研究者詳細 - 田中　伸之

論文 - 田中　伸之

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Risk factors for haemodynamic instability and its prolongation during laparoscopic adrenalectomy for pheochromocytoma.

Takeda T, Hakozaki K, Yanai Y, Masuda T, Yasumizu Y, Tanaka N, Matsumoto K, Morita S, Kosaka T, Mizuno R, Kurihara I, Asanuma H, Itoh H, Oya M

Clinical endocrinology （Clinical Endocrinology） 95 （ 5 ） 716 - 726 2021年07月

ISSN 0300-0664

Objective: Pheochromocytoma is a rare neuroendocrine tumour that secretes catecholamines and originates in the adrenal gland. Although surgical resection is the only curative therapy for pheochromocytoma, it is associated with a risk of haemodynamic instability (HDI), such as extremely high blood pressure and/or post tumour removal hypotension and shock. We investigated the risk factors for HDI during pheochromocytoma surgery. Design and Patients: Eighty-two patients who underwent laparoscopic adrenalectomy for pheochromocytoma between July 2002 and February 2020 were examined. We excluded 3 patients with bilateral disease and 11 without detailed 24 h urinary data. We defined HDI as systolic blood pressure ≥ 200 or <80 mmHg. We investigated the risk factors for HDI during laparoscopic adrenalectomy for pheochromocytoma. Results: There were 29 males and 39 females with a median age of 50.5 years. Tumours were localised on the right adrenal gland in 28 patients and on the left in 40. The median tumour diameter was 37.5 mm and the median pneumoperitoneum time was 93.5 min. Twenty-five out of sixty-eight patients (37%) developed HDI. A multivariate analysis identified diabetes mellitus (DM; odds ratio: 3.834; 95% confidence interval: 1.062–13.83; p =.04) as an independent predictor of HDI. In terms of hormonal data, median 24 h urinary epinephrine levels (p =.04) and metanephrine levels (p =.01) were significantly higher in the HDI group. DM was also considered as a risk factor for prolonged HDI (p =.02). Conclusion: Surgeons and anaesthesiologists need to be aware of the risk of HDI and its prolongation during laparoscopic adrenalectomy for pheochromocytoma for DM patients.

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Xp11.2転座型腎細胞癌においてInterleukin-6はprogrammed cell death-1 ligand(PDL1)発現を誘導する

高松公晴, 水野隆一, 田中伸之, 浅沼宏, 大家基嗣

日本小児泌尿器科学会雑誌（日本小児泌尿器科学会） 30 （ 1 ） 17 - 20 2021年06月

ISSN 1341-0784

【目的】Xp11.2転座/transcription factor enhancer3融合遺伝子関連腎細胞癌(Xp-RCC)は小児〜AYA世代の腎細胞癌(RCC:renal cell carcinoma)で最多の組織型だが、PDL1発現に関する報告は少ない。本研究ではXp-RCCにおけるPDL1発現と、炎症性サイトカインであるInterleukin-6(IL6)とPDL1発現の関連を評価した。【方法】RCC112検体(Xp-RCC7例、淡明細胞型RCC105例)を対象に免疫染色によりPDL1発現率を評価した。更に各種ヒトRCC細胞株(786-O、Caki2、ACHN)とXp-RCC細胞株(S-TFE)を用いてIL6刺激によるPDL1発現の変化を評価した。【結果】Xp-RCCではPDL1陽性率が57%で、淡明細胞型(25%)よりもPDL1陽性率が高い傾向がみられた(p=0.091)。IL6刺激によりS-TFE(p=0.014)、786O(p=0.011)、Caki2(p=0.016)、ACHN(p=0.002)でPDL1発現が上昇した。IL6+IL6中和抗体付加により、S-TFE(p=0.006)、786O(p=0.026)、Caki2(p=0.025)、ACHN(p=0.021)でIL6によるPDL1発現誘導効果は有意に抑制された。【結論】Xp-RCCでは淡明細胞型RCCと比較してPDL1発現が高い傾向を認めた。Xp-RCC細胞株(S-TFE)ではIL6刺激によりPDL1発現が誘導されることが示唆された。(著者抄録)

Grading of Multifocal Prostate Cancer Cases in which the Largest Volume and the Highest Grade do Not Coincide within One Lesion.

Matsumoto K, Omura M, Takeda T, Kosaka T, Hashiguchi A, Takamatsu K, Yasumizu Y, Tanaka N, Morita S, Mizuno R, Asanuma H, Oya M

The Journal of urology （The Journal of urology） 206 （ 2 ） 101097JU0000000000001765 - 345 2021年04月

ISSN 0022-5347

PURPOSE: In general, the index lesion of prostate cancer has the largest tumor volume, the highest Grade Group (GG), and the highest stage (concordant cases). However, these factors sometimes do not coincide within one lesion (discordant cases). In such discordant cases, the largest tumor may not be of biological significance and the secondary tumor may more greatly impact the prognosis. MATERIALS AND METHODS: We retrospectively reviewed the medical records of patients who underwent radical prostatectomy, and we identified 580 (85.3%) concordant cases and 100 (14.7%) discordant cases. The end point of this study was biochemical recurrence, and median followup was 4.2 years. RESULTS: Among discordant cases in which GGs of the largest tumor and the highest GG tumor differed, the majority (67 patients) had the largest tumor of GG 2, and we set them as the study cohort. On the other hand, we regarded 212 concordant cases with an index tumor of GG 2 as the control cohort. The study cohort comprised 48 (71.6%) patients with a secondary tumor of GG 3 and 19 (28.4%) with a secondary tumor of GG 4/5. Kaplan-Meier curves revealed that the 5-year biochemical recurrence-free survival rates were 76%, and 67%, respectively. The 5-year biochemical recurrence-free survival rate of the control cohort was 91%, which was significantly better than that of the study cohort (p=0.013 and p=0.014, respectively). CONCLUSIONS: Our study suggests that the prognosis of discordant cases is better determined by the secondary cancer lesion with the highest GG instead of the largest lesion.

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Long-term follow-up comparing salvage radiation therapy and androgen-deprivation therapy for biochemical recurrence after radical prostatectomy.

Matsumoto K, Niwa N, Hagiwara M, Kosaka T, Takeda T, Yasumizu Y, Tanaka N, Morita S, Mizuno R, Shinojima T, Hara S, Asanuma H, Oya M

International journal of clinical oncology （International Journal of Clinical Oncology） 26 （ 4 ） 744 - 752 2021年01月

ISSN 1341-9625

© 2021, Japan Society of Clinical Oncology. Background: The salvage treatments for biochemical recurrence (BCR) include local external beam radiation therapy (RT) and systemic androgen-deprivation therapy (ADT). Methods: We reviewed patients who underwent radical prostatectomy (RP) and developed BCR at three institutions. After excluding patients whose nadir prostate-specific antigen (PSA) was higher than 0.2 ng/mL, those who received neoadjuvant/adjuvant therapy, and those whose BCR was not treated until their PSA exceeded 4.0 ng/mL, the remaining 335 patients comprised the cohort of this study. Salvage RT and ADT were performed for 154 and 181 patients, respectively. After the failure of salvage RT, all patients received subsequent ADT. The starting point of this study was the timing of BCR and the endpoint was the development of castration-resistant prostate cancer (CRPC). Results: During the mean follow-up period of 8.5 years after BCR, CRPC was observed in 13 patients administered RT and 24 patients administered ADT. Kaplan–Meier curves demonstrated no significant difference in CRPC-free survival between the RT and ADT groups (10-year CRPC-free survival 89.9 vs. 86.3%, p = 0.199). On the other hand, we found a significant difference in CRPC-free survival between the RT and ADT groups in 50 high-risk patients with two risk factors of Grade Group ≥ 4 and PSA-doubling time < 6 months (10-year CRPC-free survival 73.4 vs. 40.3%, p = 0.040). Conclusion: This study revealed that salvage RT increases the CRPC-free survival rate compared with salvage ADT in high-risk patients with Grade Group ≥ 4 and PSA-doubling time < 6 months.

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On-treatment C-reactive protein control could predict response to subsequent anti-PD-1 treatment in metastatic renal cell carcinoma

Takamatsu K., Mizuno R., Baba Y., Yasumizu Y., Tanaka N., Shirotake S., Takeda T., Morita S., Matsumoto K., Kosaka T., Asanuma H., Oyama M., Mikami S., Oya M.

International Journal of Clinical Oncology （International Journal of Clinical Oncology） 26 （ 8 ） 1500 - 1505 2021年

ISSN 13419625

Objective: The aim of this study was to evaluate the clinical significance of the on-treatment C-reactive protein (CRP) status during systemic treatment as the predictive marker for the response of subsequent nivolumab monotherapy in patients with refractory metastatic renal cell carcinoma (mRCC). Patients and methods: A total of 73 mRCC patients treated with nivolumab were retrospectively reviewed. We evaluated the serum CRP levels before and after molecular-targeted treatments. Patients whose CRP did not exceed baseline value were defined as the CRP-control group and the others were defined as the CRP-progression group. The clinical impact of CRP-control on the efficacy of nivolumab was assessed. Results: Twenty-four patients (33%) were categorized into the CRP-control group. The CRP-control group patients (median PFS not reached) had significantly longer PFS than the CRP-progression group (median PFS 11.9 months, 95% confidence interval, CI 4.1–19.8, p = 0.038). The CRP-control group had a tendency of longer OS from nivolumab initiation than the CRP-progression group (p = 0.071). By multivariate analysis, the on-treatment CRP-control was the independent predictive factor for PFS (hazard ratio HR 0.37, 95% CI 0.14–0.99, p = 0.047). Conclusion: The on-treatment CRP-control could be the predictive factor for the efficacy of nivolumab in refractory mRCC patients.

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Negative impact of neoadjuvant hormonal therapy on detecting biochemical recurrence after radical prostatectomy

Matsumoto K., Niwa N., Kosaka T., Takeda T., Yasumizu Y., Tanaka N., Morita S., Mizuno R., Shinojima T., Asanuma H., Oya M.

International Journal of Clinical Oncology （International Journal of Clinical Oncology） 26 （ 9 ） 1722 - 1728 2021年

ISSN 13419625

Background: Routine use of neoadjuvant hormonal therapy (NHT) before radical prostatectomy (RP) is not recommended, but it is sometimes performed to reduce the prostate size and tumor volume or to prevent tumor progression during the wait times for surgery in clinical practice. On the other hand, the impact of NHT on the pattern of biochemical recurrence (BCR) is unknown. Methods: We retrospectively examined 1749 consecutive patients who underwent RP between 1996 and 2017. Among the patients who met the inclusion criteria, BCR developed in 240 of non-NHT patients and in 120 of NHT patients during the mean follow-up period of 6.9 years. We examined the impact of NHT on the PSA-doubling time (DT) following BCR at different times after RP. Results: The median PSA-DTs in non-NHT patients who experienced BCR in the first year after surgery, between 1 and 2 years, between 2 and 3 years, between 3 and 4 years, between 4 and 5 years, and at > 5 years were 5.5, 8.8, 11.3, 17.7, 18.2, and 18.4 months, respectively. On the other hand, those in NHT patients were 1.4, 4.1, 9.1, 13.4, 27.2, and 19.3 months, respectively. The differences of PSA-DTs in the first year after surgery (p < 0.001) and between 1 and 2 years (p = 0.005) were significant between non-NHT and NHT patients. Conclusion: Patients who received NHT had a higher risk of a rapid PSA increase when they experienced BCR, especially within 2 years after RP. In order to not miss the optimal timing of salvage treatment for BCR, intensive PSA follow-up is necessary.

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Does neoadjuvant chemotherapy have therapeutic benefit for node-positive upper tract urothelial carcinoma? Results of a multi-center cohort study

Shigeta K., Matsumoto K., Ogihara K., Murakami T., Anno T., Umeda K., Izawa M., Baba Y., Sanjo T., Shojo K., Tanaka N., Takeda T., Morita S., Kosaka T., Mizuno R., Arita Y., Akita H., Jinzaki M., Kikuchi E., Oya M.

Urologic Oncology: Seminars and Original Investigations （Urologic Oncology: Seminars and Original Investigations） 40 （ 3 ） 105.e19 - 105.e26 2021年

ISSN 10781439

Objective: The indications of neoadjuvant chemotherapy (NAC) for lymph node-positive upper tract urothelial carcinoma (UTUC) have not been investigated regarding improved survival outcomes. Our specific aim was to compare the clinical outcomes of clinically node-positive UTUC patients who were treated by NAC followed by radical nephroureterectomy (RNU) or upfront RNU followed by adjuvant chemotherapy (AC). Materials and methods: Among 966 UTUC patients, we identified 89 with clinical nodal involvement who received either NAC before RNU nor AC after upfront RNU. Cox proportional hazard models were employed to evaluate the impact of chemotherapy modality on the oncological outcomes. Results: Of the patient cohort, 36 (40.4%) received NAC followed by RNU, whereas 53 (59.6%) underwent RNU followed by AC. Multivariate analysis revealed that tumor size ≥3 cm, clinical T4, and gemcitabine and cisplatin regimen were independent risk factors for disease recurrence, whereas NAC followed by RNU was an independent factor for favorable RFS. Furthermore, regarding cancer-specific survival (CSS), NAC followed by RNU remained an independent factor for favorable CSS. According to Kaplan-Meier analysis, the 1-year and 2-year RFS were 67.9% and 47.0%, respectively, in the NAC+RNU group, which were significantly higher than those in the RNU+AC group (43.9% and 24.6%, respectively, P = 0.006). Moreover, the 1-year and 2-year CSS were 80.5% and 64.2%, respectively, in the NAC+RNU group, which were higher than those in the RNU+AC group (68.6% and 48.2%, respectively, P = 0.016). Conclusion: For node-positive UTUC patients, NAC followed by RNU was more clinically beneficial than RNU followed by AC.

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The Clinicopathological Characteristics of Muscle-Invasive Bladder Recurrence in Upper Tract Urothelial Carcinoma.

Shigeta K, Matsumoto K, Ogihara K, Murakami T, Anno T, Umeda K, Izawa M, Baba Y, Sanjo T, Shojo K, Tanaka N, Takeda T, Kosaka T, Mizuno R, Mikami S, Kikuchi E, Oya M

Cancer science （Cancer Science） 112 （ 3 ） 1084 - 1094 2020年12月

ISSN 1347-9032

© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. This study aimed to clarify the clinical characteristics and oncological outcomes of patients with upper tract urothelial carcinoma (UTUC) who developed muscle-invasive bladder cancer (MIBC) after radical nephroureterectomy (RNU). We identified 966 pTa-4N0-2M0 patients with UTUC who underwent RNU and clarified the risk factors for MIBC progression after initial intravesical recurrence (IVR). We also identified 318 patients with primary pT2-4N0-2M0 MIBC to compare the oncological outcomes with those of patients with UTUC who developed or progressed to MIBC. Furthermore, immunohistochemical examination of p53 and FGFR3 expression in tumor specimens was performed to compare UTUC of MIBC origin with primary MIBC. In total, 392 (40.6%) patients developed IVR after RNU and 46 (4.8%) developed MIBC at initial IVR or thereafter. As a result, pT1 stage on the initial IVR specimen, concomitant carcinoma in situ on the initial IVR specimen, and no intravesical adjuvant therapy after IVR were independent factors for MIBC progression. After propensity score matching adjustment, primary UTUC was a favorable indicator for cancer-specific death compared with primary MIBC. Subgroup molecular analysis revealed high FGFR3 expression in non-MIBC and MIBC specimens from primary UTUC, whereas low FGFR3 but high p53 expression was observed in specimens from primary MIBC tissue. In conclusion, our study demonstrated that patients with UTUC who develop MIBC recurrence after RNU exhibited the clinical characteristics of subsequent IVR more than those of primary UTUC. Of note, MIBC subsequent to UTUC may have favorable outcomes, probably due to the different molecular biological background compared with primary MIBC.

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Factors affecting renal function preservation among patients not achieving trifecta after laparoscopic partial nephrectomy for clinical T1a renal masses.

Takeda T, Komatsuda A, Yanai Y, Tanaka N, Matsumoto K, Morita S, Kosaka T, Mizuno R, Shinojima T, Asanuma H, Oya M

Asian journal of endoscopic surgery （Asian journal of endoscopic surgery） 13 （ 4 ） 526 - 531 2020年10月

ISSN 1758-5902

© 2019 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and John Wiley & Sons Australia, Ltd. INTRODUCTION: The goal of partial nephrectomy for renal tumors is complete tumor removal with the preservation of renal function and no complications. Trifecta (total ischemia time < 25 minutes, negative surgical margins, and no surgical complications) is widely used to evaluate success after partial nephrectomy. We investigated factors affecting renal function preservation among patients not achieving trifecta after laparoscopic partial nephrectomy. METHODS: Sixty-six patients who underwent laparoscopic partial nephrectomy for clinical T1a renal masses between December 2006 and March 2016 were examined. We defined preserved renal function as the preservation of an estimated glomerular filtration rate ≥ 90% 1 year after surgery. We examined factors affecting renal function preservation among patients not achieving trifecta after laparoscopic partial nephrectomy. RESULTS: Thirty out of 66 patients (45%) did not achieve trifecta. In an evaluation of 66 patients, a multivariate analysis identified tumor size (P = .04) as an independent predictor affecting the achievement of trifecta. Tumor size was significantly smaller in the trifecta achievement group (1.9 ± 0.1 cm) than in the non-achievement group (2.2 ± 0.6 cm) (P = .04). We found that renal function was preserved 1 year after surgery in 14 out of the 30 patients not achieving trifecta. In univariate analysis, age (P = .01) was significantly associated with affecting the preservation of renal function among these patients. Patients with preserved renal function were significantly younger (47.8 ± 2.5 years) than those without (58.5 ± 2.9 years) (P = .01). CONCLUSION: Renal function may be preserved in younger patients even if they do not achieve trifecta after partial nephrectomy for small renal masses.

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Three-dimensional single-cell imaging for the analysis of RNA and protein expression in intact tumour biopsies

Tanaka N., Kanatani S., Kaczynska D., Fukumoto K., Louhivuori L., Mizutani T., Kopper O., Kronqvist P., Robertson S., Lindh C., Kis L., Pronk R., Niwa N., Matsumoto K., Oya M., Miyakawa A., Falk A., Hartman J., Sahlgren C., Clevers H., Uhlén P.

Nature Biomedical Engineering （Nature Biomedical Engineering） 4 （ 9 ） 875 - 888 2020年09月

© 2020, The Author(s), under exclusive licence to Springer Nature Limited. Microscopy analysis of tumour samples is commonly performed on fixed, thinly sectioned and protein-labelled tissues. However, these examinations do not reveal the intricate three-dimensional structures of tumours, nor enable the detection of aberrant transcripts. Here, we report a method, which we name DIIFCO (for diagnosing in situ immunofluorescence-labelled cleared oncosamples), for the multimodal volumetric imaging of RNAs and proteins in intact tumour volumes and organoids. We used DIIFCO to spatially profile the expression of diverse coding RNAs and non-coding RNAs at the single-cell resolution in a variety of cancer tissues. Quantitative single-cell analysis revealed spatial niches of cancer stem-like cells, and showed that the niches were present at a higher density in triple-negative breast cancer tissue. The improved molecular phenotyping and histopathological diagnosis of cancers may lead to new insights into the biology of tumours of patients.

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Appropriate timing for a biochemical evaluation after adrenalectomy for unilateral aldosterone-producing adenoma

Takamatsu K., Takeda T., Hattori S., Tanaka N., Morita S., Matsumoto K., Kosaka T., Mizuno R., Shinojima T., Kikuchi E., Asanuma H., Kurihara I., Itoh H., Oya M.

Clinical Endocrinology （Clinical Endocrinology） 92 （ 6 ） 503 - 508 2020年06月

ISSN 03000664

© 2020 John Wiley & Sons Ltd Context: The oversecretion of plasma aldosterone by unilateral aldosterone-producing adenoma (APA) can be cured by adrenalectomy. However, the time needed for the endocrine environment to normalize remains unclear. Objective: To clarify adequate timing for a biochemical evaluation in unilateral APA patients after adrenalectomy. Design and patients: A total of 166 unilateral APA patients were retrospectively reviewed. We evaluated the plasma aldosterone concentration (PAC) (pg/mL), active renin concentration (ARC) (pg/mL), aldosterone-renin ratio (ARR; PAC/ARC), serum potassium concentration and estimated glomerular filtration rate (eGFR) at 1, 3 and 6 postoperation months (POM). Results: PAC was significantly lower at 1POM than at presurgery (presurgery; 407.2, 1 POM; 90.0 pg/mL, P <.001). ARC did not increase from baseline at 1POM, but significantly increased at 3POM (presurgery; 4.43, 1POM; 4.87, 3POM; 11.3 pg/mL, P <.001). ARR significantly decreased at 1POM (presurgery; 146.9, 1 POM; 26.3, P <.001) although ARC did not increase at 1POM. Among the 34 patients who had hypokalaemia presurgery, it was resolved in 28 (82%) at 1POM and in all (100%) at 3POM. The biochemical outcomes at 1POM were 131 (79%) complete, 20 (12%) partial and 15 (9%) absent successes, while at 3POM, 147 (89%) were complete, 9 (5%) partial and 10 (6%) absent. Twenty-three (14%) patients were reclassified into different biochemical outcomes between 1 and 3POM, whereas only 5 (3%) changed between 3 and 6POM. Conclusion: The appropriate timing for a biochemical evaluation of unilateral APA patients treated with laparoscopic adrenalectomy appears to be 3 months or more after surgery.

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External validation of the "optimal PSA follow-up schedule after radical prostatectomy” in a new cohort

Yanai Y., Matsumoto K., Kosaka T., Takeda T., Tanaka N., Morita S., Mizuno R., Shinojima T., Asanuma H., Oya M.

International Journal of Clinical Oncology （International Journal of Clinical Oncology） 25 （ 7 ） 1393 - 1397 2020年

ISSN 13419625

© 2020, Japan Society of Clinical Oncology. Background: Biochemical recurrence (BCR) after radical prostatectomy (RP) is most commonly diagnosed by detecting an increase in asymptomatic prostate-specific antigen (PSA). We previously reported the “optimal PSA follow-up schedule after RP”. The aim of this study was to confirm the usefulness and safety of that follow-up schedule in another cohort. Methods: We retrospectively reviewed the clinicopathological data of 798 consecutive patients who underwent radical prostatectomy between 2009 and 2017. We examined all PSA values measured during follow-up. Furthermore, we estimated the PSA value when we observed the “optimal PSA follow-up schedule” at each timing in the virtual follow-up. BCR was defined as an elevation of PSA to greater than 0.2 ng/ml, and the ideal PSA range for detection of BCR was regarded to be 0.2–0.4 ng/ml. Results: During the mean follow-up period of 5.8 years, BCR occurred in 115 (14.9%) patients and the frequency of virtual follow-up was significantly lower than the actual frequency. However, overlooking of BCR (detecting BCR when PSA exceeded 0.4 ng/ml) was observed in 17 patients, which is higher than the actual frequency of overlooking (12 patients). Therefore, we modified the follow-up schedule, which could achieve the lower follow-up frequency and a limited number of overlooking of BCR (7 patients). Conclusion: This external validation study revealed that the "modified optimal PSA follow-up schedule after RP" can reduce the frequency of PSA measurement with a limited risk of overlooking BCR.

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Evaluation of Gleason Grade Group 5 in a Contemporary Prostate Cancer Grading System and Literature Review

Kamitani R., Matsumoto K., Kosaka T., Takeda T., Hashiguchi A., Tanaka N., Morita S., Mizuno R., Shinojima T., Asanuma H., Oya M.

Clinical Genitourinary Cancer （Clinical Genitourinary Cancer） 19 （ 1 ） 69 - 75.e5 2020年

ISSN 15587673

© 2020 Elsevier Inc. Introduction: The aim of this study was to validate contemporary grading systems, in particular, the Gleason grade group (GGG) 5. Patients and Methods: We retrospectively reviewed the clinicopathologic data of 176 patients who underwent radical prostatectomy and whose pathologic results were GGG 4 or 5. The endpoints were biochemical recurrence (BCR) and castration-resistant prostate cancer (CRPC). Results: The GGG 4 group was composed of 69 patients. The GGG 5 group consisted of 78 patients with GS 4+5 and 29 patients with GS 5+4 or higher. The 5-year BCR-free survival rates for men with GGG 4, GS 4+5, and GS 5+4 or higher were 59%, 54%, and 20%, respectively, and the 5-year CRPC-free survival rates were 98%, 100%, and 88%, respectively. Both the BCR- and CRPC-free survival rates were significantly higher in GS 4+5 than in GS 5+4 or higher (P < .001 and P = .002, respectively), but there were no significant differences between GGG 4 and GS 4+5 (P = .702 and P = .803, respectively). The multivariate analysis demonstrated that GS 5+4 or higher (hazard ratio, 3.4; P = .002) and lymphovascular invasion (hazard ratio, 3.4; P < .001) greatly affected BCR. Conclusion: Our follow-up study revealed that men with GS 4+5 and those with GGG 4 had a similar prognosis. However, there was a significant discrepancy in prognosis between GS 4+5 and GS 5+4 or higher. This suggested that GGG 4 and 5 in the contemporary prostate cancer grading system should be reviewed. Furthermore, lymphovascular invasion may be useful to subgroup these pathologically high-risk patients.

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Significance of tumor microenvironment in acquiring resistance to vascular endothelial growth factor-tyrosine kinase inhibitor and recent advance of systemic treatment of clear cell renal cell carcinoma

Mikami S., Mizuno R., Kosaka T., Tanaka N., Kuroda N., Nagashima Y., Okada Y., Oya M.

Pathology International （Pathology International） 70 （ 10 ） 712 - 723 2020年

ISSN 13205463

© 2020 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd The development of systemic therapies, including vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKI) and mammalian target of rapamycin (mTOR) inhibitors, represents a major breakthrough in the treatment of patients with renal cell carcinoma (RCC). However, inherent resistance is observed in some patients and acquired resistance commonly develops in many patients within several months of the initiation of systemic therapies. Since these treatments rarely cure patients, their aim is to suppress tumor progression and prolong survival. Therefore, the establishment of dependable criteria that predict responses and resistance to systemic therapies is clinically important, and the underlying molecular mechanisms also need to be elucidated for the future development of more effective therapies. We herein review recent advances in research on the molecular mechanisms underlying resistance, with a focus on morphological characteristics, tumor angiogenesis, and the tumor immune microenvironment in RCC and their relationships with VEGF-TKI treatments. Recent therapies using immune checkpoint inhibitors (ICI) and newly developed VEGF-TKI also appear to be effective for advanced RCC, with stable and durable responses to ICI being observed in some RCC patients. These new drugs and their outcomes have been briefly described.

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Evaluating the Oncological Outcomes of Pure Laparoscopic Radical Nephroureterectomy Performed for Upper-Tract Urothelial Carcinoma Patients: A Multicenter Cohort Study Adjusted by Propensity Score Matching

Shigeta K., Matsumoto K., Takeda T., Hattori S., Kaneko G., Matsushima M., Abe T., Tanaka N., Mizuno R., Asanuma H., Kikuchi E., Oya M.

Annals of Surgical Oncology （Annals of Surgical Oncology） 28 （ 1 ） 465 - 473 2020年

ISSN 10689265

© 2020, Society of Surgical Oncology. Purpose: To evaluate the oncological feasibility of pure laparoscopic radical nephroureterectomy (p-LRNU) for upper tract urothelial carcinoma (UTUC) compared with conventional LRNU (c-LRNU) using a propensity-adjusted multi-institutional collaboration dataset. Methods: Among the 503 UTUC patients who underwent RNU, we identified 219 who underwent c-LRNU (laparoscopic nephrectomy with open bladder cuff resection) and 72 who underwent p-LRNU (dissecting the kidney, ureter, and bladder cuff under complete laparoscopy). We adopted a propensity score (PS) matching method to achieve homogeneity with respect to patient backgrounds. PS matching-adjusted Cox-regression analysis was performed to evaluate the risk factors that influenced oncological outcomes. Results: Sixty-eight p-LRNU and 68 c-LRNU patients were matched. Overall, 51 (37.0%) developed intravesical recurrence (IVR), 21 (15.4%) had disease recurrence, and 20 (14.7%) died. Patients who underwent p-LRNU had a significantly shorter operation time and less blood loss than those who underwent c-LRNU. Although no significant differences in 3-year recurrence-free survival were found between the two methods, atypical recurrence sites were observed in the p-LRNU group, including the brain, sigmoid colon, vagina, and peritoneum. Regarding IVR, the 3-year IVR-free survival rate was 41.8% in the p-LRNU group, which was significantly lower than that in the c-LRNU group (66.6%, p = 0.004). Multivariate analysis demonstrated that a history of bladder cancer, ureteral cancer, and p-LRNU were independent risk factors for subsequent IVR. Conclusion: Although p-LRNU is less invasive, the current technique may increase the incidence of atypical disease recurrence and subsequent IVR due to extravesical and intravesical tumor dissemination.

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Can random bladder biopsies be eliminated after bacillus Calmette–Guérin therapy against carcinoma in situ?

Takamatsu K., Matsumoto K., Kikuchi E., Ogihara K., Hayakawa N., Tanaka N., Takeda T., Morita S., Kosaka T., Mizuno R., Asanuma H., Mikami S., Oyama M., Oya M.

International Urology and Nephrology （International Urology and Nephrology） 53 （ 3 ） 465 - 469 2020年

ISSN 03011623

© 2020, Springer Nature B.V. Purpose: Intravesical bacillus Calmette–Guérin (BCG) is the standard of care for bladder carcinoma in situ (CIS). The response to BCG therapy against CIS is generally assessed by random bladder biopsy (RBB). In this study, we examined the necessity of routine RBB after BCG therapy. Methods: We retrospectively identified 102 patients who were initially diagnosed with CIS with or without papillary tumor and received subsequent 6–8-week BCG therapy. Thereafter, all patients underwent voiding cytology analysis, cystoscopy, and RBB to evaluate the effects of BCG therapy. We evaluated the association between clinical parameters (voiding cytology and cystoscopy findings) and the final pathological results by RBB specimens. Results: According to the pathological results of RBB, 30 (29%) patients had BCG-unresponsive disease (remaining urothelial carcinoma was confirmed pathologically) and 20 were diagnosed with CIS. Positive/suspicious voiding cytology and positive cystoscopy findings were well observed in patients who had BCG-unresponsive disease compared with their counterparts (p = 0.116, and p < 0.001, respectively). The sensitivity (Sen.), specificity (Spe.), positive predictive value (PPV), and negative predictive value (NPV) of voiding cytology were 50%, 68%, 39%, and 77%, respectively. The values for cystoscopy findings were as follows: Sen.: 87%, Spe.: 57%, PPV: 46%, and NPV: 91%. The values for their combination (having either of them) were as follows: Sen.: 100%, Spe.: 44%, PPV: 43%, and NPV: 100%. Conclusion: RBB after BCG therapy for patients with negative voiding cytology and negative cystoscopy may be omitted because their risk of BCG-unresponsive disease is significantly low (NPV: 100%).

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TNFAIP2 expression induces epithelial-to-mesenchymal transition and confers platinum resistance in urothelial cancer cells

Niwa N., Tanaka N., Hongo H., Miyazaki Y., Takamatsu K., Mizuno R., Kikuchi E., Mikami S., Kosaka T., Oya M.

Laboratory Investigation （Laboratory Investigation） 99 （ 11 ） 1702 - 1713 2019年11月

ISSN 00236837

© 2019, The Author(s), under exclusive licence to United States and Canadian Academy of Pathology. Cisplatin (CDDP)-based chemotherapy is the gold standard treatment for many types of cancer. However, the phenotypic hallmark of tumors often changes after CDDP treatment, with the acquisition of epithelial-to-mesenchymal transition (EMT) and platinum resistance. Furthermore, the mechanisms by which cancer cells acquire EMT under the control of CDDP remain unclear. Following an investigation of urothelial carcinoma (UC) before and after the acquisition of platinum resistance, we offer the new target TNFAIP2, which led to EMT and tumor invasion in platinum-treated UC cells. TNFAIP2 expression in cancer was examined at the protein and transcriptional levels. A potential target for TNFAIP2 during EMT was assessed by microarray. Clinically, upregulated TNFAIP2 expression was identified as a significant predictor of mortality following surgery in three different cohorts of patients with UC (n = 156, n = 119, and n = 54). Knockdown of TNFAIP2 resulted in upregulation of E-cadherin expression and downregulation of TWIST1 expression, which decreased motile function in platinum-resistant UC cells. TNFAIP2 overexpression led to downregulation of E-cadherin expression and upregulation of TWIST1 expression in platinum-naïve UC cells. Clinical investigation of matched pre- and post-CDDP-treated UC sections confirmed upregulation of TNFAIP2 expression in CDDP-treated tumors but downregulation of E-cadherin expression. Global gene expression analysis following TNFAIP2 knockdown identified MTDH as a positive regulator of TNFAIP2-derived EMT acquisition in cancer cells. The present results suggest a relationship between TNFAIP2 and EMT in cancers under the control of CDDP, in which MTDH expression levels in cancer cells are vital for promoting TNFAIP2-derived EMT acquisition.

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Sub-classification of patients with intermediate-risk metastatic renal cell carcinoma treated with targeted therapy

Kaneko G., Shirotake S., Nishimoto K., Miyazaki Y., Ito K., Ito Y., Hagiwara M., Kanao K., Nakagawa K., Momma T., Asano T., Tanaka N., Mizuno R., Oya M., Oyama M.

Japanese Journal of Clinical Oncology （Japanese Journal of Clinical Oncology） 49 （ 8 ） 780 - 785 2019年08月

ISSN 03682811

© The Author(s) 2019. Published by Oxford University Press. All rights reserved. Background: International Metastatic Renal Cell Carcinoma Database Consortium model predicts the outcomes of metastatic renal cell carcinoma stratified into favorable, intermediate, and poor risk groups (FG, IG, and PG, respectively), with approximately 50% of patients being classified as IG. We aimed to generate better risk model based on the sub-classification of IG. Methods: We analyzed records of 213 consecutive patients receiving molecular targeted therapy. Age, gender, histology, type of initial molecular targeted therapy, serum laboratory data, previous nephrectomy and immunotherapy, and metastatic sites were used for IG sub-stratification. Modified and original models were compared using a concordance correlation coefficient analysis. Results: Median follow-up was 17.8 months. Serum albumin, serum C-reactive protein, and bone metastases were independent predictors of overall survival (OS) in IG. IG was sub-classified into low-, middle-, and high-risk IG according to the number of predictors. The following modified model was developed: modified FG (FG & low-risk IG), modified IG (middle-risk IG), and modified PG (PG & high-risk IG). Concordance indices for original and modified models were 0.68 and 0.73, respectively (P < 0.001). OS was significantly longer in modified PG treated with mammalian target of rapamycin inhibitors as second-line therapy than with tyrosine kinase inhibitors, whereas this was not observed in the original model. Conclusions: We successfully developed modified IMDC model using a two-step process: the original IMDC plus an IG sub-stratification, and demonstrated that it predicts outcomes more accurately than original model.

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限局性前立腺がんに対する腫瘍発生領域の臨床的検討

高松公晴, 松本一宏, 服部盛也, 田中伸之, 武田利和, 森田伸也, 小坂威雄, 水野隆一, 篠島利明, 菊地栄次, 浅沼宏, 大家基嗣

泌尿器外科（医学図書出版(株)） 32 （ 8 ） 1011 - 1012 2019年08月

ISSN 0914-6180

TVT術後の難治性切迫性尿失禁に対して仙骨神経電気刺激療法が有効であった1例

篠島利明, 茂田啓介, 田中伸之, 大家基嗣

日本排尿機能学会誌（(一社)日本排尿機能学会） 29 （ 2 ） 460 - 463 2019年06月

ISSN 1347-6513

症例は53歳女性。尿パッドを1日10枚必要とする尿失禁にて当科紹介。ストレステスト、Qチップテストともに強陽性だが、OABSSは5点と過活動膀胱症状は軽度であった。腹圧性尿失禁を主とする混合性尿失禁に対して保存的治療を行うも有効でなくTVT手術を施行した。術後にストレステストは陰性化したが切迫性尿失禁が顕著となった。メッシュ露出、尿路感染や残尿を認めず、テープによる尿道の屈曲や圧排等の閉塞所見も明らかでなかった。ウロダイナミクス検査では排尿筋過活動、ならびに低尿流率かつ高排尿筋圧の所見を認めた。過活動膀胱治療薬による症状の改善は乏しい上、抗コリン剤は副作用で継続困難であった。OABSSは14点、切迫性尿失禁の回数は1位平均3回以上であった。また膀胱内圧検査では排尿筋過活動の所見を認めた。TVT術後9ヵ月目に仙骨神経電気刺激療法のリード留置術を施行したところ試験刺激により切迫性失禁が消失、刺激装置植え込み術後も有害事象を認めず、本症例では有効な治療法であった。(著者抄録)

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