Interleukin-23 inhibitors decrease Fibrosis-4 index in psoriasis patients with elevated Fibrosis-4 index but not inteleukin-17 inhibitors.

Recent studies indicate that hepatic diseases are associated with psoriasis. Non-invasive tests, including the Fibrosis-4 (FIB-4) index, which can confidently rule out the presence of advanced fibrosis, are currently receiving attention. However, data on the FIB-4 index in psoriasis patients and the effects of biologics on the FIB-4 index are limited. We investigated the relationships between the FIB-4 index and demographic or clinical characteristics as well as the effects of biologics on the FIB-4 index in psoriasis patients. Psoriasis patients aged 36-64 years, whose treatment was initiated with interleukin (IL)-17 inhibitors or IL-23 inhibitors for psoriasis from May 2015 to December 2022, were consecutively included. Data were collected retrospectively from the patients' charts. A total of 171 psoriasis patients were included in this study. Thirty-four, 43, 21, 32, and 41 psoriasis patients were treated with secukinumab, ixekizumab, brodalumab, guselkumab, or risankizumab, respectively. In biologics-naïve patients, a significant but weak positive correlation was observed between the FIB-4 index and age (r = 0.3246, p = 0.0018). There was no significant correlation between the FIB-4 index and other demographic or clinical characteristics. Regarding the effects of biologics on the FIB-4 index, no significant change was observed in psoriasis patients treated with any biologics. However, in psoriasis patients with a baseline FIB-4 index of >1.3, patients treated with guselkumab and those treated with either IL-23 inhibitor showed significantly decreased FIB-4 index scores 6 months after initiating the biologics (p = 0.0323, p = 0.0212). In contrast, no change was observed in FIB-4 index scores in patients treated with IL-17 inhibitors. In conclusion, our study revealed that the FIB-4 index was correlated with age in psoriasis patients. Furthermore, IL-23 inhibitors (but not IL-17 inhibitors) decreased the FIB-4 index score at 6 months in psoriasis patients with elevated FIB-4 index scores at baseline. Further studies are needed to clarify whether IL-23 inhibitors improve liver fibrosis physiologically and functionally.

308-nm excimer light is effective for palmoplantar pustulosis regardless of the presence or absence of focal infection: Single-center real-world experience of treatment for palmoplantar pustulosis.

Palmoplantar pustulosis (PPP) is relatively rare and recognition of PPP is different in different countries. Therefore, real-world data are limited. Local phototherapy for the palms and the soles is commonly used to treat PPP due to tolerable safety. However, data on the effectiveness of 308-nm excimer light are limited. In our study, we retrospectively investigated the effectiveness of treatments for PPP, especially phototherapy (308-nm excimer light), in our department. In addition, we examined whether smoking status and focal infection affected responsiveness to treatment of PPP. Patients who were diagnosed with PPP by board-certified dermatologists and visited our hospital from April 2015 to August 2018 were analyzed in this study. We collected data on PPP area severity index (PPPASI) before treatment. We also collected data on PPPASI in May to August 2018 as "after treatment" from all patients. Patients who received any treatment for less than 3 months were excluded. Nineteen patients (16 women and three men) were analyzed in this study. In patients treated with phototherapy (n = 12), PPPASI significantly decreased from a mean ± SD of 16.5 ± 10.3 to 4.5 ± 3.6 (p = 0.004), whereas it did not in patients treated without phototherapy (n = 7). Patients who quit smoking showed a significant decrease in PPPASI after treatment (16.8 ± 12.7 to 2.4 ± 2.9, p = 0.008). Regarding focal infection, in patients treated without phototherapy, the reduction rate of PPPASI was significantly lower in patients with focal infection than in those without focal infection (17.7 ± 21.5%, 71.1 ± 19.3%, p = 0.035), indicating that focal infection is associated with intractability. Meanwhile, in patients treated with phototherapy, PPPASI decreased regardless of the presence or absence of focal infection. In conclusion, our study demonstrated the effectiveness of local phototherapy consisting of 308-nm excimer light, regardless of focal infection. Patients who quit smoking were responsive to any treatment, indicating the importance of smoking cessation.

Brain metastasis in a patient with BRCA2-mutated treatment-related neuroendocrine prostate carcinoma and long-term response to radiotherapy and Olaparib: A case report and literature review.

BACKGROUND: A new subtype of prostate cancer called treatment-related neuroendocrine prostate carcinoma (t-NEPC) was added to the revised World Health Organization classification of prostate cancer in 2022. t-NEPC cases are increasing, and there is no established standard treatment. METHODS: A 49-year-old male patient was referred to our department for dysuria. A rectal examination and a prostate biopsy revealed stony hardness and prostate adenocarcinoma, respectively. Imaging studies confirmed the presence of multiple bone and lymph node metastases. The patient was started on upfront treatment with androgen deprivation therapy and an androgen receptor signaling inhibitor, which resulted in a significant (>90%) decrease in prostate-specific antigen (PSA) levels. The patient experienced postrenal failure 6 months later, attributable to local disease progression. Concurrently, there was an elevation in neuron-specific enolase (NSE) levels and an enlargement of pelvic lymph node metastases, without PSA progression. RESULTS: Biopsy specimen for cancer genome profiling revealed deletion of BRCA 2 and PTEN, AR amplification, and the presence of the TMPRSS2-ERG fusion gene. Based on increased NSE and BRCA2 mutations, a diagnosis of t-NEPC with BRCA2 mutation was eventually made. The patient received docetaxel chemotherapy and pelvic radiotherapy. Subsequently, he was treated with olaparib. His NSE levels decreased, and he achieved a complete response (CR). However, 18 months following the olaparib administration, brain metastases appeared despite the absence of pelvic tumor relapse, and the patient's PSA levels remained low. Consequently, the patient underwent resection of the brain metastases using gamma knife and whole-brain radiotherapy but died approximately 3 months later. CONCLUSION SUBSECTIONS: Platinum-based chemotherapy is often administered for the treatment of t-NEPC, but there are few reports on the effectiveness of olaparib in patients with BRCA2 mutations. In a literature review, this case demonstrated the longest duration of effectiveness with olaparib alone without platinum-based chemotherapy. Additionally, the occurrence of relatively rare, fatal brain metastases in prostate cancer after a long period of CR suggests the necessity of regular brain imaging examinations.

Structural Assignment of the Product Ion Generated from a Natural Ciguatoxin-3C Congener, 51-Hydroxyciguatoxin-3C, and Discovery of Distinguishable Signals in Congeners Bearing the 51-Hydroxy Group.

Ciguatoxins (CTXs) stand as the primary toxins causing ciguatera fish poisoning (CFP) and are essential compounds distinguished by their characteristic polycyclic ether structure. In a previous report, we identified the structures of product ions generated via homolytic fragmentation by assuming three charge sites in the mass spectrometry (MS)/MS spectrum of ciguatoxin-3C (CTX3C) using LC-MS. This study aims to elucidate the homolytic fragmentation of a ciguatoxin-3C congener. We assigned detailed structures of the product ions in the MS/MS spectrum of a naturally occurring ciguatoxin-3C congener, 51-hydroxyciguatoxin-3C (51-hydoxyCTX3C), employing liquid chromatography/quadrupole time-of-flight mass spectrometry with an atmospheric pressure chemical ionization (APCI) source. The introduction of a hydroxy substituent on C51 induced different fragmentation pathways, including a novel cleavage mechanism of the M ring involving the elimination of 51-OH and the formation of enol ether. Consequently, new cleavage patterns generated product ions at m/z 979 (C55H79O15), 439 (C24H39O7), 149 (C10H13O), 135 (C9H11O), and 115 (C6H11O2). Additionally, characteristic product ions were observed at m/z 509 (C28H45O8), 491 (C28H43O7), 481 (C26H41O8), 463 (C26H39O7), 439 (C24H39O7), 421 (C24H37O6), 171 (C9H15O3), 153 (C9H13O2), 141 (C8H13O2), and 123 (C8H11O).

Impact of 1-year treatment with dupilumab on work productivity in Japanese patients with atopic dermatitis.

Atopic dermatitis (AD) places a burden on work productivity. Recently, dupilumab was approved for AD, but its impact on work productivity in Japanese patients has not been reported. Furthermore, data on the effect of long-term treatment with dupilumab on work productivity are limited. We investigated the work productivity and activity in Japanese patients with moderate-to-severe AD, utilizing the Japanese version of the Work Productivity and Activity Impairment (WPAI-AD-Japan) questionnaire. Furthermore, we examined the impact of dupilumab on work productivity. Adult moderate-to-severe AD patients treated with dupilumab for more than 12 months from March 2020 to June 2022 who filled out the WPAI-AD-Japan questionnaire were included. Twenty-eight adult AD patients were analysed. Absenteeism was low (mean: 5.3%), but presenteeism, work productivity loss and activity impairment were high (36.8%, 39.7%, 48.9%, respectively). Significant positive correlations were observed between work productivity loss and visual analogue scale (VAS) score of pruritus and between activity impairment and dermatology life quality index (DLQI). Dupilumab treatment significantly reduced presenteeism, work productivity loss and activity impairment at both 6 and 12 months. The extent of their amelioration was numerically higher at 12 months than at 6 months. The reduction rates in presenteeism, work productivity loss and activity impairment were positively correlated with the reduction rates in DLQI and VAS score of pruritus at 12 months. Dupilumab improved work productivity in Japanese AD patients. Long-term remission of pruritus and improved quality of life are important for comprehensive improvement of work productivity.

Assignment of product ions produced from ciguatoxin-3C provides a deep insight into the fragmentation mechanism of polycyclic ether compounds.

RATIONALE: Marine polycyclic ethers have drawn attention owing to their unique chemical structures and involvement in food poisoning and fish killing. To study structural diversity, we performed a structural assignment of product ions produced from a representative ladder-shaped polycyclic ether, ciguatoxin-3C, and elucidated the mechanism of generation. METHODS: The product ions used for the structural assignment were produced from a precursor ion [M + H]+ using liquid chromatography/quadrupole time-of-flight mass spectrometry, by employing an atmospheric pressure chemical ionization source. RESULTS: Three charged sites were considered at both terminals of a molecule. Typical charge-remote fragmentation was produced at the respective charge sites, yielding a hybrid spectrum. C-C bonds bordering two ethers could cleave and trigger the fission of two other bonds. Prominent ions indicating the serial loss of water molecules resulted from the simultaneous deprivation of ethereal oxygen and hydrogen atoms. The resultant double bonds formed long chains of conjugated polyenes, which stabilized charge via resonance. CONCLUSIONS: Three alternative charge sites produce a hybrid spectrum. The simultaneous fission of three bonds was explained. For the first time, intense ions due to serial dehydration were explained by the elimination of ether oxygen atoms and the subsequent conjugation of double bonds. All product ions were considered by the structural features of polycyclic ether that facilitates the formation of conjugated polyenes.

Expression of interleukin-36 receptor antagonist in a patient with generalized pustular psoriasis harboring the p.Pro82Leu variant in the IL36RN gene.

It has recently been revealed that mutation of the IL36RN gene contributes to the development of generalized pustular psoriasis (GPP). The IL36RN gene encodes interleukin (IL)-36 receptor antagonist (IL-36Ra), which has antagonistic roles against IL-36α, -36ß, and -36γ. Previously, sanger sequencing performed in 62 Chinese GPP patients to identify IL36RN mutations revealed a new variant, c.245C>T (p.Pro82Leu), in a single heterozygous state in a patient with adult-onset GPP with psoriasis vulgaris. Since this p.Pro82Leu variant was not found in the psoriasis vulgaris or control groups in their study, they speculated that this variant might lead to exacerbated inflammatory responses. Meanwhile, Sorting Intolerant From Tolerant and PolyPhen-2, pathogenicity prediction tools, predict this variant as tolerated and benign. To date, its pathogenicity is unknown. We experienced a patient with GPP harboring the p.Pro82Leu variant, and investigated mRNA and protein expressions of IL-36Ra. Polymerase chain reaction conducted on hair follicle samples obtained from the scalp of the patient with GPP harboring the p.Pro82Leu using primers to detect mRNA of exons 2 and 5 in IL36RN demonstrated mRNA expression of IL36RN. Immunohistochemical staining revealed IL-36Ra expression in the keratinocytes of the patient with GPP harboring the p.Pro82Leu as in those of a GPP patient without the mutation (positive control). Furthermore, quantitative analysis of the immunofluorescent staining by ImageJ revealed that the expression level of IL-36Ra in the keratinocytes of the patient with GPP harboring p.Pro82Leu was higher than that in the healthy control and not lower than that in the GPP patients without the mutation. Our results indicate no aberrant splicing in this variant. In addition, according to the 1000 Genomes Project, this variant could be a founder mutation. Considering these factors together, this variant is unlikely to be associated with the development of GPP.

Real-world retrospective review of monotherapy following platinum-based chemotherapy for metastatic urothelial cancer.

OBJECTIVE: To compare estimated survival times of patients who had received maintenance monotherapy with gemcitabine (GEM), or an immuno-oncology (IO) drug (i.e., pembrolizumab or avelumab) or both therapies (one after the other) following platinum-based combination chemotherapy for metastatic urothelial carcinoma (UC) in a real-world setting. METHODS: For this retrospective study, we included consecutive patients with metastatic UC who had received first-line platinum-based chemotherapy followed by second-line treatment at our centre from March 2008 to June 2020. RESULTS: Of the 74 patients identified, 58 had received monotherapy as second line treatment, and 16 had received combination chemotherapy (i.e., non-monotherapy). The estimated median duration of survival was significantly longer in the monotherapy group compared with the non-monotherapy group (29 vs 7 months). Multivariate analysis showed that the outcome of the first-line chemotherapy treatment was the most important prognostic factor for survival. There was no significant difference in survival times between monotherapy with GEM or IO drugs. In addition, survival was significantly prolonged when GEM therapy was administered following IO drugs compared with GEM therapy alone. CONCLUSION: Monotherapy following primary chemotherapy for advanced UC significantly prolonged survival times, and IO drug therapy remained effective when followed by GEM single agent maintenance therapy.

Clinical characteristics of patients with metastatic castration-resistant prostate cancer after treatment with combined androgen blockade.

BACKGROUND: Although the second-generation androgen receptor inhibitors and taxanes have recently been recommended for the initial treatment of metastatic prostate cancer, bicalutamide and flutamide are still used in a large number of cases. Therefore, it is important to elucidate the clinical characteristics of these treated CRPC cases and their sensitivity to the currently used therapeutic agents. We aimed to examine the outcomes of metastatic castration-resistant prostate cancer following combined androgen blockade as initial therapy at our institution. METHODS: Ninety-four patients who developed metastatic castration-resistant prostate cancer after hormonal treatment with combined nonsteroidal androgen receptor antagonists and continuous androgen deprivation therapy between January 2015 and December 2020 were included. The presence of visceral metastases, duration of efficacy of each treatment, and overall survival after castration-resistant prostate cancer were evaluated. RESULTS: Patients with a longer duration of castration-resistant prostate cancer tended to have a longer response duration to subsequent enzalutamide administration (p = 0.003). Patients who achieved a 90% reduction in prostate-specific antigen levels with enzalutamide had a significantly better castration-resistant prostate cancer prognosis (p = 0.002). Meanwhile, those with visceral metastases at the time of castration-resistant prostate cancer diagnosis had a significantly poorer prognosis (p < 0.001). A positive correlation was observed between the treatment efficacy of abiraterone and taxanes for castration-resistant prostate cancer. CONCLUSION: The study provides scientific evidence to support that patients with longer time to castration-resistant prostate cancer are more sensitive to enzalutamide, and the use of abiraterone between docetaxel and cabazitaxel has favorable prognostic impact. These findings provide instrumental evidence that can enable better treatment selection for prostate cancer patients.

Serum levels of angiogenesis-related factors in patients with psoriasis.

Psoriasis is characterized by increased dermal vascularity, indicating that aberrant angiogenesis is associated with the pathogenesis of psoriasis. Data on angiogenesis-related factors in psoriasis patients are limited. We explored serum levels of angiogenesis-related factors in patients with psoriasis, and investigated their association with clinical severity and laboratory data. Psoriasis patients visiting our hospital from April 2013 to April 2018 and healthy controls were included in this study. Serum levels of angiopoietin-1, fibroblast growth factor (FGF)-basic, epidermal growth factor (EGF), platelet endothelial cell adhesion molecule (PECAM)-1, placental growth factor, and vascular endothelial growth factor (VEGF) were measured by LEGENDplex. Serum samples obtained from 10 healthy controls, 18 patients with psoriasis vulgaris (PsV), 24 patients with psoriatic arthritis (PsA), and 13 patients with generalized pustular psoriasis (GPP) were analyzed. The serum angiopoietin-1 level was elevated in the PsV, PsA, and GPP patients. GPP patients had a higher serum VEGF level than healthy controls. In contrast, serum levels of EGF and PECAM-1 were lower in the PsV, PsA, and GPP patients than in healthy controls. The serum FGF-basic level was lower in the PsA and GPP patients than in healthy controls. Serum levels of FGF-basic in PsA and GPP patients, PECAM-1 in PsA patients, and VEGF in GPP patients became closer to the respective levels in healthy controls after systemic therapy. The serum FGF-basic level was positively correlated with the psoriasis area and severity index and the number of circulating eosinophils in GPP patients. The serum VEGF level was correlated positively with the serum C-reactive protein (CRP) level and erythrocyte sedimentation rate, and negatively with the serum albumin level in GPP patients. In conclusion, our exploratory study revealed that psoriasis affects serum levels of certain angiogenesis-related factors. Some of these factors could be biomarkers of treatment outcomes, clinical severity, and systemic inflammation.

Impact of the COVID-19 pandemic on biologic treatment in psoriasis patients: A single-center retrospective study in Japan.

The impact of the COVID-19 pandemic on biologic treatment for psoriasis in Japan remains to be elucidated. This study aimed to investigate changes in biologic treatment and patients' behavior of visiting our department, especially in psoriasis patients treated with biologics before and during the pandemic. Data were collected from medical records retrospectively. The numbers of new psoriasis patients before (2019) and during (2020) the pandemic were compared. Patients' behavior of visiting our department was evaluated. The number of new psoriasis patients who visited our department in 2020 decreased by 35.7% compared with that in 2019. The reduction rate of new patients with psoriasis vulgaris was 49.3%, whereas the numbers of new patients with psoriatic arthritis (PsA) and generalized pustular psoriasis (GPP) were almost the same in 2019 and 2020. The number of patients who newly initiated biologics did not decrease in 2020 compared with that in 2019. As of January 1, 2020, 215 psoriasis patients were treated with biologics. Six patients (2.8%) discontinued biologics treatment possibly due to COVID-19 in 2020. Among 212 patients with good adherence to visiting our department in the previous year, 24 patients (11.3%) refrained from their visits for at least 1 month. In most cases, refrainment was observed in April and May when the first state of emergency was in effect in Japan. In conclusion, the COVID-19 pandemic hindered patients from visiting our department. However, its impact on patients who needed intensive care, such as patients with PsA and GPP, and psoriasis patients treated with biologics, was limited.

Apremilast downregulates interleukin-17 production and induces splenic regulatory B cells and regulatory T cells in imiquimod-induced psoriasiform dermatitis.

BACKGROUND: Apremilast, a selective inhibitor of the enzyme phosphodiesterase 4, is efficacious for psoriasis. However, detailed in vivo effects of apremilast on psoriasis remain to be elucidated. OBJECTIVE: To examine the in vivo effects of apremilast on psoriasis. METHODS: Psoriasiform dermatitis was induced by applying imiquimod (IMQ) on the murine shaved back skin for six days. Mice were treated with apremilast or vehicle intraperitoneally daily. RESULTS: Apremilast alleviated IMQ-induced psoriasiform dermatitis clinically and pathologically on days 3-6 by reducing infiltration of antigen-presenting cells and interleukin (IL)-17A-positive cells and increasing infiltration of Foxp3-postive cells into the skin on day 6, although a significant increase in IL-10 mRNA level was not observed on day 2. In addition, mRNA expression of IL-17A, IL-17F, and IL-22 was lower in the skin of IMQ-applied mice treated with apremilast than in those without apremilast on day 2, and apremilast inhibited infiltration of IL-17A-producing γδ T cells into the dermis on day 6. Furthermore, apremilast induced regulatory T cells and regulatory B cells in the spleen but not in the draining lymph nodes. CONCLUSION: Apremilast downregulated IL-17 production and induced splenic regulatory B cells and regulatory T cells in an IMQ-induced psoriasiform dermatitis mouse model.