Phase II, multicenter study of plasminogen activator inhibitor-1 inhibitor (TM5614) plus nivolumab for treating anti-PD-1 antibody-refractory malignant melanoma: TM5614-MM trial.

BACKGROUND: Anti-programmed cell death 1 antibodies (anti-PD-1 Abs) are widely used for advanced melanoma, but the efficacy of an anti-PD-1 Abs is limited in the Asian population. There remains an unmet need to improve the therapeutic effects of anti-PD-1 Abs treatment, particularly in melanoma patients who are refractory to anti-PD-1 Abs. The aim was to evaluate anti-PD-1 Abs treatment in combination with TM5614 (plasminogen activator inhibitor-1: PAI-1 inhibitor) in patients with unresectable melanoma. METHODS: The TM5614-MM study was a multicentre, open-label, single-arm, phase 2 clinical trial to evaluate the efficacy and safety of nivolumab in combination with TM5614 in patients with advanced, unresectable malignant melanoma recruited at 7 Japanese institutes between 13 September 2021 and 31 March 2023. Patients with metastatic or unresectable melanoma previously treated with anti-PD-1 Abs were enrolled. Nivolumab 480 mg was administered intravenously every 4 weeks for 8 weeks, while TM5614 was administered orally at a dose of 120 mg (0-4 weeks) and 180 mg once daily (5-8 weeks). The primary endpoint was the overall response rate after 8 weeks of concomitant use of TM5614. RESULTS: Thirty nine patients were enrolled, and 34 patients in the anti-PD-1 Abs-refractory cohort. The overall response rate at 8 weeks was 25.9% (95% CI: 12.9-44.9%; P = .027) in 27 anti-PD-1-Abs refractory patients by investigator assessment in the protocol per set cohort. Seven patients discontinued treatment due to progressive disease or adverse events. Treatment-related grade 3 or higher adverse events occurred in 3 of 39 patients (7.7%) in the intention-to-treat cohort. CONCLUSIONS: TM5614 in combination with nivolumab is well-tolerated and effective in anti-PD-1 Abs-refractory, unresectable melanoma. TRIAL REGISTRATION: This trial was registered with Clinical Trial gov, jRCT2021210029.

Patient-physician perception gaps in setting treatment goals and communication including shared decision making: Results from the survey illuminating dialogues and insights in onychomycosis management (IDIOM survey).

Onychomycosis, an infectious disease affecting the nails, can spread within oneself and to others, potentially leading to functional disabilities, therefore achieving a complete cure is necessary. Additionally, shared decision making (SDM) has been gaining attention in the treatment of various diseases in recent years. This study aimed to uncover the realities of patient-physician communication and perception in onychomycosis treatment, particularly in setting treatment goals and the SDM process for selecting therapeutic agents. We conducted a web-based survey of both patients and dermatologists to identify issues in the decision-making process for onychomycosis treatment. The survey revealed several communication challenges between patients and dermatologists regarding onychomycosis treatment. First, a notable percentage of dermatologists do not prioritize a complete cure for onychomycosis in their treatment goals. Second, the dermatologists' treatment explanations tended to emphasize risks, information necessary for appropriate decision-making was not adequately conveyed to patients, and SDM practice was insufficient (the mean scores of SDM-Q-9 and SDM-Q-Doc were 49.0 and 70.9, respectively). Third, dermatologists overestimated the reluctance of older patients to take oral medications. Dermatologists should recognize their patients' expectations for a complete cure for onychomycosis and choose a therapeutic agent that meets patients' needs. Furthermore, dermatologists should explain the benefits and risks of treatment options in a balanced manner, strive for improved patient-physician communication, and aim for a complete cure by administering suitable treatment.

Real-world experience of Doxorubicin Monotherapy for Advanced or Metastatic Retroperitoneal Sarcoma: A Single Institutional Study of 16 Cases.

BACKGROUND/AIM: Anthracycline-based chemotherapies including doxorubicin monotherapy are recommended in major guidelines for patients with advanced or metastatic retroperitoneal sarcoma (RPS); however, few studies have reported the outcomes of doxorubicin monotherapy for these patients. We herein investigated the oncological efficacy and safety of doxorubicin monotherapy for patients with advanced or metastatic RPS in real-world clinical practice. PATIENTS AND METHODS: Sixteen patients diagnosed with advanced or metastatic retroperitoneal sarcoma, receiving doxorubicin monotherapy as first-line treatment between February 2017 and March 2023 at our Institution were analyzed. Response rate, progression-free survival (PFS) periods, overall survival (OS) period, and adverse event (AE) profiles were retrospectively investigated. RESULTS: The median age of patients was 69.5 years. Best responses to doxorubicin were as follows: complete response, 0 patients (0.0%); partial response, 3 (18.8%); stable disease, 9 (56.3%); and progressive disease, 4 (25.0%). The objective response rate and disease control rate were 18.8 and 75.0%, respectively. During the observation period (median, 22 months, range=2-53 months), median PFS and OS periods were 8.0 and 24.0 months, respectively. The following AEs Grade ≥3 occurred: neutropenia in 14 patients (87.5%), febrile neutropenia in 5 (31.3%), leukopenia in 2 (12.5%), thrombocytopenia in 1 (6.3%), and heart failure in 1 (6.3%). Grade ≥3 nausea and vomiting did not occur and there was no treatment-related death. CONCLUSION: The oncological outcomes of doxorubicin monotherapy for RPS in real-world clinical practice were not inferior to those of the EORTC trial. The incidence of hematological AEs was higher; however, severe gastrointestinal AEs were prevented by prophylactic antiemetics and there were no treatment-related deaths. Collectively, doxorubicin monotherapy with appropriate prophylactic agents is a valid option for patients with advanced or metastatic RPS.

Patient and family burden in pediatric atopic dermatitis and its treatment pattern in Japan.

BACKGROUND: This study evaluated the level of burden in pediatric and adolescent atopic dermatitis (AD) patients in Japan, the associated burden on caregivers/families, and whether this burden varied with age. METHODS: Data were drawn from the Adelphi Pediatric AD Disease Specific Programme (DSP)™, a cross-sectional survey of physicians and their patients conducted in Japan between July and December 2022. Physicians reported patient demographics, clinical characteristics, disease burden, and current/previous therapies. Patients and/or caregivers reported perceived disease severity and impact of AD, including the Children's Dermatology Life Quality Index (CDLQI) and Dermatitis Family Impact questionnaire (DFI). RESULTS: Overall, 55 physicians provided data for 537 AD patients aged ≤17. Mean (SD) overall scores for CDLQI, POEM, and DFI were 9.3 (6.3), 8.3 (6.8), and 11.7 (7.2), respectively. Age was associated with higher patient and/or caregiver-reported CDLQI scores, which increased by 0.543 points per year of age (P = 0.01). Patients with severe disease reported a more significant impact on quality of life factors compared with mild patients (P < 0.001). Age was associated with higher caregiver-reported burden, with DFI scores increasing by 0.325 per year (P = 0.01). Physician-reported impact on caregivers showed that age was significantly associated with increased burden on sleep, daily activities, work, and mood (P < 0.05), with disease severity associated with impact across all factors (P < 0.01). CONCLUSIONS: Both increasing age and disease severity were associated with the increased impact of AD on patients and their caregivers. Disease control/modification through appropriate therapeutic intervention at a younger age may relieve the burden of pediatric AD on patients and their families.

Interplay of cytokines in the pathophysiology of atopic dermatitis: insights from Murin models and human.

The pathogenesis of atopic dermatitis (AD) is understood to be crucially influenced by three main factors: dysregulation of the immune response, barrier dysfunction, and pruritus. In the lesional skin of AD, various innate immune cells, including Th2 cells, type 2 innate lymphoid cells (ILC2s), and basophils, produce Th2 cytokines [interleukin (IL)-4, IL-5, IL-13, IL-31]. Alarmins such as TSLP, IL-25, and IL-33 are also produced by epidermal keratinocytes, amplifying type 2 inflammation. In the chronic phase, not only Th2 cells but also Th22 and Th17 cells increase in number, leading to suppression of filaggrin expression by IL-4, IL-13, and IL-22, which further deteriorates the epidermal barrier function. Dupilumab, which targets IL-4 and IL-13, has shown efficacy in treating moderate to severe AD. Nemolizumab, targeting IL-31RA, effectively reduces pruritus in AD patients. In addition, clinical trials with fezakinumab, targeting IL-22, have demonstrated promising results, particularly in severe AD cases. Conversely, in murine models of AD, several cytokines, initially regarded as promising therapeutic targets, have not demonstrated sufficient efficacy in clinical trials. IL-33 has been identified as a potent activator of immune cells, exacerbating AD in murine models and correlating with disease severity in human patients. However, treatments targeting IL-33 have not shown sufficient efficacy in clinical trials. Similarly, thymic stromal lymphopoietin (TSLP), integral to type 2 immune responses, induces dermatitis in animal models and is elevated in human AD, yet clinical treatments like tezepelumab exhibit limited efficacy. Therapies targeting IL-1α, IL-5, and IL-17 also failed to achieve sufficient efficacy in clinical trials. It has become clear that for treating AD, IL-4, IL-13, and IL-31 are relevant therapeutic targets during the acute phase, while IL-22 emerges as a target in more severe cases. This delineation underscores the necessity of considering distinct pathophysiological aspects and therapeutic targets in AD between mouse models and humans. Consequently, this review delineates the distinct roles of cytokines in the pathogenesis of AD, juxtaposing their significance in human AD from clinical trials against insights gleaned from AD mouse models. This approach will improve our understanding of interspecies variation and facilitate a deeper insight into the pathogenesis of AD in humans.

Assessment of Therapeutic Effects of Combined Treatment With Cisplatin and Anti-mouse Programmed Death (PD)-1 Antibody in a Mouse Urothelial Cancer Model.

BACKGROUND/AIM: The therapeutic impact of combination treatment with an immune checkpoint inhibitor (ICI) and chemotherapeutic agent on patients with urothelial cancer (UC) remains controversial. Therefore, the present study investigated differences in the therapeutic effects of combination therapy with cisplatin plus anti-mouse programmed death (PD)-1 antibody according to the dose of cisplatin using the mouse bladder tumor model MBT2. MATERIALS AND METHODS: The effects of treatment with two different doses cisplatin and/or anti-mouse PD-1 antibody on tumor growth after the subcutaneous injection of MBT2 cells were compared. Infiltrating patterns of lymphocytes into tumors after treatment were assessed using immunohistochemical staining. RESULTS: MBT2 tumor volumes were significantly larger in mice receiving high-dose cisplatin alone than in those receiving low-dose cisplatin alone. Combination treatment with cisplatin plus anti-mouse PD-1 antibody exerted significantly stronger growth inhibitory effects on MBT2 tumors than treatment with either agent alone, irrespective of cisplatin doses; however, no significant differences were observed in MBT2 tumor volumes between mice receiving anti-mouse PD-1 antibody plus high-dose cisplatin and those receiving anti-mouse PD-1 antibody plus low-dose cisplatin. Furthermore, CD8+ to CD3+ and CD8+ to CD11b+ T-lymphocyte ratios in MBT2 tumors were both significantly higher in the low-dose cisplatin alone group than in the high-dose cisplatin alone group, whereas no significant differences were noted in either ratio between the two different combination treatment regimens. CONCLUSION: When combined with ICI, a lower dose of cisplatin may achieve favorable antitumor effects in UC patients by preventing lymphocyte exhaustion.

Robot-assisted radical nephrectomy and inferior vena cava tumor thrombectomy using the novel surgical robot platform, hinotori: Initial experience with two cases.

Introduction: A newly developed surgical robot system, hinotori, with various unique advantages has been in clinical use in Japan; however, there have not been any studies of robot-assisted radical nephrectomy and inferior vena cava tumor thrombectomy using hinotori. Case presentation: We describe two male patients aged 67 and 76 years old with right renal cell carcinoma and a level II and I inferior vena cava tumor thrombus, respectively, undergoing robot-assisted radical nephrectomy and inferior vena cava tumor thrombectomy using hinotori. Both operations were successfully completed with a purely robotic procedure without any major perioperative complications, resulting in the following findings: time using robotic system, 158 and 156 min; total operative time, 228 and 214 min; estimated blood loss, 535 and 200 mL, respectively. Conclusion: Based on our first experience, robot-assisted radical nephrectomy and inferior vena cava tumor thrombectomy using hinotori may be an effective treatment for renal cell carcinoma with inferior vena cava tumor thrombus ≤level II.

Relationship Between Adverse Events and Progression-free Survival in Patients Receiving Cabozantinib for Previously Treated Metastatic Renal Cell Carcinoma.

BACKGROUND/AIM: Although the adverse events (AEs) of drugs, such as sunitinib and axitinib, have been shown to predict treatment responses, evidence to support cabozantinib-induced AEs as predictors of responses to treatment for metastatic renal cell carcinoma (mRCC) is limited. Therefore, we herein investigated the relationship between AE profiles and progression-free survival (PFS) in patients receiving cabozantinib for previously treated mRCC. PATIENTS AND METHODS: The present study retrospectively analyzed 40 patients receiving cabozantinib for previously treated mRCC between July 2020 and August 2022. PFS was estimated using the Kaplan-Meier method and the impact of several parameters, including cabozantinib-induced AEs, on PFS was investigated by a Cox proportional regression analysis. RESULTS: The median observation period was 15 (2-29) months, during which time 31 patients (77.5%) progressed, with median PFS of 11 months. Thirty-nine patients (97.5%) developed at least one AE. Liver toxicity occurred in 16 patients (40.0%) and hand-foot syndrome, hypertension, and diarrhea in 14 each (17.5%). Only hypertension correlated with longer PFS. A multivariate analysis identified hypertension as an independent prognostic factor for PFS (p=0.049). CONCLUSION: These results suggest the potential of treatment-induced hypertension as a significant predictor of prolonged PFS in patients receiving cabozantinib for mRCC.

Receipt survey of prescription continuation rates for patients with onychomycosis and web-based survey of dermatologists on prescribing policies for onychomycosis therapeutics.

Onychomycosis can be treated with topical and oral medications. However, it is important to appropriately select these medications according to the type and severity of the disease and ensure treatment is continued for the recommended duration. In Japan, treatment options for onychomycosis have increased in recent years. Moreover, in 2019, the guidelines for dermatomycosis treatment were revised. In this study, we conducted a receipt survey to clarify the actual treatment status of onychomycosis cases as indicated by the continuation rates of prescribed treatment drugs, together with a web-based survey to ascertain the prescribing policy of dermatologists regarding drugs for onychomycosis treatment. In agreement with past surveys, this receipt survey showed that the prescription continuation rate for oral medications was higher than that for topical medications. The 1-year prescription continuation rate for topical onychomycosis medications was found to be low (<10%). The web-based survey showed that the percentage of physicians who prescribed oral medications as their first choice increased by approximately 10% for each disease type, compared with the results of the previous survey conducted around 7 years ago. However, the study also confirmed that topical drugs are still prescribed for some disease types for which oral drugs are better suited. To ensure complete cure without patient drop-out, oral drugs with a high probability of achieving complete cure and a high continuation rate should be prescribed for patients with onychomycosis.

TRPV1-positive sensory nerves and neuropeptides are involved in epidermal barrier repair after tape stripping in mice.

BACKGROUND: The integumentary system of the skin serves as an exceptional protective barrier, with the stratum corneum situated at the forefront. This outermost layer is composed of keratinocytes that biosynthesize filaggrin (encoded by the gene Flg), a pivotal constituent in maintaining skin health. Nevertheless, the precise role of sensory nerves in restoration of the skin barrier after tape stripping-induced epidermal disruption, in contrast to the wound-healing process, remains a tantalizing enigma. OBJECTIVE: This study aimed to elucidate the cryptic role of sensory nerves in repair of the epidermal barrier following tape stripping-induced disruption. METHODS: Through the implementation of resiniferatoxin (RTX)-treated denervation mouse model, we investigated the kinetics of barrier repair after tape stripping and performed immunophenotyping and gene expression analysis in the skin or dorsal root ganglia (DRG) to identify potential neuropeptides. Furthermore, we assessed the functional impact of candidates on the recovery of murine keratinocytes and RTX-treated mice. RESULTS: Ablation of TRPV1-positive sensory nerve attenuated skin barrier recovery and sustained subcutaneous inflammation, coupled with elevated IL-6 level in ear homogenates after tape stripping. Expression of the keratinocyte differentiation marker Flg in the ear skin of RTX-treated mice was decreased compared with that in control mice. Through neuropeptide screening, we found that the downregulation of Flg by IL-6 was counteracted by somatostatin or octreotide (a chemically stable somatostatin analog). Furthermore, RTX-treated mice given octreotide exhibited a partial improvement in barrier recovery after tape stripping. CONCLUSION: Sensory neurons expressing TRPV1 play an indispensable role in restoring barrier function following epidermal injury. Our findings suggest the potential involvement of somatostatin in restoring epidermal repair after skin injury.

Robot-assisted radical nephrectomy using novel surgical robot platform, hinotori: Report of initial series of 13 cases.

OBJECTIVES: The aims of the present study were to describe the perioperative findings of the first series of patients undergoing robot-assisted radical nephrectomy (RARN) with a newly launched platform, the hinotori surgical robot system, and compare the findings with a similar set receiving RARN with the existing system, da Vinci. METHODS: This study included 34 patients, consisting of 13 and 21 undergoing RARN using the hinotori and da Vinci robotic systems, respectively. As a rule, RARN was performed via an intraperitoneal approach employing 3 robotic arms, irrespective of the robotic systems. RESULTS: In the hinotori group, the median age, body mass index and tumor diameter were 65 years, 23.3 kg/m2 and 50 mm, respectively. All surgical procedures with hinotori could be completed by a purely robotic approach. In the hinotori group, the median operative time, time using the robotic system, estimated blood loss and length of hospital stay were 157, 83 min, 11 mL and 6 days, respectively, and major perioperative complications did not occur. In this group, 3, 1 and 9 patients were pathologically diagnosed with pT1a, pT1b and pT3a tumors, respectively. No significant differences in baseline characteristics were noted between the hinotori and da Vinci groups, and there were also no significant differences in perioperative findings between them. CONCLUSIONS: Despite a case series with a small sample size, this is the first report evaluating RARN using the hinotori surgical robot system, which could be safely conducted and achieved perioperative outcomes similar to that using the da Vinci system.

Efficacy of salvage therapies for advanced acral melanoma after anti-PD-1 monotherapy failure: a multicenter retrospective study of 108 Japanese patients.

Background: Anti-programmed cell death protein 1 (PD-1) monotherapy is one of the standard systemic therapies for advanced melanoma; however, the efficacy of salvage systemic therapies after PD-1 monotherapy failure (PD-1 MF), particularly in acral melanoma (AM), the main clinical melanoma type in Japanese patients, is unclear. This study aimed to investigate the efficacy of salvage systemic therapies in Japanese patients with AM after PD-1 MF. Patients and methods: The study included 108 patients with advanced AM (palm and sole, 72; nail apparatus, 36) who underwent salvage systemic therapy at 24 Japanese institutions. We mainly assessed the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: Thirty-six (33%) patients received ipilimumab, 23 (21%) received nivolumab and ipilimumab (nivo/ipi), 10 (9%) received cytotoxic chemotherapy, 4 (4%) received BRAF and MEK inhibitors (BRAFi/MEKi), and the remaining 35 (32%) continued with PD-1 monotherapy after disease progression. The ORRs in the ipilimumab, nivo/ipi, cytotoxic chemotherapy, and BRAFi/MEKi groups were 8, 17, 0, and 100%, respectively. The nivo/ipi group showed the longest OS (median, 18.9 months); however, differences in ORR, PFS, and OS between the groups were insignificant. The OS in the nivo/ipi group was higher in the palm and sole groups than in the nail apparatus group (median: not reached vs. 8.7 months, p < 0.001). Cox multivariate analysis demonstrated that nail apparatus melanoma independently predicted unfavorable PFS and OS (p = 0.006 and 0.001). The total OS (from PD-1 monotherapy initiation to death/last follow-up) was insignificant between the groups. Conclusion: Nivo/ipi was not more effective than cytotoxic chemotherapy and ipilimumab after PD-1 MF in patients with advanced AM. The prognosis after PD-1 MF would be poorer for nail apparatus melanoma than for palm and sole melanoma.

Assessments of therapeutic effects according to timings for combined therapy with axitinib and immune check point inhibitor in a mouse renal cell carcinoma model.

Recently, several types of systemic therapy using tyrosine kinase inhibitor (TKI) and immune checkpoint inhibitor (ICI) have been performed for advanced renal cell carcinoma (aRCC) patients; however, the optimal strategy of sequential treatment with these agents has not been well established. The objective of this study was to determine the differences of therapeutic effects according to timing for the introduction of TKI and ICI using a mouse RCC, RenCa model. The effects of combined treatment of TKI and/or ICI with axitinib, anti-mouse programmed death (PD)-1, or PD-ligand 1 (PD-L1) antibody on tumor growth and survival after subcutaneous and intravenous injection of RenCa cells, respectively, were compared according to three different treatment schedules: simultaneous administration, initial axitinib administration, and initial ICI administration. Infiltrating patterns of lymphocytes into tumors after combined treatments were evaluated by immunohistochemical staining. In mice treated with anti-PD-1 and anti-PD-L1 antibodies, significantly marked inhibitory effects on subcutaneous growth of tumors were observed in the simultaneous and initial ICI treatment groups, but not the group with the initial axitinib administration, compared to controls without treatment. Survival intervals of mice after intravenous injection of RenCa cells were significantly longer in the simultaneous and initial ICI administration, but not the initial axitinib administration, compared to the control. Furthermore, both CD8+ to CD3+ and CD8+ to CD11b+ T-lymphocyte ratios in subcutaneous RenCa tumors were significantly higher in the simultaneous and initial ICI administration, but not the initial axitinib administration, compared to the control. Favorable control against aRCC progression may be achieved by administering TKI and ICI simultaneously or ICI followed by TKI.

Perioperative outcomes of robot-assisted partial nephrectomy using hinotori versus da Vinci surgical robot system: a propensity score-matched analysis.

The purpose of this study was to evaluate perioperative outcomes of robot-assisted partial nephrectomy (RAPN) using hinotori, a recently developed robot-assisted surgical platform, by comparing them with those using da Vinci. This study included 303 and 40 consecutive patients who underwent RAPN using da Vinci and hinotori, respectively. To adjust potential baseline parameters between da Vinci and hinotori groups, 1:2 propensity score-matching was performed, and perioperative outcomes in these two groups were comprehensively evaluated. Propensity score-matched analysis generated two groups, consisting of 74 and 37 patients undergoing RAPN using da Vinci and hinotori, respectively, and no significant differences in major baseline parameters were noted between the two groups. RAPN could be completed without conversion to nephrectomy or open surgery in all patients. There were no significant differences in major perioperative outcomes between da Vinci and hinotori groups, including the operative time, time using the robotic system and warm ischemia time. No patient in either group was diagnosed with a positive surgical margin or experienced perioperative complications, corresponding to Clavien-Dindo 3 ≤ . There were no significant differences in the achievements of trifecta and margin, ischemia and complications outcomes between the two groups, and changes in the estimated glomerular filtration rate 1 and 28 days after RAPN were also similar between them. In conclusion, these findings showed that the hinotori platform could facilitate similar perioperative outcomes in patients undergoing RAPN in comparison with the existing robotic system, da Vinci.

A CCR4 antagonist attenuates atopic dermatitis-like skin inflammation by inhibiting the recruitment and expansion of Th2 cells and Th17 cells.

CCR4 is a major trafficking receptor for T-helper (Th) 2 cells and Th17 cells and is considered as a potential therapeutic target for atopic dermatitis (AD). The CCR4 ligands CCL17 and CCL22 have been reported to be upregulated in the skin lesions of AD patients. Of note, thymic stromal lymphopoietin (TSLP), a master regulator of the Th2 immune response, promotes the expression of CCL17 and CCL22 in AD skin lesions. Here, we investigated the role of CCR4 in an AD mouse model induced by MC903, a TSLP inducer. Topical application of MC903 to ear skin increased the expression of not only TSLP but also CCL17, CCL22, the Th2 cytokine IL-4, and the Th17 cytokine IL-17A. Consistently, MC903 induced AD-like skin lesions as shown by increased epidermal thickness; increased infiltration of eosinophils, mast cells, type 2 innate lymphoid cells, Th2 cells, and Th17 cells; and elevated serum levels of total IgE. We also found increased expansion of Th2 cells and Th17 cells in the regional lymph nodes (LNs) of AD mice. Compound 22, a CCR4 inhibitor, ameliorated AD-like skin lesions with reduction of Th2 cells and Th17 cells in the skin lesions and regional LNs. We further confirmed that compound 22 diminished the expansion of Th2 cells and Th17 cells in the coculture of CD11c+ dendritic cells (DCs) and CD4+ T cells derived from the regional LNs of AD mice. Collectively, CCR4 antagonists may exhibit anti-allergic effects by inhibiting both the recruitment and expansion of Th2 cells and Th17 cells in AD.

Robot-assisted adrenalectomy using a hinotori surgical robot system: Report of first series of six cases.

AIM: The hinotori surgical robot system, a newly launched platform, has already been utilized in several urological robotic surgeries; however, limited information is available in terms of its feasibility and safety in each type of surgery. The objectives of this study were to describe the perioperative outcomes of the first series of six patients who underwent robot-assisted adrenalectomy (RAA) using hinotori, and compare the outcomes with a similar set of five patients undergoing RAA with the existing system, da Vinci. METHODS: This study included a total of 11 consecutive patients with adrenal tumors undergoing RAA between July 2020 and November 2022 at our institution. Comprehensive perioperative outcomes in these patients were retrospectively analyzed. RESULTS: Median age, body mass index (BMI), and tumor diameter in the hinotori group were 48 years, 27.5 kg/m2 , and 36 mm, respectively, and four patients were diagnosed with a functioning tumor, consisting of three and one with hypersecretion of cortisol and catecholamine, respectively. All procedures using hinotori were performed via the transperitoneal approach, and could be completed without conversion to open surgery. Median operative time, time using robotic system, the estimated blood loss, and length of hospital stay in this group were 119 min, 58 min, 8 mL, and 7 days, respectively, and no patient experienced major perioperative complications. There were no significant differences in clinical characteristics between the hinotori and da Vinci groups, and no significant differences in the perioperative outcomes were noted between these two groups. CONCLUSION: Despite being a small case series, this is the first study focusing on RAA using the hinotori surgical robot system, which could be efficaciously performed, resulting in the achievement of perioperative findings comparable with those of the da Vinci system.

Initial Experience of Robot-Assisted Partial Nephrectomy Using Hinotori Surgical Robot System: Single Institutional Prospective Assessment of Perioperative Outcomes in 30 Cases.

Introduction: Innovation of robotic surgery is still actively growing, and various novel robotic systems are in the process of development. The objective of this study was to assess the perioperative outcomes of robot-assisted partial nephrectomy (RAPN) using the hinotori surgical robot system, a recently developed robot-assisted surgical platform, for patients with small renal tumors. Methods: This study prospectively included a total of 30 consecutive patients who were found to have small renal tumors and subsequently underwent RAPN using hinotori between April and November 2022. Major perioperative outcomes in these 30 patients were comprehensively analyzed. Results: The median tumor size and R.E.N.A.L. nephrometry score in the 30 patients were 28 and 8 mm, respectively. Of these 30, 25 and 5 received RAPN by intra- and retroperitoneal approaches, respectively. RAPN could be completed in all 30 patients without conversion to nephrectomy or open surgery. The median operative time, time using hinotori, and warm ischemia time were 179, 106, and 13 minutes, respectively. No patient was found to have a positive surgical margin or experienced major perioperative complications, corresponding to Clavien-Dindo 3≤. Achievements of trifecta and margin, ischemia, and complications (MIC) outcomes in this series were 100% and 96.7%, respectively, and median changes in the estimated glomerular filtration rate 1 day and 1 month after RAPN were -20.9% and -11.7%, respectively. Conclusions: This is the first study focusing on RAPN using hinotori, which showed favorable perioperative outcomes, considering the findings of trifecta and MIC. Although it will be necessary to investigate the long-term effects of RAPN using hinotori on oncologic and functional outcomes, the present findings strongly suggest that the hinotori surgical robot system could be safely applied to RAPN for patients with small renal tumors.

Cutaneous manifestations of COVID-19 and COVID-19 vaccination.

In December 2019, a new infectious pathogen named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified in Wuhan, China. Transmitted through respiratory droplets, SARS-CoV-2 is the causative pathogen of coronavirus disease 2019 (COVID-19). Although this new COVID-19 infection is known to cause primarily interstitial pneumonia and respiratory failure, it is often associated with cutaneous manifestations as well. These manifestations with COVID-19 can be classified into seven categories: (i) chilblain-like skin eruption (e.g., COVID toes), (ii) urticaria-like skin eruption, (iii) maculopapular lesions, (iv) vesicular eruptions, (v) purpura, (vi) livedo reticularis and necrotic lesions, (vii) urticarial vasculitis, and others such as alopecia and herpes zoster. The pathogenesis of skin eruptions can be broadly divided into vasculitic and inflammatory skin eruptions. Various cutaneous adverse reactions have also been observed after COVID-19 mRNA vaccination. The major cutaneous adverse reactions are type I hypersensitivity (urticaria and anaphylaxis) and type IV hypersensitivity (COVID arm and erythema multiform). Autoimmune-mediated reactions including bullous pemphigus, vasculitis, vitiligo, and alopecia areata have also been reported. Several cases with chilblain-like lesions and herpes zoster after COVID-19 mRNA vaccination have been published. Various skin diseases associated with COVID-19 and COVID-19 vaccination have been reported, and the mechanism has been partly elucidated. In the process, for example, some papers have reported that it is not related to COVID-19 infection, although it was initially called COVID-toe and considered a COVID-19-associated cutaneous eruption. In fact, some COVID-19-associated skin reactions are indistinguishable from drug eruptions. In the future, the mechanisms of COVID-19- or COVID-19 vaccine-associated skin reactions need to be elucidated and verification of causal relationships is required.

Therapeutic effects of KCC2 chloride transporter activation on detrusor overactivity in mice with spinal cord injury.

This study aimed to clarify whether downregulation of K+-Cl- cotransporter 2 (KCC2) in the sacral parasympathetic nucleus (SPN) of the lumbosacral spinal cord, from which the efferent pathway innervating the bladder originates, causes cellular hyperexcitability and triggers detrusor overactivity (DO) in spinal cord injury (SCI). SCI was produced by Th8-9 spinal cord transection in female C57BL/6 mice. At 4 wk after SCI, CLP290, a KCC2 activator, was administered, and cystometry was performed. Thereafter, neuronal activity with c-fos staining and KCC2 expression in cholinergic preganglionic parasympathetic neurons in the SPN was examined using immunohistochemistry. Firing properties of neurons in the SPN region were evaluated by extracellular recordings in the spinal cord slice preparations. DO evident as nonvoiding contractions was significantly reduced by CLP290 treatment in SCI mice. The number of c-fos-positive cells and coexpression of c-fos in choline acetyltransferase-positive cells were decreased in the SPN region of the SCI CLP290-treated group versus the SCI vehicle-treated group. KCC2 immunoreactivity was present on the cell membrane of SPN neurons and normalized fluorescence intensity of KCC2 in choline acetyltransferase-positive SPN neurons was decreased in the SCI vehicle-treated group versus the spinal intact vehicle-treated group but recovered in the SCI CLP290-treated group. Extracellular recordings showed that CLP290 suppressed the high-frequency firing activity of SPN neurons in SCI mice. These results indicated that SCI-induced DO is associated with downregulation of KCC2 in preganglionic parasympathetic neurons and that activation of KCC2 transporters can reduce DO, increase KCC2 expression in preganglionic parasympathetic neurons, and decrease neuronal firing of SPN neurons in SCI mice.NEW & NOTEWORTHY This study is the first report to suggest that activation of the Cl- transporter K+-Cl- cotransporter 2 may be a therapeutic modality for the treatment of spinal cord injury-induced detrusor overactivity by targeting bladder efferent pathways.