研究者詳細 - 成田　伸太郎

The intravesical administration of bacillus Calmette-Guérin (BCG) is widely used to control the intravesical recurrence of non-muscle-invasive bladder cancer (NMIBC). This study aimed to reveal the effects of zygosity on human leukocyte antigen (HLA) genes and individual HLA genotypes on intravesical recurrence after intravesical BCG therapy for NMIBC. This study included Japanese patients who had received intravesical BCG for NMIBC. HLA genotyping of HLA-A, B, C, and DRB1 was performed. The effect of HLA zygosity and HLA genotype on intravesical recurrence was evaluated. Among 195 patients, those homozygous for the HLA-B supertype were more likely than those heterozygous for the HLA-B supertype to experience intravesical recurrence by univariate analysis (hazard ratio [HR], 95% confidence interval [CI]; 1.87, 1.14-3.05, P = 0.012) and multivariate analysis (HR, 95% CI; 2.26, 1.02-5.01, P = 0.045). Patients with B07 or B44 had a decreased risk of intravesical recurrence by univariate analysis (HR, 95% CI; 0.43, 0.24-0.78, P = 0.0056) and multivariate analysis (HR, 95% CI; 0.36, 0.16-0.82, P = 0.016). This study suggests the importance of the diversity and specificity of HLA-B loci in the antitumor effect of BCG immunotherapy for NMIBC. These findings may contribute to the delineation of risk strata for BCG therapy and improve the medical management of NMIBC.

DOI PubMed

Management of bladder cancer in older patients

Hatakeyama S.

Japanese Journal of Clinical Oncology ( Japanese Journal of Clinical Oncology ) 52 ( 3 ) 203 - 213 2022年03月

Evidence has shown that patients with bladder cancer are diagnosed at a much older age compared with those with other cancers. Given that co-morbidities and frailty are prevalent in older patients with advanced bladder cancer, they are easily excluded from randomized controlled trials. As little evidence has been available regarding assessment tools for frailty, the management of those patients remains challenging. This weakness is strongly manifested in muscle-invasive bladder cancer. Despite radical cystectomy is the standard of care for bladder cancer, there is an extensive undertreatment of older adult patients with potentially curative muscle-invasive bladder cancer. However, it is also true that radical cystectomy is often unsuitable for vulnerable or frail patients. Bladder preservation using trimodality therapy has been utilized as an alternative option, but the appropriate selection criteria for trimodality therapy remain unclear. Cisplatin-based regimens have been the first choice for advanced disease among eligible patients. Moreover, immunotherapy appears to have similar benefits and tolerability in both older and younger patients. Furthermore, palliative or supportive interventions need to be initiated earlier in patients with metastatic disease. Accumulating evidence suggests that frailty may play a key role in the selection of treatment modalities. Older patients should be considered for standard treatment based on frailty and not chronological age. Moreover, older patients with bladder cancer need to undergo geriatric assessment for proper decision-making.

DOI PubMed

Prognostic impact of proton pump inhibitors for immunotherapy in advanced urothelial carcinoma.

Yoshiharu Okuyama, Shingo Hatakeyama, Kazuyuki Numakura, Takuma Narita, Toshikazu Tanaka, Yuki Miura, Daichi Sasaki, Daisuke Noro, Noriko Tokui, Teppei Okamoto, Hayato Yamamoto, Shintaro Narita, Takahiro Yoneyama, Yasuhiro Hashimoto, Tomonori Habuchi, Chikara Ohyama

BJUI compass 3 ( 2 ) 154 - 161 2022年03月

OBJECTIVE: To evaluate the effects of the concomitant use of proton pump inhibitors (PPIs) and/or antibiotics (Abs) on oncological outcomes in patients with advanced urothelial carcinoma. PATIENTS AND METHODS: We retrospectively evaluated 155 patients with advanced urothelial carcinoma who were treated with immune checkpoint inhibitors (ICIs) between August 2015 and April 2021. The concomitant use of PPI or Abs was defined as any PPI or Abs administered within 30 days before ICI initiation and during ICI therapy. The primary outcomes were the effect of PPI and/or Abs use on the objective response rate (ORR) and immune-related adverse events (irAEs). The secondary outcomes were the effects of PPI and/or Abs use on progression-free survival (PFS) and overall survival (OS) after ICI therapy analyzed using the inverse probability of treatment weighting-adjusted Cox regression analysis. RESULTS: Of the 155 patients enrolled in the study, 99 (64%) were PPI users and 56 (36%) Abs users. PPI users were associated with a significantly poorer ORR than non-PPI users (41% vs. 20%, respectively), whereas Abs use was not significantly associated with changes in ORR. The rate of irAEs was not significantly associated with the use of PPIs or Abs. Multivariate inverse probability of treatment weighting-adjusted Cox regression analysis revealed significantly poorer PFS and OS in PPI users than in non-PPI users, whereas Abs use was not associated with poorer outcomes. CONCLUSION: The concomitant use of PPI may adversely affect oncological outcomes in patients with locally advanced or metastatic urothelial carcinoma treated with ICI therapy.

DOI PubMed

PD-1の遺伝子多型とニボルマブの臨床結果との関連

小林瑞貴, 沼倉一幸, 畠山真吾, 嘉島相輝, 山本竜平, 小泉淳, 奈良健平, 齋藤満, 成田伸太郎, 大山力, 羽渕友則

日本腎泌尿器疾患予防医学研究会誌 ( 日本腎泌尿器疾患予防医学研究会 ) 30 ( 1 ) 60 - 62 2022年03月

抗PD-1抗体であるニボルマブは、転移性腎細胞癌(mRCC)に対する標準治療薬であるが、完全奏効例がある一方で、まったく効果なく病勢進行することもあり、また免疫関連有害事象(irAE)のため投与を中止せざるをえない例もある。PD-1タンパク質コード遺伝子(PDCD1)には幾つかの一塩基多型(SNP)が存在し、それらがPD-1の機能に関連する可能性がある。そこで今回、PDCD1のSNPとニボルマブの効果・有害事象との関連について、mRCC患者70例を対象に検討した。結果、PDCD1のSNPとニボルマブの効果との間には有意な関連は認められなかったが、有害事象についてはSNPのうちPD-1.6が複数のirAEと有意に関連していた。

Clinical Utility of Germline Genetic Testing in Japanese Men Undergoing Prostate Biopsy

Akamatsu S.

JNCI Cancer Spectrum ( JNCI Cancer Spectrum ) 6 ( 1 ) 2022年02月

BACKGROUND: Multiple common variants and also rare variants in monogenic risk genes such as BRCA2 and HOXB13 have been reported to be associated with risk of prostate cancer (PCa); however, the clinical setting in which germline genetic testing could be used for PCa diagnosis remains obscure. Herein, we tested the clinical utility of a 16 common variant-based polygenic risk score (PRS) that has been developed previously for Japanese men and also evaluated the frequency of PCa-associated rare variants in a prospective cohort of Japanese men undergoing prostate biopsy. METHODS: A total of 1336 patients undergoing first prostate biopsy were included. PRS was calculated based on the genotype of 16 common variants, and sequencing of 8 prostate cancer-associated genes was performed by multiplex polymerase chain reaction based target sequencing. PRS was combined with clinical factors in logistic regression models to assess whether addition of PRS improves the prediction of biopsy positivity. RESULTS: The top PRS decile was associated with an odds ratio of 4.10 (95% confidence interval = 2.46 to 6.86) with reference to the patients at average risk, and the estimated lifetime absolute risk approached 20%. Among the patients with prostate specific antigen 2-10 ng/mL who had prebiopsy magnetic resonance imaging, high PRS had an equivalent impact on biopsy positivity as a positive magnetic resonance imaging finding. Rare variants were detected in 19 (2.37%) and 7 (1.31%) patients with positive and negative biopsies, respectively, with BRCA2 variants being the most prevalent. There was no association between PRS and high-risk rare variants. CONCLUSIONS: Germline genetic testing could be clinically useful in both pre- and post-PSA screening settings.

DOI PubMed

Specific Gut Microbial Environment in Lard Diet-Induced Prostate Cancer Development and Progression

Sato H.

International Journal of Molecular Sciences ( International Journal of Molecular Sciences ) 23 ( 4 ) 2022年02月

Lard diet (LD) is a risk factor for prostate cancer (PCa) development and progression. Two immunocompetent mouse models fed with isocaloric specific fat diets (LD) enriched in saturated and monounsaturated fatty acid (SMFA), showed significanftly enhanced PCa progression with weight gain compared with a fish oil diet (FOD). High gut microbial divergency resulted from difference in diets, and the abundance of several bacterial species, such as in the orders Clostridiales and Lactobacillales, was markedly altered in the feces of LD- or FOD-fed mice. The proportion of the order Lactobacillales in the gut was negatively involved in SMFA-induced body weight gain and PCa progression. We found the modulation of lipid metabolism and cholesterol biosynthesis pathways with three and seven commonly up- and downregulated genes in PCa tissues, and some of them correlated with the abundance of the order Lactobacillales in mouse gut. The expression of sphingosine 1-phosphate receptor 2, which is associated with the order Lactobacillales and cancer progression in mouse models, was inversely associated with aggressive phenotype and weight gain in patients with PCa using the NCBI Gene Expression Omnibus database. Therefore, SMFA may promote PCa progression with the abundance of specific gut microbial species and overexpression of lipogenic genes in PCa. Therapeutics with alteration of gut microbiota and candidate genes involved in diet-induced PCa progression may be attractive in PCa.

DOI PubMed

術前レシピエント肥満が腎移植後のアウトカムに与える影響

山本竜平, 齋藤満, 藤山信弘, 齋藤拓郎, 提箸隆一郎, 嘉島相輝, 小泉淳, 奈良健平, 沼倉一幸, 成田伸太郎, 佐藤滋, 羽渕友則

日本臨床腎移植学会プログラム・抄録集 ( (一社)日本臨床腎移植学会 ) 55回 233 - 233 2022年02月

レムデシビルが奏功した生体腎移植後患者におけるCOVID-19の一例

青山有, 齋藤満, 齋藤拓郎, 提箸隆一郎, 山本竜平, 藤山信弘, 嘉島相輝, 小泉淳, 奈良健平, 沼倉一幸, 成田伸太郎, 佐藤滋, 羽渕友則

日本臨床腎移植学会プログラム・抄録集 ( (一社)日本臨床腎移植学会 ) 55回 222 - 222 2022年02月

免疫抑制療法 mTOR阻害薬最適化各施設のプロトコールから mTOR阻害薬を含む免疫抑制プロトコール見えてきた効果と課題

齋藤満, 佐藤滋, 藤山信弘, 青山有, 提箸隆一郎, 齋藤拓郎, 山本竜平, 沼倉一幸, 成田伸太郎, 羽渕友則

日本臨床腎移植学会プログラム・抄録集 ( (一社)日本臨床腎移植学会 ) 55回 101 - 101 2022年02月

Comparison of parenchymal volume loss assessed by three-dimensional computed tomography volumetry and renal functional recovery between conventional and robot-assisted laparoscopic partial nephrectomy

Kanda S.

Asian journal of endoscopic surgery ( Asian journal of endoscopic surgery ) 15 ( 1 ) 63 - 69 2022年01月

OBJECTIVES: We retrospectively investigated if robot-assisted laparoscopic partial nephrectomy (RAPN) contributes to a decrease in resected parenchymal volume (RPV), an increase in postoperative parenchymal volume (PPV), and an improvement of postoperative renal function when compared with conventional laparoscopic partial nephrectomy (LPN) using a three-dimensional image analysis system. METHODS: Patients who underwent LPN (n = 37) and RAPN (n = 66) from November 2013 to November 2018 were included in this study. All patients had a tumor diameter of 4 cm or less. Patients with an anatomical or functional single kidney were excluded. RPV and PPV were measured using SYNAPSE VINCENT®. The surgical outcomes were compared between the two groups. RESULTS: Warm ischemic time in the RAPN group was significantly shorter than that in the LPN group (p < 0.001). The ratio of RPV to tumor volume (RPV/TV) in the RAPN group was significantly lower than that in the LPN group (p = 0.016). PPV in the RAPN group was significantly higher than that in the LPN group (p = 0.049). The decreased estimated glomerular filtration rate in the RAPN group was significantly lower than that in the LPN group on days 1, 7, 30, 90, and 180 after surgery. CONCLUSIONS: Postoperative renal function in the RAPN group was significantly better than that in the LPN group in both the short and long term. In addition to a short warm ischemia time, the decreased RPV/TV and increased PPV may have contributed to the improvement of postoperative renal function.

DOI PubMed

Efficacy and safety of pembrolizumab for older patients with chemoresistant urothelial carcinoma assessed using propensity score matching

Nishiyama N.

Journal of Geriatric Oncology ( Journal of Geriatric Oncology ) 13 ( 1 ) 88 - 93 2022年01月

BACKGROUND: We used real-world and large-scale data to assess the clinical efficacy and safety of pembrolizumab in older patients with advanced urothelial carcinoma (UC). METHODS: A total of 608 patients who received pembrolizumab for the treatment of chemoresistant UC were retrospectively analyzed. All patients were histologically diagnosed with pure UC. Using propensity score matching (PSM) (ECOG performance status, site of metastasis, hemoglobin level and neutrophil-to-lymphocyte ratio, 1:1 matching), the overall survival (OS) and adverse events (AEs) of patients <75 and ≥75 years old were compared. RESULTS: The median follow-up (IQR) period was 16.1 (9.9-20.5) months. After PSM, there were 215 patients each in the aged <75 years and aged ≥75-year-old groups. The median OS of all patients was estimated to be 10.4 months (95% confidence interval [CI] = 8.8-12.1). After PSM, the median OS was 7.8 months (95% CI = 5.2-10.4) in the <75-year-old group and 10.4 months (95% CI = 7.3-13.5) in the ≥75-year-old group (P = 0.186). Any-grade AEs were more frequently reported in the ≥75-year-old group in comparison to the age <75-year-old group (55.3% vs. 41.9%, P = 0.007), whereas there was no significant difference between the two groups in the incidence of grade ≥3 AEs (10.2% vs. 12.6%, P = 0.544). The objective response rate, defined as complete remission or a partial response, was 22.8% in the <75-year-old group and 25.1% in the ≥75-year-old group (P = 0.651). CONCLUSIONS: The present study demonstrates that age does not affect the efficacy and safety of pembrolizumab treatment for advanced chemoresistant UC. Pembrolizumab treatment should not be avoided based on chronological age; however, close monitoring for the development of treatment-related AE should be considered for older patients.

DOI PubMed

Association of Increased Age With Decreased Response to Intravesical Instillation of Bacille Calmette-Guérin in Patients With High-Risk Non-Muscle Invasive Bladder Cancer: Retrospective Multi-Institute Results From the Japanese Urological Oncology Research Group JUOG-UC-1901-BCG

Inoue T.

Urology ( Urology ) 167 158 - 164 2022年

OBJECTIVE: To compare the therapeutic effect of Bacille Calmette-Guérin (BCG) intravesical instillation in older and younger patients with high-risk non-muscle-invasive bladder cancer. The comparison was performed with propensity score matching (PSM) without terminating the death of the older patients using relatively large-scale retrospective data from multiple institutes in Japan. MATERIALS AND METHODS: Overall, 3283 patients diagnosed with non-muscle-invasive bladder cancer treated with intravesical BCG instillation during 2000-2018 in 31 institutes were examined; 1437 and 602 patients with high-grade T1 and Tis tumors were divided into those aged ≥75 and <75 years. Multivariate analysis using the Fine-Gray competing risks regression model before PSM and survival analysis using the cumulative incidence method after PSM were performed. RESULTS: In the pre-PSM series of high-grade T1 tumors, age ≥75 years was an independent prognostic factor for both recurrence and progression in multivariate analysis (P = .015 and P = .013). In the pre-PSM series with Tis tumor, no variables to predict recurrence and progression was found. In the post-PSM series of 870 high-grade T1 tumors, cumulative probability of recurrence after BCG intravesical instillation were significantly higher in patients aged ≥75 years than in those aged <75 years (P = .008). The frequency of discontinuation of BCG instillation in patients aged ≥75 years with high-grade T1 and Tis was not significantly different from those in patients aged <75 years (P = .564 and P = .869). CONCLUSION: The cumulative probability of recurrence after intravesical BCG instillation was significantly higher in older than in younger patients with high-grade T1 bladder cancer.

DOI PubMed

Combination of docetaxel versus nonsteroidal antiandrogen with androgen deprivation therapy for high-volume metastatic hormone-sensitive prostate cancer: a propensity score-matched analysis

Yanagisawa T.

World Journal of Urology ( World Journal of Urology ) 2022年

PURPOSE: The aim of this study was to investigate the oncologic efficacy of combining docetaxel with androgen deprivation therapy (ADT) versus nonsteroidal antiandrogen (NSAA) with ADT in patients with high-volume metastatic hormone-sensitive prostate cancer (mHSPC) with focus on the effect of sequential therapy in a real-world clinical practice setting. METHODS: The records of 382 patients who harbored high-volume mHSPC, based on the CHAARTED criteria, and had received ADT with either docetaxel (n = 92) or NSAA (bicalutamide) (n = 290) were retrospectively analyzed. The cohorts were matched by one-to-one propensity scores based on patient demographics. Overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS), including time to castration-resistant prostate cancer (CRPC), and time to second-line progression (PFS2) were compared. 2nd-line PFS defined as the time from CRPC diagnosis to progression after second-line therapy was also compared. RESULTS: After matching, a total of 170 patients were retained: 85 patients treated with docetaxel + ADT and 85 patients treated with NSAA + ADT. The median OS and CSS for docetaxel + ADT versus NSAA + ADT were not reached (NR) vs. 49 months (p = 0.02) and NR vs. 55 months (p = 0.02), respectively. Median time to CRPC and PFS2 in patients treated with docetaxel + ADT was significantly longer compared to those treated with NSAA (22 vs. 12 months; p = 0.003 and, NR vs. 28 months; p < 0.001, respectively). There was no significant difference in 2nd-line PFS between the two groups. CONCLUSIONS: Our analysis suggested that ADT with docetaxel significantly prolonged OS and CSS owing to a better time to CRPC and PFS2 in comparison to NSAA + ADT in high-volume mHSPC.

DOI PubMed

Effect of Levofloxacin on the Efficacy and Adverse Events in Intravesical Bacillus Calmette-Guerin Treatment for Bladder Cancer: Results of a Randomized, Prospective, Multicenter Study

Numakura K.

European Urology Focus ( European Urology Focus ) 8 ( 6 ) 1666 - 1672 2022年

BACKGROUND: Although bacillus Calmette-Guerin (BCG) is a standard treatment for high-risk non-muscle-invasive bladder cancer (NMIBC), a high rate of adverse events with a variety of grades remains a difficulty. OBJECTIVE: In this randomized, prospective, multicenter study, we examined whether levofloxacin, given after each intravesical instillation of BCG, could improve its tolerance in patients with intermediate- to high-risk urothelial carcinoma of the bladder without compromising its efficacy. DESIGN, SETTING, AND PARTICIPANTS: Overall, 106 Japanese patients (85 men and 21 women; age: median, 69.5 yr) with primary or recurrent NMIBC were randomized after transurethral resection to induce treatment with intravesical BCG plus levofloxacin (group 1) or BCG alone (group 2). INTERVENTION: Patients who underwent intravesical instillation of BCG were randomized with or without levofloxacin administration. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Adverse events were assessed using the National Cancer Institute-Common Toxicity Criteria version 3.0. Cumulative incidence functions and Kaplan-Meier methods were applied to estimate survival outcomes. RESULTS AND LIMITATIONS: There was no significant difference in baseline characteristics between the groups. The completion rate of group 1 (85.5%) was not significantly lower than that of group 2 (76.5%; p = 0.321). There was no significant difference in the completion rate of patients with pollakisuria, painful micturition, gross hematuria, fever elevation, and others between the groups. The incidence of adverse events in patients with high-grade pollakisuria (7.3% vs 25.4%, p = 0.041) and fever (0% vs 9.1%, p = 0.034) was significantly lower in group 1. The 5-yr progression-free and cancer-specific survival rates were significantly better in group 1. CONCLUSIONS: Prophylactic levofloxacin administration may reduce the severity of adverse events and contribute to better outcomes from BCG intravesical therapy in patients with NMIBC. PATIENT SUMMARY: Levofloxacin administration seems to be a safe and effective therapy for non-muscle-invasive bladder cancer patients treated with bacillus Calmette-Guerin intravesical therapy.

DOI PubMed

Impact of germline HLA genotypes on clinical outcomes in patients with urothelial cancer treated with pembrolizumab

Takahashi S.

Cancer Science ( Cancer Science ) 113 ( 12 ) 4059 - 4069 2022年

Human leukocyte antigen class I (HLA-I) genotypes are suggested to influence the cancer response to checkpoint blockade immunotherapy. This study assessed the impact of germline HLA genotypes on clinical outcomes in patients with chemoresistant advanced urothelial cancer (UC) treated with pembrolizumab. Zygosity, supertypes, evolutionary divergency, and specific alleles of germline HLA-I and -II were evaluated using the Luminex technique in 108 patients with chemoresistant metastatic or locally advanced UC treated with pembrolizumab. Among the 108 patients, 69 died and 83 showed radiographic progression during follow-up. Homozygous for at least one HLA-I locus, absence of the HLA-A03 supertype, and high HLA-I evolutionary divergence were associated with a radiographic response, but were not associated with survival outcomes. Patients with the HLA-DQB1*03:01 allele had significantly lower disease control rates than patients without the allele (17.4% vs. 53.8%, p = 0.002); its presence was also an independent risk factor for progressive disease (hazard ratio 4.35, 95% confidence interval 1.03-18.46). Furthermore, patients with the HLA-DQB1*03:01 allele had significantly worse progression-free survival than patients without the allele (median progression-free survival 3.1 vs. 4.8 months, p = 0.035). There was no significant relationship between any HLA status and the incidence of severe adverse events. Several germline HLA genotypes, especially HLA-DQB1*03:01, may be associated with radiographic progression. However, their impact on treatment response is limited, and germline HLA genotypes was not independently associated with survival outcomes. Further prospective studies are needed to confirm the relationship between germline HLA genotypes and clinical outcomes in patients with chemoresistant advanced UC treated with pembrolizumab.

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