[Show abstract][Hide abstract] ABSTRACT: Cancer stem cells (CSCs) have been reported to play an important role in chemoradiation resistance. Although the association of CSC markers with clinicopathological outcomes after neoadjuvant chemoradiotherapy (NACRT) has been reported in various types of cancers, there have been no such reports for pancreatic cancer. Here we examined the sequential changes in CSC marker expressions after NACRT in patients with pancreatic adenocarcinoma (PA) and the impact of these changes on the prognosis.
BMC Cancer 09/2014; 14(1):687. · 3.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Concurrent chemoradiotherapy has become one of the standard management approaches for newly diagnosed, localized, nasal NK/T-cell lymphoma (NKTCL). Few data are available on the prognostic biomarkers of NKTCL among patients treated with concurrent chemoradiotherapy. To evaluate the prognostic significance of immunophenotypic biomarkers for patients treated with concurrent chemoradiotherapy, latent membrane protein 1 (LMP1), cutaneous lymphocyte antigen (CLA), and cell origin were examined with samples from 32 patients who were enrolled in the Japan Clinical Oncology Group 0211 trial and treated with concurrent chemoradiotherapy. LMP1 and CLA were positive in 66% (19/29) and 29% (9/31) of the cases examined, respectively. The median follow-up duration was 68 months (range, 61-94). The patients with LMP1-positive tumors showed a better overall survival (OS) than the patients with LMP1-negative tumors [hazard ratio, 0.240; 95% confidence interval (CI), 0.057-1.013; 80% CI, 0.093-0.615; P=0.035]. All five patients with LMP1-negative tumors who experienced disease progression died of lymphoma, and both patients with local failure had LMP1-negative tumors. There was no significant difference in OS according to CLA expression. Twenty-seven (84%) cases were of NK-cell origin, two were of αβ T-cell origin, and three were of γδ T-cell origin. In contrast to those with tumors of NK-cell origin, all five patients with NKTCL of T-cell origin were alive without relapse at the last follow-up. Our results indicate that LMP1 expression is a favorable prognostic marker and suggest that a T-cell origin of the tumor may be a favorable prognostic marker for patients with localized NKTCL treated with concurrent chemoradiotherapy.This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Background:Epithelial-mesenchymal transition (EMT) is characterised by the loss of cell-to-cell adhesion and gaining of mesenchymal phenotypes. Epithelial-mesenchymal transition is proposed to occur in various developmental processes and cancer progression. 'Cadherin switch', a process in which cells shift to express different isoforms of the cadherin transmembrane protein and usually refers to a switch from the expression of E-cadherin to N-cadherin, is one aspect of EMT and can have a profound effect on tumour invasion/metastasis. The aim of this study was to investigate the clinicopathological significance of EMT-related proteins and cadherin switch in extrahepatic cholangiocarcinoma (EHCC).Methods:We investigated the association between altered expression of 12 EMT-related proteins and clinical outcomes in patients with EHCC (n=117) using immunohistochemistry on tissue microarrays.Results:Univariate and multivariate analyses revealed that, in addition to N classification (P=0.0420), the expression of E-cadherin (P=0.0208), N-cadherin (P=0.0038) and S100A4 (P=0.0157) was each an independent and a significant prognostic factor. We also demonstrated that cadherin switch was independently associated with poor prognosis (P=0.0143) in patients with EHCC.Conclusions:These results may provide novel information for selection of patients with EHCC who require adjuvant therapy and strict surveillance.British Journal of Cancer advance online publication 31 July 2014; doi:10.1038/bjc.2014.415 www.bjcancer.com.
British Journal of Cancer 07/2014; · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Extraskeletal chondroma is an unusual benign tumor, which rarely arises in the diaphragm. We report a case of chondroma of the diaphragm in a 31-year-old woman. Initially, a benign liver tumor with calcification was suspected, based on pre and intraoperative examination findings. Although parts of the tumor were contiguous with the diaphragm, its connections with the diaphragm were much narrower than its connection with the liver, which suggested a liver tumor. Pathological examination subsequently revealed that the chondroma was contiguous with the diaphragm and that there was a distinct border between the tumor and the liver; thus, the tumor was diagnosed as a chondroma of the diaphragm.
[Show abstract][Hide abstract] ABSTRACT: Entamoeba histolytica is estimated to infect approximately 1% of the global population. In Japan, the prevalence of amebic dysentery has been increasing, with more than 800 patients newly diagnosed annually. However, genital infection with E. histolytica is uncommon even in endemic areas. We present a case of vaginitis caused by E. histolytica. A 50-year-old Japanese woman without history of overseas travel presented to a nearby clinic with increased vaginal discharge. She had hemorrhagic erosion at the uterine cervix with yellowish vaginal discharge, and was referred to our hospital for exclusion of malignancy. Cervical cytology revealed periodic acid-Schiff-positive protozoa not aggregating around squamous cells, and thus amebic vaginitis was suspected. We performed polymerase chain reaction (PCR) analyses and identified E. histolytica. The vaginitis was treated with metronidazole, and the disappearance of amebic protozoa was confirmed by cytology and PCR. Therefore, it may be important to obtain early diagnosis by cervical cytology and PCR.
Journal of Obstetrics and Gynaecology Research 05/2014; · 0.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Solid-pseudopapillary neoplasm (SPN), a rare neoplasm of the pancreas, frequently harbors mutations in exon 3 of the cadherin-associated protein beta 1 (CTNNB1) gene. Here, we analyzed SPN tissue for CTNNB1 mutations by deep sequencing using next-generation sequencing (NGS).
Tissue samples from 7 SPNs and 31 other pancreatic lesions (16 pancreatic ductal adenocarcinomas (PDAC), 11 pancreatic neuroendocrine tumors (PNET), 1 acinar cell carcinoma, 1 autoimmune pancreatitis lesion, and 2 focal pancreatitis lesions) were analyzed by NGS for mutations in exon 3 of CTNNB1.
A single-base-pair missense mutations in exon 3 of CTNNB1 was observed in all 7 SPNs and in 1 of 11 PNET samples. However, mutations were not observed in the tissue samples of any of the 16 PDAC or other four pancreatic disease cases. The variant frequency of CTNNB1 ranged from 5.4 to 48.8 %.
Mutational analysis of CTNNB1 by NGS is feasible and was achieved using SPN samples obtained by endoscopic ultrasound-guided fine needle aspiration.
Journal of Gastroenterology 04/2014; · 3.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Despite recent advances in cancer therapeutics in general, the survival of patients with head and neck squamous cell carcinomas (HNSCCs) has not improved substantially over the past few decades. HNSCC cells often exhibit invasive and metastatic phenotypes, and expression of epidermal growth factor receptor (EGFR) and cortactin has been highly implicated in the development of malignancy in HNSCCs. We have shown previously that an Arf6 pathway, in which Arf6 is activated by GEP100 and employs AMAP1 (also called DDEF1 or ASAP1) as its downstream effector, is pivotal for the invasion and metastasis of different breast cancer cells. This pathway is activated by receptor tyrosine kinases, including EGFR; and moreover, AMAP1 physically associates with cortactin, in which inhibition of this binding effectively blocks invasion and metastasis. We here investigated whether the expression of Arf6 pathway components correlates with the poor prognosis of HNSCC patients. We have shown previously that AMAP1 protein levels are not correlated with its mRNA levels, and hence we here employed immunohistochemical staining of HNSCC clinical specimens to investigate AMAP1 protein levels.
We found that high levels of AMAP1 protein expression on its own, as well as its co-overexpression with EGFR statistically correlates with poor disease-free survival and poor overall survival, while high levels of cortactin expression or its co-expression with EGFR did not.
Our identification of predictive biomarkers, together with our previous findings on the coherent signaling pathway that these biomarkers ultimately generate should be powerful information for the further development of HNSCC therapeutics.
Cell Communication and Signaling 03/2014; 12(1):17. · 5.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although initial rituximab-containing chemotherapies achieve high response rates, indolent B-cell non-Hodgkin lymphoma (B-NHL), such as follicular lymphoma (FL), is still incurable. Therefore, new effective agents with novel mechanisms are anticipated. In this multicentre phase II study, patients with relapsed/refractory indolent B-NHL and mantle cell lymphoma (MCL) received vorinostat 200 mg twice daily for 14 consecutive days in a 21-d cycle until disease progression or unacceptable toxicity occurred. The primary endpoint was overall response rate (ORR) in FL patients and safety and tolerability in all patients. Secondary endpoints included progression-free survival (PFS). Fifty-six eligible patients were enrolled; 50 patients (39 with FL, seven with other B-NHL, and four with MCL) were evaluable for ORR, and 40 patients had received rituximab-containing prior chemotherapeutic regimens. For the 39 patients with FL, the ORR was 49% [95% confidence interval (CI): 32·4, 65·2] and the median PFS was 20 months (95% CI: 11·2, 29·7). Major toxicities were manageable grade 3/4 thrombocytopenia and neutropenia. Vorinostat offers sustained antitumour activity in patients with relapsed or refractory FL with an acceptable safety profile. Further investigation of vorinostat for clinical efficacy is warranted.
British Journal of Haematology 03/2014; · 4.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Estrogen receptor (ER) is essential for estrogen-dependent growth, and its level of expression is considered a crucial determinant of response to endocrine therapy and prognosis in ER-positive breast cancer. On the other hand, the clinical role of progesterone receptor (PgR) in ER-positive breast cancer remains controversial, although testing of PgR by immunohistochemistry (IHC) has become routine. Recent studies indicated that plasma estradiol levels were related to the expression levels of estrogen-responsive genes in ER-positive breast cancer tissues in both pre- and postmenopausal women. In this study, we analyzed the expression levels of estrogen-responsive genes (PgR and TFF1), a progesterone-responsive gene (RANKL), ER-related genes (FOXA1 and GATA3), HER2, Ki67 and p53 in ER-positive, HER2-negative breast cancer tissues by IHC. Correlations between the expression levels of these molecular markers and clinicopathological factors, including prognosis, were compared between pre- and postmenopausal women. Serum levels of estrone, estradiol, progesterone, and testosterone were also measured. Expression levels of PgR, TFF1, RANKL, and GATA3 were significantly higher in premenopausal women than in postmenopausal women. Serum estradiol levels were positively correlated with Ki67 labeling index (LI) in premenopausal women, but not in postmenopausal women. High expression of FOXA1 and GATA3 was significantly associated with improved disease-free survival in premenopausal women, but not in postmenopausal women, whereas high expression of PgR and low expression of p53 were significantly correlated with the improved disease-free survival in postmenopausal women, but not in premenopausal women. Moreover, the best cutoff points of Ki67 LI for disease-free survival were 30 % for premenopausal women and 14 % for postmenopausal women. Expression levels of ER, TFF1, and RANKL were not associated with the disease-free survival in either pre- or postmenopausal women. Our results suggest that the mechanisms of development and estrogen-dependent growth of ER-positive breast cancer might differ according to menopausal status.
Breast Cancer Research and Treatment 02/2014; · 4.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Idiopathic cytopenias are frequently observed in patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We have previously reported the effect of graft-versus-host disease (GVHD) on bone marrow (BM) in murine models, indicating that the osteoblast injury mediated by donor T cells was associated with bone marrow suppression and delayed immune reconstitution ("BM GVHD"). In this study, we prospectively evaluated the relevance of these findings in 51 patients. Patients with chronic GVHD manifested the loss of osteoblasts, contributing to cytopenic symptoms (P = 0.0427, vs. patients without cytopenic symptoms). The loss of osteoblasts was significantly associated with the extensive type of chronic GVHD (P = 0.012) and flow cytometric analyses revealed lower numbers of CD19+ B cells and significantly increased CD4/CD8 ratio (P = 0.0002) in these patients. Our data for the first time summarize the detailed analyses of the effect of GVHD on BM in the clinical allo-HSCT patients.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 12/2013; · 3.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Type AB thymoma is a thymic epithelial tumour composed of lymphocyte-poor type A and lymphocyte-rich type B components. Although it is categorised as a single entity in the classification of WHO, it shows a broad range of morphology. To investigate whether the functional characteristic of neoplastic cells in type AB thymoma relates to morphological diversity, we performed immunohistochemical analysis using anti-β5t antibody in 20 cases of type AB thymoma. β5t is a recently discovered proteasomal β subunit expressed exclusively in cortical thymic epithelial cells and tumour epithelial cells of thymomas with cortical differentiation. Consistent with our previous observation, β5t was predominantly expressed in the type B component. When the type B component was divided into three groups morphologically, β5t was expressed more frequently in cases with round to polygonal than spindle to oval tumour cells. Furthermore, the ratio of terminal deoxynucleotidyl transferase (TdT)-positive lymphocytes was increased in components with higher expression of β5t. These results indicate that the histological diversity of type AB thymoma correlates with expression of a functional marker β5t and abundance of TdT-positive lymphocytes.
Journal of clinical pathology 11/2013; · 2.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Heat shock factor 1 (HSF1), a major transactivator of stress responses, has been implicated in carcinogenesis in various organs. However, little is known about the biological functions of HSF1 in the development of hepatocellular carcinoma (HCC). To clarify the functional role of HSF1 in HCC, we established HSF1-knockdown KYN2 HCC cells by stably expressing either small hairpin RNA (shRNA) against HSF1 (HSF1-KD) or control shRNA (HSF1-control). Tumorigenicity was significantly reduced in orthotopic mice with HSF1-KD cells compared to those with HSF1-control cells. Reduced tumorigenesis in HSF1-KD cells appeared attributable to increased apoptosis and decreased proliferation. Tumor necrosis factor α-induced apoptosis was increased in HSF1-KD cells and HSF1(-/-) mouse hepatocytes compared with controls. Decreased expression of IκB kinase (IKK)γ, a positive regulator of nuclear factor κB, was also observed in HSF1-KD cells and HSF1(-/-) mouse hepatocytes, and might have been associated with the increased apoptosis. Furthermore, expression of bcl-2-associated athanogene domain 3 (BAG3), was dramatically reduced in HSF1-KD cells and HSF1(-/-) mouse hepatocytes. We also found that epidermal growth factor-stimulated mitogen-activated protein kinase signaling was impaired in HSF1-KD cells. Clinicopathological analysis demonstrated frequent overexpression of HSF1 in human HCCs. Significant correlations between HSF1 and BAG3 protein levels and prognosis were also observed. In summary, these results identify a mechanistic link between HSF1 and liver tumorigenesis and may provide as a potential molecular target for the development of anti-HCC therapies.
[Show abstract][Hide abstract] ABSTRACT: Aromatase inhibitors have played a central role in endocrine therapy for estrogen receptor (ER)-positive breast cancer in postmenopausal women. However, factors predictive of the efficacy of aromatase inhibitors, and prognostic factors, both for early and late recurrence in women treated with adjuvant aromatase inhibitors have not been identified. Whole genome analysis identified that a TP53 gene mutation exists in ER-positive breast cancers, although the frequency of TP53 gene mutation in luminal tumors is lower compared to basal-like or HER2-positive breast cancers. We examined expression of p53, as well as ER, progesterone receptor (PgR), HER2 and Ki67 by immunohistochemistry in postmenopausal ER-positive breast cancer patients who were treated with aromatase inhibitors as adjuvant endocrine therapy. There were 53 tumors (21%) which contained 10% or more p53-positive cells. High p53 expression was positively correlated with tumor grade, HER2 score and Ki67 expression. Significant association was observed between disease-free survival and high p53 expression in multivariate analysis (P < 0.0001). Compared to women without recurrence, women with early recurrence had significantly higher p53 expression (P < 0.0001), as did women with late recurrence (P = 0.037). Our study demonstrates that p53 accumulation is a strong predictor of both early and late recurrence in ER-positive breast cancer patients treated with aromatase inhibitors as adjuvant endocrine therapy. TP53 gene alteration might be a key biological characteristic of ER-positive breast cancer. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Fluorine-18-fluorodeoxyglucose uptake on positron emission tomography is reported to have prognostic significance in patients after resection of lung adenocarcinoma. However, its relationship with histopathologic features remains unknown.
We conducted a retrospective analysis of 205 patients who had undergone surgical resection of primary lung adenocarcinoma (>1.0 cm) after preoperative fluorine-18-fluorodeoxyglucose-positron emission tomography between January 1999 and December 2008 at Hokkaido University Hospital. Fluorine-18-fluorodeoxyglucose uptake was measured by the maximum standardized uptake value. A histopathologic review was performed according to the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification, and various histopathologic factors were evaluated semi-quantitatively. Correlations between these clinicopathologic factors and the maximum standardized uptake value (high ≥2.0 vs low <2.0) were analyzed.
Univariate analysis of clinicopathologic factors demonstrated that the following were significantly correlated with a high maximum standardized uptake value: an elevated carcinoembryonic antigen level, larger tumor size, upgraded pT, pN, pStage, non-lepidic histology, abundant fibroblastic/hyalinized stroma, necrosis, presence of pleural involvement, lymphatic and vascular invasion and more intra- and extracellular mucin. Multivariate analysis demonstrated that a tumor size of >2.0 cm, non-lepidic histology and abundant fibroblastic/hyalinized stroma were significantly correlated with the high maximum standardized uptake value.
More histopathologic factors are known to correlate with poor prognosis in lung adenocarcinomas showing high maximum standardized uptake values than in those showing low maximum standardized uptake values. Therefore, prognostication of patients with a resectable lung adenocarcinoma on the basis of preoperative fluorine-18-fluorodeoxyglucose uptake is histopathologically valid. Such observations may also help us to clarify the pathobiological mechanism responsible for the increased fluorine-18-fluorodeoxyglucose uptake in lung adenocarcinomas with a poor prognosis.
Japanese Journal of Clinical Oncology 08/2013; · 1.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Recent studies have indicated that response to chemotherapy and the prognostic impact of a pathologic complete response (pCR) after neoadjuvant chemotherapy differ among breast cancer subtypes. METHODS: Women with Stage I to III breast cancer treated with anthracycline and taxane-based neoadjuvant chemotherapy (four cycles of docetaxel every 3 weeks followed by four cycles of FEC every 3 weeks) between 2006 and 2011 were retrospectively analyzed. Trastuzumab was concurrently added to docetaxel for HER2-positive breast cancer. Expression of estrogen receptor (ER), progesterone receptor (PgR), HER2, and Ki67 was examined by immunohistochemistry in pre- and post-treatment specimens. Predictive factors for neoadjuvant chemotherapy and prognosis were analyzed by breast cancer subtype. RESULTS: Of 64 patients, 30 (47 %) were ER-positive (ER+) HER2-negative (HER2-), including eight as luminal A (Ki67 labeling index (LI) <14 %) and 22 as luminal B (Ki67 LI ≥ 14 %) subtypes, 11 (17 %) were ER+ HER2-positive (HER2+), 12 (19 %) were ER-negative (ER-) HER2+, and 11 (17 %) were ER- HER2-. The clinical response rates were significantly higher in luminal B, ER+ HER2+, and ER- HER2+ subtypes compared with luminal A subtype. Patients whose tumors contained high Ki67 expression effectively responded to neoadjuvant chemotherapy. Ki67 LI was a predictive marker for pCR, and all patients whose tumors achieved pCR are currently disease-free. Furthermore, high Ki67 expression in post-treatment tumors was strongly correlated with poor disease-free and overall survival regardless of subtype. CONCLUSIONS: It is necessary to establish additional strategies to improve survival for patients whose residual tumors show high Ki67 expression after neoadjuvant chemotherapy.
[Show abstract][Hide abstract] ABSTRACT: Background:Pancreatic ductal carcinoma (PDC) is one of the most lethal human carcinomas. Expression patterns of some genes may predict gemcitabine (GEM) treatment efficacy. We examined predictive indicators of survival in GEM-treated patients by quantifying the expression of several genes in pre-treatment endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) samples from patients with PDC.Methods:The expressions of human equilibrative nucleoside transporter 1 (hENT1), deoxycitidine kinase, ribonucleoside reductase 1, ribonucleoside reductase 2 and Notch3 in EUS-FNA tissue samples from 71 patients with unresectable PDC were quantified using real-time reverse transcription-polymerase chain reactions and examined for correlations with GEM sensitivity.Results:The log-rank test detected no significant differences in overall survival between GEM-treated patients with low and high mRNA levels of all genes examined. However, low Notch3 mRNA expression was significantly associated with longer overall survival in a multivariate analysis for survival (P=0.0094). High hENT1 expression level was significantly associated with a longer time to progression (P=0.039). Interaction tests for GEM administration and hENT1 or Notch3 mRNA expression were statistically significant (P=0.0054 and 0.0047, respectively).Conclusion:hENT1 and Notch3 mRNA expressions in EUS-FNA specimens were the key predictive biomarkers of GEM effect and GEM sensitivity in patients with unresectable PDC.British Journal of Cancer advance online publication, 14 March 2013; doi:10.1038/bjc.2013.108 www.bjcancer.com.
British Journal of Cancer 03/2013; · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
CD133 is a membrane glycoprotein containing five transmembrane loops. Previous reports suggest that a CD133-positive subpopulation of multipotent cells with extensive proliferative and self-renewal characteristics has biological features of a cancer stem cell. In addition, the presence of CD133-positive cells was associated with a significantly poorer prognosis for some solid tumors, compared to those with CD133-negative cells. However, the clinicopathological significance of CD133 in non-small cell lung cancer (NSCLC) remains controversial.
We conducted immunohistochemical assessment of 161 NSCLCs surgically resected at Hokkaido University Hospital between 1982 and 1994 to evaluate correlations between CD133 expression and various clinicopathological features.
CD133 expression was significantly correlated with pathological stages (pStages) II, III, and IV for the various NSCLC types analyzed and was an independent factor for unfavorable prognosis in this population (hazard ratio = 3.157, P = 0.015).
CD133 expression was correlated with pStage and was predictive of unfavorable prognosis in patients with pStages II, III, and IV NSCLC. These results suggest the possibility of using CD133 as a novel prognostic marker in these patients.
International Journal of Clinical Oncology 03/2013; · 1.73 Impact Factor