Vitamin D deficiency in children with severe disabilities under limited ultraviolet exposure.

INTRODUCTION: Nutritional prevention of osteoporosis management is an important issue for children with severe disabilities. Due to the coronavirus disease 2019 (COVID-19) pandemic that started in 2020, children admitted to institutions had fewer opportunities for ultraviolet (UV) exposure owing to restrictions on attending school and going out. Hence, the vitamin D (VD) status of these children has been a cause of concern. This study aimed to assess the correlation between VD intake and VD status among children with severe disabilities who had limited UV exposure. MATERIALS AND METHODS: This research included patients admitted to Iwate Prefectural Rehabilitation and Nursery Center for Disabled Children. Serum 25-hydroxyvitamin D [25(OH)D] levels were assessed during school/outing restriction periods and after restriction removal and the introduction of sunbathing periods. The trends in 25(OH)D levels and oral VD intake before the two measurements were analyzed. RESULTS: Although 17 of 32 patients had VD intake above the recommended level of Dietary Reference Intakes for Japanese during the first measurement, 31 patients had VD deficiency. The 25(OH)D levels of 13 patients without UV exposure before the first evaluation and those with UV exposure before the second evaluation were 2.03 times higher, despite of constant VD intakes. In contrast, there were no remarkable changes in both VD intakes and 25(OH)D levels in five patients without UV exposure before both assessments. CONCLUSION: Japanese children with severe disabilities who consume the recommended oral VD intake but who have limited UV exposure can still present VD deficiency.

Vitamin D Supplementation at a Dose of 10 µg/Day in Institutionalized Children with Severe Motor and Intellectual Disabilities.

Vitamin D (VD) deficiency can lead to health-related consequences. This study determined the effects of VD administration in VD-deficient children with severe motor and intellectual disabilities (SMID). Twenty-eight subjects were included. Among them, 25 subjects with parental consent for VD administration were given 10 µg/day (400 IU/day) of VD in April 2021. Serum 25-hydroxyvitamin D [25(OH)D] levels were measured at least 30 days after the start of VD administration. The total VD intake, serum 25(OH)D levels, and ultraviolet (UV) exposure before the blood tests were investigated. The results showed that the median serum 25(OH)D levels were 8.7 ng/mL (4.3-17.2) and 24.0 ng/mL (7.8-39 ng/mL) from March to May in 2020 and 2021, respectively. Among the 25 subjects, 22 with UV exposure had >20 ng/mL serum 25(OH)D level, and 2 without UV exposure had <20 ng/mL serum 25(OH)D level. Three subjects who did not receive VD supplementation had <20 ng/mL serum 25(OH)D level. Taken together, VD supplementation (10 µg/day) is effective in children with SMID in institutional care. Moreover, it may be sufficient for children with UV exposure, but not for those without.

Case series of modified dermis graft for skin defects of the nasal region.

Local skin flap from the surrounding area is often chosen for reconstruction of skin defects in the nasal region, but it is problematic because it creates new facial scar and requires skill of design. On the other hand, full-thickness skin graft is associated with problems such as color mismatch and scar contracture at the recipient site. We reconstructed nasal defects of seven patients using modified dermis graft technique. In this method, de-epithelialized full-thickness skin graft is transplanted and then epithelialized from the surrounding area. This is a simple and easy procedure without causing a new scar on the face and is aesthetically and functionally superior to a standard full-thickness skin graft; therefore, it is a useful method of reconstruction of the nasal area.

Quantitative evaluation of posture control in rats with inferior olive lesions.

Impairment of inferior olivary neurons (IONs) affects whole-body movements and results in abnormal gait and posture. Because IONs are activated by unpredicted motion rather than regular body movements, the postural dysfunction caused by ION lesions is expected to involve factors other than simple loss of feedback control. In this study, we measured the postural movements of rats with pharmacological ION lesions (IO rats) trained to stand on their hindlimbs. The coordination of body segments as well as the distribution and frequency characteristics of center of mass (COM) motion were analyzed. We determined that the lesion altered the peak properties of the power spectrum density of the COM, whereas changes in coordination and COM distribution were minor. To investigate how the observed properties reflected changes in the control system, we constructed a mathematical model of the standing rats and quantitatively identified the control system. We found an increase in linear proportional control and a decrease in differential and nonlinear control in IO rats compared with intact rats. The dystonia-like changes in body stiffness explain the nature of the linear proportional and differential control, and a disorder in the internal model is one possible cause of the decrease in nonlinear control.

Possible Roles of Proinflammatory Signaling in Keratinocytes Through Aryl Hydrocarbon Receptor Ligands for the Development of Squamous Cell Carcinoma.

Aryl hydrocarbon receptor (AhR) provides a deeper insight into the pathogenesis of cutaneous squamous cell carcinoma (cSCC). AhR ligands, such as 6-formylindolo[3,2-b] carbazole (FICZ), and 7,12-Dimethylbenz[a]anthracene (DMBA), constitute major substrates for the cytochrome P450 (CYP) family, and influence the expression of various cytokine genes, including IL-17 and IL-23-related genes via the AhR. On the other hand, proinflammatory cytokines could drive tumor progression through the TRAF-ERK5 signaling pathway in cSCC. From the above findings, we hypothesized that AhR ligands might enhance the mRNA expression of proinflammatory cytokines via the AhR, leading to the development of cSCC. The purpose of this study was to investigate (1) the immunomodulatory effects of FICZ and DMBA on normal human keratinocytes (NHKCs), focusing on IL-17, and related cytokines/chemokines (IL-23, IL-36γ, and CCL20), (2) the expression of these factors in AhR-dependent pathways using a two-stage chemically induced skin carcinogenesis mouse model, and (3) the expression of these factors in lesion-affected skin in cSCC. Both FICZ and DMBA augmented the expression of CYP1A1, p19, CCL20, and IL-36γ mRNA in NHKCs in vitro. Moreover, the mRNA expression of these proinflammatory factors, as well as IL-17, in mouse cSCC is significantly decreased in the AhR-(fl/fl) Krt5-(Cre) mice compared to wild type mice, leading to a decrease in the number of developed cSCC lesions. Furthermore, CCL20, IL-23, as well as IL-17, are detected in the lesion-affected skin of cSCC patients. Our study demonstrates a possible mechanism for the development of cSCC involving AhR-mediated signaling by epidermal keratinocytes and recruitment of Th17 cells.

Increased serum CCL26 level is a potential biomarker for the effectiveness of anti-PD1 antibodies in patients with advanced melanoma.

Nivolumab plus ipilimumab combined therapy is among the most effective therapies for advanced melanoma. However, this therapy is also associated with a high frequency of immune-related adverse events (irAEs). To avoid such severe irAEs caused by additional administration of anti-CTLA4 antibodies, biomarkers to distinguish responders from non-responders among patients treated with anti-PD1 antibodies are important. The purpose of this study is to evaluate the increased serum levels of CCL11, CCL24, and CCL26 as a predictive biomarker for the efficacy of anti-PD1 antibodies in advanced cutaneous melanoma patients. This study analyzed increased serum levels of CCL11, CCL24, and CCL26 in 46 cases of advanced cutaneous melanoma treated with anti-PD1 antibodies. Serum levels on day 42 were compared to baseline (day 0) and analyzed statistically. Receiver operating characteristic curves were established to evaluate the correlation between serum levels of CCL11, CCL24, and CCL26 and efficacy of anti-PD1 antibodies. Increased serum levels of CCL26 correlated significantly with the efficacy of anti-PD1 antibodies. In contrast, no significant correlations were seen between increased serum levels of CCL11 and CCL24 and efficacy of anti-PD1 antibodies. Increased serum levels of CCL26 may be a useful biomarker for identifying those patients with advanced cutaneous melanoma most likely to benefit from anti-melanoma immunotherapy.

Successful treatment of mogamulizumab-resistant mycosis fungoides with mogamulizumab plus etoposide combined therapy: Investigation of the immunomodulatory effects of etoposide on the tumor microenvironment.

Mogamulizumab shows cytotoxicity against CCR4+ lymphoma cells by antibody-dependent cell-mediated cytotoxicity (ADCC) in advanced cutaneous T-cell lymphoma (CTCL) patients. Although mogamulizumab is used as one of the anchor drugs for the treatment of advanced CTCL, its efficacy is unsatisfactory, especially in mycosis fungoides (MF). Therefore, additional drugs to enhance the antitumor effects of mogamulizumab are needed to further optimize its use for the treatment of MF. In this report, two cases of mogamulizumab-resistant MF successfully treated with additional administration of etoposide are presented. Moreover, the possible mechanisms of mogamulizumab-etoposide combined therapy for the treatment of MF were investigated based on the modulation of chemokine profiles in vivo using an EL-4 mouse T-cell lymphoma model. Intraperitoneal administration of etoposide significantly increased the mRNA expressions of CCL17, CXCL5, and CXCL10, suggesting that CCR4+ CTCL cells gather around the tumor-associated macrophagess. Furthermore, the immunomodulatory effects of etoposide on the mRNA expressions of these chemokines were validated using monocyte-derived M2 macrophages in vitro. Since mogamulizumab shows cytotoxicity against CCR4+ lymphoma cells by ADCC that depends on the contact between the lymphoma cells and the effector cells, these chemokines could enhance the therapeutic effect of mogamulizumab.

Severe pyrexia from nivolumab-resistant advanced melanoma after successful combined therapy with encorafenib plus binimetinib.

Various serious adverse events (AE) have been reported to occur at a high rate in patients treated with BRAF plus mitogen-activated protein kinase kinase (MEK) inhibitor combination therapy, but their subtypes differ among the BRAF/MEK inhibitors. Pyrexia or a spike of fever are well-known AE of BRAF inhibitors, with or without MEK inhibitors, and have been reported to have a high incidence after dabrafenib/trametinib, but not after encorafenib/binimetinib. In this report, we describe three cases of severe pyrexia in nivolumab-resistant advanced melanoma after successful combined therapy with encorafenib plus binimetinib. Interestingly, in all cases, the serum levels of soluble CD163 C-X-C motif chemokine (CXCL)9, CXCL10 and CXCL11, which are known biomarkers for adult-onset Still's disease (AOSD), increased in parallel with the development of pyrexia. Our present cases suggest that pyrexia caused by BRAF/MEK inhibitors may possess a similar pathophysiology as that of AOSD.

Successful Treatment of a Patient with anti-PD1 Antibody-Resistant Advanced Mucosal Melanoma with Nivolumab, Ipilimumab plus Denosumab Combination Therapy.

Since the incidence of mucosal melanoma is higher in the Japanese population compared to Caucasians, and since mucosal melanoma possesses a lower mutation burden compared to cutaneous melanoma, the efficacy of anti-PD1 antibody (Ab) monotherapy for mucosal melanoma is limited. Therefore, other targeting molecules that enhance the anti-tumor effects of immune checkpoint inhibitors are needed. In this report, we present a case with anti-PD1 Ab-resistant recurrent malignant melanoma of the nasal cavity successfully treated with nivolu-mab, ipilimumab plus denosumab combination therapy.

Case series of cutaneous T-cell lymphomas treated with bexarotene-based therapy.

Bexarotene is useful for both early and advanced cutaneous T-cell lymphoma (CTCL), and is sometimes applied to ultraviolet-tolerant early CTCL patients as one of the first-line therapies in the real world. However, continuous administration of bexarotene is sometimes difficult because of its adverse events (AE). Development of an appropriate protocol for bexarotene that can induce a consistent response for CTCL without severe AE (SAE) is needed. We retrospectively investigated 29 Japanese cases of CTCL and evaluated the efficacy of treatment and incident ratios of all AE and SAE. Objective response rate (ORR) for the overall cohort was 65.5%. ORR of the 300 mg/m2 cohort (conventional dose) was 76.2%, while that of the 150-300 mg/body (low dose) with narrowband ultraviolet B light (NBUVB) cohort was 37.5%. Mean event-free survival was 10.0 months for all patients, 6.7 months for the bexarotene conventional-dose cohort and 19.1 months for the low-dose with NBUVB cohort. The incident ratio of total SAE for all patients was 20.7%. The incident ratio of total SAE was 23.8% for the conventional-dose cohort and 12.5% for the low-dose with NBUVB cohort. Our present study suggests that low-dose bexarotene plus NBUVB therapy is well-tolerated and could be one of the optimal therapies for advanced CTCL.

Bexarotene Reduces Production of CCL22 From Tumor-Associated Macrophages in Cutaneous T-Cell Lymphoma.

Bexarotene is a third-generation retinoid X receptor-selective retinoid that has been approved for use in the treatment of both early and advanced cutaneous T-cell lymphoma (CTCL). Although bexarotene has been used for decades in the treatment of CTCL, little is known about the mechanisms underlying its anti-tumor effects in CTCL patients. This study therefore focused on the immunomodulatory effects of bexarotene in vivo using an EL4 mouse T-cell lymphoma model, followed by investigation in CTCL patients treated with bexarotene. Intraperitoneal injection of bexarotene significantly decreased expressions of CCL22, CXCL5, CXCL10, and p19 in the tumor microenvironment. Based on those results, we then evaluated serum levels of CCL22, CXCL5, and CXCL10 in 25 patients with CTCL, revealing that CCL22 was significantly increased in advanced CTCL compared with early CTCL. Next, we evaluated serum levels of CCL22, CXCL5, and CXCL10 in CTCL patients treated with bexarotene. Serum levels of CCL22 were significantly decreased in 80% of CTCL patients who responded to bexarotene therapy. In addition, immunofluorescence staining revealed CD163+ M2 macrophages as the main source of CCL22. Moreover, bexarotene decreased the production of CCL22 by M2 macrophages generated from monocytes in vitro. Our findings suggest that the clinical benefits of bexarotene are partially attributable to suppressive effects on the production of CCL22 by M2-polarized tumor-associated macrophages.

A novel technique to diagnose non-melanoma skin cancer by thermal conductivity measurements: Correlations with cancer stromal factors.

The skin surface temperature reflects the physiological state of the human body. Quantitative methods of identification of skin cancers based on accurate measurement of effective thermal conductivity (ETC) are among the promising diagnostic tools for differentiating non-invasive and invasive melanomas before surgical treatment. To validate these findings, in this report, the diagnostic methods for invasive and non-invasive extramammary Paget's disease (EMPD) and squamous cell carcinoma (SCC) were further tested by measuring the absolute value of skin surface temperature and the ETC of the skin. In addition, to investigate the stromal factors that might affect ETC, immunohistochemical staining for LL37, periostin (POSTN), MMP12, and MMP28 was performed. The invasive SCC and EMPD group showed a relatively higher skin surface temperature compared to the in situ SCC group. The non-invasive EMPD and SCC group showed significantly lower values of ETC at lesions, whereas the invasive EMPD group showed significantly higher ETC values at lesions compared to healthy skin. Immunohistochemical staining showed that the percentage of LL37-producing cells was significantly increased in invasive EMPD and SCC compared to that in non-invasive EMPD and SCC. Moreover, Spearman's rank correlation test showed a significant inverse correlation between the percentage of MMP12-positive cells and increased levels of ETC-expressing areas in EMPD and SCC (r = -.5997). The present study suggested that differences in ETC could be a novel high-accuracy diagnostic technique for non-melanoma skin cancer, especially for detecting dermal invasion of SCC and EMPD.

Successful Treatment of Unresectable Advanced Melanoma by Administration of Nivolumab With Ipilimumab Before Primary Tumor Resection.

Ipilimumab, in combination with nivolumab, is one of the promising drugs that enhance the anti-tumor immune response of patients with advanced melanoma. Since the co-administration of nivolumab with ipilimumab in the neoadjuvant setting expands melanoma-reactive T cells at the primary site of melanoma and has a high rate of histological complete response, the pre-surgical administration of this combination could be the optimal therapy for unresectable advanced melanoma. In this report, a case of unresectable advanced melanoma treated successfully with administration of nivolumab with ipilimumab before primary tumor resection is presented. In addition, CD8+ T cells increased among the tumor-infiltrating lymphocytes that were surrounding melanoma cells and caspase 3+ cells. The present case suggests that pre-surgical administration of nivolumab with ipilimumab could be the optimal therapy for the treatment of unresectable advanced melanoma.

Association of Baseline Serum Levels of CXCL5 With the Efficacy of Nivolumab in Advanced Melanoma.

Anti-programmed cell death protein 1 (PD1) antibodies are in wide use for the treatment of various cancers. PD1 antibody-based immunotherapy, co-administration of nivolumab and ipilimumab, is one of the optimal immunotherapies, especially in advanced melanoma with high tumor mutation burden. Since this combined therapy leads to a high frequency of serious immune-related adverse events (irAEs) in patients with advanced melanoma, biomarkers are needed to evaluate nivolumab efficacy to avoid serious irAEs caused by ipilimumab. This study analyzed baseline serum levels of CXCL5, CXCL10, and CCL22 in 46 cases of advanced cutaneous melanoma treated with nivolumab. Baseline serum levels of CXCL5 were significantly higher in responders than in non-responders. In contrast, there were no significant differences in baseline serum levels of CXCL10 and CCL22 between responders and non-responders. These results suggest that baseline serum levels of CXCL5 may be useful as a biomarker for identifying patients with advanced cutaneous melanoma most likely to benefit from anti-melanoma immunotherapy.

Malassezia-derived aryl hydrocarbon receptor ligands enhance the CCL20/Th17/soluble CD163 pathogenic axis in extra-mammary Paget's disease.

Malassezia yeast play a role in the pathogenesis of chronic dermatitis, especially in apocrine areas, by polarizing the local immunologic background to a Th2/Th17 state through aryl hydrocarbon receptor (AhR)-dependent pathways. Extra-mammary Paget's disease (EMPD) is an adenocarcinoma of apocrine origin, and except for cases associated with Malassezia yeast and their metabolites, the lesions typically develop in areas not exposed to environmental material. The purpose of this study was to investigate (a) the immunomodulatory effects of Malassezia metabolites on normal human keratinocytes (NHKCs), focusing on interleukin (IL)-17 and related cytokines/chemokines (IL-23, IL-36γ, CCL20), (b) the expression of these factors in lesion-affected skin in EMPD and (c) the activation of tumor-associated macrophages (TAMs) by these factors. Malassezia metabolites augmented the expression of cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1), CCL20 and IL-36γ mRNA in NHKCs in vitro. In lesion-affected skin of patients with EMPD, epidermal keratinocytes expressed CYP1A1 and CCL20. In addition, Paget cells expressed CCL20 and IL-23. IL-17-producing cells were distributed adjacent to Paget cells. Compared to healthy donors, patients with EMPD exhibited significantly increased serum levels of soluble (s)CD163, CXCL5, CXCL10 and CCL20. In addition, serum levels of sCD163 decreased significantly following tumor resection. Our study demonstrates a possible mechanism for the development of EMPD involving AhR-mediated signalling by epidermal keratinocytes and RANKL-induced recruitment of Th17 cells and TAMs.

Three cases of nivolumab therapy-failed advanced melanoma successfully controlled by ipilimumab with intensity-modulated radiotherapy.

Anti-programmed death 1 antibody monotherapy is a first-line and widely used immunotherapy for the treatment of advanced melanoma. However, its efficacy rate is lower in the Japanese population compared with the Caucasian population. Ipilimumab is another immune checkpoint inhibitor (ICI) that activates and increases T cells, which suppress the function of regulatory T cells. Previous reports have suggested that ipilimumab is useful for treating advanced melanoma, particularly in combination with radiation therapy. In this report, we described three cases of nivolumab-resistant melanoma successfully controlled by ipilimumab with intensity-modulated radiotherapy, which may enhance the therapeutic effects of the sequential administration of ICI.