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1.  A 90Y-labelled anti-ROBO1 monoclonal antibody exhibits antitumour activity against hepatocellular carcinoma xenografts during ROBO1-targeted radioimmunotherapy 
EJNMMI Research  2014;4:29.
ROBO1 is a membrane protein that functions in axon guidance. ROBO1 contributes to tumour metastasis and angiogenesis and may have potential as a target protein of immunotherapy because ROBO1 is specifically expressed at high levels in hepatocellular carcinoma. In this study, we examined biodistribution and radioimmunotherapy (RIT) using a radioisotope-labelled anti-ROBO1 monoclonal antibody (MAb) against hepatocellular carcinoma models.
ROBO1-positive HepG2 human hepatocellular carcinoma xenograft nude mice were used in this study. We conjugated anti-ROBO1 MAb with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), and the conjugates were labelled with 111In and 90Y. To study biodistribution, the 111In-DOTA-anti-ROBO1 MAb was injected into HepG2 xenograft mice via the tail vein. To evaluate any antitumour effect, a RIT study was performed, and the 90Y-DOTA-anti-ROBO1 MAb was injected via the tail vein. Tumour volume, mouse weight, and blood cell count were periodically measured throughout the experiments. The tumours and organs of mice were collected, and a histopathological analysis was carried out.
The tumour uptake of 111In-anti-ROBO1 MAb in HepG2 xenograft mice was 15.0% ± 0.69% injected dose per gram at 48 h after injection.
Immunotherapy with cold-anti-ROBO1 MAb (70 μg) did not cause a significant antitumour effect. RIT with 6.7 MBq of 90Y-anti-ROBO1 MAb caused significant tumour growth suppression. Transient body weight loss and bone-marrow suppression were observed. Histopathological analyses of tumours revealed the fatal degeneration of tumour cells, significant reduction of the Ki-67 index, and an increase of the apoptosis index. Normal organs showed no significant injury, but a transient reduction of hematopoietic cells was observed in the spleen and in the sternal bone marrow.
These results suggest that RIT with 90Y-anti-ROBO1 MAb is a promising treatment for ROBO1-positive hepatocellular carcinoma.
PMCID: PMC4077627
Hepatocellular carcinoma; Radioimmunotherapy; ROBO1; 90Y; Biodistribution
2.  A Case of Urinary Bladder Urothelial Carcinoma with Squamous, Glandular, and Plasmacytoid Differentiation 
Case Reports in Oncology  2014;7(2):362-368.
We report an extremely rare case of urothelial carcinoma (UC) of the urinary bladder with diverse histological differentiation into squamous, glandular, and plasmacytoid components. A 65-year-old man presented with gross hematuria. Cystoscopy showed a papillary-growing tumor with a wide-based stalk on the left wall of the urinary bladder. Based on the clinical diagnosis of locally invasive bladder cancer, the patient underwent radical cystectomy. Histological examination of the cystectomy specimen revealed UC with histological differentiation into multiple tumor subtypes. The tumor was composed of squamous cell carcinoma with marked keratinization, adenocarcinoma characterized by tall columnar cells with scattered goblet cells, conventional high-grade invasive UC and UC in situ, and plasmacytoid UC composed of discohesive cancer cells with eccentric nuclei and eosinophilic cytoplasm that diffusely infiltrated the bladder wall through the serosal surface. Immunohistochemically, the loss of membranous E-cadherin expression was noted only in the plasmacytoid UC component. The patient developed local recurrences 2 months postoperatively and died of the disease 6 months postoperatively. It is critical to correctly diagnose the histological variants of UC to predict a patient's prognosis and to determine the optimal treatment.
PMCID: PMC4067719  PMID: 24987357
Bladder cancer; E-cadherin; Histological variant; Immunohistochemistry; p63; Pathological diagnosis; Prognosis
3.  Esophageal intramucosal hematoma after peripheral blood stem cell transplantation: case report and review of literature 
Esophageal complications occur after hematopoietic stem cell transplantation (HSCT). There are, however, only limited reports on the etiology or management of esophageal complications. Here, we report the occurrence of intramucosal hematoma presenting continuous esophageal hemorrhage in a 34 year-old man following the second peripheral blood stem cell transplantation for acute myeloid leukemia. His hematemesis started 2 months after HSCT and was repeated in supportive care. On day 156, he underwent total esophagectomy as a result of uncontrollable massive hematemesis. Histopathological testings of the resected esophagus confirmed intramucosal hematoma as a cause of hematemesis. This case highlights intramucosal hematoma as one of the important etiologies of esophageal complications following HSCT.
PMCID: PMC4069927  PMID: 24966988
Esophageal hemorrhage; intramucosal hematoma; esophagectomy; hematopoietic stem cell transplantation
4.  DNA methylation in gastric cancer, related to Helicobacter pylori and Epstein-Barr virus 
Gastric cancer is a leading cause of cancer death worldwide, and significant effort has been focused on clarifying the pathology of gastric cancer. In particular, the development of genome-wide analysis tools has enabled the detection of genetic and epigenetic alterations in gastric cancer; for example, aberrant DNA methylation in gene promoter regions is thought to play a crucial role in gastric carcinogenesis. The etiological viewpoint is also essential for the study of gastric cancers, and two distinct pathogens, Helicobacter pylori (H. pylori) and Epstein-Barr virus (EBV), are known to participate in gastric carcinogenesis. Chronic inflammation of the gastric epithelium due to H. pylori infection induces aberrant polyclonal methylation that may lead to an increased risk of gastric cancer. In addition, EBV infection is known to cause extensive methylation, and EBV-positive gastric cancers display a high methylation epigenotype, in which aberrant methylation extends to not only Polycomb repressive complex (PRC)-target genes in embryonic stem cells but also non-PRC-target genes. Here, we review aberrant DNA methylation in gastric cancer and the association between methylation and infection with H. pylori and EBV.
PMCID: PMC3983447  PMID: 24744581
Gastric cancer; Epigenetics; DNA methylation; Epstein-Barr virus; Helicobacter pylori
5.  Alpha-synuclein immunohistochemistry of gastrointestinal and biliary surgical specimens for diagnosis of Lewy body disease 
In Lewy body disease, Lewy pathology (LP: the accumulation of α-synuclein in neuronal perikarya and processes as Lewy bodies and Lewy neurites and dots, respectively) is observed in the central and peripheral nervous systems. Previous autopsy or biopsy studies of individuals with Lewy body diseases (LBDs) indicated that LP could be observed in the peripheral nerves of the gastrointestinal (GI) systems. The aim of this study is to clarify whether examination of GI and biliary surgical specimens would be useful for diagnosing LBD. We analyzed eight patients diagnosed clinically with LBD and with medical histories of GI or biliary surgery at our hospital. LP was identified by using α-synuclein immunohistochemistry in GI and biliary surgical specimens obtained before, at or after the clinical onset of LBD. LP was frequently observed in Auerbach’s plexus, Meissner’s plexus and the subserosal nerve fascicles within the GI and biliary surgical specimens. LP was observed in the specimens obtained 7 years before the onset of LBD. Our approach does not require any invasive procedures for patients. The immunohistochemical analysis of anti- α-synuclein antibody to archival GI or biliary surgical specimens from patients with clinically suspected LBD may contribute to clinical diagnosis of LBD.
PMCID: PMC4014253  PMID: 24817969
α-synuclein; gastrointestinal and biliary tract; Lewy body disease; Lewy pathology; surgical specimen
6.  Concurrent Activation of Acetylation and Tri-Methylation of H3K27 in a Subset of Hepatocellular Carcinoma with Aggressive Behavior 
PLoS ONE  2014;9(3):e91330.
Analysis of acetylation and tri-methylation of the same residue of histone molecules might identify a subset of hepatocellular carcinoma (HCC) with aggressive behavior. In the present study, we examined acetylation and tri-methylation of lysine 27 on histone H3 (H3K27ac and H3K27me3, respectively) because these two modifications are known to exhibit opposite effects (enhancing and silencing) on gene expression. Neoplastic and non-neoplastic tissues from 198 HCC cases were immunostained with specific monoclonal antibodies against H3K27ac and H3K27me3. The stained tissues were evaluated by an image analyzing program to generate histological scores (H-scores, range 0–300), which were determined by multiplying the percentage of positive-stained cells with the classified immunohistochemical marker intensity (0–3). HCC tissues showed significantly higher H3K27ac (156.7±86.8) and H3K27me3 H-scores (151.8±78.1) compared with the background liver (40.3±33.0 and 64.7±45.6, respectively) (both P<0.001). The cases with H-scores of high-H3K27ac/high-H3K27me3 (n = 54) showed significant correlation with poor differentiation of morphology (P<0.01) and p53-positive staining (P<0.05), and poor prognosis (P<0.01). Confocal microscopy revealed segregated intranuclear localization of both modifications in the individual cancer cells: H3K27ac localization in central euchromatin regions and H3K27me3 in peripheral heterochromatin regions. Concurrent acetylation and methylation at H3K27 occurs in HCC cells in association with p53 abnormalities. These findings demonstrate that image analyzer-assisted H-scores of H3K27ac and H3K27me3 identified an aggressive subgroup of HCC, and could serve as a prognostic marker for HCC.
PMCID: PMC3948868  PMID: 24614346
7.  Long-term results of radical prostatectomy with immediate adjuvant androgen deprivation therapy for pT3N0 prostate cancer 
BMC Urology  2014;14:13.
Radical prostatectomy is used to treat patients with clinically localized prostate cancer, but there have been few reports of its use in locally advanced disease. We evaluated the long-term results of radical prostatectomy and immediate adjuvant androgen deprivation therapy in Japanese patients with pT3N0M0 prostate cancer.
We retrospectively reviewed 128 patients with pT3N0M0 prostate cancer who underwent radical prostatectomy at our institute from 2000 to 2006. All pT3N0 patients were treated with adjuvant androgen deprivation therapy shortly after radical prostatectomy. Immediate adjuvant androgen deprivation therapy was continued for at least 5 years. Twenty-three were excluded because of preoperative hormonal therapy, missing data, or others. Death from any cause, death from prostate cancer, clinical recurrence and hormone-refractory biochemical progression were analyzed by Kaplan-Meier graphs. Relative risks of progression were estimated using Cox proportional hazards models with 95% confidence intervals.
The 10-year hormone-refractory biochemical progression-free survival rate was 88.3% and the cancer-specific survival rate was 96.3% after a median follow-up period of 8.2 years (range 25.6-155.6 months). Higher clinical stage (p = 0.013), higher Gleason score at biopsy (p = 0.001), seminal vesicle invasion (p = 0.003) and microlymphatic invasion (p = 0.006) were predictive factors for hormone-refractory biochemical progression by univariate analyses. Multivariate analyses identified Gleason score at biopsy (p = 0.027) and seminal vesicle invasion (p = 0.030) as independent prognostic factors for hormone-refractory biochemical progression. None of the patients with clinical T1 cancers (n = 20), negative surgical margin (n = 12), or negative perineural invasion (n = 11) experienced hormone-refractory biochemical progression.
Radical prostatectomy with immediate adjuvant androgen deprivation therapy may be a valid treatment option for patients with pT3N0M0 prostate cancer.
PMCID: PMC3912934  PMID: 24476554
Adjuvant androgen deprivation therapy; Pathological T3; Prognosis; Prognostic factor; Prostate cancer; Radical prostatectomy
8.  Plexiform angiomyxoid myofibroblastic tumor (PAMT) of the stomach. A case report focusing on its characteristic growth pattern 
Plexiform angiomyxoid myofibroblastic tumor (PAMT) is a rare mesenchymal tumor of the stomach. We report herein a case with CT findings, which illustrate the characteristic growth pattern of PAMT. A 27-year-old female patient visited our hospital because of epigastric pain and anemia. The CT scan showed a heterogeneous tumor in the gastric antrum, which was drastically enhanced with contrast medium, and consisted of a number of highly stained small nodules around the tumor rim. The resected tumor, 4.6 cm in size, was c-kit negative and SMA-positive by immunohistochemistry, and composed of bland spindle cells which were separated by abundant myxomatous stroma. The tumor showed plexiform growth in the entire stomach wall, with multiple nodules protruding outward within the serosa. The CT findings in this case reflect the characteristic PAMT growth pattern, and are distinct enough to differentiate it from gastrointestinal stromal tumor (GIST).
PMCID: PMC3925914  PMID: 24551290
PAMT; GIST; diagnosis; CT
9.  HER2 protein overexpression and gene amplification in upper urinary tract urothelial carcinoma-an analysis of 171 patients 
Upper urinary tract urothelial carcinomas (UUTUC) are infrequent and show an occurrence of about 5-10% of all urothelial carcinomas. In this study, we investigated the HER2 status of 171 UUTUC patients with nephroureterectomy. The number of patients is the largest of any HER2 study. All 171 cases were analyzed for both HER2 overexpression using immunohistochemistry and HER2 gene amplification using dual-color in situ hybridization. The scoring system proposed by the ASCO/CAP and ToGA trials was used. Out of 171 patients, 140 patients had a HER2 score-0 or score-1 (81.9%), 17 a score-2 (9.9%), and 14 a score-3 (8.2%) with immunohistochemistry. HER2 gene amplification was observed in 31 out of 171 cases (18.1%). A good correlation was observed between protein overexpression and gene amplification (p<0.0001). Twenty-three UUTUC (13.5%) were determined as HER2-positive cancer according to ASCO/CAP and ToGA criteria. HER2 positivity in patients over 70 years old was higher than that of patients under 70 years old (p=0.0132). HER2 expression correlated to a high histological grade (p=0.0003) and the coexistence of a high grade carcinoma in situ (p=0.0089). No HER2-positive cancer was observed in patients with renal pelvic UUTUC (0 out of 76, p<0.0001). HER2-positive UUTUC showed a shorter recurrence time in the residual urinary bladder after nephroureterectomy with Kaplan-Meier analysis (p=0.0284) and multivariate analysis (p=0.0034). The results suggest that HER2 positivity in UUTUC is an independent predictive marker for early recurrence of urothelial carcinoma in the residual urinary bladder after surgery.
PMCID: PMC3925916  PMID: 24551292
HER2; immunohistochemistry; DISH; urothelial carcinoma; upper urinary tract; tissue microarray
10.  Poorly differentiated mesenteric carcinoma of unknown primary site detected by abscess formation: case report 
Carcinoma of unknown primary site (CUP) is said to account for approximately 3 to 5% of all carcinomas. However, an isolated lesion in the abdominal cavity is rare, and there are no reports describing associated abscess formation.
Case presentation
A 76-year-old woman had consulted a previous physician complaining of fever and right lower quadrant abdominal pain. Enhanced computed tomography (CT) showed an abscess formation around the cecum. She was treated conservatively with antibiotics, but the symptoms relapsed and she consulted our hospital. Enhanced CT showed a persistent abscess, a tumorous lesion in the mesentery and right hydronephrosis. Because malignancy could not be ruled out, surgical treatment was selected. At laparotomy, encapsulated abscesses were found on the mesenteric side and outside of the ileocecal region. When we raised the ileocecal region, a tumor was found to be fixed to the right ureter, and there was leakage of white, solid tumor content. This tumor content was submitted to intraoperative frozen section diagnosis which revealed a carcinoma. Ileocecal resection with D3 lymph node dissection and retroperitoneal tumor resection was thus performed. There were no abnormal findings in the uterus and adnexa, nor any evidence of peritoneal dissemination. We regarded this case as an incomplete resection and chemotherapy with paclitaxel and carboplatin was administered. The patient has remained alive and disease-free for almost one year since the primary operation.
We described a case with mesenteric CUP discovered during surgery for an intra-abdominal abscess. It is necessary to pay attention to treatment-resistant intraperitoneal abscesses as they may accompany a tumor.
PMCID: PMC3896797  PMID: 24397776
Carcinoma of unknown primary site; Abscess; Mesentery
11.  Transformation of follicular lymphoma in the retroperitoneal muscles demonstrated by CT-guided needle biopsy of FDG-avid lesions; case series 
We herein report two cases of relapsed follicular lymphoma (FL) with transformation in the retroperitoneal muscles. Fluorodeoxyglucose (FDG)-positron emission tomography (PET) combined with computed tomography (CT) showed high uptakes in the retroperitoneal muscles. We considered excisional biopsy at first, since it is definitely the most reliable means to obtain histological diagnosis. However, excisional biopsy of the retroperitoneal muscles is challenging for anatomical reasons. Moreover, our patients were kept under poor performance status. Thus, CT-guided percutaneous needle biopsy of FDG-avid retroperitoneal muscles was performed. Histopathological examination of the biopsied specimens demonstrated proliferation of transformed large B cells in both cases. Sheets of large B cells were also recorded in one case. CT-guided needle biopsy is less prioritized than excisional biopsy because of limited information on tissue architecture and increasingly complicated WHO classification. Our series indicate that image-guided needle biopsy of FDG-avid lesions is sufficient for the diagnosis of transformation. Higher priority should be given to this method in the setting of transformed aggressive lymphoma.
PMCID: PMC3885497  PMID: 24427363
Follicular lymphoma; transformation; retroperitoneum; FDG-avid; CT-guided needle biopsy
12.  High expression of heat shock protein 105 predicts a favorable prognosis for patients with urinary bladder cancer treated with radical cystectomy 
Heat shock protein 105 (Hsp105) is one of the cancer/testis antigens, which is overexpressed in a variety of cancer cells, including urinary bladder cancer, and has been investigated as a target molecule for immunotherapy due to its immunogenicity. In this study, we assessed the expression of Hsp105 in primary bladder cancer samples from 84 patients treated with radical cystectomy, using immunohistochemical analysis, and investigated its correlation with clinicopathological characteristics and cancer-specific survival. The immunoreactivity of Hsp105 expression was evaluated as a score of 0–3, according to the intensity of the signal. The Hsp105 expression was high (score 2 or 3) in 31 cases and low (score 0 or 1) in 53 cases; however, it was not significantly correlated with age, nuclear grade, pathological tumor stage and previous intravesical Bacillus Calmette-Guérin immunotherapy. Female gender, lymphovascular invasion and lymph node metastasis were associated with low Hsp105 scores, although the differences were not statistically significant (P=0.071, 0.061 and 0.175, respectively). However, a high Hsp105 score was significantly associated with a favorable prognosis (P=0.017) and was identified as an independent prognostic factor by multivariate analysis (P=0.032; hazard ratio, 2.34). These findings suggested that the expression of Hsp105 may be a novel indicator of a favorable prognosis in bladder cancer.
PMCID: PMC3915630  PMID: 24649305
heat shock protein 105; immunohistochemistry; bladder cancer; prognostic marker
13.  Correction: Heart Wall Is Thicker on Postmortem Computed Tomography Than on Ante Mortem Computed Tomography: The First Longitudinal Study 
PLoS ONE  2013;8(10):10.1371/annotation/7bae7ece-15f5-43ca-9f98-592df8543978.
PMCID: PMC3805600  PMID: 24204443
14.  Simple preoperative computed tomography image analysis shows good predictive performance for pathological vessel invasion in clinical stage IA non-small cell lung cancer† 
Pathological vessel invasion is a well-known prognostic factor in early-stage, non-small cell lung cancer and preoperative predicting vessel invasion may enable us to improve prognosis by additional interventions. We evaluated the importance of vessel invasion as a prognostic factor in clinical stage IA non-small cell lung cancer and predictive performance of simple diameter-based computed tomography image analysis for vessel invasion.
The study design was retrospective, and we reviewed 398 patients who underwent surgical resection of clinical stage IA non-small cell lung cancer from 1999 to 2009. The prognostic factors for recurrence-free survival were examined by univariate and multivariate analyses. Additionally, we analyzed preoperative high-resolution computed tomography images of patients with adenocarcinoma. The greatest diameter of the tumor in the lung window and the length of the consolidation part of L in the mediastinal window were measured. Then the ratio (mediastinal window/lung window) was calculated, and the correlation between the ratio (mediastinal window/lung window) and vessel invasion was analyzed by receiver operating characteristic analysis.
Sixty-eight recurrences occurred. Multivariate analysis revealed that vessel invasion, high preoperative serum carcinoembryonic antigen, and history of other malignancy were independent prognostic factors; their hazard ratios were 2.98, 2.45, and 1.98, respectively. The receiver operating characteristic analysis showed that the area under the curve was 0.75. When we set the cut-off value of the ratio (mediastinal window/lung window) at 0.67, the sensitivity and specificity were 75% and 72%, respectively.
Vessel invasion had the greatest impact on recurrence in clinical stage IA non-small cell lung cancer. Our simple computed tomography image analysis showed good predictive performance for vessel invasion.
PMCID: PMC3445341  PMID: 22740516
Lung cancer; Diagnosis; Pathology; Computed tomography
15.  Successful Treatment of Mediastinal Unicentric Castleman's Disease Using Video-Assisted Thoracoscopic Surgery with Preoperative Embolization 
Case Reports in Medicine  2013;2013:354507.
Unicentric Castleman's disease is a rare, benign lymphoproliferative disorder that is curable with surgical resection. However, significant bleeding often occurs during surgery because of tumor hypervascularity. We herein present a case of hyaline-vascular-type mediastinal unicentric Castleman's disease, successfully resected using video-assisted thoracoscopic surgery with preoperative embolization. In the present case, tumor hypervascularity and feeding vessels were revealed by computed tomography (CT), which led us to perform preoperative angiography and embolization to the tumor feeding arteries to reduce intraoperative bleeding. Castleman's disease should be considered in the differential diagnosis of hypervascular mediastinal tumors. Tumor vascularity should be assessed prior to surgery, and preoperative embolization should be considered.
PMCID: PMC3806124  PMID: 24198836
16.  Heart Wall Is Thicker on Postmortem Computed Tomography Than on Ante Mortem Computed Tomography: The First Longitudinal Study 
PLoS ONE  2013;8(9):e76026.
To evaluate the postmortem changes of the heart wall on postmortem (PM) computed tomography (CT) in comparison with those on ante mortem CT (AMCT), and in comparison with the pathological findings, obtained in the same patients.
Materials and Methods
We studied 57 consecutive patients who had undergone AMCT, PMCT, and pathological autopsy in our tertiary care hospital between April 2009 and December 2010. PMCT was performed within 20 hours after death, followed by pathological autopsy. The cardiac chambers were measured at five sites on both AMCT and PMCT by two board-certified radiologists who were not provided with clinical information. The differences in heart wall thickness between AMCT with and without contrast medium, between AMCT and PMCT, and between PMCT and pathological anatomy were evaluated statistically. Confounding factors of postmortem change such as gender, presence of arteriosclerosis, the organ related to cause of death, age, and elapsed time since death were examined statistically.
No significant differences were observed on AMCT in comparison of contrasted and non-contrasted images. The heart wall was significantly thicker on PMCT than on AMCT (p < 0.0001) at all five measurement sites. The heart wall was significantly thicker on PMCT than on pathology specimens when measured in accordance with pathological standard mensuration. However, no significant difference was observed between PMCT measurements and those of pathology specimens at any site when the papillary muscles and epicardial fat were included. No significant association was found between postmortem change in heart wall thickness and gender, presence of arteriosclerosis, the organ related to cause of death, age, or elapsed time since death.
This is the first longitudinal study to confirm greater thickness of heart wall on postmortem images compared with ante mortem images, in the same patients. Furthermore, the postmortem changes on CT were supported by the pathological findings.
PMCID: PMC3785517  PMID: 24086680
17.  Preoperative Iodine Staining May Complicate the Demarcation of Esophageal Carcinoma 
Gut and Liver  2013;7(4):492-496.
A 53-year-old man was suspected of having an esophageal neoplasm. An endoscopic examination including Lugol chromoendoscopy suggested an esophageal squamous cell neoplasm limited to the lamina propria. A targeted biopsy showed atypical squamous cells, and an endoscopic submucosal dissection was performed 22 days after the previous endoscopy. Although a single 40 mm unstained area was observed by preoperative Lugol chromoendoscopy, intraoperative endoscopy revealed a 25 mm iodine-unstained area, with small unstained areas scattered on the oral side. We included the small unstained areas in the extent of the resection through assessment by preoperative endoscopy. Histopathologically, the tumor extent appeared to coincide with the preoperative assessment. Tumor cells were found in the basal-parabasal layers of the mucosa, in which small unstained areas were scattered, although the superficial layers exhibited well-differentiated cells containing glycogen in the cytoplasm. Although Lugol chromoendoscopy, which can induce chemical esophagitis, is widely used, re-epithelialization after mucosal damage by preoperative iodine staining may complicate the intraoperative demarcation of tumors.
PMCID: PMC3724041  PMID: 23898393
Lugol chromoendoscopy; Esophageal squamous cell neoplasm; Re-epithelialization
18.  UBE2C is a marker of unfavorable prognosis in bladder cancer after radical cystectomy 
It has been suggested that ubiquitin-conjugating enzyme E2C (UBE2C, also known as UBCH10) represents a promising cancer biomarker. However, the clinicopathological or prognostic significance as well as the functions of UBE2C in bladder cancer are largely unknown. To investigate the significance of UBE2C expression in bladder cancer, immunohistochemical analysis was performed using a tissue microarray. UBE2C positivity was observed in 51 of 82 (62%) bladder urothelial carcinoma cases treated with radical cystectomy. In contrast, UBE2C was negative in all of the non-neoplastic urothelium examined. UBE2C positivity was significantly associated with higher tumor stage (p=0.0061) and presence of lymphovascular invasion (p=0.0045). In addition, UBE2C positivity was significantly associated with shorter cancer-specific survival after cystectomy (log rank p=0.0017; multivariate hazard ratio, 2.49; 95% confidence interval, 1.09-5.71). Small interfering RNA-mediated suppression of UBE2C in UM-UC-3 bladder cancer cells inhibited cell proliferation in vitro. Taken together, our results suggest that UBE2C is a novel prognostic biomarker as well as a potential therapeutic target in bladder cancer.
PMCID: PMC3693202  PMID: 23826418
Cell cycle; immunohistochemistry; pathology; prognosis; urinary tract
19.  Successful treatment with recombinant thrombomodulin for B-cell lymphoma-associated hemophagocytic syndrome complicated by disseminated intravascular coagulation 
We report here a 47-year-old male with the diagnosis of high-grade B-cell lymphoma and hemophagocytosis accompanying disseminated intravascular coagulation (DIC). Lymphoma-associated hemophagocytic syndrome (LAHS) is a life-threatening disorder, and LAHS secondary to B-cell lymphoma is relatively rare compared to that secondary to T- or NK/T-cell lymphoma in Western countries. T- or NK/T-cell LAHS is sometimes combined with DIC, which makes patients’ outcomes even worse, but few reports of B-cell LAHS accompanying DIC has been published so far. We successfully treated a patient with this condition with recombinant thrombomodulin (rTM), a novel agent for DIC. We believe that rTM is a therapeutic option in cases with B-cell LAHS accompanying DIC.
PMCID: PMC3657377  PMID: 23696942
B-cell lymphoma; lymphoma-associated hemophagocytic syndrome; disseminated intravascular coagulation; recombinant thrombomodulin
20.  FER overexpression is associated with poor postoperative prognosis and cancer-cell survival in non-small cell lung cancer 
Here, we show that overexpression of fer tyrosine kinase (FER), a non-receptor tyrosine kinase, predicts poor postoperative outcome and might be involved in cancer-cell survival in non-small cell lung cancer (NSCLC). Systematic screening using in silico analyses and quantitative RT-PCR revealed that FER was overexpressed in about 10% of NSCLC patients. Evaluation of FER expression using immunohistochemistry (IHC) on tissue microarrays was consistent with the mRNA level detected using quantitative RT-PCR. In analyses of 135 NSCLC patients who had undergone potential curative resection, we found that FER overexpression detected using IHC had no association with clinicopathological features such as age, sex, smoking history, histological type, disease stage, T factor, N factor, adjuvant chemotherapy history, or EGFR mutation, but was correlated with poor postoperative survival periods. A multivariate Cox regression analysis showed that this prognostic impact was independent of other clinicopathological features. In functional analyses of FER in vitro, FER exhibited a transforming activity, suggesting that it possesses oncogenic functions. We also found that human lung cancer NCI-H661 cells, which exhibited FER-outlier expression, were led to apoptosis by the knockdown of FER using RNA interference. FER overexpression might serve as a prognostic biomarker and be involved in cancer-cell survival in NSCLC.
PMCID: PMC3606849  PMID: 23573306
Non-small cell lung cancer; FER overexpression; prognostic factor
21.  Metastatic seminomas in lymph nodes: CD10 immunoreactivity can be a pitfall of differential diagnosis 
Metastatic seminoma can potentially be confused with lymphoma in a lymph node biopsy. Here, we report a case in which the immunohistochemistry of CD10 was a pitfall in the differential diagnosis of a metastatic seminoma, and further present a brief study of CD10 expression in a seminoma series. A 67-year-old man, who had a history of lobectomy of the lung due to squamous cell carcinoma 2 years prior, showed lymphadenopathy of the neck and the paraaorta on follow-up study by fluorodeoxyglucose-positron emission computer tomography scan. The biopsy of the cervical node demonstrated infiltration of large atypical cells. The results of the screening immunohistochemistry were CD20(-), CD3(-), CD10(+), CD30(-), AE1/AE3(-), and placental alkaline phosphatase(-), providing the impression of CD10-positive lymphoma. However, the following studies revealed germ cell characteristics [OCT3/4(+), SALL4(+), and CLDN6(+)], confirming the diagnosis of seminoma. We further evaluated CD10 expression in a series of seminomas (n=16). Strong positivity was observed in 14 cases; partial and weak positivity, in 2 cases. These findings should be considered in the differential diagnosis of seminoma.
PMCID: PMC3563185  PMID: 23411938
Testicular seminoma; CD10; PLAP; OCT3/4
22.  Quantitative Analysis of Viral Load per Haploid Genome Revealed the Different Biological Features of Merkel Cell Polyomavirus Infection in Skin Tumor 
PLoS ONE  2012;7(6):e39954.
Merkel cell polyomavirus (MCPyV) has recently been identified in Merkel cell carcinoma (MCC), an aggressive cancer that occurs in sun-exposed skin. Conventional technologies, such as polymerase chain reaction (PCR) and immunohistochemistry, have produced conflicting results for MCPyV infections in non-MCC tumors. Therefore, we performed quantitative analyses of the MCPyV copy number in various skin tumor tissues, including MCC (n = 9) and other sun exposure-related skin tumors (basal cell carcinoma [BCC, n = 45], actinic keratosis [AK, n = 52], Bowen’s disease [n = 34], seborrheic keratosis [n = 5], primary cutaneous anaplastic large-cell lymphoma [n = 5], malignant melanoma [n = 5], and melanocytic nevus [n = 6]). In a conventional PCR analysis, MCPyV DNA was detected in MCC (9 cases; 100%), BCC (1 case; 2%), and AK (3 cases; 6%). We then used digital PCR technology to estimate the absolute viral copy number per haploid human genome in these tissues. The viral copy number per haploid genome was estimated to be around 1 in most MCC tissues, and there were marked differences between the MCC (0.119–42.8) and AK (0.02–0.07) groups. PCR-positive BCC tissue showed a similar viral load as MCC tissue (0.662). Immunohistochemistry with a monoclonal antibody against the MCPyV T antigen (CM2B4) demonstrated positive nuclear localization in most of the high-viral-load tumor groups (8 of 9 MCC and 1 BCC), but not in the low-viral-load or PCR-negative tumor groups. These results demonstrated that MCPyV infection is possibly involved in a minority of sun-exposed skin tumors, including BCC and AK, and that these tumors display different modes of infection.
PMCID: PMC3386999  PMID: 22768181
23.  Co-localisation of advanced glycation end products and d-β-aspartic acid-containing proteins in gelatinous drop-like corneal dystrophy 
The British Journal of Ophthalmology  2012;96(8):1127-1131.
Gelatinous drop-like corneal dystrophy (GDLD), also known as familial subepithelial corneal amyloidosis, is an autosomal recessive disorder that causes progressive corneal opacity due to accumulation of amyloid fibrils in the corneal stroma. Genetic analyses have revealed that a mutation in membrane component chromosome 1 surface marker 1 gene is responsible for GDLD. However, the mechanism of amyloid formation in the corneal stroma remains unclear. The present study attempted to reveal the role of advanced glycation end products (AGE) and d-amino acids in amyloid formation in GDLD.
Informed consent was obtained from five patients with GDLD, three patients with bullous keratopathy and three patients with interstitial keratitis and all the specimens were analysed. Localisation of amyloid fibrils was analysed using Congo-red and thioflavin T staining. In addition, the localisation of AGE (Nɛ-carboxy(methyl)-l-lysine, pyrraline and pentosidine) and d-β-aspartic acid-containing proteins, a major form of d-amino acid-containing proteins, was analysed immunohistochemically.
In all GDLD specimens, strong immunoreactivity to AGE and d-β-aspartic acid-containing proteins was detected in the subepithelial amyloid-rich region. In contrast, amyloid fibrils, AGE, or d-amino acid-containing proteins were slightly detected in the corneal stroma of patients with bullous keratopathy and interstitial keratitis.
Abnormally accumulated proteins rich in AGE and d-β-aspartic acid co-localise in the amyloid lesions in GDLD. These results indicate that non-enzymatic post-translational modifications of proteins, including AGE formation and isomerisation of aspartyl residues, will be the cause as well as the result of amyloid fibril formations in GDLD.
PMCID: PMC3404710  PMID: 22694960
Advanced glycation end products; biochemistry; cornead-amino acids; d-β-aspartic acid; familial subepithelial corneal amyloidosis; GDLD; gelatinous drop-like corneal dystrophy; M1S1; Nɛ-(carboxy)methyl-l-lysin; optics and refraction; pathology; pentosidine; physiology; pyrraline; treatment surgery; tumour-associated calcium signal transducer 2 (TACSTD2)
24.  Rsf-1 (HBXAP) expression is associated with advanced stage and lymph node metastasis in ovarian clear cell carcinoma 
Ovarian clear cell carcinoma (CCC) is a unique type of ovarian cancer characterized by distinct clinicopathological and molecular features. CCC is considered to be a highly malignant disease because it is resistant to conventional chemotherapy, and, when presented at advanced stages, has a dismal overall survival. Identifying and characterizing biomarkers associated with its malignant behavior is fundamental toward elucidating the mechanisms underlying its aggressive phenotype. In this study, we performed immunohistochemical analysis on 89 CCCs to assess their expression of Rsf-1 (HBXAP), a chromatin remodeling gene frequently amplified and overexpressed in several types of human cancer. We found that 73 (82%) of 89 CCCs expressed Rsf-1 and most importantly, there was a statistically significant correlation between Rsf-1 immunostaining intensity and two disease parameters: advanced stage (p= 0.008) and status of retroperitoneal lymph node metastasis (p= 0.023). However, there was no correlation between Rsf-1 expression and patient age, peritoneal tumor dissemination, or overall survival. In conclusion, a higher expression level of Rsf-1 is associated with advanced clinical stage and lymph node metastasis in CCC. Our data suggest that Rsf-1 participates in tumor progression in CCC, and indicates that the contribution of Rsf-1 to disease aggressiveness deserves further study.
PMCID: PMC3052874  PMID: 21131837
25.  Expression of DBC1 is associated with nuclear grade and HER2 expression in breast cancer 
DBC1/KIAA1967 (deleted in breast cancer 1) is a putative tumor-suppressor gene cloned from breast cancer specimens and is reported to regulate p53-dependent apoptosis through its specific inhibition of SIRT1 deacetylase. Although SIRT1 plays a pivotal role in carcinogenesis by regulating cellular proliferation, survival and death, its role in breast cancer remains controversial. Therefore, we aimed to investigate the expression status and clinicopathological significance of DBC1 and SIRT1 in breast cancer tissues. We evaluated the expression of DBC1 and SIRT1 in breast core-needle biopsy specimens from 48 primary breast cancer patients between 2005 and 2008. These patients were treated with primary systemic chemotherapy and subsequent surgical resection of the lesions. Immunohistochemical expression scores of DBC1 and SIRT1 were evaluated, and the relationship between their expression levels and clinicopathological features of breast cancer was analyzed. The expression was observed exclusively in the nuclei of normal and neoplastic ductal cells. In breast biopsy specimens, positive expression of DBC1 and SIRT1 was noted in 85 and 98% of patients, respectively. Expression of DBC1 was significantly associated with the tumor nuclear grade (P=0.019). DBC1 and SIRT1 expression was inversely correlated with HER2 expression (P=0.026 and 0.003, respectively). Lower expression of DBC1 and SIRT1 indicated a tendency for a favorable pathological response to chemotherapy, although this was not statistically significant. Our results reveal that the expression of DBC1 and SIRT1 in breast tissues is associated with tumor characteristics.
PMCID: PMC3440794  PMID: 22977628
DBC1; SIRT1; breast cancer; nuclear grade; HER2

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