Published papers

Hereditary leiomyomatosis and renal cell carcinoma (HL (RCC)) entails cutaneous and uterine leiomyomatosis with aggressive type 2 papillary RCC-like histology. HLRCC is caused by pathogenic variants in the FH gene, which encodes fumarate hydratase (FH). Here, we describe an episode of young-onset RCC caused by a genomic FH deletion that was diagnosed via clinical se-quencing. A 35-year-old woman was diagnosed with RCC and multiple metastases: histopathological analyses supported a diagnosis of FH-deficient RCC. Although the patient had neither skin tumors nor a family history of HLRCC, an aggressive clinical course at her age and pathological diagnosis of FH-deficient RCC suggested a germline FH variant. After counseling, the patient provided written informed consent for germline genetic testing. She was simultaneously subjected to paired tumor profiling tests targeting the exome to identify a therapeutic target. Although conventional germline sequencing did not detect FH variants, exome sequencing revealed a heterozygous germline FH deletion. As such, paired tumor profiling, not conventional sequencing, was required to identify this genetic deletion. RCC caused by a germline FH deletion has hitherto not been described in Japan, and the FH deletion detected in this patient was presumed to be of maternal European origin. Although the genotype-phenotype correlation in HLRCC-related tumors is unclear, the patient’s family was advised to undergo genetic counseling to consider additional RCC screening.

Purpose: Genomic characterization of the predisposition of tumors to metastasize to specific sites has been performed in a few studies using mainly tissue-derived genomes. This nationwide prospective observational study investigated the association between genomic characteristics using circulating tumor DNA (ctDNA), and the synchronous and metachronous metastasis of tumors to specific target organs in advanced prostate cancer. Methods: Patients with advanced prostate cancer undergoing systemic treatment were included. ctDNA was analyzed using the FoundationOne®Liquid CDx assay at enrollment. Associations between genomic characteristics and metastatic status were examined. Results: Alterations in the genes MYC, APC, and BRCA2 and the DNA repair, MYC, and WNT pathways were associated with lung and liver metastasis. PTEN gene alterations and PI3K pathway alteration were associated with synchronous lung metastasis. RB1 gene alteration and RAS/RAF/MAPK pathway alteration were associated with synchronous liver metastasis. RB1 and BRCA2 gene alterations predicted metachronous lung metastasis, while TP53 and MYC gene alterations predicted metachronous liver metastasis. Conclusions: This study identifies genomic alterations in ctDNA associated with synchronous and metachronous metastases. These findings may be clinically helpful for treating, managing, and monitoring cancer.

Background: Artificial intelligence (AI) has shown potential in various fields; however, its practical application in surgery remains limited. We developed an AI system capable of automatically recognizing surgical phases in robot-assisted radical prostatectomy (RARP) and confirmed its accuracy through cross-surgeon validation. Materials and Methods: We analyzed clinical data from 102 patients who underwent RARP, including 81 consecutive patients operated on by one surgeon (surgeon A) and 21 operated on by five other surgeons (surgeons B–F). In total, 65 of the 81 patients were used for AI development, while the remaining 16, in addition to the 21 patients operated on by surgeons B–F, were used for AI validation. We classified surgical operations into nine phases. Well-trained surgeons annotated the time corresponding to each surgical phase for each video. We used Temporal Convolutional Networks for the Operating Room (TeCNO) to develop the AI model and evaluated its precision. Results: In AI development, 919,231 frames were utilized. Testing involved 216,357 frames from surgeon A and 249,553 frames from surgeons B–F. When the developed AI was used to analyze surgical videos from surgeon A, precision reached 0.94. In contrast, when the AI was applied to videos from surgeons B–F, precision was 0.83. Conclusions: The AI we developed not only showed high accuracy, but also demonstrated generalizability across different surgeons. By comprehensively evaluating surgical videos, our AI may be used to assess the quality of surgeries, thereby providing valuable feedback to surgeons and enhancing the effectiveness of surgical education.

症例は79歳女性。右腎盂癌(pT1N0M0)にて右腎尿管全摘除術を施行後の約1年後に血液透析導入となった。術後2年で多発肺転移にて再発し,救援化学療法を2コース施行するもPDであったため,2次化学療法としてペムブロリズマブを開始した。6コース投与後に持続する発熱,倦怠感,脱力,意識障害にて当院に入院し,ACTH単独欠損症の診断となりirAEと考えられた。維持透析下でヒドロコルチゾンを補充し症状は改善,そのままペムブロリズマブを投与再開し,9ヵ月間PRを維持できた。(著者抄録)

症例は14歳男子.12歳時に水腎症と腎機能の増悪を認め,近医で膀胱腫瘍,左尿管腫瘍の診断となった.前医で経尿道的膀胱腫瘍切除術,尿管腫瘍生検が施行され,線維上皮性ポリープの診断となった.尿管ポリープに対して経尿道的切除を試みられたが尿道狭窄を併発したため到達困難となり,左腎瘻造設,経皮的レーザー焼灼術が施行された.術後4ヵ月,尿管狭窄もきたし,尿路再建の目的に当院へ紹介となった.尿道狭窄に対して13歳時に包皮利用Palminteri法尿道形成術を施行した.逆行性腎盂造影,腎瘻造影検査で脊椎L4レベルに2cmの尿管狭窄,尿管鏡検査で脊椎L5レベルに残存ポリープを認めた.14歳時に尿管再建術を行った.端々吻合では吻合部の緊張が強いと考えられ,口腔粘膜利用拡大onlay法尿管形成術を行う方針とした.完全閉塞部と残存ポリープ部のみを最小限切除し,緊張のかからない尿管壁同士を一部端々吻合した.吻合部の対側の尿管壁は健常部まで十分にspatulateし,尿管ステントを留置後に15×40mm大の頬粘膜を縫着,頬粘膜のグラフト床として腹腔内から遊離した大網を吻合部に全周性に縫着した.術後13日で腎瘻を抜去,術後4ヵ月で尿管ステントを抜去した.術後1年および2年の逆行性腎盂造影,尿管鏡検査で再狭窄やポリープの再発は認めず,術後3年現在,左側腹部痛,腎盂腎炎,腎盂拡張などを認めず経過良好である.(著者抄録)

＜文献概要＞QTVT(あるいはTOT)手術を開始した症例.術中に300mLを膀胱に注入しストレステストを行ったが,テープの張力調整前にもかかわらず漏れない.

免疫療法の登場に伴い、がん治療は新たな変革期を迎えている。泌尿器科がんは腎細胞がん、尿路上皮がん(いわゆる膀胱がん、腎盂尿管がん)、前立腺がんが主であるが、このうち腎細胞がん、尿路上皮がんが、抗PD-1/PD-L1抗体への反応が強い免疫感受性腫瘍である。両者は固形がんにおけるがん免疫療法の先がけであるが、同じ泌尿器科臓器でも生物学的特徴に真逆の要素が多い。腎細胞がんは古典的には抗がん剤や放射線治療に抵抗性であるが、尿路上皮がんは両治療に感受性を有する。そのため尿路上皮がんの全身治療は、がん免疫療法時代においても化学療法が重要である。また、腎細胞がんの遺伝子変異には挿入/欠失(インデル)が多く、尿路上皮がんを含めた多くのがん種と遺伝学的な立ち位置も異質である。本稿では、腎細胞がん、尿路上皮がんへの免疫療法の現状や展望に加えて、バイオマーカー開発や泌尿器科がんの腫瘍免疫環境における特殊性について述べる。(著者抄録)

＜文献概要＞処方のポイント　●アナフィラキシー治療の要はアドレナリンである.●アドレナリン投与時に注意すべき症例がある.●注入時反応(IRR)予防目的に前投薬が用いられる.

＜文献概要＞ポイント　・「複合がん免疫療法」の成功に免疫微小環境の理解は欠かせない.・腎細胞癌の免疫微小環境は,ほかの免疫感受性腫瘍と異なり,「腫瘍内のCD8+T細胞密度の高いほうが予後が悪い」という点で異質性が際立つ.・腎細胞癌の遺伝子変異は挿入・欠失が多いため,ネオアンチゲン増加と関連するTMBが,通常は低く推定される.

前立腺肥大症への接触レーザー蒸散術(CVP)は,光ファイバーを通して980nmダイオードレーザーを照射し,肥大した前立腺組織を気化させる。本邦では人口の高齢化に伴い,抗血栓療法を受ける患者数は増加傾向にある。ダイオードレーザーの有する蒸散力・止血能によって,抗血栓療法の休薬が難しい症例でも,安全な手術が可能となった。われわれは,抗血栓療法下のCVP安全性と有効性を評価した前向き観察研究を中心に,CVP治療の現状と展望について述べる。(著者抄録)

【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)

症例1は60歳代女性。主訴は肉眼的血尿であった。MRI T2強調像で膀胱左側壁に21mm大の広基性腫瘤を認め、経尿道的膀胱腫瘍切除術を行った。病理学的に膀胱小細胞癌と診断した。2年後のFDG-PETで右腋窩・右側腹部の皮下腫瘤、左腸骨動脈リンパ節にFDGの強い集積亢進を認め、膀胱小細胞癌の転移と考えられた。症例2は60歳代男。主訴は肉眼的血尿であった。MRI T2強調像で膀胱前壁に12mm大の広基性腫瘤を認め、経尿道的膀胱腫瘍切除術、その後膀胱全摘術を行った。病理学的に膀胱小細胞癌と診断した。1年後のCTで両肺に多発する増大傾向の結節を認め、膀胱小細胞癌の転移と考えられた。

Background: Upper tract urothelial carcinoma (UTUC) often requires nephroureterectomy. The retroperitoneal robotic approach, particularly using the hinotori system, may offer advantages, especially for smaller-framed patients. Methods: Five UTUC patients (≤ 162 cm) underwent pure retroperitoneal robot-assisted nephroureterectomy (RANU) using the hinotori system (July–December 2024). Standardized trocar placement was used without port relocation. Outcomes included operative time, re-docking, and complications. Results: Median patient age was 82 years. All surgeries were completed without peritoneum opening, conversion to open surgery, or major complications. Mean operative time was 257 min, with re-docking averaging 18 min. All cases achieved negative margins, and no readmissions occurred within 30 days. Conclusions: Pure retroperitoneal RANU using the hinotori system is safe and feasible, particularly for smaller patients. This approach minimizes procedural interference and may serve as an alternative to transperitoneal nephroureterectomy. Further studies are needed to evaluate oncological outcomes and refine surgical techniques.

This prospective study evaluated the clinical significance of circulating tumor DNA (ctDNA) profiling in patients with advanced urothelial carcinoma (aUC) using FoundationOne®Liquid CDx. A total of 133 Japanese patients (SCRUM-Japan cohort) were analyzed, including serial ctDNA sampling before and after platinum-based chemotherapy or pembrolizumab. Cross-sectional comparison was made with 1059 patients from the U.S.-based Foundation Medicine cohort (FMI cohort). The most frequent genomic alterations in the SCRUM-Japan cohort were TP53 (43%), MLL2 (26%), and TERT (19%). Compared to the FMI cohort, the prevalence of TP53 and TERT alterations was lower, while KRAS alterations were more frequent in upper tract urothelial carcinoma (UTUC) than in bladder cancer (BC) across both cohorts. High ctDNA tumor fraction (≥10%) was associated with significantly worse overall survival, and alterations in TERT, and TP53 were also linked to significantly worse prognosis. The concordance rate of gene alterations before and after chemotherapy was 61%, and 66% for pembrolizumab. In contrast, concordance between tissue and ctDNA profiling was only 46%, with ctDNA identifying additional actionable mutations not detected in tissue. These findings underscore the potential of ctDNA as a non-invasive tool for dynamic molecular monitoring and prognostication in aUC, supporting its integration into clinical practice.

Cabozantinib, a newly developed vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI), is an effective treatment for advanced renal cell carcinoma (RCC). However, the molecular mechanisms responsible for the superior effectiveness of cabozantinib to other drugs remain unclear. Since cabozantinib inhibits AXL and c-MET in addition to VEGFR, the expression of these molecules was immunohistologically examined in 110 cases of primary clear cell RCC (ccRCC) and eight of sunitinib (VEGFR-TKI)-treated primary ccRCC. AXL expression correlated with the primary tumor stage, while c-MET expression correlated with distant metastasis, the histological grade, and overall survival. Furthermore, the number of programmed death-ligand 1 (PD-L1)-positive tumor-infiltrating immune cells was higher in ccRCC tissues with high c-MET expression than in those with low c-MET expression. The expression of AXL and c-MET was higher in sunitinib-treated ccRCC tissues than in untreated tissues. These results suggest that AXL and c-MET play important roles in the progression of ccRCC and resistance to sunitinib. Furthermore, c-MET may modify the immune microenvironment by inducing PD-L1 expression in immune cells within RCC tissues. These molecular pathways may be related to responses to cabozantinib.

Repeated oncogenic mutations and polyclonal proliferation are evident in cancers. However, little is known about the polyclonal principles governing the systemic cancerous lineage during immunotherapy. Here, we examine a unique autopsy case of metastatic urothelial carcinoma that exhibits different treatment responses to anti-PD-1 therapy at each tumor site. By performing in-depth analyses of different multiregional bulk tumor masses, we reveal that subsets of subclones acquire potential driver mutations under treatment selection pressure. Spatial transcriptomics analysis reveals that subclones resistant to immunotherapy form distinct immunosuppressive environments consistent with their habitats. Furthermore, different cancer hallmarks are identified in each of the subclones that expand under immunotherapy at single-cell level; for example, one subclone is more proliferative, and another is more stem-cell-like. In summary, this study provides an overall picture of the polyclonal competition and changes in the immune microenvironment that are related to resistance to immunotherapy in patients with malignancies.

Background: Undetectable circulating tumor DNA (ctDNA) is an obstacle to performing comprehensive genomic profiling in daily practice to identify genomic alterations. We investigated the associations between clinicopathological factors and undetectable ctDNA using a commercially available comprehensive genomic profiling assay in metastatic prostate cancer. Patients and methods: Patients treated with systemic treatment for metastatic prostate cancer were included. ctDNA was analyzed by FoundationOne®Liquid CDx at enrollment. The associations between clinicopathological characteristics and ctDNA detection were analyzed. Results: The number of bone metastasis was associated with ctDNA detection (odds ratio [95% confidence interval], 13.6 [1.71–108], P = 0.014). An algorithm predicting ctDNA detection using clinicopathological parameters was created. If ≥ 4 bone metastases were observed, ctDNA detection was estimated to be 98.9%. Among the patients with < 4 bone metastases, if two or three features among ISUP grade group 5, PSA level ≥ 10 ng/ml, and castration resistance were present, the ctDNA detection rate was 96.7% while the ctDNA detection rate was 86.3% if no or only one feature was present. Conclusions: An algorithm created in this study is helpful in determining when to undertake comprehensive genomic profiling assay using blood.

Despite the high sensitivity of renal cell carcinoma (RCC) to immunotherapy, RCC has been recognized as an unusual disease in which CD8+ T-cell infiltration into the tumor beds is related to a poor prognosis. To approach the inner landscape of immunobiology of RCC, we performed multiplexed seven-color immunohistochemistry (CD8, CD39, PD-1, Foxp3, PD-L1, and pan-cytokeratin AE1/AE3 with DAPI), which revealed the automated single-cell counts and calculations of individual cell-to-cell distances. In total, 186 subjects were included, in which CD39 was used as a marker for distinguishing tumor-specific (CD39+) and bystander (CD39−) T-cells. Our clear cell RCC cohort also revealed a poor prognosis if the tumor showed increased CD8+ T-cell infiltration. Intratumoral CD8+CD39+ T-cells as well as their exhausted CD8+CD39+PD-1+ T-cells in the central tumor areas enabled the subgrouping of patients according to malignancy. Analysis using specimens post-antiangiogenic treatment revealed a dramatic increase in proliferative Treg fraction Foxp3+PD-1+ cells, suggesting a potential mechanism of hyperprogressive disease after uses of anti-PD-1 antibody. Our cell-by-cell study platform provided spatial information on tumors, where bystander CD8+CD39− T-cells were dominant in the invasive margin areas. We uncovered a potential interaction between CD8+CD39+PD-1+ T-cells and Foxp3+PD-1+ Treg cells due to cell-to-cell proximity, forming a spatial niche more specialized in immunosuppression under PD-1 blockade. A paradigm shift to the immunosuppressive environment was more obvious in metastatic lesions; rather the infiltration of Foxp3+ and Foxp3+PD-1+ Treg cells was more pronounced. With this multiplexed single-cell pathology technique, we revealed further insight into the immunobiological standing of RCC.