機能的腎体積測定による術後分腎機能評価の検討

PURPOSE:The change in functional renal volume (FRV) has an absolute influence on renal function after nephrectomy (Nx) or nephron-sparing surgery (NSS). In this study, we prospectively examined whether the postoperative renal function following Nx and NSS could be accurately predicted and assessed the reproducibility of our newly developed 3-D image reconstruction system (Kashihara) to measure the FRV. METHODS:We enrolled 98 patients who underwent Nx and 41 patients who underwent NSS from April 2006 to September 2009 to predict postoperative FRV and renal function. FRV was measured before and after (1 month and 1 year) renal surgery. The postoperative estimated glomerular filtration rate (eGFR) was predicted from the preoperative eGFR calculated from the serum creatinine (sCr) level and the ratio of the postoperative/preoperative FRV. To assess the reproducibility and accuracy of our newly developed 3-dimensional (3-D) image reconstruction system, FRV was measured by five examiners using images obtained by CT (five cases) and MRI (five cases). RESULTS:Significant correlation was found both for FRV and for renal function between the predictive values and the actually measured values at 1 month and 1 year after surgery, not only in the Nx group, but also in the NSS group. The accuracy and reproducibility could be confirmed both with CT and MRI studies. CONCLUSIONS:The postoperative FRV and renal function could be predicted preoperatively using a 3-D image reconstructive system, preoperative routine diagnostic imaging, and preoperative sCr level.博士（医学）・乙第1369号・平成27年11月27日© Springer-Verlag Berlin Heidelberg 2015The final publication is available at Springer via http://dx.doi.org/10.1007/s00345-014-1470-

前立腺癌マウスモデルにおけるジクロフェナク局所投与によるCOX-2発現の阻害はTRAILの増幅を介して放射線感受性を増強させる

BACKGROUND: COX-2 inhibitors have an antitumor potential and have been verified by many researchers. Treatment of cancer cells with external stressors such as irradiation can stimulate the over-expression of COX-2 and possibly confer radiation resistance. In this study, we tested if topical diclofenac, which inhibits both COX-1 and COX-2, administration rendered prostate tumor cells sensitize to the effects of radiation. METHODS: LNCaP-COX-2 and LNCaP-Neo cells were treated with 0 to 1000 μM diclofenac. Next, a clonogenic assay was performed in which cells were subjected to irradiation (0 to 4 Gy) with or without diclofenac. COX-2 expression and other relevant molecules were measured by real-time PCR and immunohistochemistry after irradiation and diclofenac treatment. In addition, we assessed the tumor volumes of xenograft LNCaP-COX-2 cells treated with topical diclofenac with or without radiation therapy (RT). RESULTS: LNCaP-COX-2 and LNCaP-Neo cell lines experienced cytotoxic effects of diclofenac in a dose related manner. Clonogenic assays demonstrated that LNCaP-COX-2 cells were significantly more resistant to RT than LNCaP-Neo cells. Furthermore, the addition of diclofenac sensitized LNCaP-COX-2 not but LNCaP-Neo cells to the cytocidal effects of radiation. In LNCaP-COX-2 cells, diclofenac enhanced radiation-induced apoptosis compared with RT alone. This phenomenon might be attributed to enhancement of RT-induced TRAIL expression as demonstrated by real-time PCR analysis. Lastly, tumor volumes of LNCaP-COX-2 cells xenograft treated with diclofenac or RT alone was >4-fold higher than in mice treated with combined diclofenac and radiation (p<0.05). CONCLUSIONS: These in vitro and in vivo findings suggest that conventional COX inhibitor, diclofenac enhances the effect of RT on prostate cancer cells that express COX-2. Thus, diclofenac may have potential as radiosensitizer for treatment of prostate cancer.博士（医学）・甲第606号・平成25年11月27日© 2013 Inoue 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/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

日本人男性における携帯式尿流量計(P-Flowdiary®)を用いた排尿量/尿流量に関する年齢階層別ノモグラムの作成

Background: To develop a nomogram of urinary volume and flow based on the data of Japanese men without lower urinary tract symptoms and multiple flows per participant whose characteristics were clear. Methods: Overall, 101 Japanese male volunteers without lower urinary tract symptoms aged between 20 and 59 years were enrolled. A portable uroflowmeter (P-Flowdiary®) was used to record urinary information (flow rate and volume) for 2 successive days. The model (quadratic, linear, or logarithmic regression) most fit for the relationship between maximum flow rate and voided volume was determined. The maximum flow rate at > 150 mL was compared among the 20-29-, 30-39-, 40-49-, and 50-59-year age groups. Nomograms appropriate for the age groups were created. Results: The mean age, International Prostate Symptom Score, and Overactive Bladder Symptom Score were 38.5 years, 0.42, and 0.24, respectively. The quadratic regression model was the most fit because its mean coefficient determination was 0.93 ± 0.06. The mean maximum flow rate was significantly lower in the 50-59-year age group (21.8 ± 5.05 mL/s, P < 0.01) than in the younger groups (24.14 ± 4.94, 24.05 ± 6.99, and 24.64 ± 5.72 mL/s). The 2 nomograms are Y = 28.99 {1 - exp(- 0.01 × X)} and Y = 25.67 {1 - exp(- 0.01 × X)} for the 20-49- and 50-59-year age groups, respectively. Conclusions: The nomogram can predict maximum flow rate based on voided volume in Japanese men aged 20-59 years without lower urinary tract symptoms.博士（医学）・甲第858号・令和4年12月22日© 2022. The Author(s). Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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 in a credit line to the data

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

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

機能的腎体積あたりの腎機能の影響を考慮した腎摘除後の残存腎機能の検討

BACKGROUND: To evaluate the clinical usefulness of estimated glomerular filtration rate (eGFR) divided by functional renal volume (FRV) measured by three-dimensional image reconstruction (eGFR/FRV) for the prediction of functional outcomes after nephrectomy. METHODS: Eighty-three patients who underwent nephrectomy were enrolled. The FRV of each patient was measured before surgery. Preoperative medical information on proteinuria, blood pressure, blood glucose level, body mass index (BMI), hemoglobin level and serum cholesterol level were also obtained. We evaluated the relationships between eGFR/FRV and each of these parameters before surgery. We also assessed the potential relationship between eGFR/FRV and the 3-year postoperative eGFR. Stepwise multiple regression analyses were conducted to elucidate independent factors. RESULTS: The median FRV and eGFR were 310.15 cm3 and 79.0 ml/min/1.73 m² before surgery, respectively. The correlation between FRV and eGFR was statistically significant (r = 0.465, P < 0.001). The median eGFR/FRV was 0.24 ml/min/1.73 m²/cm³. Stepwise multiple regression analysis showed that the independent parameters (multiple correlation coefficient, r = 0.389, P = 0.031) associated with eGFR/FRV were proteinuria, BMI, age and hypertension. Proteinuria was statistically associated with eGFR/FRV, and the independent parameters (multiple correlation coefficient, r = 0.694, P < 0.001) associated with the 3-year postoperative eGFR were age, BMI and eGFR/FRV. The eGFR/FRV was statistically associated with the 3-year postoperative eGFR (r = 0.559, P < 0.001). CONCLUSION: The present results demonstrated that patients with proteinuria are expected to have a lower eGFR/FRV than those without proteinuria. The present study also supports the notion that eGFR/FRV is the primary determinant of the long-term functional outcome after nephrectomy. It should be taken into consideration that patients with a low eGFR/FRV may develop chronic kidney disease after nephrectomy.博士（医学）・乙第1354号・平成27年3月16日© 2014 Hosokawa 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/2.0), 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

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

FADDのリン酸化の状態と根治的前立腺全摘除術後の生化学的再発は関連する

OBJECTIVE: To assess whether the phosphorylated Fas-associated death domain protein (FADD) at 194 serine (p-FADD) is valuable as a marker of biochemical recurrence in hormone-naive patients who had undergone radical prostatectomy. MATERIALS AND METHODS: We used radical prostatectomy specimens from 106 patients. None of the patients had received neoadjuvant or adjuvant therapy. The percentage of positive p-FADD cells (nuclear staining) was immunohistochemically evaluated. The correlation between FADD phosphorylation and the clinicopathologic parameters was assessed. The correlation between the biochemical recurrence-free rate and the p-FADD expression level was analyzed using the Kaplan-Meier method. RESULTS: Overall, 39 patients developed biochemical recurrence. We investigated the expression of p-FADD in 106 patients with prostate cancer using immunohistochemistry. We compared our findings with the clinicopathologic parameters, including the follow-up data. Patients with a greater positive p-FADD rate had a significantly lower biochemical recurrence rate than those with a lower positive p-FADD rate (P < .001). A significant inverse correlation was found between the positive p-FADD rate and the Gleason score. CONCLUSION: A low expression of p-FADD could be a predictor of biochemical recurrence in hormone-naive patients who have undergone radical prostatectomy.博士（医学）・乙第1313号・平成25年5月29

Phase II clinical trial of sorafenib plus interferon-alpha treatment for patients with metastatic renal cell carcinoma in Japan

Comparison of the current study with other sorafenib-interferon combination studies and with single-agent sorafenib studies [25]. (XLSX 12 kb

TUMOR MARKERS IN BONE MARROW IN PATIENTS WITH PROSTATIC CANCER

We compared prostatic specific acid phosphatase (PAP), prostatic specific antigen (PA) and γ-seminoprotein (γ-SM) levels between bone marrow and serum for the purpose of assessing of the usefulness of these tumor markers in early detection of bone metastasis in cases with prostatic cancer. Thirty-three patients were entered into this study. Of the patients, 20 had prostatic cancer including 11 with bone metastasis, and 13 patients had benign prostatic hypertrophy (BPH) served as controls. It seemed unlikely that bone marrow PAP, PA and γ-SM are more useful than their serum levels for detection of bone metastasis of prostatic cancer. Because correlation between bone marrow and serum levels of each marker was observed not only in cases with prostate cancer accompanied by bone metastasis but also in metastasis-free prostatic cancer and BPH cases, it seems likely that PAP, PA and γ-SM in bone marrow circulate from peripheral blood rather than from bone metastasis of prostatic cancer