終末糖化産物(AGE) は高リノール酸および高グルコース摂取下のアゾキシメタン投与F344 ラットの大腸粘膜においてAGE 受容体(RAGE) を発現誘導する

BACKGROUND:Advanced glycation end products (AGE) and the receptor for advanced glycation end products (RAGE) are closely associated with colorectal cancer progression. The association between RAGE and AGE in colon carcinogenesis needs to be clarified.METHODS:Levels of RAGE and AGE were examined in azoxymethane (AOM)-injected Fischer 344 rats fed a control diet (Group C), a 15 % linoleic acid (LA) diet (Group L), a control diet with 10 % glucose drink (Group G), and a 15 % LA diet with 10 % glucose drink (Group L + G). Group L + G showed the most pronounced increase of body weight, blood sugar, and serum insulin.RESULTS:The rats in Group L + G showed the most pronounced multiplicity of aberrant crypt foci (ACF) and carcinomas with increased mucosal RAGE and AGE. IEC6 rat intestinal epithelial cells treated with AGE showed increased RAGE expression, which was inhibited by treatment with metformin or losartan. In the AOM-injected rat colon cancer model, the levels of RAGE and AGE, and the multiplicity of ACF and carcinomas, in Group L + G rats were suppressed by treatment with metformin or losartan.CONCLUSIONS:These results suggest that AGE-RAGE induced by high-LA and high-glucose diets substantially enhances colon cancer development; thus, suppression of AGE-RAGE could be a potential target for colon cancer chemoprevention.博士（医学）・乙第1307号・平成25年3月15日© Springer International Publishing AG,2012© Japanese Society of Gastroenterology 201

Calculated Tumor Volume Is an Independent Predictor of Biochemical Recurrence in Patients Who Underwent Retropubic Radical Prostatectomy

Purpose. The purpose of this study is to investigate whether the clinicopathological biopsy findings can predict the oncological outcome in patients who undergo radical prostatectomy. Materials and Methods. Between January 1997 and March 2006, 255 patients with clinically localized adenocarcinoma of the prostate (clinical T1-3N0M0) who had undergone retropubic radical prostatectomy were enrolled in this study. None of the patients received neoadjuvant or adjuvant therapy. Clinicopathological parameters were assessed to determine a predictive parameter of biochemical recurrence. Results. Of the total 255 patients, 77 showed biochemical recurrence during the follow-up period. The estimated 5-year overall survival, 5-year cause-specific survival, and 5-year biochemical recurrence-free survival rates were 97.7%, 99.5%, and 67.3%, respectively. Multivariate analysis using the Cox proportional hazards model showed that calculated cancer volume was an independent predictor among the preoperative clinicopathological parameters (P < 0.05). SVI and PSM were independent predictors among the postoperative parameters (SVI; P < 0.001, PSM; P = 0.049). Among the significant preoperative and postoperative parameters, calculated cancer volume remained an independent predictive parameter in multivariate analysis (P < 0.01). Conclusions. Tumor volume, as calculated by preoperative parameters, is an independent predictor of biochemical recurrence in patients who had undergone radical prostatectomy

尿中剥離前立腺癌細胞における5-ALA を用いた光力学的診断の有用性

BACKGROUND:Past attempts at detecting prostate cancer (PCa) cells in voided urine by traditional cytology have been impeded by undesirably low sensitivities but high specificities. To improve the sensitivities, we evaluate the feasibility and clinical utility of photodynamic diagnosis (PDD) of prostate cancer by using 5-aminolevulinic acid (5-ALA) to examine shed prostate cancer cells in voided urine samples. METHODS:One hundred thirty-eight patients with an abnormal digital rectal exam (DRE) and/or abnormal prostate-specific antigen (PSA) levels were recruited between April 2009 and December 2010. Voided urine specimens were collected before prostate biopsy. Urine specimens were treated with 5-ALA and imaged by fluorescence microscopy and reported as protoporphyrin IX (PPIX) positive (presence of cells demonstrating simultaneous PPIX fluorescence) or PPIX negative (lack of cells demonstrating fluorescence). RESULTS:Of the 138 patients, PCa was detected on needle biopsy in 81 patients (58.7%); of these 81 patients with PCa, 60 were PPIX-positive (sensitivity: 74.1%). Although 57 patients did not harbor PCa by conventional diagnostic procedures, 17 of these at-risk patients were found to be PPIX-positive (specificity: 70.2%). PPIX-PDD was more sensitive compared with DRE and transrectal ultrasound and more specific compared with PSA and PSA density. The incidence of PPIX-PDD positivity did not increase with increasing total PSA levels, tumor stage or Gleason score.CONCLUSIONS:To our knowledge, this is the first successful demonstration of PPIX in urine sediments treated with 5-ALA used to detect PCa in a noninvasive yet highly sensitive manner. However, further studies are warranted to determine the role of PPIX-PPD for PCa detection.博士（医学）・甲第633号・平成27年3月16日© 2014 Nakai et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated

Novel missense mutation in the FH gene in familial renal cell cancer patients lacking cutaneous leiomyomas

BACKGROUND: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare tumor predisposition syndrome characterized by cutaneous and uterine leiomyomas and papillary type 2 renal cell cancer. Germline mutation of the fumarate hydratase (FH) gene is known to be associated with HLRCC. CASE PRESENTATION: We describe a 64-year-old father and his 39-year-old son with HLRCC who developed papillary type 2 RCCs lacking cutaneous leiomyomas at any site. A common missense mutation in the FH gene, (c.1021G > A, p.D341N) in exon 7, was detected in the 2 cases. Functional prediction with the bioinformatics programs, SIFT and Polyphen-2, reported “damaging (SIFT score 0.00)” and “probably damaging (PSIC score 1.621)” values, respectively. In 162 healthy individuals, there were no cases of a G transition to any base. Finally, (c.1021G > A) in exon 7, was identified as a point mutation. CONCLUSION: We report a family with HLRCC in which a novel missense mutation was detected. A familial papillary type 2 renal cancer should be considered HLRCC unless typical cutaneous leiomyomas do not occur

Pretreatment Platelet-to-Lymphocyte Ratio as Biomarker for Neoadjuvant Chemotherapy Prior to Radical Cystectomy in Muscle-Invasive Bladder Cancer.

Objectives : To evaluate the clinical benefit of neoadjuvant chemotherapy with gemcitabine and cisplatin (GC) in patients with muscle-invasive bladder cancer treated with radical cystectomy and to identify patients who may benefit from neoadjuvant chemotherapy and predictors of therapeutic response to it. Methods : In this prospective study, we enrolled 37 patients with muscle-invasive bladder cancer (cT2-4aNanyM0). The primary endpoint was the pathological response rate at cystectomy after receiving neoadjuvant GC chemotherapy. Univariable and multivariable analyses were used to determine predictive factors of pT0N0 and ≦pT1N0. The secondary endpoints were adverse events during chemotherapy, surgical complications, as well as overall, disease-specific, and recurrence-free survival. Results : A mean of 2.7 cycles of neoadjuvant GC was administered. Pathological complete response (pT0N0), partial response (pTisN0/pT1N0), and pathological response (≦pT1N0) rates were 24.3%, 27.0%, and 5l.3%, respectively. Grade 3 or 4 non-hematologic adverse events were rare. Three-year overall, disease-specific, and recurrence-free survival rates were 70.7%, 8l.3%, and 63.9%, respectively. Patients with pathological response (≦pT1N0) demonstrated a significantly improved 3-year overall survival rate (94.7% vs. 42.8%), disease-specific survival rate (94.7% vs.62.9%), and recurrence-free survival rate (80.6% vs.45.5%), compared with pathological non-responders (≦pT2Nany). Clinical stage cT2 and low pre-chemotherapy platelet-to-lymphocyte ratios were significant indicators of favorable pathological response to neoadjuvant Gc. Conclusions : Neoadjuvant chemotherapy using GC is safe and effective in patients with muscle-invasive bladder cancer, Pretreatment clinical T2 stage and low platelet-to-lymphocyte ratios were predictive markers for successful neoadjuvant treatment of muscle-invasive bladder cancer with GC

膀胱癌における抗クローディン4細胞外ドメイン中和抗体の化学療法増感効果

Bladder cancer displays an aggressive phenotype in the muscle-invasive phase, and is associated with a high mortality rate. Therefore, novel molecular therapeutic targets are needed to improve patient survival. A monoclonal antibody against the extracellular domain of the claudin-4 (CLDN4) tight junction protein was established by immunizing rats with a plasmid vector encoding human CLDN4. A hybridoma clone, producing a rat monoclonal antibody recognizing CLDN4 (clone 4D3), was obtained. Immunohistochemistry by using the 4D3 antibody showed that CLDN4 expression was associated with local invasion, nodal metastasis, distant metastasis, and advanced stage in 86 cases of bladder cancer. The 4D3 antibody inhibited growth, invasion, and survival, associated with abrogation of the intratumoral microenvironment; lowered concentrations of epidermal growth factor and vascular endothelial growth factor were found in three-dimensional cultures of T24 and RT4 cells. In combination with cisplatin therapy, 4D3 enhanced cisplatin cytotoxicity by increasing cellular permeability, leading to increased intracellular cisplatin concentrations. In mouse models of subcutaneous tumors and lung metastasis, 4D3 enhanced tumor growth inhibition, alone and with concurrent cisplatin treatment. The anti-tumor activity of the newly established 4D3 antibody suggests that it may be a powerful tool in CLDN4-targeting therapy, and in combination with chemotherapy.博士（医学）・甲第649号・平成28年3月15日Copyright © 2015 Elsevier Ireland Ltd. All rights reserved

Evaluation of metastatic potential of prostate cancer

We aimed to establish a method for evaluating malignant potential of prostate cancer using prostatic core needle biopsy (PCNB) before prostatectomy. If we can know the final pathological stage before treatment, we can select the most suitable therapeutic tactics. We then examined the expression of E-cadherin and type IV collagenase (MMP-9/-2), which play essential role in cancer cell invasion and metastasis. The expression ratio of MMP-9/-2 to E-cadherin (MER) is revealed as the relevant marker correlated with the final pathological stage and Gleason score by prostatectomy specimens. We next confirmed the significance of MER in PCNB, which means PCNB MER enables the prediction of the final pathologic stage at the cancer diagnosis. However, the methodology measuring MER is complicated to produce an observer-to-observer deviation. We then establish a bicolor fluorescent ISH (bicolor FISH) with a computerized fluorescence detector- based system. By this method, we can reduce an observer-to-observer deviation and a slide-to-slide deviation. The bicolor FISH-based MER is a useful tool for the preoperative evaluation of the final pathologic stage, by which we can assure a decision of prostatectomy indication

The roles of HMGB1 related angiogenesis and lymphangiogenesis in oral cancer

Angiogenesis and lymphangiogenesis are the vital factors in tumor progression and metastasis. In this review, we show that high-mobility group box 1 (HMGB1) is responsible for both angiogenesis and lymphangiogenesis in oral squamous cell carcinoma (OSCC). HMGB1 possesses the dual role as a cytokine and as a chromatin protein. HMGB1 as a cytokine is the ligand of receptor for advanced glycation end products (RAGE). RAGE activation upregulates secretion of vascular endothelial growth factor (VEGF). Then co-expression of HMGB1 and RAGE accelerates angiogenesis. In contrast, nuclear HMGB1 transcriptionally induces the expression of melanoma inhibitory activity (MIA) gene with NFkB. MIA upregulates expression of VEGF-C and VEGF-D via p38 phosphorylation by integrin activation. Then HMGB1 and MIA is associated with lymphangiogenesis. According to the differential roles of HMGB1 on angiogenesis and lymphangiogenesis, local invasion, disease recurrence, and poor prognosis are associated with HMGB1–RAGE system, whereas lymph node metastasis is associated with HMGB1–MIA system in OSCC