and were included in this study.
For all 6 pathologists, the Ki67 labeling index were significantly different between grade 3 and grade 1 cases and between grade 3 and grade 2 cases, whereas the index tended to be different between grade 1 and grade 2 cases. Further, the Ki67 labeling indexes measured by the 6 pathologists were strongly correlated (rho: 0.73-0.88). The IHC scores recorded by pathologist A were in moderate to good agreement with those recorded by the others in patients with a Ki67 labeling index of &lt; 13.25 % and in those with a Ki67 labeling index of &gt; 13.25 % (kappa = 0.429-0.660). The Ki67 low and high concordance rates between pathologist A and the others were 0.452-0.778 and 0.862-0.979, respectively. The most pertinent reason for discrepancy in scores seemed to be the selection of the area for counting and the quality of nuclear staining.
The Ki67 labeling index measured by 6 pathologists without method standardization was in fair to good agreement. We plan to undertake a second ring study, pending recommendations by the international Ki67 panel.

DOI： 10.1007/s12282-014-0536-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：E-CENTURY PUBLISHING CORP  

Signet ring cell (SRC) carcinoma is a unique subtype of adenocarcinoma; however, the clinicopathological profiles of SRCs in breast carcinoma are yet to be determined. Here, we investigated cyto-histological findings of 11 breast carcinoma cases with SRCs comprising more than 20% of the tumor cells; invasive ductal carcinoma (IDC) (n=4), invasive lobular carcinoma (ILC) (n=4), pleomorphic lobular carcinoma (PLC) (n=1), and mucinous carcinoma (MC) (n=2). The mean age of the patients was 60.2 +/- 13 years, and the mean tumor size was 2.0 +/- 0.8 cm. Three cases of IDC, 1 PLC, and 1 of MC had grade 2 or 3 nuclear atypia, whereas 1 case of IDC, 4 of ILC, and 1 of MC had grade 1 nuclear atypia. Axillary lymph nodes were positive for metastatic carcinoma in 1 patient with IDC and 1 with ILC. In fine needle aspiration smears, intracytoplasmic lumen (ICL) type SRCs were found to be major constituents of SRCs in ILC and PLC, while non-ICL type SRCs were predominant in IDC. MC tumors had SRCs of both ICL and non-ICL types. During our follow-up period ranging from 97 to 3650 (mean 1458 +/- 1055) days, all the patients were alive without recurrence of the tumor. Our results indicate that the nature of SRCs may vary with the histological subtype of breast cancer, but its presence may not indicate poor prognosis. A large study with more cases of breast cancer with SRCs for a longer period may be needed to determine the clinical significance of SRCs.

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PURPOSE: We hypothesized that a reduction in the size of the lymph nodes after neoadjuvant therapy for locally advanced rectal carcinoma would be associated with decreased lymph node metastases and/or a better prognosis. METHODS: Between March 2006 and April 2012, 71 patients with primary rectal cancer received neoadjuvant chemoradiation therapy (CRT). For all lymph nodes 5 mm or larger in size, the major and minor axes were measured on CT scan images, and the product was calculated. The lymph node size was determined before and after CRT. The patients were divided into three groups based on the lymph node size before and after treatment. Group A exhibited a reduction in size of 60% or more, Group B a reduction of less than 60% and Group C had no lymph node enlargement before treatment. RESULTS: The incidence of lymph node metastases on pathological examination was 15% in Group A and 50% in Group B (p = 0.006). The five-year disease-free survival in Group A was 84% compared with 78% in Group B (log rank p = 0.34). The five-year overall survival in Group A was 92% compared with 74% in Group B (log rank p = 0.088). CONCLUSIONS: A reduction in the size of enlarged lymph nodes after neoadjuvant therapy may be a useful prognostic factor for recurrence and survival.

DOI： 10.1007/s00595-014-1007-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Although an important biomarker in breast cancer, Ki67 lacks scoring standardization, which has limited its clinical use. Our previous study found variability when laboratories used their own scoring methods on centrally stained tissue microarray slides. In this current study, 16 laboratories from eight countries calibrated to a specific Ki67 scoring method and then scored 50 centrally MIB-1 stained tissue microarray cases. Simple instructions prescribed scoring pattern and staining thresholds for determination of the percentage of stained tumor cells. To calibrate, laboratories scored 18 'training' and 'test' web-based images. Software tracked object selection and scoring. Success for the calibration was prespecified as Root Mean Square Error of scores compared with reference &lt;0.6 and Maximum Absolute Deviation from reference &lt;1.0 (log2-transformed data). Prespecified success criteria for tissue microarray scoring required intraclass correlation significantly &gt;0.70 but aiming for observed intraclass correlation &gt;= 0.90. Laboratory performance showed non-significant but promising trends of improvement through the calibration exercise (mean Root Mean Square Error decreased from 0.6 to 0.4, Maximum Absolute Deviation from 1.6 to 0.9; paired t-test: P=0.07 for Root Mean Square Error, 0.06 for Maximum Absolute Deviation). For tissue microarray scoring, the intraclass correlation estimate was 0.94 (95% credible interval: 0.90-0.97), markedly and significantly &gt;0.70, the prespecified minimum target for success. Some discrepancies persisted, including around clinically relevant cutoffs. After calibrating to a common scoring method via a web-based tool, laboratories can achieve high inter-laboratory reproducibility in Ki67 scoring on centrally stained tissue microarray slides. Although these data are potentially encouraging, suggesting that it may be possible to standardize scoring of Ki67 among pathology laboratories, clinically important discrepancies persist. Before this biomarker could be recommended for clinical use, future research will need to extend this approach to biopsies and whole sections, account for staining variability, and link to outcomes.

DOI： 10.1038/modpathol.2015.38

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We performed an immunohistochemical analysis of the expression of zinc-finger E-box binding homeobox 1 (ZEB1), a master regulator of epithelial-mesenchymal transition (EMT), and determined its relationship with E-cadherin in 157 non-small cell lung carcinomas (93 adenocarcinomas, 36 squamous cell carcinomas, 18 large cell carcinomas, and 10 pleomorphic carcinomas). Although the expression of E-cadherin was low in the subset of adenocarcinomas (10%) and squamous cell carcinomas (11%), ZEB1 expression was only observed in one case of squamous cell carcinoma and none of the adenocarcinomas. In contrast, the low expression of E-cadherin (50% and 90%, respectively) and the positive expression of ZEB1 (11% and 50%, respectively) were more frequently observed in poorly differentiated carcinomas (large cell carcinomas and pleomorphic carcinomas). Overall, the expression of ZEB1 was inversely correlated with that of E-cadherin. Furthermore, the distribution of ZEB1-positive cancer cells was more restricted than in the area in which the expression of E-cadherin was lost, and the former was detected within the latter. We concluded that the expression of ZEB1 was not necessarily associated with the low expression of E-cadherin in lung adenocarcinomas and squamous cell carcinomas. The expression of ZEB1 correlated with an undifferentiated and/or sarcomatoid morphology that may occur in the late stage of EMT.

DOI： 10.1111/pin.12214

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

The effectiveness of neoadjuvant chemotherapy is evaluated on the basis of pathological responses and survival outcome, because achievement of a pathological complete response (pCR) is a good predictor of long-term survival. However, few studies have assessed the survival of breast cancer patients who received neoadjuvant chemotherapy including trastuzumab.
The records of 161 breast cancer patients who received neoadjuvant chemotherapy between January 2006 and December 2011 were retrospectively reviewed. The patients were categorized into 4 subgroups on the basis of the status of the estrogen receptor (ER), the progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). HER2-positive patients received trastuzumab-based regimens. Pathological responses and survival were analyzed on the basis of breast cancer subtypes.
The pCR results obtained were: luminal A and B (ER and/or PR-positive, HER2-negative), 6.3 % (5/79 cases); luminal-HER2 hybrid (ER and/or PR-positive, HER2-positive), 25.0 % (5/20 cases); HER2-enriched (ER and PR-negative, HER2-positive), 63.0 % (17/27 cases); and triple-negative (ER and PR-negative, HER2-negative), 25.7 % (9/35 cases). Achievement of pCR was a good predictor of disease-free survival in the HER2-enriched group. Overall survival of patients with pCR was slightly, but not significantly, better in the HER2-enriched and triple-negative subgroups.
Responses and survival after neoadjuvant chemotherapy including trastuzumab of patients with HER2-positive tumors differed among disease subtypes. Our findings suggest that disease subtype is an important determinant of the efficacy of neoadjuvant chemotherapy.

DOI： 10.1007/s12282-012-0424-4

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BRG1 and BRM, two core catalytic subunits in SWI/SNF chromatin remodeling complexes, have been suggested as tumor suppressors, yet their roles in carcinogenesis are unclear. Here, we present evidence that loss of BRG1 and BRM is involved in the progression of lung adenocarcinomas. Analysis of 15 lung cancer cell lines indicated that BRG1 mutations correlated with loss of BRG1 expression and that loss of BRG1 and BRM expression was frequent in E-cadherin-low and vimentin-high cell lines. Immunohistochemical analysis of 93 primary lung adenocarcinomas showed loss of BRG1 and BRM in 11 (12%) and 16 (17%) cases, respectively. Loss of expression of BRG1 and BRM was frequent in solid predominant adenocarcinomas and tumors with low thyroid transcription factor-1 (TTF-1, master regulator of lung) and low cytokeratin7 and E-cadherin (two markers for bronchial epithelial differentiation). Loss of BRG1 was correlated with the absence of lepidic growth patterns and was mutually exclusive of epidermal growth factor receptor (EGFR) mutations. In contrast, loss of BRM was found concomitant with lepidic growth patterns and EGFR mutations. Finally, we analyzed the publicly available dataset of 442 cases and found that loss of BRG1 and BRM was frequent in E-cadherin-low, TTF-1-low, and vimentin-high cases and correlated with poor prognosis. We conclude that loss of either or both BRG1 and BRM is involved in the progression of lung adenocarcinoma into solid predominant tumors with features of epithelial mesenchymal transition and loss of the bronchial epithelial phenotype. BRG1 loss was specifically involved in the progression of EGFR wild-type, but not EGFR-mutant tumors. © 2012 Japanese Cancer Association.

DOI： 10.1111/cas.12065

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Rearranged during transfection (RET) fusions have been newly identified in approximately 1% of patients with primary lung tumors. However, patient-derived lung cancer cell lines harboring RET fusions have not yet been established or identified, and therefore, the effectiveness of an RET inhibitor on lung tumors with endogenous RET fusion has not yet been studied. In this study, we report identification of CCDC6-RET fusion in the human lung adenocarcinoma cell line LC-2/ad. LC-2/ad showed distinctive sensitivity to the RET inhibitor, vandetanib, among 39 non-small lung cancer cell lines. The xenograft tumor of LC-2/ad showed cribriform acinar structures, a morphologic feature of primary RET fusion-positive lung adenocarcinomas. LC-2/ad cells could provide useful resources to analyze molecular functions of RET-fusion protein and its response to RET inhibitors. © 2012 by the International Association for the Study of Lung Cancer.

DOI： 10.1097/JTO.0b013e3182721ed1

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Strangulation of the gallbladder by the omentum is extremely rare. We report what to our knowledge is only the second documented case of strangulation of a floating gallbladder by the lesser omentum. A 61-year-old Japanese woman presented to a local hospital after the sudden onset right upper quadrant pain. Her clinical features suggested a gallbladder volvulus, and the patient was referred to our hospital for investigation and treatment. Ultrasonography and computed tomography showed no cholecystolithiasis, but the fundus and body of the gallbladder were markedly swollen without wall thickening, whereas the neck of the gallbladder was normal. A narrowed, twisted area was seen between the body and neck of the gallbladder. Based on these findings, gallbladder volvulus was diagnosed and she underwent emergency laparoscopic cholecystectomy. The fundus and body of the gallbladder were grossly necrotic. The narrowest part of the gallbladder was tightly strangulated by the lesser omentum, but the gallbladder neck was normal. Histopathologic examination of the resected gallbladder showed ischemic changes in the wall of the fundus and body. This case highlights that the clinical features and imaging findings of a gallbladder strangulated by the lesser omentum are similar to those of gallbladder volvulus and that a positive outcome is dependent on a correct diagnosis and prompt surgical management.© 2012 Springer.

DOI： 10.1007/s00595-012-0171-3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Extranodal non-Hodgkin's lymphoma (NHL) is a rare breast disease. Here we report three cases of primary NHL of the breast. The first patient was a 29-year-old woman with a firm mass in her right breast with ipsilateral axillary lymphadenopathy. An excisional biopsy revealed NHLs. Clinical stage was IIAE. The tumor and enlarged lymph nodes had successfully been treated following the combination therapy. The second patient was a 70-year-old women with an elastic hard mass in her left breast. An excisional biopsy revealed NHLs and clinical stage was 1AE. The tumor disappeared following the combination therapy. The third patient was a 67-year-old women with a hard mass in her left breast. Core needle biopsy revealed NHLs and clinical stage was 1AE. The tumor disappeared following chemotherapy. All patients are alive with no evidence of recurrence 4-8 years after the initial treatment. Although a standard treatment has yet to be established, an initial treatment with combination therapy without surgical intervention including axillary dissection appears to be appropriate for this rare disease.

DOI： 10.1007/s12282-009-0107-y

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Background: Gastric cancer (GC) is a major cancer, sometimes associated with Epstein-Barr virus (EBV). Some transcriptional factors (TFs) are specific to the digestive tract and related to the character of the tumors. Methods: We studied three TFs, SOX2, CDX2, and hepatocyte nuclear factor 4 alpha-promoter 1 (HNF4aP1) in GC. First, 255 tumors including 31 EBV-associated GC were immunohistochemically examined using tissue arrays and compared TF type and mucin phenotype. We classified them into 4 TF types: N-TF type as SOX2-/HNF4aP1- tumor, G: SOX2+/HNF4aP1-, GI: SOX2+/HNF4aP1+, and I: SOX2-/HNF4aP1+. Next, 915 GCs were intensely investigated and compared with their clinicopathological factors.Results: In the first study, 255 GCs were classified into N-TF 44%, GTF 31%, GI-TF 3%, and I-TF 2%. The TF type did not strictly accord with the mucin phenotype, classified by MUC2/5AC/6/CD10 expression. EBV status was the only factor related to both the TF and mucin phenotype classifications (P&lt
0.0001, &lt
0.0001). TF classification is related to more factors including tumor stage, than mucin phenotype classification. The second study using 915 GCs revealed that N-TF gradually increased and I-TF decreased as GC invaded deeper. TF classification was not related to nodal involvement in each tumor stage. HNF4aP1 and CDX2 were independent factors for early stage tumor in logistic regression analysis. Conclusions: EBV-associated GC is a discriminating group in both TF and mucin phenotype. TF classification, especially the absence of HNF4aP1 and CDX2, is related to tumor invasion. TF classification is a useful marker to study the carcinogenesis of GC further.

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Ribonucleotide reductase M2 subunit is one of two subunits that constitute ribonucleotide reductase, the enzyme that catalyzes the conversion of ribonucleotide 5′-diphosphates into 2′-deoxyribonucleotides, which are required for DNA synthesis. This study was conducted to investigate the roles of ribonucleotide reductase M2 subunit in gastric cancer. The expression of ribonucleotide reductase M2 subunit protein was examined by immunohistochemistry. In normal gastric mucosa, ribonucleotide reductase M2 subunit expression was restricted to the neck regions of gastric pits and no expression was observed in the surface epithelium. Among 112 gastric cancer tissues, ribonucleotide reductase M2 subunit overexpression (≥10% cancer cells stained) was observed in 72 cases (64.3%). Ribonucleotide reductase M2 subunit overexpression was significantly associated with male sex (P = .015), presence of muscularis propria invasion (P = .020), presence of Epstein-Barr virus (P = .045), expression of survivin (P = .0014), and DNA methyltransferase 1 (P = .043), but not with age, histology, tumor size, lymph node metastasis or expression of phosphatase and tensin homolog, phosphorylated signal transducer, and activator of transcription 3 or p53. Suppression of ribonucleotide reductase M2 subunit synthesis, using small interfering RNA, inhibited the growth of 3 gastric cancer cell lines, MKN-1, MKN-7, and SNU-719. Our data suggest that ribonucleotide reductase M2 subunit overexpression could be associated with the gastric cancer progression and that suppression of its function is a potential therapeutic strategy in gastric cancer. © 2010 Elsevier Inc.

DOI： 10.1016/j.humpath.2010.06.001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

EBV-associated gastric carcinoma is a distinct gastric carcinoma subtype with characteristic morphologic features similar to those of cells that undergo epithelial-to-mesenchymal transition. The effect of microRNA abnormalities in carcinogenesis was investigated by measuring the expression of the epithelial-to-mesenchymal transition-related microRNAs, miR-200a and miR-200b, in 36 surgically resected gastric carcinomas using quantitative reverse transcription-PCR analysis. MiR-200 family expression was decreased in EBV-associated gastric carcinoma, as compared with that in EBV-negative carcinoma. Downregulation of the miR-200 family was found in gastric carcinoma cell lines infected with recombinant EBV (MKN74-EBV, MKN7-EBV, and NUGC3-EBV), accompanied by the loss of cell adhesion, reduction of E-cadherin expression, and upregulation of ZEB1 and ZEB2. E-cadherin expression was partially restored by transfection of EBV- infected cells with miR200-family precursors. Reverse transcription-PCR analysis of primary precursors of miR-200 (pri-miR-200) revealed that the transcription of pri-miR-200 was decreased in EBV- infected cells. Transfection of MKN74 cells with BARF0, EBNA1, and LMP2A resulted in a decrease of pri-miR-200, whereas transfection with EBV- encoded small RNA (EBER) did not. These four latent genes contributed to the downregulation of the mature miR-200 family and the subsequent upregulation of ZEB1/ZEB2, resulting in the reduction of E-cadherin expression. These findings indicate that all the latency type I genes have a synergetic effect on the downregulation of the miR-200 family that leads to reduced E-cadherin expression, which is a crucial step in the carcinogenesis of EBV-associated gastric carcinoma. Cancer Res; 70(11); 4719-27. (c) 2010 AACR.

DOI： 10.1158/0008-5472.CAN-09-4620

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japan Endocrine Society  

A 70-year old man with a 14 year history of Sjögren syndrome, interstitial pneumonia, and autoimmune hepatitis (AIH) was admitted to our hospital due to hyponatremia with a one month history of fatigue, thirst, and nausea. Laboratory tests on admission revealed that this patient had a central adrenal insufficiency. Pituitary magnetic resonance imaging (MRI) further showed swelling of the stalk and posterior lobe of his pituitary, suggesting infundibulo-hypophysitis. Based on his past history of autoimmune disease, his serum IgG4 levels were measured and found to be remarkably high (924 mg/ dL). Previous biopsy specimens from his liver, lung, and parotid gland were immunostained for IgG4, which revealed a marked infiltration of IgG4-positive plasma cells. As a result of our tests, we made a diagnosis of IgG4-related systemic disease. Interestingly, a subsequent MRI scan at three weeks after the patient commenced glucocorticoid replacement therapy for adrenal insufficiency showed that the swelling of his pituitary stalk was reduced. This finding suggested that IgG4-related hypophysitis may improve either as a result of a supplemental dose of glucocorticoid or possibly spontaneously. Although six cases of IgG4-related hypophysitis have been reported in the scientific literature published in English, our current case is the first in which IgG4-related hypophysitis likely occurred as a result of a long-term history of IgG4-related systemic disease. We report this case herein and review the relevant literature.

DOI： 10.1507/endocrj.K09E-356

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：8  

Epstein-Barr virus (EBV)-associated gastric carcinoma (GC) is a distinct subtype with characteristic clinicopathological features. To better characterize its cellular characteristics, 43 cases of EBV-associated GC, 68 cases of EBV-negative GC, and non-neoplastic gastric mucosa in adults and fetuses were examined immunohistochemically. We quantified the expression of the major tight-junction protein claudin (CLDN) -1, -3, -4, -7, and -18 together with gastric mucins (MUC5AC and MUC6), intestinal mucin (MUC2), and CD10. EBV-associated GC showed a high frequency of CLDN18 expression (84%) and a low frequency of CLDN3 expression (5%). This expression profile corresponded to that of normal gastric epithelium in adults and fetuses. Almost half of the EBV-associated GC cases demonstrated gastric mucin expression, whereas the other half lacked mucin or CD10 expression. In contrast, as demonstrated by the expression profiles of CLDN3 and CLDN18, EBV-negative GC comprised a heterogeneous group of four different CLDN phenotypes: gastric, intestinal, mixed, and an undifferentiated type with variable expression patterns of mucins. These results indicate that EBV-associated GC is considerably homogenous with regard to cellular differentiation and that it preserves well the nature of the cells of origin. EBV-associated GC may undergo distinct carcinogenic processes, which differ from those of EBV-negative GC. © The Histochemical Society, Inc.

DOI： 10.1369/jhc.2009.953810

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CpG island promoter methylation of tumor suppressor genes is one of the most characteristic abnormalities in EBV- associated gastric carcinoma (GC). Aberrant promoter meth- ylation and expression loss of FTEN were evaluated in cancer tissues of GC by methylation-specific PCR and immunohisto- chemistry, respectively, showing that both abnormalities occurred concurrently in EBV-associated GC. FTEN abnor- malities were reiterated in GC cell lines MKN-I and MKN-7 infected with recombinant EBY, and DNA methyltransferase 1 (DNMTl) was commonly overexpressed in both cell lines. Stable and transient transfection systems in MKN-I similarly showed that viral latent membrane protein 2A (LMF2A) upregulated DNMTl, leading to an increase in methylation of the PTEN promoter. Importantly, the level of phosphorylated signal transducer and activator of transcription 3 (pSTAT3) increased in the nuclei of LMP2A-expressing GC cells, and knockdown of STAT3 counteracted LMP2A mediated DNMTl overexpression. Immunohistochemistry for both pSTAT3 and DNMTl showed diffuse labeling in the nuclei of the cancer cells in GC tissues, especially in EBV-associated GC. Taken together, LMF2A induces the phosphorylation of STAT3, which activates DNMTl transcription and causes FTEN expression loss through CpG island methylation of the PTEN promoter in EBV-associated GC. LMP2A plays an essential role in the epigenetic abnormalities in host stomach cells and in the development and maintenance of EBV-associated cancer. ©2009 American Association for Cancer Research.

DOI： 10.1158/0008-5472.CAN-08-3070

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：5  

EBV-associated gastric carcinoma is a distinct subset of gastric carcinoma infected with EBV, which shows latency I type expression of EBV latent genes (EBNA1, EBER, BARF0, and LMP2A). To clarify the role of EBV in this type of gastric carcinoma, the cell biological characteristics (growth, apoptosis, and migration) were evaluated in gastric carcinoma cell lines (MKN-1, TMK1, MKN-74 and MKN-7) with and without infection of recombinant EBV harboring the neomycin resistance gene. The infection reiterated the latency I type infection, and the only difference observed in EBV-infected gastric carcinoma cell lines was the resistance to serum deprivation-induced apoptosis. Comparative analyses of transcripts of apoptosis-associated genes in MKN-1 and EBV-MKN-1 and subsequent quantitative reverse transcription-PCR analysis showed up-regulation of the cellular survivin gene in EBV-infected gastric carcinoma cell lines. Small interfering RNA-mediated knockdown of survivin increased apoptosis in EBV-MKN-1 to the level of the original MKN-1 cells. Transfection of EBV-latent genes into MKN-1 showed that LMP2A, but not EBNA1, EBER, or BARF0, up-regulated survivin gene expression. LMP2A-mediated survivin up-regulation in gastric carcinoma cells was inhibited with a nuclear factor-κB (NF-κB) inhibitor, Bay 11-7082. In parallel with these findings in vitro, survivin expression was frequent in carcinoma tissues of gastric carcinoma by immunohistochemistry, and significantly more in EBV-associated gastric carcinoma (12 of 13) than in EBV-negative gastric carcinoma in the advanced stage (P = 0.0307). Thus, EBV uses its latent protein, LMP2A, to activate the NF-κB-survivin pathway to rescue EBV-infected epithelial cells from serum deprivation, and up-regulation of survivin may play a role in the progression of this specific type of gastric carcinoma infected with EBV. ©2008 American Association for Cancer Research.

DOI： 10.1158/0008-5472.CAN-07-3027

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC ADVANCEMENT SCIENCE  

Loss of imprinting (LOI) of the insulin-like growth factor II gene (IGF2) is an epigenetic alteration that results in a modest increase in IGF2 expression, and it is present in the normal colonic mucosa of about 30% of patients with colorectal cancer. To investigate its role in intestinal tumorigenesis, we created a mouse model of lgf2 LOI by crossing female H19(+/-) mice with mate Apc(+/min) mice. Mice with LOI developed twice as many intestinal tumors as did control littermates. Notably, these mice also showed a shift toward a less differentiated normal intestinal epithelium, reflected by an increase in crypt length and increased staining with progenitor,cell markers. A similar shift in differentiation was seen in the normal colonic mucosa of humans with LOI. Thus, altered maturation of nonneoplastic tissue may be one mechanism. by which epigenetic changes affect cancer risk.

DOI： 10.1126/science.1108080

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC  

Genomic imprinting is the phenomenon by which the two alleles of certain genes are differentially expressed according to their parental origin. Extensive analysis of allelic expression at multiple imprinted loci in a normal population has not performed so far. In the present study, we examined the allelic expression pattern of three imprinted genes in a panel of 262 Japanese normal individuals. We observed differences in the extent of maintenance of allele-specific expression of the three genes. The allelic expression of small nuclear ribonucleoprotein N (SNRPN) was stringently regulated while that of multimembrane-spanning polyspecific transporter-like gene 1 (IMPT1) showed a large degree of variation. Significant biallelic expression of insulin-like growth factor II (IGF2) was observed in about 10% of normal individuals. Our findings add to the accumulating evidence for variable allelic expression at multiple loci in a normal human population. This epigenetic heterogeneity can be a stable trait and potentially influence individual phenotypes. (C) 2001 Academic Press.

DOI： 10.1006/bbrc.2001.4916

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Language：English   Publishing type：Research paper (scientific journal)  

Background. In hepatocellular carcinoma (HCC), new tumors develop in the residual liver within a few years after hepatectomy. However, the biological risk factors of multifocal occurrence of cancers remains unclear. In this study, the thymidine phosphorylase (TP) activity, which is known as an angiogenic factor, of cancerous and non-cancerous liver tissues in HCC was analyzed to determine its suitability as a biological marker of the multifocal occurrence of HCCs. Materials and Methods: Fresh tissues (tumor: HCC and adjacent liver tissue: N-HCC) from 63 patients with HCC and normal liver tissues (NL) from 6 patients without HCC were obtained. The TP activities of the tissues were analyzed by an enzyme-linked immunosorbent assay (ELISA). Results: The mean TP activity of 63 HCCs (136 U/mg protein) was higher than that of 63 N-HCCs (81 U/mg protein) and that of 6 NLs (47 U/mg protein, p &lt
0.001). Multifocal occurrence of HCCs were detected in 17 patients. In these 17 patients, the mean TP activity of HCCs (145 U/mg protein) was not different from that of HCCs from the remaining 46 patients (133 U/mg protein, p = 0.272), however the mean TP activity of N-HCCs (110 U/mg protein) was significantly higher than of N-HCCs from the remaining 46 patients (71 U/mg protein, p = 0.038). Moreover, only a high TP activity of N-HCCs was detected as a significant risk factor of multifocal occurrence of HCCs. Conclusion: Patients who have tumors with high TP activity in the non-cancerous livers may have a risk of multifocal occurrence of HCCs in the residual liver.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PROFESSOR D A SPANDIDOS  

We examined the clinical and pathological significance of thymidine phosphorylase (dThdPase) and vascular endothelial growth factor (VEGF) in human gastric carcinomas, in terms of intratumoral microvessel density (IMVD), P53 expression, and patient prognosis in a total of 128 patients. Mean IMVD was significantly higher in the carcinomas with dThdPase or VEGF expression than in carcinomas without the expression. The simultaneous expression of dThdPase and VEGF was correlated with increased IMVD of human gastric carcinomas. VEGF expression was associated with P53 expression and poor patient prognosis, but dThdPase expression was not.

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Language：Japanese   Publisher：日本医科大学医学会  

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Language：Japanese   Publisher：(公社)日本臨床細胞学会  

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Language：English   Publisher：日本癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：English   Publisher：(一社)日本病理学会  

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Language：Japanese   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：(公社)日本臨床細胞学会  

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Language：Japanese   Publisher：(公社)日本臨床細胞学会  

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Language：Japanese   Publisher：(公社)日本臨床細胞学会  

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Language：English   Publisher：日本癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(公社)日本超音波医学会  

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Language：Japanese   Publisher：(公社)日本超音波医学会  

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Language：Japanese   Publisher：(NPO)日本乳腺甲状腺超音波医学会  

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Language：Japanese   Publisher：(一社)日本病理学会  

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Language：Japanese  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC CLINICAL ONCOLOGY  

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J-GLOBAL

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Language：Japanese   Publisher：(公社)日本臨床細胞学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(公社)日本臨床細胞学会  

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Language：Japanese   Publisher：(一社)日本病理学会  

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Language：Japanese   Publisher：(一社)日本病理学会  

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Language：Japanese   Publisher：一般社団法人 日本プライマリ・ケア連合学会  

DOI： 10.14442/generalist.35.363

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Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)   Publisher：SPRINGER HEIDELBERG  

DOI： 10.1007/s00404-009-1086-0

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Language：Japanese   Publisher：(公社)日本臨床細胞学会  

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Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)   Publisher：WILEY-LISS  

Epstein-Barr virus (EBV) associated lymphoproliferative disease (LPD) comprises a wide spectrum of clinical and pathological features [1]. This variety is most systematically categorized in post-transplant lymphoproliferative disorders (PTLD) [2], in which subtypes are ordered according to disease progression from reactive polyclonal proliferation to large cell lymphoma. However, whether this categorization Is applicable to LPDs other than PTLD is not well explored. Here, we present a nontransplant case of EBV-LPD that initially presented as a polyclonal self-limiting proliferation and later transited to large cell lymphoma. This transition was associated with the progression of lung cancer and its therapy. Our case demonstrates that stepwise progression of LPD is a feature that can be observed in non-PTLD cases of EBV-LPD.

DOI： 10.1002/ajh.21479

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Suppression of apoptosis is important for carcinogenesis and tumor growth. Recent studies revealed that survivin not only inhibited apoptosis but also accelerated cancer cell proliferative activity. To investigate the prognostic role of expression of the antiapoptosis gene, survivin, in hepatocellular carcinoma (HCC), the authors analyzed the correlation between the expression pattern of survivin messenger RNA (mRNA) and clinicopathologic findings of patients. Tissues were obtained by surgical resection of livers from 51 patients with HCC and 6 patients without HCC. Expression of survivin mRNA was evaluated using reverse transcription-polymerase chain reaction in 51 tumors, 51 adjacent histologically noncancerous livers, and 6 normal livers. Survivin protein expression was evaluated using Western blotting, and apoptotic cancer cells were detected by immunostaining with polyclonal rabbit anti-single-stranded DNA. Survivin mRNA expression was detected in 21 of 51 (41%) tumors, 2 of 51 (4%) noncancerous livers, and none of the 6 normal livers. Survivin mRNA expression did not correlate with tumor size or stage of HCC. Percentage of apoptotic cancer cells of 30 survivin mRNA-negative tumors (5.2 +/- 3.4%) was significantly higher than that of 21 survivin mRNA-positive tumors (2.2 +/- 2.3%, P = 0.0019). The disease-free 5-year survival rate of 21 patients positive for survivin mRNA (19%) was significantly poorer than that of 30 patients negative for survivin mRNA (39%, P = 0.0148). Survivin mRNA was detected in 57% (17/30) patients with HCC recurrence but in only 19% (4/21) of patients without recurrence (P = 0.0072). These results indicated that survivin mRNA expression could be used as an independent prognostic factor for patients with HCC after hepatectomy.

DOI： 10.1097/00019606-200203000-00007

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：UNIV CHICAGO PRESS  

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Language：English   Publisher：KARGER  

Objective: An estrogen-regulated lysosomal protease, cathepsin D, has been detected in a variety of tissues. This proteinase has been described as closely associated with tumor progression and metastasis in malignant tumors. The purpose of this study was to determine the clinicopathological and prognostic significance of cathepsin D expression in gastric adenocarcinoma. Methods: In a consecutive series of 478 patients with gastric carcinoma (median follow-up period: 93 months, range: 1-285 months), cathepsin D expression in tumors was quantitatively analyzed with immunohistochemistry using a monoclonal antibody against cathepsin D (clone: 1C11). The percentage of cathepsin-D-positive cancer cells (the CD index) was calculated. In addition, the amount of cathepsin-D-positive stromal cells was evaluated; three grades (high, intermediate, and low) were used for the classification. Results: The mean CD index of 478 tumors was 12.8% (range: 0-100%, median: 8%). The mean CD index of diffuse-type gastric carcinomas (14.9%) was significantly higher than that of intestinal-type carcinomas (10.1%, p &lt; 0.0001). Cathepsin D expression of cancer cells was significantly associated with the depth of tumor invasion in both types. The percentage of tumors with high cathepsin D expression in stromal cells was significantly higher in well-differentiated tumors (25.5%) than in moderately differentiated (12.8%) or in poorly differentiated tumors (19.1%). Cathepsin D expression of stromal cells was significantly associated with the depth of tumor invasion in the intestinal type, in contrast to the diffuse type. Highly expressed cathepsin D in cancer cells was associated with a poor prognosis in both types of carcinoma, but in stromal cells highly expressed cathepsin D was associated to a poor prognosis in the intestinal type only. Conclusion: These results indicate that cathepsin D expression in cancer cells may play an important role in tumor progression in diffuse-type gastric carcinoma, whereas in the intestinal type of carcinoma, cathepsin D expression in stromal cells may play an important role in tumor progression. Copyright (C) 2001 S. Karger AG, Basel.

DOI： 10.1159/000055356

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Language：English   Publisher：WILEY-LISS  

BACKGROUND. Nuclear profiles have been reported to be useful prognostic predictors in various cancers. Data from computerized morphometry are objective and are quickly obtained by conventional microscopic analysis. However, this image analysis of nuclear features has been only rarely applied to investigations of colorectal adenocarcinoma. The aim of this study was to evaluate the correlation between the morphologic nuclear features and clinicopathologic parameters in cases of colorectal adenocarcinoma.
METHODS. Morphometric nuclear features (nuclear area, perimeter, and shape) were analyzed in 343 patients with colorectal carcinoma and in 57 patients with colorectal adenoma. In each case, 300 nuclei of carcinoma or adenoma cells were analyzed on routine hematoxylin and eosin stained slides by means of a computer-assisted image analysis system that involved tracing the nuclear profiles (magnification x400) on a computer monitor. The morphometric data were compared with patients' survival, clinicopathologic status, and DNA ploidy pattern of tumors.
RESULTS. The mean nuclear area (NA) enlarged from normal colorectal mucosa to adenoma and carcinoma (normal mucosa: n = 343, mean NA = 19 mu m(2); adenoma: n = 57, mean NA = 34 mu m(2); mucosal carcinoma: n = 15, mean NA = 45 mu m(2); P &lt; 0.001). In 343 colorectal carcinomas, NAs of cancer cells in tumors with lymphatic invasion, venous invasion, lymph node metastasis, or hepatic metastasis were significantly larger than those of cancer cells in tumors without such factors. The mean NA of DNA aneuploid tumors was larger than that of DNA diploid tumors (P &lt; 0.001). re nuclear area of cancer cells was determined to be one of the independent prognostic factors in multivariate analysis (P &lt; 0.001). Moreover, the large nuclear area of cancer cells was recognized as one of the risk factors of metachronous hematogenic metastasis in patients after curative surgery.
CONCLUSIONS. Data from computerized morphometry are objective and can be obtained rapidly by conventional microscopic analysis. The nuclear area of cancer cells appears to predict 1) the ability of cancer cells to invade the microvessels in the colorectal wall and 2) the ability of cancer cells to metastasize to die lymph nodes or Liver. Therefore, nuclear morphometry is beneficial in mass screening to select patients who are at risk of hematogenic or lymph node metastatic recurrence after curative surgery for colorectal carcinoma. Cancer 1999;86:1944-51. (C) 1999 American Cancer Society.

DOI： 10.1002/(SICI)1097-0142(19991115)86:10<1944::AID-CNCR10>3.0.CO;2-2

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Presentation type：Public lecture, seminar, tutorial, course, or other speech  

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Language：Japanese  

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Language：English   Presentation type：Symposium, workshop panel (nominated)  

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Presentation type：Symposium, workshop panel (nominated)  

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