A prospective cohort study of the association between the Apgar score and developmental status at 3 years of age: the Japan Environment and Children's Study (JECS).

Apgar score (AS) is a well-established tool for assessing viability of newborns, and its association with subsequent child development has been suggested. We aimed to assess whether Apgar scores (ASs) ≥ 7 (generally considered normal) are associated with the developmental status at 3 years of age while adjusting for perinatal and socioeconomic confounders. We extracted the data of ASs at 1 and 5 min among participants of the Japan Environment and Children's Study datasets, which were used in this nationwide cohort study. The outcomes comprised developmental status that was less than each cutoff value for the following five domains of the Ages & Stages Questionnaire (Japanese version, 3rd edition): communication, gross and fine motor, problem-solving, and personal-social domains. For this objective, we conducted multivariable logistic regression analyses on the data of 54,716 children. Compared with ASs ≥ 9 at 5 min, the adjusted odds ratios (aOR) for delayed development in children with ASs ≤ 8 were 1.31 (95% confidence interval, 1.11-1.56), 1.20 (1.04-1.38), and 1.16 (1.01-1.34), respectively, for gross and fine motor, and problem-solving domains. Among neonates with ASs ≤ 8 at 1 min, when those with ASs ≤ 8 at 5 min were compared with those with ASs ≥ 9 at 5 min, the aOR for gross motor domain was 1.34 (1.11-1.61).Conclusion: ASs ≤ 8 compared with those ≥ 9 at 5 min, even considering the change of AS from 1 to 5 min, were associated with increased ORs for developmental delay in 3-year-olds. Even ASs that are considered normal might affect the subsequent development. What is Known: • Apgar score is a general tool for evaluating the vitality of newborns. It is also basically measured at 1 minute and 5 minutes after birth and the scores of ≥7 are considered normal. • The Apgar scores at each minute affect clinical findings of neonates after birth and the subsequent long-term development. What is New: • Neonates with Apgar scores of ≤8 at 5 minutes compared with those of ≥9, including the change in Apgar score from 1 minute to 5 minutes, are associated with increased odds ratios for developmental status at 3 years of age adjusting for perinatal and socioeconomic confounders.

Large-scale health insurance study showed that antibiotic use in infancy was associated with an increase in atopic dermatitis.

AIM: This retrospective large-scale study examined the association between prescribing antibiotics for infants and subsequent atopic dermatitis (AD). METHODS: The data covered the period from 1 January 2005 to 31 December 2014 and were extracted from a Japanese health insurance claims database. The exposure was being prescribed antibiotics at less than 12 months of age and the outcome was a subsequent diagnosis of AD. The primary analysis method was multivariable Cox proportional hazard regression analysis. A sibling-matched analysis was also performed to adjust for shared familial and environmental confounders. RESULTS: This study comprised 85 954 infants: 8654 (10.1%) who had received antibiotics and 77 300 who had not. AD was diagnosed in 1183 (13.7%) and 10 325 (13.4%) infants respectively. The exposed group was more likely to develop AD than the non-exposed group, but this association disappeared when we carried out the secondary, sibling-matched analysis of the two groups. Other risk factors for AD were macrolides, aminoglycosides, food allergies and histamine H1 receptor antagonists. CONCLUSION: Antibiotic use in infancy was associated with a subsequent increase in the incidence of AD. This association should be considered when prescribing antibiotics, but antibiotic use may not be a critical factor for the development of AD.

[Pathogenic and Compensatory Mechanisms in Epidermis of Sphingomyelin Synthase 2-Deficient Mice].

Sphingomyelin (SM) is a constituent of cellular membranes, while ceramides (Cer) produced from SM on plasma membranes serve as a lipid mediator that regulates cell proliferation, differentiation, and apoptosis. In the skin, SM also is a precursor of Cer, an important constituent of epidermal permeability barrier. We investigated the role of epidermal SM synthase (SMS)2, an isoform of SMS, which modulates SM and Cer levels on plasma membranes. Although SMS2-knockout (SMS2-KO) mice were not neonatal lethal, an ichthyotic phenotype with epidermal hyperplasia and hyperkeratosis was evident at birth, which persisted until 2 weeks of age. These mice showed abnormal lamellar body morphology and secretion, and abnormal extracellular lamellar membranes in the stratum corneum. These abnormalities were no longer evident by 4 weeks of age in SMS2-KO mice. Our study suggests that (1) exposure to a dry terrestrial environment initiates compensatory responses, thereby normalizing epidermal ichthyotic abnormalities and (2) that a nonlethal gene abnormality can cause an ichthyotic skin phenotype.

Systemic Immunotherapy for Advanced Cutaneous Squamous Cell Carcinoma.

OPINION STATEMENT: Advanced (i.e., unresectable) cutaneous squamous cell carcinoma (cSCC) is a rare condition with a dismal prognosis. Although less than 5% of cSCC patients develop metastases or local recurrence after complete excision, advanced cSCC is difficult to treat. These conditions tend to develop in elderly patients, although, at times, metastases are noted in middle-aged patients. Once metastasis occurs in cSCC, the 10-year survival rates fall to less than 20% for patients with regional lymph node involvement and less than 10% for patients with distant metastases, indicating that cSCC can be difficult to treat effectively when it is advanced. Traditionally, platinum-based therapy has been considered as a conventional option for advanced cSCC. It is efficacious to some degree, but the toxic effects of the combination treatments often prohibit their use in elderly patients. It has been a decade since the development of epidermal growth factor receptor (EGFR) inhibitors as agents that are less toxic. However, evidence regarding systemic therapy for advanced cSCC is limited because of a lack of high-quality prospective studies. Remarkably, the US Food and Drug Administration (FDA) approved an anti-PD-1 antibody treatment (cemiplimab) for the treatment of patients who are not candidates for curative surgery or curative radiation. It will be a promising treatment option for these types of rare conditions.

Randomized phase III trial of adjuvant therapy with locoregional interferon beta versus surgery alone in stage II/III cutaneous melanoma: Japan Clinical Oncology Group Study (JCOG1309, J-FERON).

The Dermatologic Oncology Group of Japan Clinical Oncology Group has started a randomized phase III trial to confirm the superiority of adjuvant therapy with locoregional interferon beta in overall survival over surgery alone for patients with pathological stage II/III cutaneous melanoma (JCOG1309). Patients in the interferon beta arm receive intra- or subcutaneous injections of interferon beta directly into the surgical site at a flat dose of 3 million units once per day. Treatment is repeated for 10 consecutive days every 8 weeks for a total of 3 courses during the induction phase, then 1-day injection every 4 weeks for 2.5 years. A total of 240 patients will be accrued from 17 Japanese institutions within 6.5 years. Primary endpoint is overall survival. Secondary endpoints are relapse-free survival, distant metastasis-free survival, pattern of recurrence, and adverse events. This trial has been registered at the UMIN Clinical Trials Registry as UMIN000017494 [http://www.umin.ac.jp/ctr/index.htm].

T-Cell Responses to Tyrosinase-Derived Self-Peptides in Patients with Leukoderma Induced by Rhododendrol: Implications for Immunotherapy Targeting Melanoma.

BACKGROUND: Rhododendrol, a phenolic compound contained in lightening/whitening cosmetics, can bind and inhibit tyrosinase and was reported to induce leukoderma in Japan. Only 2% of the cosmetics users are affected, and tacrolimus is effective in treatment of the condition. OBJECTIVE: To test the hypothesis that the disease is an autoimmune disorder. METHODS: Short-term T-cell lines were established using peripheral blood mononuclear cells from 8 patients with human melanoma-associated and tyrosinase-derived synthetic peptides. The effects of rhododendrol on melanoma immunization were also examined. RESULTS: Seven out of 8 patients were positive for HLA-DR4. Both class I- and class II-restricted and tyrosinase peptide-specific T-cell responses were observed. Immunization of mice with rhododendrol-treated and irradiated B16 melanoma cells successfully delayed the growth of melanoma cells in vivo. CONCLUSION: Rhododendrol-induced leukoderma is an autoimmune disorder, with rhododendrol as an environmental factor and HLA-DR4 as a genetic factor. Rhododendrol might be effective in treating melanomas.

Postmarketing surveillance of nivolumab plus ipilimumab combination therapy in Japanese patients with unresectable malignant melanoma.

Although malignant melanoma is relatively rare in Japan, it is often diagnosed at a later stage than in Western countries. Nivolumab and ipilimumab are immune checkpoint inhibitors targeting programmed death 1 and cytotoxic T-lymphocyte-associated protein 4, respectively. Owing to their complementary anticancer effects, nivolumab and ipilimumab combination therapy (N + I) has been studied and approved for treating malignant melanoma in various countries including Japan. Real-world postmarketing surveillance was implemented to record treatment-related adverse events (TRAEs) in patients treated with N + I following its approval in Japan. Patients were eligible for registration if they had unresectable malignant melanoma and started N + I between September 2018 and August 2019. The observation period was 13 weeks from starting N + I. Only safety information was collected and evaluated. The final case report form lock was March 2021. Overall, 173 patients (median age, 66.0 years; performance status 0-1, 88.4%; skin: 53.2%; mucosal: 32.4%) were eligible for the analyses. Overall, 34.1% of patients completed 4 doses of N + I. N + I was discontinued by 63.0% (due to adverse events in 67.9% and disease progression/death in 22.9%). Any grade and grade ≥3 TRAEs were reported in 73.41% and 52.02%, respectively. TRAEs in ≥10 patients were hepatic function abnormal (any grade/grade ≥3: 23.12%/13.29%), pyrexia (10.40%/0.58%), diarrhea (9.25%/2.89%), rash (8.67%/0.58%), hypophysitis (5.78%/5.20%), interstitial lung disease (5.78%/2.89%), and liver disorder (5.78%/4.62%). TRAEs were classified as recovered (36.99% of patients), recovering (44.51%), unrecovered (13.29%), recovered with sequelae (2.31%), and death (1.73%). Overall, 24 of 34 patients (70.59%) with gastrointestinal-related and 53 of 65 (81.54%) liver-related TRAEs received treatment, such as a steroid with/without an immunosuppressant; most patients recovered within 1 to 2 months. In conclusion, this postmarketing surveillance of N + I in patients with unresectable malignant melanoma revealed no new safety concerns compared with results of prior studies. Immune-related TRAEs were generally manageable by appropriate treatment including a steroid.

Application of fluorescence in situ hybridization in distinguishing acral melanoma in situ from acral junctional melanocytic nevus on the volar skin in Japanese patients.

Four-colored fluorescence in situ hybridization (FISH) is an ancillary diagnostic tool for melanoma. However, most studies that have investigated the usefulness of FISH primarily focused on advanced melanomas. The aim of the current study was to evaluate the effectiveness of FISH in distinguishing acral melanoma (AM) in situ from benign acral junctional nevus (AJN), two types of lesions that are difficult to differentiate via traditional clinical means. The authors investigated the usefulness of FISH in 91 acral melanocytic lesions, including 50 lesions with diagnostic discrepancies between dermoscopic and pathologic approaches or difficulty diagnosing between AM in situ and AJN, on the volar skin of Japanese patients. The authors classified the lesions based on the diagnosis of dermatologists and pathologists into four groups: (I) lesions with a unanimous diagnosis by dermatologists and pathologists as AM in situ or AJN (n = 41); (II) lesions with a unanimous diagnosis by dermatologists only as AM in situ or AJN (n = 21); (III) lesions with a unanimous diagnosis by pathologists only as AM in situ or AJN (n = 15); and (IV) all other lesions (n = 14). The dermatologists diagnosed the lesions by clinical and dermoscopic photographs alone, while the pathologists diagnosed the lesions by microscopy of hematoxylin and eosin-stained slides alone. In group I (AM in situ [n = 20] and AJN [n = 21]), four-colored FISH demonstrated 90% sensitivity and 81% specificity in distinguishing AM in situ from AJN. There was a significant correlation between the FISH results and the unanimous diagnoses by pathologists alone (p = 0.03) in group III. However, FISH results were not significantly correlated with the unanimous diagnoses by dermatologists alone (p = 0.33) in group II. In conclusion, the four-colored FISH probe kit was useful in distinguishing between AM in situ and AJN and may be an ancillary method when pathologists who are not experts of dermatopathology diagnose melanocytic lesions.

Safety and effectiveness of nivolumab in Japanese patients with malignant melanoma: Final analysis of a post-marketing surveillance.

Nivolumab, a monoclonal antibody against human programmed death 1, was approved for the treatment of melanoma in July 2014 in Japan. Because the Japanese phase II studies (ONO-4538-02, ONO-4538-08) enrolled small numbers of melanoma patients, post-marketing surveillance (PMS; JapicCTI-163 272) was conducted to collect safety data in a larger patient population. We report data for melanoma patients who received nivolumab between July 4, 2014 and February 28, 2017. Data collected included baseline characteristics, laboratory tests, treatment-related adverse events (TRAE), and overall survival (OS). Of 2069 enrolled patients, 2008 patients were included in the safety analysis population. There were 1030 (51.3%) males, the median age was 69 years, and 269 patients (13.4%) had a performance status of ≥2. The primary tumor sites were cutaneous (34.4%), mucosal (34.2%), acral lentiginous (18.6%), others (6.8%), and unknown (6.3%). TRAE occurred in 62.1% of patients, the most common being hypothyroidism (14.0%), increased aspartate aminotransferase (8.5%), and increased alanine aminotransferase (6.9%). TRAE of special interest in ≥5% of patients were thyroid dysfunction (24.9%), hepatic dysfunction (20.6%), infusion reactions (11.4%), colitis/severe diarrhea (6.3%), and interstitial lung disease (ILD; 5.0%). Several types of TRAE of special interest, which included myasthenia gravis/myocarditis/myositis/rhabdomyolysis (0.9%), venous thromboembolism (0.2%), immune thrombocytopenic purpura (0.1%), and encephalitis (0.0%), were observed in this PMS. Although these TRAE were not reported in previous studies (ONO-4538-02, ONO-4538-08, CheckMate 066, and CheckMate 037), they have been listed in the current Risk Management Plan. History of ILD and male sex were risk factors for ILD in a multivariable analysis. Age <75 years was a risk factor for hepatic dysfunction. At 12 months, median OS was not reached. In conclusion, these results suggested that there was no concern requiring additional precautions for the safety of nivolumab in Japanese patients with melanoma other than the safety information in the Risk Management Plan.

Relationship between the three-dimensional structure of the human plantar epidermis and the dermoscopic patterns seen in melanocytic nevi.

OBJECTIVE: Our aim was to investigate the relationship between the distribution of the dermoscopic patterns seen in plantar melanocytic nevi and the 3-dimensional structures of the epidermis. METHODS: The precise locations of 69 melanocytic nevi on the sole and the border areas were investigated, with attention paid to each dermoscopic pattern. In addition, the basal surfaces of the plantar epidermis from 14 anatomical areas were observed by scanning electron microscopy (SEM). RESULTS: In the weight-bearing area, melanocytic nevi with a fibrillar pattern were preferentially observed. Those with a lattice-like pattern were observed in the arch area, whereas those with a crista reticulated pattern were seen in the border area. On SEM observations, transverse ridges formed a couple of parallel lamellae on the crista profunda limitans (limiting ridges). Between the limiting ridges and the crista profunda intermedia (intermediate ridges), the transverse ridges had different shapes according to the anatomical location of the sole. CONCLUSION: These results suggest that the characteristic dermoscopic patterns seen in plantar melanocytic nevi simulate the arrangement of transverse ridges.

Distribution of CD1a-positive cells is not different between pseudolymphomatous folliculitis and primary cutaneous marginal zone lymphoma.

Pseudolymphomatous folliculitis (PLF) is a subtype of cutaneous pseudolymphoma that is recognized as an independent disease. PLF is characterized by dermal lymphocytic infiltration surrounding an irregular hyperplastic pilosebaceous unit (i.e., activated pilosebaceous unit). An interstitial distribution of CD1a-positive cells is regarded as an important feature of PLF, especially in distinguishing it from primary cutaneous marginal zone lymphoma (PCMZL), which is associated with a peripheral concentration of CD1a-positive cells. We undertook a clinicopathological investigation of PLF, with a reassessment of CD1a immunohistochemistry. We defined diagnostic criteria for PLF based on past studies and consequently identified 79 cases. In addition, we collected 32 cases of PCMZL and performed detailed clinical, pathological, and immunohistochemical investigations using antibodies to CD3, CD20, and CD1a. We found an interstitial concentration of CD1a-positive cells in 90.2% of PLF and 34.5% of PCMZL cases. The peripheral concentration of CD1a-positive cells was seen in 9.8% of PLF and 34.5% of PCMZL cases. In both diseases, CD1a-positive cells appeared in T-cell nests (88.5% in PLF and 92.9% in PCMZL) but were absent in B-cell nests (0% in both groups). All 79 cases of PLF showed activated pilosebaceous units while 22 of the 32 PCMZL cases displayed pilosebaceous units, although none of these were activated. In summary, regarding the distribution patterns of CD1a-positive cells as a diagnostic feature in distinguishing between PLF and PCMZL is somewhat inconclusive. To differentiate PLF and PCMZL, determining the presence or absence of activated pilosebaceous units is essential.

Normolipemic xanthomatized Sweet's syndrome: A variant of Sweet's syndrome with myelodysplastic syndrome.

We report a rare case of xanthomatized Sweet's syndrome with myelodysplastic syndrome (MDS) in a patient who presented with erythematous plaques on his chest that were elevated and became yellowish. A diagnosis of MDS with single lineage dysplasia was made during the development of the eruption. Bone marrow biopsy showed an increased number of megakaryoblasts. Histopathologically, there was neutrophil infiltration with leukocytoclasia and the infiltration of xanthomatous cells. Immunohistochemical analysis revealed that the xanthomatized cells were predominantly CD163 positive. We propose that our case of xanthomatized neutrophilic dermatosis is a rare clinicopathological variant of Sweet's syndrome associated with a hematologic disorder.

Reassessment of histopathology and dermoscopy findings in 145 Japanese cases of melanocytic nevus of the sole: toward a pathological diagnosis of early-stage malignant melanoma in situ.

Recently, dermoscopic visualization has been improved, allowing for the identification of malignant melanoma (MM) of the sole in situ. When the parallel ridge pattern is evident on dermoscopy, the proliferation of solitarily arranged melanocytes in the crista profunda intermedia should be examined histologically, since this may be a clue to the early diagnosis of MM in situ. We reviewed 145 Japanese cases of melanocytic nevus on the sole, and investigated several useful histological features for the diagnosis of MM in situ using a recent proposal as well as several standard histological criteria of MM in situ. Five cases were considered to be an early-stage MM in situ out of 145 cases previously diagnosed as melanocytic nevi of the sole. These cases showed several specific features, including solitarily arranged melanocytes or melanocyte nests comprising fewer than four cells. Our findings indicate that early-stage MM of the sole in situ can be diagnosed by using new dermoscopy-related histological findings. They are (i) irregular distribution of solitary melanocytes at the crista profunda intermedia with or without small nests (up to three melanocytes) on the slope of rete ridges; and (ii) larger melanocytes with a halo around the nucleus.

Telepathology Support System with Gross Specimen Image Using High Resolution 4K Multispectral Camera.

This study reports on the development of a high-resolution 4K multispectral camera designed to enhance telepathology support systems for remote gross-pathological diagnosis. We experimentally examine and evaluate the camera's effectiveness in three subjects: the reconstruction of precise color images, the emphasis of cancerous tissue areas, and pre-fixed image reproduction from fixed images. The evaluation results of the first and second subjects showed that the camera and supporting methods could be effectively used in gross pathology diagnosis. The images obtained in the third subject received positive evaluations from some pathologists, but others expressed reservations as to its utility.

Real-world safety and efficacy data of ipilimumab in Japanese radically unresectable malignant melanoma patients: A postmarketing surveillance.

Treatment with immune checkpoint inhibitors has improved prognosis among patients with cutaneous melanoma, but there are still unmet medical needs in Japan, especially for mucosal melanoma and acral lentiginous melanoma (ALM) subtypes. Ipilimumab, a fully human monoclonal antibody that specifically blocks cytotoxic T-lymphocyte-associated antigen 4 and potentiates antitumor T-cell response, was approved in Japan in 2015 for the treatment of radically unresectable malignant melanoma. This postmarketing surveillance (prospective, non-interventional, multicenter, observational study) evaluated the safety (occurrence of adverse drug reactions [ADR]) and efficacy (overall survival [OS]) of ipilimumab in a real-world setting in Japan. All patients with radically unresectable malignant melanoma undergoing treatment with ipilimumab in Japan during the registration period between August 2015 and February 2017 were enrolled. In total, 547 patients were analyzed; 67.5% were 60 years old or more, 85.7% had an Eastern Cooperative Oncology Group performance status of 0-1, 50.3% had melanoma of the skin (mainly of the ALM subtype) and 73.5% had negative BRAF mutation status. Most patients had experienced recurrence and received multiple treatments. The overall incidence of ADR and serious ADR was 69.5% and 40.8%, respectively. The most common ADR and serious ADR were liver disorder, colitis and diarrhea. The most common ADR of special interest were liver-related ADR (22.5%), skin-related ADR (22.1%), gastrointestinal-related ADR (20.3%) and endocrine system-related ADR (16.3%). Most of these events had recovered or were in remission by the last evaluation. The median OS was 7.52 months (95% confidence interval, 6.47-8.74). Median OS was 6.31 and 8.44 months in patients with mucosal melanoma and melanoma of the skin; 9.43 and 3.75 months in patients with and without ADR; and 10.32 and 6.11 months in patients with and without serious ADR, respectively. Ipilimumab was tolerable and showed efficacy in improving OS for these patients.

Systemic treatment of patients with advanced cutaneous squamous cell carcinoma: response rates and outcomes of the regimes used.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is the second most common type of skin cancer. Few patients with cSCC experience metastases, but the prognosis of advanced cSCC (acSCC) is dismal. Evidence regarding systemic therapy for acSCC is limited. Therefore, we aimed to determine the most effective systemic treatment for acSCC. PATIENTS AND METHODS: This retrospective study involved 16 Japanese institutions. We documented patient and tumour characteristics and disease course of patients with acSCC who received systemic therapy between 1st January 2006 and 31st December 2015. We compared the overall survival (OS) and progression-free survival (PFS) for (1) platinum versus non-platinum groups, (2) radiation plus chemotherapy first-line therapy (RCT) versus non-RCT groups and (3) platinum-based RCT versus non-platinum-based RCT groups. RESULTS: Although the use of platinum-based systemic therapy was not associated with statistically significant improvements in PFS and OS, there were significant differences between the RCT and non-RCT groups (PFS: p < 0.001, OS: p = 0.003). In the subgroup analysis, RCT significantly prolonged PFS and OS in the nodal SCC (nSCC) group. For the RCT and non-RCT groups, the median OS was 110 and 14 months, respectively, and the 5-year OS rate was 54% and 21%, respectively. CONCLUSION: RCT could improve OS in patients with nSCC. However, further multicenter prospective studies are needed to establish evidence for superiority of RCT.

Two cases of childhood bullous pemphigoid.

This report describes two cases of childhood bullous pemphigoid (BP). These cases showed vesiculobullous lesions on the face, trunk, extremities, hands and feet. Histopathological analysis of skin lesions showed infiltration of numerous lymphocytes and eosinophils in the superficial dermis. Immunofluorescent analysis showed a linear IgG deposit along the basement membrane zone. In both cases ELISA showed circulating IgG autoantibodies against the NC16A domain of 180-KDa BP antigen (BP180). Both IgG and IgA (faint deposit) autoantibodies against the NC16A domain of BP180 were detected by an immunoblot analysis in both cases. Both patients showed a similar clinical course with a rapid remission after treatment with topical corticosteroids. Both patients received vaccinations within two weeks before the appearance of the eruption. These cases were considered to be childhood BP presenting both IgG and IgA autoantibodies against the NC16A domains of BP180.

[Systemic Lupus Erythematosus].

The cutaneous manifestations of lupus erythematosus (LE) include LE-specific and LE-nonspecific skin lesions. LE-specific skin lesions are divided into chronic, subacute, and acute types. The representatives of the chronic and acute types are discoid lupus erythematosus (DLE) and butterfly rash, respectively. Based on the systemic manifestations, we can classify LE into cutaneous-limited LE and systemic LE (SLE). Chronic LE eruptions tend to be seen in cutaneous-limited LE, and acute LE eruptions mainly appear in SLE. Some skin lesions are related to the neurological manifestations of SLE.