筋層浸潤性膀胱癌における壁浸潤長は予後予測因子であり、血清cell-free DNAと関連する

Background: We investigated the potential of the depth of invasion (DOI) as a prognostic factor in patients with muscle-invasive bladder cancer (MIBC) who underwent radical cystectomy (RC). Moreover, we examined the association between the preoperative levels of circulating cell-free DNA and DOI.博士（医学）・甲第876号・令和5年3月15

KLHDC10 Activates ASK1 by Suppressing PP5

Reactive oxygen species (ROS)-induced activation of Apoptosis signal-regulating kinase 1 (ASK1) plays crucial roles in oxidative stress-mediated cell death through the activation of the JNK and p38 MAPK pathways. However, the regulatory mechanism of ASK1 in the oxidative stress response remains to be elucidated. Here, we identified the kelch repeat protein, Slim, as an activator of ASK1 through a Drosophila misexpression screen. We also performed a proteomics screen and revealed that Kelch domain containing 10 (KLHDC10), a mammalian ortholog of Slim, interacted with Protein phosphatase 5 (PP5), which has been shown to inactivate ASK1 in response to ROS. KLHDC10 bound to the phosphatase domain of PP5 and suppressed its phosphatase activity. Moreover, KLHDC10 was required for H2O2-induced sustained activation of ASK1 and cell death in Neuro2A cells. These findings suggest that Slim/KLHDC10 is an activator of ASK1, contributing to oxidative stress-induced cell death through the suppression of PP5

Preoperative MRI Parameters Predict Urinary Continence after Robot-Assisted Laparoscopic Prostatectomy in Prostatic Cancer Patients

We aimed to investigate whether preoperative MRI findings could predict the bladder neck location on postoperative cystography and recovery of urinary incontinence after robot-assisted laparoscopic radical prostatectomy (RALP). We retrospectively reviewed 270 consecutive patients who had complete preoperative data, including MRI, and underwent postoperative observation for more than three months. Preoperative MRI parameters consisted of the membranous urethral length (MUL) and pubic symphysis-prostate apex length (PAL) on sagittal images. The bladder neck location on a postoperative cystography was defined as the lowest extension of the tapering contrast medium in the bladder, and its relation to the pubic symphysis (above (higher group) and below (lower group) the middle of the pubic symphysis height) was evaluated. Those who required no pad or a safety pad were defined as being continent. PAL was significantly shorter in the higher group than that in the lower group (25.5 vs. 29.1 mm; p < 0.0001). The continent group at three months had a significantly longer MUL and shorter PAL than those in the incontinent group (8.1 vs. 6.7 mm; p < 0.05, and 26.0 vs. 28.1 mm; p < 0.05, respectively). Preoperative MRI parameters could predict the bladder neck location on postoperative cystograms and the recovery of urinary incontinence after RALP

Feasibility of ovarian stimulation for fertility preservation during and after blinatumomab treatment for Ph-negative B-cell acute lymphoblastic leukemia

It is challenging to preserve the fertility of female patients with B-cell acute lymphoblastic leukemia (B-ALL) before allogeneic hematopoietic stem cell transplantation (allo-HSCT) while maintaining treatment intensity. We report two cases of female patients with Philadelphia chromosome-negative (Ph -) B-ALL whose oocytes were retrieved after controlled ovarian stimulation during and after blinatumomab treatment. The first patient was a 30-year-old woman with relapsed Ph-B-ALL who received prednisolone (PSL) and cytoreductive chemotherapy with cyclophosphamide, vincristine, doxorubicin, and dexamethasone, followed by three courses of blinatumomab bridging to allo-HSCT. Ovarian stimulation was performed twice during blinatumomab administration, and two oocytes were retrieved during each course. The second patient was a 26-year-old woman with newly diagnosed Ph-B-ALL who received PSL, one course of conventional chemotherapy, and one course of high-dose methotrexate and cytarabine followed by two courses of blinatumomab bridging to allo-HSCT. Immediately after completion of the first course of blinatumomab, ovarian stimulation was performed, and three oocytes were retrieved. Use of a 2-week rest period enabled ovarian stimulation and oocyte retrieval to be performed without delaying treatment. Blinatumomab may be an option for preserving fertility while maintaining treatment intensity

Intracardiac Echocardiography as a Guide for Transcatheter Closure of Patent Ductus Arteriosus

Background. Transcatheter closure of patent ductus arteriosus (TC-PDA), conventionally guided by aortography, has become the standard treatment of this disease. The purposes of this study were to evaluate whether intracardiac echocardiography (ICE) may be used for measuring PDA size and be used as a guide for TC-PDA. Methods. This study had 2 phases. In phase 1, we compared the measurements of PDA size: pulmonary artery side diameter (PA-D), length, and aortic side diameter (Ao-D) of PDA, as measured by ICE with those measured by aortography or cardiac computed tomography (AoG/CCT) in 23 patients who underwent TC-PDA. In phase 2, we compared the demographics, fluoroscopic time, contrast volume, and complications of the TC-PDAs between 10 adult patients with ICE guidance and 16 without it. Results. In phase 1, we found great correlation and agreement between ICE and AoG/CCT in PA-D (r = 0.985, bias −0.077 to 0.224), but moderate to poor correlation and agreement in length (r = 0.653, bias −0.491 to 3.065) and Ao-D (r = 0.704, bias 0.738 to 4.732), respectively. Nevertheless, all patients underwent successful TC-PDA with ICE guidance that allowed us to continuously monitor the whole process. In phase 2, TC-PDA required a significantly lower contrast volume with ICE guidance than without it, and there was no significant difference in the remaining variables between the 2 groups. Conclusion. ICE is comparable to AoG/CCT in providing accurate PA-D of the PDA and may be a safe alternative to guide TC-PDA as compared to conventional aortography

Depth of invasion to the bladder wall as a prognostic factor and its association with circulating cell-free DNA levels in patients with muscle-invasive bladder cancer

Background: We investigated the potential of the depth of invasion (DOI) as a prognostic factor in patients with muscle-invasive bladder cancer (MIBC) who underwent radical cystectomy (RC). Moreover, we examined the association between the preoperative levels of circulating cell-free DNA and DOI.博士（医学）・甲第876号・令和5年3月15日© 2023 The Authors. Published by Wolters Kluwer Health, Inc. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.identifier:Current Urology (2023 Mar)identifier:16617649identifier:http://ginmu.naramed-u.ac.jp/dspace/handle/10564/4108identifier:Current Urolog

骨転移を有する泌尿器科がんに特化した予後予測スコアリングモデル(B-FOM model)の外部検証および他のスコアリングモデルとの予後予測精度の比較

Objective: We previously developed genitourinary (GU) cancer-specific scoring system for prediction of survival in patients with bone metastasis (the Bone-Fujimoto-Owari-Miyake [B-FOM] scoring model) based on five prognostic factors: the type of primary tumor (prostate cancer (PCa) vs renal cell carcinoma (RCC) and PCa vs urothelial carcinoma (UC)), poor performance status (PS), visceral metastasis, high Glasgow-prognostic score (GPS), elevated neutrophil-to-lymphocyte ratio (NLR). The aim of this study was to externally validate and further improve the performance of the B-FOM score. Methods: The external validation cohort comprised 309 patients with GU cancer with bone metastasis from multiple institutions. Clinical factors were analyzed using Kaplan-Meier method and COX regression hazard model. Performance of a modified B-FOM score was compared to that of other scoring models by the Kaplan-Meier method and the area under the curve (AUC) of receiver operating characteristic curves. Results: The median follow-up period of development and validation cohort were 25 and 17 months, respectively. Kaplan-Meier curve demonstrated that the type of primary tumor (RCC and UC vs PCa), poor PS, presence of visceral metastasis, high GPS, elevated NLR were significantly associated with shorter cancer-specific survival. Risk groups were successfully stratified by the modified B-FOM score classification. Moreover, the AUC of the modified B-FOM scoring model for predicting mortality at 6, 12, and 24 months were 0.895, 0.856, and 0.815, respectively, which were the highest among evaluated models. Conclusions: The B-FOM scoring model is a simple and accurate prediction tool. By using this scoring model at the time of the diagnosis of bone metastasis in patients with GU cancers, an individualized optimal treatment strategy can be selected.博士（医学）・甲第835号・令和4年3月15日© 2020 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license(https://creativecommons.org/licenses/by-nc-nd/4.0/)

Clinical Impact of Sarcopenia and Inflammatory/Nutritional Markers in Patients with Unresectable Metastatic Urothelial Carcinoma Treated with Pembrolizumab

Sarcopenia is a muscle loss syndrome known as a risk factor of various carcinomas. The impact of sarcopenia and sarcopenia-related inflammatory/nutritional markers in metastatic urothelial carcinoma (mUC) treated with pembrolizumab was unknown, so this retrospective study of 27 patients was performed. Psoas muscle mass index (PMI) was calculated by bilateral psoas major muscle area at the L3 with computed tomography. The cut-off PMI value for sarcopenia was defined as ≤6.36 cm2/m2 for men and ≤3.92 cm2/m2 for women. Neutrophil-to-lymphocyte ratio (NLR) ≥ 4.0 and sarcopenia correlated with significantly shorter progression-free survival (PFS) (hazard ratio (HR) 3.81, p = 0.020; and HR 2.99, p = 0.027, respectively). Multivariate analyses identified NLR ≥ 4.0 and sarcopenia as independent predictors for PFS (HR 2.89, p = 0.025; and HR 2.79, p = 0.030, respectively). Prognostic nutrition index < 45, NLR ≥ 4.0 and sarcopenia were correlated with significantly worse for overall survival (OS) (HR 3.44, p = 0.046; HR 4.26, p = 0.024; and HR 3.92, p = 0.012, respectively). Multivariate analyses identified sarcopenia as an independent predictor for OS (HR 4.00, p = 0.026). Furthermore, a decrease in PMI ≥ 5% in a month was an independent predictor of PFS and OS (HR 12.8, p = 0.008; and HR 6.21, p = 0.036, respectively). Evaluation of sarcopenia and inflammatory/nutritional markers may help in the management of mUC with pembrolizumab

Nedd4-induced monoubiquitination of IRS-2 enhances IGF signalling and mitogenic activity

Insulin-like growth factors (IGFs) induce proliferation of various cell types and play important roles in somatic growth and cancer development. Phosphorylation of insulin receptor substrate (IRS)-1/2 by IGF-I receptor tyrosine kinase is essential for IGF action. Here we identify Nedd4 as an IRS-2 ubiquitin ligase. Nedd4 monoubiquitinates IRS-2, which promotes its association with Epsin1, a ubiquitin-binding protein. Nedd4 recruits IRS-2 to the membrane, probably through promoting Epsin1 binding, and enhances IGF-I receptor-induced IRS-2 tyrosine phosphorylation. In thyroid FRTL-5 cells, activation of the cyclic AMP pathway increases the association of Nedd4 with IRS-2, thereby enhancing IRS-2-mediated signalling and cell proliferation induced by IGF-I. The Nedd4 and IRS-2 association is also required for maximal activation of IGF-I signalling and cell proliferation in prostate cancer PC-3 cells. Nedd4 overexpression accelerates zebrafish embryonic growth through IRS-2 in vivo. We conclude that Nedd4-induced monoubiquitination of IRS-2 enhances IGF signalling and mitogenic activity.UTokyo Research掲載「動物の成長や細胞の増殖の新しい調節機構を発見」 URI: http://www.u-tokyo.ac.jp/ja/utokyo-research/research-news/novel-regulatory-mechanisms-of-animal-growth-and-cell-proliferation.htmlUTokyo Research "Novel regulatory mechanisms of animal growth and cell proliferation" URI: http://www.u-tokyo.ac.jp/en/utokyo-research/research-news/novel-regulatory-mechanisms-of-animal-growth-and-cell-proliferation.htm