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Background: Mast cells are key effector cells that elicit immunoglobulin E (IgE)-mediated allergic inflammations. Allergen cross-linking of IgE bound to the high-affinity IgE receptor, FcεRI, on mast cells triggers signaling cascades that activate signal proteins and evoke extracellular Ca 2+ influx, which are crucial for cytokine production. The β2-adrenergic receptor (Adrb2) on mast cells negatively regulates FcεRI signaling, as demonstrated by the inhibition of IgE/antigen (Ag)-induced activation by Adrb2 agonists., Objective: Although β2-adrenergic-related reagents are known to influence mast cell functions, the specific intrinsic role of Adrb2 in these cells is not fully understood, potentially because of off-target effects. In this study, the additional roles of Adrb2 in mast cells were investigated, specifically the involvement of Adrb2 in FcεRI signaling, using Adrb2 -/- mice., Methods: Adrb2 -/- mice were used to investigate the roles of Adrb2 in mast cells by examining bone marrow-derived mast cells (BMMCs) for surface expression of mast cell markers, granule numbers, and gene expression of mast cell proteases. Cytokine production, Ca 2+ influx, and nuclear factor of activated T cells (NFAT) nuclear translocation were measured in Adrb2 -/- and Adrb2 +/+ BMMCs upon IgE/Ag stimulation., Results: Adrb2 -/- did not affect the generation of BMMCs, their surface expression of mast cell markers, granule numbers, or gene expression of mast cell proteases, indicating that the absence of Adrb2 had no adverse effect on mast cell development. However, Adrb2 -/- BMMCs exhibited reduced tumor necrosis factor α (TNFα) production and diminished Ca 2 ⁺ influx upon IgE/Ag stimulation, which correlated with decreased NFAT translocation. Restoration of Adrb2 in Adrb2 -/- BMMCs rescued cytokine production. Notably, FcεRI-mediated phosphorylation of the phospholipase PLCγ1 and mitogen-activated protein kinases (MAPKs) remained unchanged in the absence of Adrb2., Conclusion: These results suggest that Adrb2 has a novel ligand-independent function, increasing Ca 2+ entry in mast cells when stimulated with IgE/Ag., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The Japanese National Clinical Database (NCD) is a large-scale, nationwide, web-based data entry system that covers the majority of surgical cases performed in Japan. An NCD specializing in urological surgery was launched based on the NCD system in 2018., Methods: All urological surgeries performed at more than 1000 institutions were registered from 2018. We herein report the number of surgeries conducted as stipulated in the "Certified Urology Surgeon Training Curriculum" between April 2018 and December 2021., Results: A total of 1 377 677 cases were registered from 1185 facilities nationwide under the initiative of the Japanese Urological Association. We examined the number of procedures performed every year for each of the 10 categories., Conclusions: The NCD system sustainably provides important information relating to the preoperative status, operational outcome, and best practice for urological surgery in Japan., (© 2024 The Japanese Urological Association.)

Objective: We investigated preoperative patient factors associated with prognosis in 263 bladder cancer (BC) patients undergoing radical cystectomy (RC). We also developed new risk stratification models for prognosis., Methods: This retrospective study included patients treated at Tottori University Hospital and affiliated hospitals between January 2010 and December 2019. The relationship between preoperative patient factors and overall recurrence-free and cancer-specific survival (CSS) was analyzed. The modified Glasgow prognosis score (mGPS) was calculated using serum albumin and C-reactive protein (CRP) levels. Statistical analyses included the log-rank test and Cox proportional hazards regression., Results: Eastern Cooperative Oncology Group performance status (ECOG-PS), mGPS, and clinical tumor stage independently predicted CSS in multivariate analysis. A new risk stratification model included ECOG-PS ≥2, clinical tumor stage ≥3, serum albumin <3.5 g/dL, and serum CRP >0.5 mg/dL. Risk groups were defined as 0 factors (low risk), 1-2 factors (intermediate risk), and 3-4 factors (high risk). High-risk patients showed significantly poorer 3-year cancer-free survival: 86.9% (low risk), 76.7% (intermediate risk), and 50.0% (high risk)., Conclusions: ECOG-PS, clinical tumor stage, and mGPS are predictive of poor cancer-free survival post-RC for BC. Our model offers the potential for prognostic prediction in these patients., (© 2024 The Japanese Urological Association.)

Introduction: The trigone/urethra (T/U) has a distinct embryologic origin and a different histologic morphology compared to the rest of the urinary bladder. We sought to determine the association between tumors involved in the T/U and the presence of variant histology, pathologic, and oncologic outcomes in patients who underwent robot-assisted radical cystectomy (RARC)., Methods: Tumor location was classified into 2 groups: tumors in the bladder walls only, or tumors in the T/U area, with or without involvement of other bladder walls. Univariable and multivariable Cox regression models were used to determine the association between T/U with recurrence-specific (RSS), cancer-specific (CSS), and overall survival (OS)., Results: 608 patients who underwent RARC were identified, T/U involvement occurred in 191 (31%). Patients in the T/U group were more likely to have pT3/pT4 (57% vs. 42%, P < 0.01), positive surgical margins (21% vs. 9%, P < 0.01), and received salvage chemotherapy more frequently (16% vs. 8%, P < 0.01). Squamous variant histology was more frequent in the T/U group (25% vs. 17%, P = 0.02). On multivariable analysis, T/U location was independently associated with RSS (HR1.63, 95% CI 1.23-2.16, P < 0.01) and CSS (HR1.50, 95% CI 1.04-2.16, P = 0.02) but not OS., Conclusion: Residual T/U tumor involvement was associated with a higher risk of an advanced tumor stage, positive margin, cancer recurrence, and cancer-specific death., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The therapeutic role of pelvic lymph node dissection (PLND) during radical prostatectomy (RP) for prostate cancer is not established. In clinical practice, PLND is primarily performed in cases of high-risk prostate cancer. The detection of lymph node metastasis plays a crucial role in determining the need for subsequent treatments. This study aims to evaluate the prognosis of prostate cancer patients with lymph node involvement (LNI) by stratifying them based on postoperative prostate-specific antigen (PSA) levels to identify biomarkers that can guide postoperative treatment strategies., Methods: Analysis was conducted on 383 patients, selected from 572 initially eligible, who underwent RP with LNI across 33 Japanese Urological Oncology Group institutions from 2006 to 2019. Patients were grouped according to postoperative PSA levels and salvage treatments received. Follow-up focused on castration resistance-free survival (CRFS), metastasis-free survival (MFS), and overall survival (OS)., Results: In the persistent PSA group (PSA ≥ 0.1 ng/mL), CRFS and MFS were significantly shorter compared to the non-persistent PSA group (PSA < 0.1 ng/mL), and there was a tendency for shorter OS. In the persistent PSA group, patients with postoperative PSA values above the median (PSA ≥ 0.52 ng/mL) showed shorter CRFS and MFS. Furthermore, in the PSA ≥ 0.52 group, androgen deprivation therapy (ADT) plus radiotherapy (RT) combination had prolonged CRFS and MFS compared with ADT alone., Conclusions: This study provides valuable insights into stratifying patients based on postoperative PSA levels to tailor postoperative treatment strategies, potentially improving the prognosis of prostate cancer patients with LNI., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Introduction and Hypothesis: Robot-assisted radical nephroureterectomy (RANU) has emerged as a valid alternative to open or laparoscopic nephroureterectomy in recent years. However, different types of robotic platforms can limit surgical maneuvers in various ways. This study aimed to describe the surgical procedure and demonstrate RANU's technical feasibility and safety using the Hugo robot-assisted surgery (RAS) system. Materials and Methods: Using the Hugo RAS system, we reported data from the first five consecutive patients who underwent RANU at Tottori University Hospital. We adjusted the docking angles of the four independent arm carts in each case and performed a complete RANU via a transperitoneal approach. We collected patients' sociodemographic and perioperative data, including complications, and compared them retrospectively with data obtained using the da Vinci surgical system. Results: Arms positions were modified after the first patient to be placed all at the back of the patient. Median overall operative time was 283 minutes (203-377) and the median time using the robotic system was 187 minutes (121-277). The median estimated blood loss was 20 mL (5-155). None of the patients required a blood transfusion and none suffered postoperative complications of Clavien-Dindo grade ≥3. These outcomes were similar to those obtained with the da Vinci Xi system. Conclusion: This series represents the first report of RANU executed using the novel Hugo RAS system. Our proposed arm-setup will assist other surgeons and help ensure safe implementation of RANU on the Hugo platform.

Pelvic lymph node dissection (PLND) is important for accurate staging and prognosis of prostate and/or bladder cancer. Several guidelines recommend extended PLND for patients with these cancers. However, the therapeutic benefits of extended PLND are unclear. One major reason is that the extent of PLND is not clearly defined. Thus, the working group for standardization of robot-assisted PLND, including nine experienced urologists for PLND in Japan, was launched in January 2023 by the Japanese Society of Endourology and Robotics. This study summarized the discussions to define the individual extent of PLND in urological surgery in a consensus meeting among these experienced urologists. The consensus meeting determined the extent of PLND based on arteries (veins) and anatomical membrane structures rather than a vague concept or approach toward PLND. This concept is expected to allow surgeons to implement the same extent of PLND. Finally, after a total of 10 online web conferences were held, we determined the extent of PLND for the obturator lymph node (LN) area, the internal iliac LN area, the external and common iliac LN area, and the presacral LN area according to the above rules. The extent of PLND suggested here currently does not have a clear therapeutic rationale. Therefore, the extent of our proposed PLND is by no means mandatory. We hope our definition of the extent of PLND will be supported by further evidence of therapeutic benefits for urologic cancers., (© 2024 The Japanese Urological Association.)

Objectives: The National Clinical Database (NCD) Urology Division commenced registration in April 2018 in Japan. This is the first report to focus on five surgeries for which detailed information is registered., Methods: We herein describe annual trends in and the complication grades of the following five surgeries: partial nephrectomy, radical nephrectomy, radical cystectomy, radical prostatectomy, and pyeloplasty, using the NCD. A total of 149 417 patients treated with the five types of surgeries based on NCD data were enrolled in this report., Results: The number of patients was 55 630 for partial/radical nephrectomy from April 2018 to December 2021, 83 653 for radical prostatectomy from April 2018 to December 2021, and 9342 for radical cystectomy from January 2020 to December 2021. In 2021, partial nephrectomy was performed on 7416 cases, radical nephrectomy on 7739 cases, radical prostatectomy on 22 692 cases, radical cystectomy on 4677 cases, and pyeloplasty on 792 cases., Conclusions: The results obtained showed that a robot-assisted or laparoscopic procedure has replaced open surgery as the common approach for all five surgeries. An analysis of NCD data may be useful for understanding trends in surgical procedures across the major field of urology., (© 2024 The Japanese Urological Association.)

Brentuximab vedotin (BV), a conjugate of anti-CD30 antibody and monomethyl auristatin E, has emerged as a promising treatment option for refractory CD30+ mycosis fungoides (MF) and primary cutaneous anaplastic large-cell lymphoma (pcALCL). BV has been shown to be safe and effective in treating Hodgkin's lymphoma and peripheral T-cell lymphoma. This multicenter, prospective, single-arm phase I/II study evaluated the efficacy of BV in Japanese patients with CD30+ cutaneous lymphomas, namely CD30+ cutaneous T-cell lymphoma. Participants were divided into two groups: those with CD30+ MF or pcALCL (cohort 1, n = 13) and those with CD30+ lymphoproliferative disorders other than those in cohort 1 (cohort 2, n = 3). The studied population included the full analysis set (FAS), modified FAS (mFAS), and safety analysis set (SAF). These sets were identified in cohorts 1 and 1 + 2 and labeled FAS1 and FAS2, mFAS1 and mFAS2, and SAF1 and SAF2, respectively. Each treatment cycle lasted 3 weeks, and BV was continued for up to 16 cycles after the third cycle based on treatment response. The primary endpoint was the 4-month objective response rate (ORR4) determined by the Independent Review Forum (IRF). ORR4 was 69.2% for FAS1 and 62.5% for FAS2 (P < 0.0001). Secondary endpoints of ORR, assessed using the global response score (53.8% in FAS1) and modified severity-weighted assessment tool (62.5% in FAS1), using the IRF, provided results comparable to the primary findings. The incidence of ≥grade 3 adverse events (≥15%) in SAF1 was peripheral neuropathy in three patients (23%) and fever and eosinophilia in two patients (15%). In conclusion, BV showed favorable efficacy, tolerability, and safety profile in Japanese patients with relapsed or refractory CD30+ primary cutaneous T-cell lymphoma. The trial was registered with University Hospital Medical Information Network Clinical Trials Registry, Japan (protocol ID: UMIN000034205)., (© 2024 The Author(s). The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

Background: Despite partial nephrectomy (PN) renal function preservation benefits, postoperative renal dysfunction may occur. Perirenal fat thickness (PFT) is associated with renal dysfunction such as diabetes; however, its role in renal tumour surgery is unclear. This study investigates the role of PFT in renal function after robot-assisted partial nephrectomy (RAPN)., Methods: Pre-operative factors for postoperative renal dysfunction were analysed in 156 patients undergoing RAPN with ≥1-year follow-up. PFT measured using computed tomography categorised patients with PFT >21.0 mm (median) as high-PFT., Results: Tumour size, total R.E.N.A.L. nephrometry score and its N component, renal calyx opening, achievement of trifecta, and PFT were risk factors for renal dysfunction 1 year postoperatively. Age ≥75 years (p = 0.024), total RNS ≥7 (p = 0.036), and PFT >21.0 mm (p = 0.002) significantly correlated with postoperative renal dysfunction., Conclusions: CT-measured PFT is a valuable predictor of postoperative renal dysfunction., (© 2024 John Wiley & Sons Ltd.)

Systemic sclerosis (SSc) is a collagen disease with immune abnormalities, vasculopathy, and fibrosis. Ca blockers and prostaglandins are used to treat peripheral circulatory disturbances. Chronic limb-threatening ischemia (CLTI) is a disease characterized by extremity ulcers, necrosis, and pain due to limb ischemia. Since only a few patients present with coexistence of CLTI and SSc, the treatment outcomes of revascularization in these cases are unknown. In this study, we evaluated the clinical characteristics and treatment outcomes of seven patients with CLTI and SSc, and 35 patients with uncomplicated CLTI who were hospitalized from 2012 to 2022. A higher proportion of patients with uncomplicated CLTI had diabetes and male. There were no significant differences in the age at which ischemic ulceration occurred, other comorbidities, or in treatments, including antimicrobial agents, revascularization and amputation, improvement of pain, and the survival time from ulcer onset between the two subgroups. EVT or amputation was performed in six or two of the seven patients with CLTI and SSc, respectively. Among those who underwent EVT, 33% (2/6) achieved epithelialization and 67% (4/6) experienced pain relief. These results suggest that the revascularization in cases with CLTI and SSc should consider factors such as infection and general condition, since revascularization improve the pain of these patients., (© 2024 The Author(s). The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

Background: Upper urinary tract urothelial carcinoma (UTUC) is uncommon. In advanced cases, radical nephroureterectomy (RNU) alone is not curative, and recurrence and metastasis are likely to occur. Adjuvant chemotherapy (AC) is an evidence-based treatment. However, the optimal number of AC cycles is not clear. This multicenter study investigated the number of cycles required for the beneficial effects of AC in Japanese patients with UTUC., Methods: Patients who were diagnosed with UTUC and underwent RNU at our hospital and affiliated hospitals from January 2010 to September 2020 were included in the study. Patients with pathological T3 or higher or lymph node metastasis were observed or given AC, and their responses were compared. The AC regimens included gemcitabine and cisplatin or carboplatin. Patients were also classified into two groups: the observation and two cycles of AC group and the three to four cycles of AC group. The survival curves for recurrence-free survival (RFS) and cancer-specific survival (CSS) were evaluated using Kaplan-Meier analyses., Results: Of the 133 patients enrolled in the study, 24 received 2 cycles of AC, 37 received 3-4 cycles, and 72 were observed only. The 5-year RFS was 67.1% for the 3-4 cycles of AC group and 41.7% for the observation and two cycles of AC group. The 5-year CSS was 72.2% for the 3-4 cycles of AC group and 35.9% for the observation and two cycles of AC group. RFS and CSS were significantly longer in the 3-4 cycles of AC group compared to the observation and 2 cycles group ( P = 0.048 and P = 0.005 respectively)., Conclusion: AC prolonged RFS and CSS in the real-world setting. However, at least three cycles of AC are required to achieve beneficial effects in patients with UTUC., Competing Interests: The authors declare no conflict of interest., (©2024 Tottori University Medical Press.)

Competing Interests: There are no conflicts of interest.

Background: This study aimed to create a prognostic model to predict disease recurrence among patients with lymph node involvement but no prostate-specific antigen (PSA) persistence and to explore its clinical utility., Methods: The study analyzed patients with lymph node involvement after pelvic lymph node dissection with radical prostatectomy in whom no PSA persistence was observed between 2006 and 2019 at 33 institutions. Prognostic factors for recurrence-free survival (RFS) were analyzed by the Cox proportional hazards model., Results: Among 231 patients, 127 experienced disease recurrence. The factors prognostic for RFS were PSA level at diagnosis (≥ 20 vs. < 20 ng/mL: hazard ratio [HR], 1.66; 95% confidence interval [CI], 1.09-2.52; P = 0.017), International Society of Urological Pathology grade group at radical prostatectomy (RP) specimen (group ≥ 4 vs. ≤ 3: HR, 1.63; 95% CI 1.12-2.37; P = 0.010), pathologic T-stage (pT3b/4 vs. pT2/3a: HR, 1.70; 95% CI 1.20-2.42; P = 0.0031), and surgical margin status (positive vs. negative: HR, 1.60; 95% CI 1.13-2.28; P = 0.0086). The prognostic model using four parameters were associated with RFS and metastasis-free survival., Conclusion: The prognostic model in combination with postoperative PSA value and number of lymph nodes is clinically useful for discussing treatment choice with patients., (© 2024. Society of Surgical Oncology.)

Background and Aims: With the development of novel therapies for advanced malignant melanoma (MM), biomarkers that can accurately reflect the progression of MM are needed. Serum levels of melanin-related indole metabolites such as 5-hydroxy-6-methoxyindole-2-carboxylic acid (5H6MI2C) and 6-hydroxy-5-methoxyindole-2-carboxylic acid (6H5MI2C) are potential biomarkers for MM. Here, we describe the development of a mass spectrometry (MS)-based assay to determine serum levels of 5H6MI2C and 6H5MI2C., Materials and Methods: We developed a stable isotope dilution-selective reaction monitoring-MS protocol using liquid chromatography tandem mass spectrometry (LC-MS/MS) to measure human serum 5H6MI2C and 6H5MI2C levels. Analytical evaluations of the method were performed and the method was applied to serum samples from MM patients (n = 81)., Results: The method established in this study showed high reproducibility and linearity. This novel method also found that serum 6H5MI2C levels were significantly elevated in patients with metastatic MM compared to those with non-metastatic MM. Unfortunately, 5H6MI2C did not show a comparable significant difference., Conclusion: We successfully established measurement methods for serum 5H6MI2C and 6H5MI2C levels using LC-MS/MS. Serum 6H5MI2C levels offer a potential marker for MM., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘Tomohiro Nakayama belongs to an endowment division, supported with a grant from JEOL Ltd. since June 2020. There are no other conflicts of interest to declare.’., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Multiparametric MRI (mpMRI) is widely used for the diagnosis, surveillance, and staging of prostate cancer. However, it has several limitations, including higher costs, longer examination times, and the use of gadolinium-based contrast agents. This study aimed to investigate the accuracy of preoperatively assessed index tumors (ITs) using biparametric MRI (bpMRI)/transrectal ultrasound (TRUS) fusion biopsy compared with radical prostatectomy (RP) specimens., Methods: We included 113 patients diagnosed with prostate cancer through bpMRI/TRUS fusion-guided biopsies of lesions with a Prostate Imaging Reporting and Data System (PI-RADS) category ≥ 3. These patients underwent robot-assisted laparoscopic radical prostatectomy (RARP) at our institution between July 2017 and March 2023. We examined the localization of preoperative and postoperative ITs, the highest Gleason score (GS), and tumor diameter in these patients., Results: The preoperative cT stage matched the postoperative pT stage in 53 cases (47%), while 31 cases (27%) were upstaged, and 29 cases (26%) were downstaged (Weighted Kappa = 0.21). The preoperative and postoperative IT localizations were consistent in 97 cases (86%). The concordance rate between Gleason groups in targeted biopsies and RP specimens was 51%, with an upgrade in 25 cases (23%) and a downgrade in 27 cases (25%) (Weighted Kappa = 0.42). The maximum diameter of the IT and the maximum cancer core length on biopsy were correlated with the RP tumor's maximum diameter (p < 0.001 for both)., Conclusion: The diagnostic accuracy of bpMRI/TRUS fusion biopsy is comparable to mpMRI, suggesting that it can be a cost-effective and time-saving alternative., (© 2024. The Author(s).)

Background: Selective activator protein (AP)-1 inhibitors are potentially promising therapeutic agents for atopic dermatitis (AD) because AP-1 is an important regulator of skin inflammation. However, few studies have investigated the effect of topical application of AP-1 inhibitors in treating inflammatory skin disorders., Methods: Immunohistochemistry was conducted to detect phosphorylated AP-1/c-Jun expression of skin lesions in AD patients. In the in vivo study, 1 % T-5224 ointment was topically applied for 8 days to the ears of 2,4 dinitrofluorobenzene challenged AD-like dermatitis model mice. Baricitinib, a conventional therapeutic agent Janus kinase (JAK) inhibitor, was also topically applied. In the in vitro study, human epidermal keratinocytes were treated with T-5224 and stimulated with AD-related cytokines., Results: AP-1/c-Jun was phosphorylated at skin lesions in AD patients. In vivo, topical T-5224 application inhibited ear swelling (P < 0.001), restored filaggrin (Flg) expression (P < 0.01), and generally suppressed immune-related pathways. T-5224 significantly suppressed Il17a and l17f expression, whereas baricitinib did not. Baricitinib suppressed Il4, Il19, Il33 and Ifnb expression, whereas T-5224 did not. Il1a, Il1b, Il23a, Ifna, S100a8, and S100a9 expression was cooperatively downregulated following the combined use of T-5224 and baricitinib. In vitro, T-5224 restored the expression of FLG and loricrin (LOR) (P < 0.05) and suppressed IL33 expression (P < 0.05) without affecting cell viability and cytotoxicity., Conclusions: Topical T-5224 ameliorates clinical manifestations of AD-like dermatitis in mice. The effect of this inhibitor is amplified via combined use with JAK inhibitors., (Copyright © 2024 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Objectives: To investigate preoperative patient factors that may predict the occurrence of perioperative complications following robot-assisted radical cystectomy at a single center in Japan., Methods: From 2013 to 2022, 103 patients underwent RARC at our institution. Complications within 90 days after surgery were assessed using the Clavien-Dindo classification. Preoperative characteristics and surgical outcomes were compared between cohorts with and without complications ≥grade 3. Logistic regression analysis was used to identify the risk factors associated with perioperative complications., Results: Overall, 27% of patients (27/103) experienced grade 3 or higher complications. The cohort that developed complications ≥grade 3 exhibited significantly higher Charlson comorbidity index (p = 0.046) and significantly lower estimated glomerular filtration rate (p = 0.048). Charlson comorbidity index ≥2 (p = 0.037) and estimated glomerular filtration rate <53 (p = 0.008) were independent predictors for the occurrence of complications ≥grade 3. The incidence of complications ≥grade 3 was 61.5% in the group possessing both factors, which was significantly higher than those in the groups possessing neither factor nor only one of the two factors., Conclusions: Our results suggest that the Charlson comorbidity index and preoperative estimated glomerular filtration rate may be predictors of perioperative complications. It is important to evaluate the patient's preoperative characteristics and choose the surgical procedure accordingly., (© 2023 The Japanese Urological Association.)

The effect of persistent skin inflammation on extracutaneous organs and blood is not well studied. Patients with recessive dystrophic epidermolysis bullosa (RDEB), a severe form of the inherited blistering skin disorder, have widespread and persistent skin ulcers, and they develop various complications including anaemia, hyperglobulinaemia, hypoalbuminaemia and secondary amyloidosis. These complications are associated with the bioactivities of IL-6, and the development of secondary amyloidosis requires the persistent elevation of serum amyloid A (SAA) level. We found that patients with RDEB had significantly higher serum levels of IL-6 and SAA compared to healthy volunteers and patients with psoriasis or atopic dermatitis. Both IL-6 and SAA were highly expressed in epidermal keratinocytes and dermal fibroblasts of the skin ulcer lesions. Keratinocytes and fibroblasts surrounding the ulcer lesions are continuously exposed to Toll-like receptor (TLR) ligands, pathogen-associated and damage-associated molecular pattern molecules. In vitro, TLR ligands induced IL-6 expression via NF-κB in normal human epidermal keratinocytes (NHEKs) and dermal fibroblasts (NHDFs). SAA further induced the expression of IL-6 via TLR1/2 and NF-κB in NHEKs and NHDFs. The limitation of this study is that NHEKs and NHDFs were not derived from RDEB patients. These observations suggest that TLR-mediated persistent skin inflammation might increase the risk of IL-6-related systemic complications, including RDEB., (© 2024 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd.)

Background: Pelvic lymph node dissection is a procedure performed in gastroenterological surgery, urology, and gynecology. However, due to discrepancies in the understanding of pelvic anatomy among these departments, cross-disciplinary discussions have not been easy. Recently, with the rapid spread of robotic surgery, the importance of visual information in understanding pelvic anatomy has become even more significant. In this project, we attempted to clarify a shared understanding of pelvic anatomy through cross-disciplinary discussions., Method: From May 2020 to November 2021, a total of 11 discussions were held entirely online with 5 colorectal surgery specialists, 4 urologists, and 4 gynecologists. The discussions focused on evidence from each specialty and surgical videos, aiming to create a universally understandable pelvic anatomical illustration., Results: The common area of dissection recognized across the three departments was identified as the obturator lymph nodes. A dynamic illustration of pelvic anatomy was created. In addition to a bird's-eye view of the pelvis, a pelvic half view was developed to enhance understanding of the deeper pelvic anatomy. The following insights were incorporated into the illustration: (1) the cardinal ligament in gynecology partly overlaps with the vesicohypogastric fascia in colorectal surgery; (2) the obturator lymph nodes continue cephalad into the fossa of Marcille in urology; and (3) the deep uterine vein in gynecology corresponds to the inferior vesical vein in colorectal surgery., Conclusion: Based on the dynamic illustration of pelvic anatomy from cross-disciplinary discussions, we anticipate advancements in pelvic lymph node dissection aiming for curative and safe outcomes., (© 2024 TheAuthors. Asian Journal of Endoscopic Surgery published by Asia Endosurgery Task Force and Japan Society of Endoscopic Surgery and John Wiley & Sons Australia, Ltd.)

Background: To investigate the impact of different urinary diversion (UD) techniques on the peri- and postoperative complications of robot-assisted radical cystectomy (RARC) with ileal conduit., Methods: We retrospectively analyzed 373 patients undergoing RARC with ileal conduit at 11 institutions in Japan between April 2018 and December 2021. Propensity score weighting was performed to adjust for confounding factors such as age, sex, body mass index, performance status, American Society of Anesthesiologists score, previous abdominal surgery, neoadjuvant chemotherapy, and preoperative high T stage (≥ cT3) and high N stage (≥ cN1). Perioperative complications were then compared among three groups: extracorporeal, intracorporeal, and hybrid urinary diversion (ECUD, ICUD, and HUD, respectively)., Results: A total of 150, 68, and 155 patients received ECUD, HUD, and ICUD, respectively. Bowel reconstruction time and UD time were significantly shorter in the ECUD group (p < 0.001), and console time was significantly longer and blood loss was significantly higher in the ICUD group (p < 0.001). For postoperative complications (Clavien-Dindo Classification grade ≥ 3), surgical site infection (p = 0.004), pelvic abscess (p = 0.013), anastomotic urine leak (p = 0.007), and pelvic organ prolapse (p = 0.011) significantly occurred in the ECUD group. For all grades, ileus was more common in the HUD group, whereas anastomotic stricture was more common in the ECUD group compared with the other groups (p < 0.05)., Conclusions: Severe complications did not increase after HUD and ICUD compared with ECUD; however, console time tended to be longer and blood loss was slightly higher during RARC., (© 2023. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Objectives: Limited information is currently available on the efficacy and safety of axitinib for metastatic renal cell carcinoma (mRCC) patients with renal impairment. Therefore, the present study investigated the efficacy and toxicity of axitinib in patients with chronic kidney disease., Methods: Post-hoc analyses were performed on a Japanese multicenter cohort study of 477 mRCC patients who received axitinib followed by 1 or 2 regimens of systemic antiangiogenic therapy between January 2012 and December 2016. Differences in clinical characteristics and the efficacy and safety of axitinib were assessed based on pretreatment renal function., Results: Patients were categorized into the following 5 renal function groups according to baseline renal function: estimated glomerular filtration rate (eGFR) ≥60 ml/min (n = 133), 45 ml/min ≤eGFR <60 ml/min (n = 153), 30 ml/min ≤eGFR< 45 ml/min (n = 130), eGFR <30 ml/min (n = 45), and dialysis (n = 16). Median progression-free survival (PFS) (95% confidence interval [CI]) in the 5 groups was 11 (8-16), 14 (11-19), 14 (10-19), 12 (8-24), and 6 (3-NR) months, respectively (p = 0.781). After adjustments for treatment-related confounders, the renal function group was not a significant prognostic factor for PFS. Objective response rates in the 5 groups were 22%, 23%, 23%, 18%, 20%, and 38%, respectively (p = 0.468). Regarding adverse events of all grades, hypertension (p = 0.0006) and renal and urinary disorders (p < 0.0001) were more frequently observed in the eGFR <30 ml/min group than in the other groups., Conclusions: Since renal function at the initiation of treatment with axitinib does not adversely affect the efficacy of VEGF-TKI therapy, clinicians do not need to avoid its administration to mRCC patients with impaired renal function in consideration of the risk of progression to end-stage renal disease., Competing Interests: Declaration of Competing Interest Takahiro Osawa has received honoraria from Takeda. Masatoshi Eto received honoraria for lectures from ONO, BMS, Pfizer, Novartis, MSD, and Chugai, and for research funding from ONO, Pfizer, Chugai, BMS, Eisai, Bayer, and MSD. Hiroyuki Nishiyama has received honoraria from Ono and Chugai, research funds from Ono, Takeda, and Astellas, and reports scholarship endowments from MSD, Astellas, AstraZeneca, and Chugai. Takahiro Kimura received honoraria from Astellas, AstraZeneca, Bayer, Janssen, and Sanofi. Akira Yokomizo received honoraria from Pfizer and MSD. Nobuo Shinohara has received honoraria from Bayer, Ono, and Astellas and reports institutional research funding from Ono, Takeda, Sanofi, Taiho, and Astellas. Yoichi M. Ito is a statistical advisor for Nipro Corporation and an IDMC member for clinical trials of Janssen Pharmaceutical K.K. The other authors have no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Considering the role of epidermal keratinocytes, they occupy more than 90% of the epidermis, form a physical barrier, and also function as innate immune barrier. For example, epidermal keratinocytes are capable of recognizing various cytokines and pathogen-associated molecular pattern, and producing a wide variety of inflammatory cytokines, chemokines, and antimicrobial peptides. Previous basic studies have shown that the immune response of epidermal keratinocytes has a significant impact on inflammatory skin diseases. The purpose of this review is to provide foundation of knowledge on the cytokines which are recognized or produced by epidermal keratinocytes. Since a number of biologics for skin diseases have appeared, it is necessary to fully understand the relationship between epidermal keratinocytes and the cytokines. In this review, the cytokines recognized by epidermal keratinocytes are specifically introduced as "input cytokines", and the produced cytokines as "output cytokines". Furthermore, we also refer to the existence of biologics against those input and output cytokines, and the target skin diseases. These use results demonstrate how important targeted cytokines are in real skin diseases, and enhance our understanding of the cytokines., Competing Interests: SM received research support from Sun Pharma Ltd., AbbVie GK, and Maruho Co., Ltd., and honoraria for lectures from Eli Lilly Japan K.K., AbbVie GK, Pfizer Japan Inc., Torii Pharmaceutical Co., Ltd, Sanofi K.K., and Maruho Co., Ltd. D. TM received scholarship donations from Eli Lilly Japan, Inc., LEO Pharma K.K., and AbbVie. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2023 Morizane, Mukai, Sunagawa, Tachibana, Kawakami and Ouchida.)

Introduction: Clinical studies have suggested a bidirectional association between non-alcoholic steatohepatitis (NASH) and psoriasis, affecting each other's development and severity. Here, we explored bidirectional causal linkages between NASH and psoriasis using a murine model., Methods: NASH was induced in mice by streptozotocin injection at 2 days of age and by high-fat diet feeding (STAM™ model). Psoriasis was induced by topical application of imiquimod (IMQ) on the ear. The severities of liver damage and psoriatic skin changes were determined using histological analysis. Gene expression in the skin tissues was evaluated using quantitative PCR analysis. Serum cytokine levels were determined using enzyme-linked immunosorbent assay. To examine the innate immune responses of normal human epidermal keratinocytes (NHEKs), the cells were treated with interleukin (IL)-17A, tumor necrosis factor (TNF)-α, and AdipoRon, an adiponectin receptor agonist., Results and Discussion: There were no differences in the degree of liver tissue damage (fat deposition, inflammation, and fibrosis) between NASH mice with and those without psoriasis. Conversely, the co-occurrence of NASH significantly augmented psoriatic skin changes, represented by epidermal hyperplasia, in psoriatic mice. Pro-inflammatory cytokines were expressed in the inflamed skin of psoriatic mice, and the expression of genes, especially Il23a , Il1b , Il36g , and Mip2 , was significantly upregulated by the co-occurrence of NASH. The expression of keratinocyte activation marker genes Defb4b and Krt16 was also upregulated by the co-occurrence of NASH. The serum TNF-α and IL-17 levels were increased by the co-occurrence of NASH and psoriasis. The serum adiponectin levels decreased in NASH mice compared with that in non-NASH mice. In NHEK culture, TNF-α and IL-17A synergistically upregulated CXCL1 , CXCL8 , and IL1B expression. The upregulated pro-inflammatory gene expression was suppressed by AdipoRon treatment, reflecting the anti-inflammatory capacity of adiponectin., Conclusion: The co-occurrence of NASH exacerbated psoriatic skin changes associated with increased serum inflammatory cytokine levels and decreased serum adiponectin levels. Combined with in vitro findings, increased inflammatory cytokine levels and decreased adiponectin levels likely promote innate immune responses in epidermal keratinocytes in psoriatic skin lesions. Overall, therapeutic intervention for co-occurring NASH is essential to achieve a favorable prognosis of psoriasis in clinical practice., Competing Interests: TM received scholarship donations from Eli Lilly Japan, Inc., Sun Pharma, and AbbVie. SM received research grants from AbbVie, Sun Pharma Japan, and Maruho and honoraria for lectures from Pfizer, Sanofi, Eli Lilly, Boehringer Ingelheim, Novartis, Kyowa Kirin, AbbVie, Sun Pharma Japan, and Maruho. YK received a research grant from Maruho. Authors TH and YSh are employed by SMC Laboratories, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Takezaki, Morizane, Ikeda, Iseki, Sakamoto, Kawakami, Hashiguchi, Shirakata, Nishina and Mukai.)

Hydroa vacciniforme lymphoproliferative disorder (HV-LPD) is a cutaneous variant of chronic active Epstein-Barr virus disease. We examined the coexpression of T- and natural killer (NK)-cell antigens in five patients with classic HV (cHV) and five with systemic HV (sHV). T-cell receptor (TCR) repertoire analysis was performed with high‑throughput sequencing. All five cHV patients had increased γδT cells (> 5%), whereas five sHV patients showed γδT- and αβT-cell dominance in two patients each, and a mixture of abnormal γδT and αβT cells in one. Circulating CD3 + T cells expressed CD16/CD56 at 7.8-42.3% and 1.1-9.7% in sHV and cHV, respectively. The percentage of CD16/CD56 + T cells was higher in the large granular lymphocyte or atypical T-cell fractions in sHV, but no TCR Vα24 invariant chain characteristic of NKT cells was detected. Considerable numbers of CD3 + cells expressing CD56 were observed in sHV skin infiltrates. Of the circulating γδT cells tested, TCR Vδ1 + cells characteristic of the epithelial type of γδT cells were dominant in two sHV cases. Thus, atypical αβT and γδT cells in HV-LPD can express NK-cell antigens, such as CD16 and CD56, and Vδ1 + epithelial-type γδT cells are a major cell type in some HV-LPD cases., (© 2023. The Author(s).)

Purpose: To investigate the feasibility and optimal port placements of robot-assisted laparoscopic nephroureterectomy (RANU) via the retroperitoneal approach in the lateral decubitus and supine positions using the da Vinci Xi (DVXi) and da Vinci SP (DVSP) systems., Materials and Methods: We performed lateral decubitus extraperitoneal RANU on the right side and supine extraperitoneal RANU on the left side using the DVXi and DVSP systems without repositioning in two fresh cadavers. In addition, paracaval and pelvic lymphadenectomies were performed simultaneously during both surgical procedures. The operative time of each procedure was calculated, and the technical details associated with these procedures were evaluated., Results: Lateral decubitus and supine extraperitoneal RANU using the DVXi and DVSP systems were achieved without repositioning. The surgeon console time ranged from 89 to 178 minutes, and no major technical complications were observed. However, carbon dioxide insufflation into the abdominal cavity was observed owing to a peritoneal breach during the creation of the surgical workspace, particularly in the supine position. Compared with the DVXi system, the DVSP system was more suitable for RANU using the retroperitoneal approach, except for renal handling., Conclusions: The DVXi and DVSP systems are feasible for performing lateral decubitus and supine extraperitoneal RANU without patient repositioning. The lateral decubitus position may be better than the supine position, and the DVSP system is more suitable for retroperitoneal RANU than the DVXi system. Nevertheless, further studies should be performed in clinical settings to validate our results., Competing Interests: SM received financial support and resources for this experimental study from Intuitive Surgical Inc., Sunnyvale, CA, USA. TK, HK, and HS are employees of Intuitive Surgical Inc. AT has nothing to disclose for this experimental study., (© The Korean Urological Association.)