Ryoji Kushima

The University of Tokyo, 白山, Tōkyō, Japan

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Publications (210)695.38 Total impact

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    ABSTRACT: Background: Preoperative N staging is essential for the best treatment planning in patients with gastric carcinoma. The aim of this study was to evaluate the accuracy of preoperative N staging using contrast-enhanced multi-detector row computed tomography (CE-MDCT) in patients with resectable cT2-4 gastric carcinoma. Methods: A total of 218 patients who underwent a gastrectomy with D2 lymphadenectomy for previously untreated cT2-4 primary gastric carcinoma were studied. Preoperative N staging was performed according to the 7th (UICC) TNM Staging System using pre-specified criteria on a 64-channel CE-MDCT and was compared with postoperative pathologic N staging. Results: In all 218 patients, a distal or total gastrectomy was performed. The overall accuracy of the preoperative N staging was 46.3 % (101/218), with the proportion of over- and under-staging being 26.6 % (58/218) and 27.1 % (59/218), respectively. The sensitivity, specificity, and accuracy for lymph node metastasis (≥pN1) were 79.1 % (106/134), 50.0 % (42/84), and 67.9 % (148/218), respectively. The sensitivity, specificity, and accuracy for multiple lymph node metastases (≥pN2) were 80.2 % (73/91), 68.5 % (87/127), and 73.4 % (160/218), respectively. Multivariate analyses showed that macroscopic type 2 and ≥6 cm-sized tumors were associated with preoperative over-N staging, while macroscopic type 1/3 tumors were associated with under-N staging. Conclusion: Preoperative N staging with pinpoint accuracy is difficult. However, CE-MDCT offers a reasonably high sensitivity and specificity for ≥pN2 and may be useful for selecting candidates for neoadjuvant therapies. The macroscopic type and size of the primary tumor may affect the accuracy of preoperative N staging.
    World Journal of Surgery 11/2015; DOI:10.1007/s00268-015-3318-8 · 2.64 Impact Factor
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    ABSTRACT: The postoperative functional advantages of a proximal gastrectomy over a total gastrectomy remain debatable. The aim of this study was to evaluate the functional outcomes of a proximal gastrectomy with jejunal interposition (PG-JI), compared with those for a total gastrectomy with Roux-en-Y esophagojejunostomy (TG-RY), in patients with early gastric cancer. Between 2007 and 2012, 65 patients underwent PG-JI and 117 underwent TG-RY for cT1 gastric cancer. Various parameters, including body weight, serum hemoglobin level, and interview-based symptoms, were prospectively evaluated in these patients. In patients who underwent PG-JI, the postoperative endoscopic findings were also assessed. All the surgeries were performed via a laparotomy alone. During a median postoperative follow-up of 42 months (range, 12-78 months), PG-JI offered significant reductions in body weight loss (12.5 ± 5.8 vs. 17.4 ± 6.4 %, P < 0.001), serum hemoglobin decline (7.0 ± 5.7 vs. 9.7 ± 5.4 %, P = 0.002), and dumping symptoms (11 % [7/65] vs. 30 % [35/117], P = 0.003), while being associated with similar incidences of anastomotic stricture (9 % [6/65] vs. 8 % [9/117], P = 0.781), small bowel obstruction (0 % [0/65] vs. 2 % [2/117], P = 0.538), stasis symptoms (51 % [33/65] vs. 44 % [51/117], P = 0.358), and reflux symptoms (34 % [22/65] vs. 23 % [27/117], P = 0.121), compared with TG-RY. Four cases of gastric remnant cancer and no cases of endoscopic reflux esophagitis were found after PG-JI. PG-JI has clear functional advantages over TG-RY, although it requires active surveillance for remnant gastric cancer.
    World Journal of Surgery 08/2015; 39(11). DOI:10.1007/s00268-015-3180-8 · 2.64 Impact Factor
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    ABSTRACT: Dimethyl sulfoxide (DMSO) is an amphipathic molecule that is used as a solvent in biological studies and as a vehicle for drug therapy. The present study was designed to evaluate the potential effects of DMSO as a solvent in the treatment of testicular embryonal carcinomas (ECs). DMSO was applied to two human EC cell lines (NEC8 and NEC14), with the treated cells evaluated in relation to cisplatin (CDDP) resistance, differentiation (using Vimentin, Fibronectin, TRA-1-60, and SSEA-1 and-3 as markers) and stemness (denoted by expression of SOX2 and OCT3/4). Furthermore, DNA methyltransferase (DNMT-1, -3A and -3L) expression and methylation status were analyzed. DMSO induced resistance to CDDP, aberrant differentiation and reduction of stemness-related markers in each of the EC cell lines. The expression levels of DNMT-3L and -3A were reduced in response to DMSO, while this treatment also affected DNA methylation. The data demonstrated that DMSO perturbed differentiation, reduced stemness and induced resistance to CDDP in human EC cells. Therefore, DMSO could reduce drug efficacy against EC cells and its use should be carefully managed in the clinical application of chemotherapy.
    Oncology letters 06/2015; 10(2). DOI:10.3892/ol.2015.3306 · 1.55 Impact Factor
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    ABSTRACT: Although endoscopic resection is widely used for the treatment of superficial colorectal neoplasms, the rate of local recurrence of lesions with a positive or indeterminate lateral margin on histologic evaluation is unclear. We aimed to demonstrate the relationship between lateral margin status and local recurrence after the endoscopic resection of intramucosal colorectal neoplasms. We retrospectively collected the clinical and pathologic data for 844 endoscopically resected colorectal intramucosal neoplasms with a size of 10 mm or larger. We investigated the relationship between the local recurrence rate and the lateral margin status (categorized as LM0 [negative], LM1 [positive], or LMX [indeterminate]). In total, 389 lesions were evaluated as LM0 and showed no local recurrence. Of the 455 lesions evaluated as LMX or LM1, 30 showed local recurrence within a median period of 6.3 months (range, 1.7 - 48.1) from the initial endoscopic resection. The local recurrence rate of the en bloc-LMX group (2.2 %) was significantly lower than that of the piecemeal-LMX group (15.2 %). Of the 30 cases of recurrence, 28 were successfully treated with a second endoscopic resection. Of the two lesions that showed further recurrence, one was treated with a third endoscopic resection, whereas the other - which was a piecemeal-LMX lesion - was eventually diagnosed as invasive cancer and treated with surgery. The local recurrence rate was lower in the en bloc-LMX group than in the piecemeal-LMX group. Thus, we believe that en bloc-LMX lesions that are completely and confidently resected endoscopically can be treated as en bloc-LM0 lesions.
    05/2015; 3(3). DOI:10.1055/s-0034-1391853
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    ABSTRACT: Endoscopic resection (ER) has been increasingly used for the treatment of rectal neuroendocrine tumors (NETs); however, only limited data are available on its long-term outcomes. This study analyzed the long-term outcomes of rectal NETs treated by ER and characterized potential risk factors for metastasis in these cases, with emphasis on lymphovascular invasion. We retrospectively analyzed the clinicopathological features and outcomes of 86 patients with 90 rectal NETs who had been treated by ER. Lymphovascular invasion was reevaluated using elastic-staining and double-staining immunohistochemistry. En bloc resection with tumor-free margins was achieved in 87 lesions (96.7 %). The median tumor size was 5 mm (range 2-13), and all the lesions were confined to the submucosal layer. The Ki-67 index was less than 3 % in all the lesions, which were therefore classified as NET G1. Elastic-staining and double-staining immunohistochemistry revealed the presence of lymphatic and venous invasion in 23 (25.6 %) and 35 lesions (36.7 %), respectively. Collectively, lymphatic and/or vascular invasion was identified in 42 lesions (46.7 %). All cases were followed up without additional surgery, and no metastasis or recurrence was detected during the median follow-up period of 67.5 months. This study showed an excellent long-term prognosis following ER of patients with rectal NETs, confirming that ER is a valid treatment option for small rectal NETs. The present study also revealed highly prevalent lymphovascular invasion even in minute rectal NETs; this observation raises a question regarding its significance as a risk factor for metastasis.
    Journal of Gastroenterology 05/2015; DOI:10.1007/s00535-015-1079-7 · 4.52 Impact Factor
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    ABSTRACT: Pyloric gland adenoma (PGA) is a unique gastric neoplasm expressing MUC6 and often associated with high-grade dysplasia and/or adenocarcinoma. MUC6 secreted from the gastric gland mucous cells such as pyloric gland cells carries unique O-glycans exhibiting terminal α1,4-linked N-acetylglucosamine residues (αGlcNAc) on its molecule. We recently demonstrated that αGlcNAc serves as a tumor suppressor for gastric adenocarcinoma, but the significance of αGlcNAc expression in PGA remains unknown. Eighteen patients with PGA were examined with immunohistochemistry for αGlcNAc and MUC6. αGlcNAc and MUC6 were co-expressed in 12 of 18 PGA. However, reduced αGlcNAc expression relative to MUC6 was observed in 6 cases. When the MIB-1 labeling index (LI) of tumor cells was examined with respect to αGlcNAc reduction, the MIB-1 LI was significantly higher in PGA showing decreased αGlcNAc expression relative to MUC6 than in PGA with unchanged αGlcNAc expression (P = 0.023). The present study indicates that co-expression of αGlcNAc and MUC6 in PGA suggests the presence of fully glycosylated MUC6 on tumor cells, consistent with pyloric gland differentiation. However, the decreased glycosylation of αGlcNAc on MUC6 is associated with high mitotic activity of tumor cells, indicative of malignant potential of PGA. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Histopathology 04/2015; DOI:10.1111/his.12728 · 3.45 Impact Factor
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    ABSTRACT: This study was performed to evaluate the concordance in pathological assessments of blood and lymphatic vessel invasion (BLI) in pT1 colorectal cancers and to assess the effect of diagnostic criterion on consistency in the assessment of BLI. Forty consecutive patients undergoing surgical resection of pT1 colorectal cancers were entered into this study. H&E-stained, D2-40-stained and elastica-stained slides from the tumours were examined by 18 pathologists from seven countries. The 40 cases were divided into two cohorts with 20 cases each. In cohort 1, pathologists diagnosed BLI using criteria familiar to them; all Japanese pathologists used a criterion of BLI from the Japanese Society for Cancer of the Colon and Rectum (JSCCR). In cohort 2, all pathologists used the JSCCR diagnostic criterion. In cohort 1, diagnostic concordance was moderate in the US/Canadian and European pathologists. There were no differences in the consistency compared with results for Japanese pathologists, and no improvement in the diagnostic concordance was found for using the JSCCR criterion. However, in cohort 2, the JSCCR criterion decreased the consistency of BLI diagnosis in the US/Canadian and European pathologists. The level of decreased consistency in the assessment of BLI was different between the US/Canadian and European pathologists. A uniform criterion strongly influences the diagnostic consistency of BLI but may not always improve the concordance. Further study is required to achieve an objective diagnosis of BLI in colorectal cancer. The varying effects of diagnostic criterion on the pathologists from Japan, the USA/Canada and Europe might reflect varied interpretations of the criterion. Internationally accepted criterion should be developed by participants from around the world. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Journal of clinical pathology 04/2015; 68(8). DOI:10.1136/jclinpath-2014-202805 · 2.92 Impact Factor
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    ABSTRACT: An 80-year-old man was under annual surveillance esophagogastroduodenoscopy after endoscopic submucosal dissection (ESD) for early gastric cancer (EGC). Two years after the initial ESD, a 0-IIc type metachronous EGC lesion, 8 mm in size, without an ulcer scar, was found in the gastric antrum. The estimated tumor depth was up to the mucosa, and biopsy revealed well and poorly differentiated adenocarcinoma. ESD was performed for this lesion and en bloc resection with negative margins was achieved. Histopathological examination revealed an adenosquamous carcinoma 8 mm in size invading the deep submucosal layer (1600 μm), with lymphovascular invasion, consistent with the diagnosis of non-curative resection. Additional gastrectomy was recommended for this patient; however, two months after the ESD, preoperative computed tomography revealed multiple liver metastases, and the patient was considered as an unsuitable candidate for surgical resection. Systemic chemotherapy was therefore started; however, the patient died of gastric cancer 27 mo after the second ESD. Early gastric adenosquamous carcinoma localized to the mucosa and submucosa is extremely rare and its clinical behavior is not well known. The present report is very significant in that it underscores the distinct possibility of gastric adenosquamous carcinoma being very aggressive and fatal even when detected at an early cancer.
    04/2015; 21(14):4385-90. DOI:10.3748/wjg.v21.i14.4385

  • World Journal of Gastroenterology 04/2015; 14(21):4385-4390. · 2.37 Impact Factor
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    ABSTRACT: The dormancy of tumor cells is a major problem in chemotherapy, since it limits the therapeutic efficacy of anti-tumor drugs that only target dividing cells. One potential way to overcome chemo-resistance is to "wake up" these dormant cells. Here we show that the opioid antagonist methylnaltrexone (MNTX) enhances the effect of docetaxel (Doc) by blocking a cell growth-suppressive pathway. We found that PENK, which encodes opioid growth factor (OGF) and suppresses cell growth, is predominantly expressed in diffuse-type gastric cancers (GCs). The blockade of OGF signaling by MNTX releases cells from their arrest and boosts the effect of Doc. In comparison with the use of Doc alone, the combined use of Doc and MNTX significantly prolongs survival, alleviates abdominal pain, and diminishes Doc-resistant spheroids on the peritoneal membrane in model mice. These results suggest that blockade of the pathways that suppress cell growth may enhance the effects of anti-tumor drugs.
    PLoS ONE 04/2015; 10(4):e0123407. DOI:10.1371/journal.pone.0123407 · 3.23 Impact Factor
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    ABSTRACT: A sessile serrated adenoma/polyp (SSA/P) is a common type of colorectal polyp that possesses malignant potential. Although narrow-band imaging (NBI) can easily differentiate neoplastic lesions from hyperplastic polyps (HPs), SSA/Ps can be a challenge to distinguish from HPs. To investigate specific endoscopic features of SSA/Ps by using NBI with optical magnification. Retrospective study. Single high-volume referral center. A total of 289 patients with histopathologically proven SSA/Ps or HPs obtained from colonoscopic polypectomy. Endoscopic images obtained by using NBI with optical magnification of 242 lesions (124 HPs, 118 SSA/Ps) removed between January 2010 and December 2012 were independently evaluated by 2 experienced endoscopists. Three external experienced endoscopists systematically validated the diagnostic accuracies by using 40 lesions (21 HPs and 19 SSA/Ps) removed between January and March 2013. Specific endoscopic features of SSA/Ps by using 5 potential characteristics: dilated and branching vessels (DBVs), irregular dark spots, a regular network pattern, a disorganized network pattern, and a dense pattern. Multivariate analysis demonstrated that DBV had a 2.3-fold odds ratio (95% confidence interval, 0.96-5.69) among SSA/Ps compared with HPs (sensitivity, 56%; specificity, 75%; accuracy, 65%). Interobserver and intraobserver agreement indicated almost perfect agreement for DBVs in both the evaluation and validation studies. When DBVs, proximal location, and tumor size (≥10 mm) were combined, the positive predictive value was 92% and the area under the curve was 0.783 in the receiver-operating characteristics by using the validation group. Retrospective study. The current study suggests that a DBV is a potentially unique endoscopic feature of a colorectal SSA/P. Copyright © 2015 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.
    Gastrointestinal endoscopy 03/2015; 79(5). DOI:10.1016/j.gie.2014.12.037 · 5.37 Impact Factor
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    ABSTRACT: The aim of this study was to clarify the significance of DNA methylation alterations during gastric carcinogenesis. Single-CpG-resolution genome-wide DNA methylation analysis using the Infinium assay was performed on 109 samples of non-cancerous gastric mucosa (N) and 105 samples of tumorous tissue (T). DNA methylation alterations in T samples relative to N samples were evident for 3,861 probes. Since N can be at the precancerous stage according to the field cancerization concept, unsupervised hierarchical clustering based on DNA methylation levels was performed on N samples (βN) using the 3,861 probes. This divided the 109 patients into three clusters: A (n=20), B1 (n=20) and B2 (n=69). Gastric carcinomas belonging to Cluster B1 showed tumor aggressiveness more frequently than those belonging to Clusters A and B2. The recurrence-free and overall survival rates of patients in Cluster B1 were lower than those of patients in Clusters A and B2. Sixty hallmark genes for which βN characterized the epigenetic clustering were identified. We then focused on DNA methylation levels in T samples (βT) of the 60 hallmark genes. In 48 of them, including the ADAM23, OLFM4, AMER2, GPSM1, CCL28, DTX1 and COL23A1 genes, βT was again significantly correlated with tumor aggressiveness, and the recurrence-free and/or overall survival rates. Multivariate analyses revealed that βT was a significant prognostic factor, being independent of clinicopathological parameters. These data indicate that DNA methylation profiles at the precancerous stage may be inherited by gastric carcinomas themselves, thus determining tumor aggressiveness and patient outcome. © The Author 2015. Published by Oxford University Press.
    Carcinogenesis 03/2015; 74(19 Supplement). DOI:10.1093/carcin/bgv013 · 5.33 Impact Factor
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    ABSTRACT: To analyze the mismatch repair (MMR) status and the ARID1A expression as well as their clinicopathological significance in gastric adenocarcinomas. We examined the expressions of MMR proteins and ARID1A by immunohistochemistry in consecutive 489 primary gastric adenocarcinomas. The results were further correlated with clinicopathological variables. The loss of any MMR protein expression, indicative of MMR deficiency, was observed in 38 cases (7.8%) and was significantly associated with an older age (68.6 ± 9.2 vs 60.4 ± 11.7, P < 0.001), a female sex (55.3% vs 31.3%, P = 0.004), an antral location (44.7% vs 25.7%, P = 0.021), and a differentiated histology (57.9% vs 39.7%, P = 0.023). Abnormal ARID1A expression, including reduced or loss of ARID1A expression, was observed in 109 cases (22.3%) and was significantly correlated with lymphatic invasion (80.7% vs 69.5%, P = 0.022) and lymph node metastasis (83.5% vs 73.7%, P = 0.042). The tumors with abnormal ARID1A expression more frequently indicated MMR deficiency (47.4% vs 20.2%, P < 0.001). A multivariate analysis identified abnormal ARID1A expression as an independent poor prognostic factor (HR = 1.36, 95%CI: 1.01-1.84; P = 0.040). Our observations suggest that the AIRD1A inactivation is associated with lymphatic invasion, lymph node metastasis, poor prognosis, and MMR deficiency in gastric adenocarcinomas.
    World Journal of Gastroenterology 02/2015; 21(7):2159-68. DOI:10.3748/wjg.v21.i7.2159 · 2.37 Impact Factor
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    ABSTRACT: Backgrounds/Aim: Colorectal laterally spreading tumors (LSTs) are sometimes difficult to visualize even with image-enhanced endoscopy. γ-Glutamyl-transpeptidase (GGT) is a cell surface-associated enzyme that is overexpressed in various types of human cancers. Furthermore, GGT expression is higher in colorectal cancer cells than in normal colorectal mucosa. γ-Glutamyl hydroxymethyl rhodamine green (gGlu-HMRG), an activatable fluorescent probe, is nonfluorescent under a neutral pH and normal cellular environment; however, it turns highly fluorescent upon reaction with GGT. We evaluated ex vivo fluorescent imaging of colorectal LSTs using this GGT-activatable fluorescent probe. Between March 2013 and March 2014, 30 endoscopically resected colorectal LSTs were prospectively included in this study. Each was analyzed by first taking a baseline image before spraying, then spraying with gGlu-HMRG onto the freshly resected specimen, and finally taking fluorescent images 15 min after spraying with a dedicated imaging machine. Of the LSTs, 67% rapidly showed positive fluorescent activity. These activities were shown in adenoma (54%) and carcinoma in adenoma (76%), and in LST-granular type (80%) and LST-nongranular type (40%). Topically spraying gGlu-HMRG enabled rapid and selective fluorescent imaging of colorectal tumors owing to the upregulated GGT activity in cancer cells. © 2015 S. Karger AG, Basel.
    Digestion 02/2015; 91(1):70-6. DOI:10.1159/000369367 · 2.10 Impact Factor
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    ABSTRACT: We assessed the clinicopathological characteristics of patients with serrated polyposis syndrome (SPS) and the incidence of advanced adenoma/colorectal cancer (CRC). We prospectively enrolled 249 consecutive patients who underwent colonoscopy at the National Cancer Center Hospital over a 6-month period. All the polyps were diagnosed using magnification colonoscopy and resection/biopsy. The enrolled patients were divided into two groups, i) those with ≥5 histologically diagnosed hyperplastic polyps (HPs) proximal to the sigmoid colon, with at least 2 polyps >10 mm in diameter and ii) those with ≥20 HPs distributed throughout the colon. The clinical characteristics of the two groups were compared, including lifestyle, family history of CRC and colonoscopic findings. HPs were identified in 228 patients, of whom 21 (8.4%) had SPS. All 21 patients had ≥20 HPs distributed throughout the colon, with none having >2 HPs ≥1 cm in diameter in the right colon. Synchronous advanced adenoma/CRC was diagnosed in 76/249 (30.5%) patients. The prevalence of advanced adenoma/CRC was higher among patients with compared to those without SPS (P=0.075). SPS was also associated with older age and higher body mass index (BMI). Our results suggested that older age and higher BMI are independent risk factors for SPS. Advanced adenoma/CRC tended to occur more frequently among patients with compared to those without SPS, although the difference was not statistically significant.
    Molecular and Clinical Oncology 01/2015; 3(1):69-72. DOI:10.3892/mco.2014.423

  • Pathology International 12/2014; 64(12). DOI:10.1111/pin.12220 · 1.69 Impact Factor
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    ABSTRACT: Background Endoscopic radiofrequency ablation (RFA) appears to be a safe and effective treatment for flat-type noninvasive squamous neoplasia of the esophagus. However, if RFA is applied to lesions containing invasive cancer (esophageal squamous cell carcinoma [ESCC]), histological features associated with lymph node metastases may remain undetected. In addition, extension of neoplasia down the ducts of esophageal submucosal glands (SMGs) may create a sheltered "niche" beyond the reach of ablation.
    Gastrointestinal Endoscopy 11/2014; 79(5). DOI:10.1016/j.gie.2014.09.004 · 5.37 Impact Factor
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    ABSTRACT: We here report on two rare cases of intrafollicular classical Hodgkin lymphoma (CHL). Case 1 was a 34-year-old man who underwent left supraclavicular lymph node biopsy. Case 2 was a 28-year-old woman who underwent surgical resection of an anterior mediastinal mass. The histology and microenvironment of both specimens resembled those of nodular lymphocyte predominant Hodgkin lymphoma. Nodular architecture was observed, which comprised normal-appearing small lymphocytes and scattered lymphocyte predominant (LP)-like cells. CD23(+) follicular dendritic cell meshworks were present in the nodules, surrounded by a mantle zone containing IgD(+) B cells. The LP-like cells were ringed by CD3(+) and PD-1(+) T cells, and numerous CD20(+) B cells were present in the background. However, the immunophenotypes of the LP-like cells resembled those of Hodgkin/Reed-Sternberg cells of CHL; they were positive for CD15, CD30, and PAX5, and negative for CD20, Bcl6, Oct2, and Bob1. These histopathological findings indicate that CHL can be derived from the germinal center.
    Pathology International 11/2014; 64(12). DOI:10.1111/pin.12221 · 1.69 Impact Factor
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    ABSTRACT: ABSTRACT This study aimed to indicate the patients' outcomes and pathological characteristics of follicular lymphoma (FL) with peripheral blood (PB) involvement. Of 533 patients with FL, 56 (11%) had PB involvement. Of the patients treated with rituximab, 39 patients with PB involvement had significantly shorter progression-free survival than 107 patients with stage IV disease without PB involvement (P = .021), but the overall survival was not different (P = .804). The histopathology of the primary sites was usually nodal (95%) low-grade (86%) FL with IGH/BCL2 fusion (75%). Flow cytometric and immunohistochemical analyses revealed that the incidence of CD10 positivity was lower in the bone marrow (55% and 58%) and PB (41% and not available) than in the primary site (86% and 93%) (P = .004 and P = .0001, respectively). Therefore, even if small lymphoma cells in the bone marrow and PB are negative for CD10, FL cannot be ruled out.
    Leukemia and Lymphoma 10/2014; 56(7):1-18. DOI:10.3109/10428194.2014.963578 · 2.89 Impact Factor
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    ABSTRACT: Purpose: Definitive chemoradiotherapy (dCRT) is one of the standard treatments for esophageal squamous cell carcinoma. Patients with a response to dCRT have a better prognosis than those resistant to dCRT while survival benefits for patients with residual tumors are limited. Nevertheless, few molecular markers to predict the response to dCRT are currently available. Here, we aimed to establish a DNA methylation marker to predict the response to dCRT. Methods: A total of 104 patients were divided into screening (n = 43) and validation (n = 61) sets. A genome-wide DNA methylation analysis was performed using an Infinium HumanMethylation450 BeadChip array. Methylation levels were measured by quantitative methylation-specific PCR and normalized by the fraction of cancer cells in a sample. Results: The genome-wide methylation analysis of seven responders and eight non-responders identified 18 genomic regions specifically (un)methylated in the responders. Among these, methylation of the promoter CpG island of ZNF695 was significantly associated with the response to dCRT in the screening set (P = 0.004), and a cutoff value was determined. In the validation set, the association was successfully validated (P = 0.021), and a high specificity (90 %) for the prediction of responders was obtained using the prefixed cutoff value. In addition, a multivariate analysis showed that ZNF695 methylation was an independent predictive factor for the response to dCRT (OR 7.55, 95 % CI 2.12-26.9, P = 0.002). Conclusion: ZNF695 methylation was significantly associated with the response to dCRT and is a promising predictive marker for the response to dCRT.
    Journal of Cancer Research and Clinical Oncology 10/2014; 141(3). DOI:10.1007/s00432-014-1841-x · 3.08 Impact Factor

Publication Stats

2k Citations
695.38 Total Impact Points


  • 2015
    • The University of Tokyo
      白山, Tōkyō, Japan
  • 2010-2015
    • National Hospital Organization Kyushu Cancer Center
      Hukuoka, Fukuoka, Japan
  • 2009-2015
    • National Cancer Center, Japan
      • Endoscopy Division
      Edo, Tōkyō, Japan
  • 1989-2015
    • Shiga University of Medical Science
      • • Department of Laboratory Medicine
      • • Department of Clinical Laboratory Medicine
      • • Department of Pathology
      • • First Department of Pathology
      • • Department of Urology
      Ōtu, Shiga Prefecture, Japan
  • 2012
    • Kyorin University
      Edo, Tōkyō, Japan
  • 2011
    • St. Luke's International Hospital
      • Department of Radiology
      Edo, Tōkyō, Japan
    • Shiga University
    • Richard L. Roudebush VA Medical Center
      Indianapolis, Indiana, United States