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Abstract High salt conditions and subsequent hyperosmolarity are injurious cellular stresses that can activate immune signaling. Nuclear factor of activated T-cells 5 (NFAT5) is an essential transcription factor that induces osmoprotective genes such as aldose reductase (AR) and betaine-GABA transporter 1 (BGT1). High salt stress-mediated NFAT5 activation is also reported to accelerate the inflammatory response and autoimmune diseases. However, the systemic regulation of NFAT5 remains unclear. Here, we performed a genome-wide siRNA screen to comprehensively identify the regulators of NFAT5. We monitored NFAT5 nuclear translocation and identified one of the Notch signaling effectors, Hairy and enhancer of split-1 (HES1), as a positive regulator of NFAT5. HES1 was induced by high salinity via ERK signaling and facilitated NFAT5 recruitment to its target promoter region, resulting in the proper induction of osmoprotective genes and cytoprotection under high salt stress. These findings suggest that, though HES1 is well known as a transcriptional repressor, it positively regulates NFAT5-dependent transcription in the context of a high salinity/hyperosmotic response.

Abstract Background While advanced gastrointestinal stromal tumors (GISTs) are primarily treated with tyrosine kinase inhibitors (TKIs), acquired resistance from specific mutations in KIT or PDGFRA frequently occurs. We aimed to assess the utility of circulating tumor DNA (ctDNA) as a modality of therapeutic decision-making in advanced GIST. Methods We conducted a pooled analysis of SCRUM-Japan studies for advanced GIST patients. We compared patient characteristics analyzed with tissue and blood samples, assessed gene alteration profiles, and evaluated prognostic implications from ctDNA status. Results In 133 patients, tissue and blood samples were analyzed for 89 and 44 patients, respectively. ctDNA was detected in 72.7% of cases; no prior treatment or progressive disease was significantly associated with ctDNA-positivity. ctDNA-positive patients had significantly shorter progression-free survival compared with ctDNA-negative patients (hazard ratio = 3.92; P = 0.007). ctDNA genotyping revealed a complex landscape of gene alterations, characterized by multi-exonic mutations in KIT, compared with tissue-based analysis. Patients who received TKIs matched to the identified KIT mutation in ctDNA demonstrated significantly longer PFS than those with unmatched treatment (median, 8.23 vs. 2.43 months; P

Background: Maintaining good asthma control minimizes the risk of exacerbations and lung function decline and is a primary goal of asthma management. The Japanese Pediatric Asthma Guidelines (JPGL) employs different classification criteria for control status from other guidelines, stressing a higher level of control. Based on JPGL, we previously developed a caregiver-completed questionnaire for assessing and achieving best asthma control in preschoolers. In this study, we aimed to develop a questionnaire for school-age children and adolescents. Methods: A working questionnaire comprising 14 items for patients and 34 items for caregivers was administered to 362 asthma patients aged 6–15 years and their caregivers. Separately, physicians filled out a questionnaire to determine JPGL-defined control. Logistic regression analysis was performed to construct a model to predict control levels using data from a randomly selected set of completed questionnaires from two-thirds of the subjects. Validation was performed using the remaining questionnaires. Results: A set of 7 questions, encompassing self-assessed control status at the time of the visit and in the past month, and nocturnal/early morning asthma symptoms for patients and frequency of asthma symptoms, dyspnea, rescue beta-agonist use, and asthma hospitalization for caregivers, were selected and the 7-item model showed a good statistical fit with AIC of 110.5. The model has been named the Best Asthma Control Test for School Children and Adolescents (Best ACT-S). Best ACT-S scores differed significantly in the hypothetical direction among the groups of different JPGL-defined control levels, step-up/down treatment decisions, and presence/non-presence of exacerbations in the previous year. Conclusions: The Best ACT-S is a valid questionnaire for children/adolescents aiming for best asthma control.

BackgroundThe significance of induction chemotherapy (IC) in the treatment of squamous cell carcinoma of the head and neck (SCCHN) with unresectable locoregional recurrence after curative surgery has not been clarified. The aim of this study was to evaluate the efficacy of IC followed by chemoradiotherapy (CRT) in these patients.MethodsAmong patients with unresectable locoregional recurrent SCCHN who had not undergone prior irradiation and were eligible for cisplatin, we conducted a retrospective analysis of patients who received CRT following IC with paclitaxel, carboplatin, or cetuximab (IC-PCE group) and those who received CRT without prior IC (CRT group) between June 2013 and August 2021.ResultForty-two patients were included. The CRT group and IC-PCE group consisted of 15 and 27 patients, respectively. Primary site was the oral cavity (n=25), oropharynx (n=3), hypopharynx (n=13) and larynx (n=1). Objective response rate (ORR) with IC-PCE was 55.6%; 24 patients (88.9%) subsequently received CRT. ORR after completion of CRT was significantly better in the IC-PCE group (95.8% in the IC-PCE group vs. 66.7% in the CRT group, p=0.024). Progression-free survival (PFS) of the total population on median follow-up of 2.4 years (range: 0.8-7.3) tended to be better in the IC-PCE group (2-year PFS: 55.6% in the IC-PCE group vs. 33.3% in the CRT group, log-rank p=0.176), especially in oral cancer (2-year PFS: 37.5% in the IC-PCE group vs. 0% in the CRT group, log-rank p=0.015).ConclusionTherapeutic strategies including IC-PCE in patients with unresectable locoregional recurrent SCCHN after curative surgery may contribute to improved prognosis, especially in oral cancer.

Background: Oral immunotherapy (OIT) can ameliorate cow's milk allergy (CMA); however, the achievement of sustained unresponsiveness (SU) is challenging. Regarding the pathogenesis of CMA, recent studies have shown the importance of gut microbiota (Mb) and fecal water-soluble metabolites (WSMs), which prompted us to determine the change in clinical and gut environmental factors important for acquiring SU after OIT for CMA. Methods: We conducted an ancillary cohort study of a multicenter randomized, parallel-group, delayed-start design study on 32 school-age children with IgE-mediated CMA who underwent OIT for 13 months. We defined SU as the ability to consume cow's milk exceeding the target dose in a double-blind placebo-controlled food challenge after OIT followed by a 2-week-avoidance. We longitudinally collected 175 fecal specimens and clustered the microbiome and metabolome data into 29 Mb- and 12 WSM-modules. Results: During OIT, immunological factors improved in all participants. However, of the 32 participants, 4 withdrew because of adverse events, and only 7 were judged SU. Gut environmental factors shifted during OIT, but only in the beginning, and returned to the baseline at the end. Of these factors, milk- and casein-specific IgE and the Bifidobacterium-dominant module were associated with SU (milk- and casein-specific IgE; OR for 10 kUA/L increments, 0.67 and 0.66; 95%CI, 0.41–0.93 and 0.42–0.90; Bifidobacterium-dominant module; OR for 0.01 increments, 1.40; 95%CI, 1.10–2.03), and these associations were observed until the end of OIT. Conclusions: In this study, we identified the clinical and gut environmental factors associated with SU acquisition in CM-OIT.

BackgroundOlfactory neuroblastoma (ONB) is a rare malignant tumor of the head and neck. Due to its rarity, standard systemic therapy for this condition has yet to be established. In particular, the use of immune checkpoint inhibitors (ICIs) for the recurrent or metastatic (R/M) ONB population remains unclear.MethodsWe retrospectively evaluated 11 patients with R/M ONB who received any systemic chemotherapy at two Japanese institutions (National Cancer Center Hospital East and Kyushu Medical Center) between January 2002 and March 2022 and analyzed outcomes by use of anti-PD-1 antibody (nivolumab or pembrolizumab) monotherapy.ResultsOf the 11 patients, 6 received ICI (ICI-containing treatment group) and the remaining 5 were treated with systemic therapy but not including ICI (ICI-non-containing treatment group). Overall survival (OS) was significantly longer in the ICI-containing group (median OS: not reached vs. 6.4 months, log-rank p-value: 0.035). The fraction of ICI systemic therapy in the entire treatment period of this group reached 85.9%. Four patients (66.7%) in the ICI-containing treatment group experienced immune-related adverse events (irAE), with grades of 1/2. No irAE of grade 3 or more was seen, and no patient required interruption or discontinuation of treatment due to toxicity.ConclusionICI monotherapy appears to be effective and to contribute to prolonged survival in R/M ONB.

Abstract Background Hypertension is the most frequently occurring adverse event of lenvatinib, recognized relatively early in its course. However, the trend in blood pressure after the initiation of lenvatinib and the outcomes with antihypertensive treatment are unclear. This study aimed to clarify the association between baseline blood pressure and the incidence of lenvatinib‐induced hypertension in patients with thyroid cancer. Methods This retrospective study included 65 patients without hypertension at the time of lenvatinib initiation. Patients were divided into two groups: those who developed hypertension grade ≥3 (HTN group) and those who did not develop hypertension grade ≥3 (non‐HTN group). Results Of the 65 patients, 46 (71%) developed hypertension grade ≥3. In both HTN and non‐HTN groups, blood pressure significantly increased the day after lenvatinib initiation. There was no significant difference in the elevated values of both the changes in systolic blood pressure (ΔSBP) and diastolic blood pressure (ΔDBP) between the two groups, with an average increase of 20 mmHg in SBP and 13 mmHg in DBP from baseline. The median (range) time to the onset of hypertension grade ≥3 was 2 days (1–12 days). In the multivariable analysis, patients with normal (SBP 120–129 mmHg and/or DBP 80–84 mmHg) or high‐normal baseline blood pressure (SBP 130–139 mmHg and/or DBP 85–89 mmHg) were at higher risk of developing hypertension grade ≥3 than those with optimal baseline blood pressure (SBP

Background: Information on changes in asthma prevalence and the treatment status for asthma is used as basic information for taking medical and administrative measures against asthma. However, this information among adults is relatively limited. Methods: To elucidate changes in the prevalence of asthma and treatment status over time among Japanese adults, health insurance claim data from some health insurance societies covering salaried employees and their dependents were studied longitudinally. Claim data from FY1999 to 2007 were obtained from two health insurance societies, and data from FY 2011 to 2019 were obtained from three different health insurance societies, and changes in standardized asthma prevalence among subjects aged 20–59 years, proportion of asthma patients prescribed ICS, leukotriene receptor antagonist (LTRA), and LABA, and the mean number of acute asthma exacerbations per year were analyzed. Results: The prevalence of asthma increased from 1.6% in 1999 to 3.0% in 2007 and 2.9% in 2011 to 4.6% in 2019. Increased trends in asthma prevalence from 2011 to 2019 were more noticeable in subjects in their 50s than those in their 20s for both sexes. The number of emergency visits related to asthma was 1.5 per year in 1999, which decreased to 0.8 per year in 2019. The proportion of people prescribed all anti-asthma medications (ICS, LTRA, and LABA) increased over time. Conclusions: The prevalence of adult asthma among Japanese salaried employees and their dependents has increased over the last 20 years, suggesting more attention should be paid to the prevention of this disease in adults.

Abstract Tools that can be used to estimate antibody waning following COVID-19 vaccinations can facilitate an understanding of the current immune status of the population. In this study, a two-compartment-based mathematical model is formulated to describe the dynamics of the anti-SARS-CoV-2 antibody in healthy adults using serially measured waning antibody concentration data obtained in a prospective cohort study of 673 healthcare providers vaccinated with two doses of BNT162b2 vaccine. The datasets of 165 healthcare providers and 292 elderly patients with or without hemodialysis were used for external validation. Internal validation of the model demonstrated 97.0% accuracy, and external validation of the datasets of healthcare workers, hemodialysis patients, and nondialysis patients demonstrated 98.2%, 83.3%, and 83.8% accuracy, respectively. The internal and external validations demonstrated that this model also fits the data of various populations with or without underlying illnesses. Furthermore, using this model, we developed a smart device application that can rapidly calculate the timing of negative seroconversion.

BackgroundImmune checkpoint inhibitors (ICIs) are essential in treating recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). However, the overall response rate (ORR) is limited to 10-20%, and subsequent chemotherapy is critical to maximizing the subjects’ prognosis.MethodsWe retrospectively reviewed 59 patients with R/M SCCHN treated with paclitaxel+cetuximab (PE)-based chemotherapy (PCE, paclitaxel+carboplatin+cetuximab; or PTX+Cmab, paclitaxel+cetuximab) following disease progression after either pembrolizumab or nivolumab monotherapy.ResultsOf 59 patients, 15 were treated with pembrolizumab, with an ORR of 13.3%, and the remaining 44 with nivolumab, with an ORR of 11.4%. All patients in the pembrolizumab cohort had platinum-sensitive disease. Following ICI treatment, 19 patients were treated with PCE and the remaining 40 with PTX+Cmab. PE-based chemotherapy induced favorable and prompt tumor shrinkage even in cases where ICI was not effective, with a median change in the summed dimensions of target lesions of -43.4%, resulting in an ORR of 62.7%. Median time to response was 1.8 months. The patients in the pembrolizumab cohort appeared to have a numerically higher response rate than those receiving nivolumab (80.0% vs. 56.8%). For the 59 patients, progression-free survival and overall survival, calculated from the initiation of PE-based chemotherapy, were 4.6 months and 17.1 months, respectively. Grade ≥3 adverse events occurred in 40.7%, and no treatment-related death was observed.ConclusionPE-based chemotherapy following ICI is encouraging for its robust antitumor efficacy in R/M SCCHN.

Pork-cat syndrome can occur in children younger than 10 years. A history of contact with animals since infancy and history of severe atopic dermatitis, which can promote epicutaneous sensitization to animal serum albumin, may be helpful in diagnosis.

BackgroundIn the phase 3 SELECT study, lenvatinib significantly improved prognostic outcomes vs. placebo in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC). However, toxicity of lenvatinib is sometimes considerable and requires frequent dose interruptions and modifications. Recently, planned drug holidays have been proposed as a means of avoiding severe adverse events (AEs).MethodsWe retrospectively reviewed medical records to compare the efficacy and safety of lenvatinib in RR-DTC patients who underwent planned drug holidays (planned holiday group) vs. those who received conventional daily oral administration (daily group).ResultsThe subjects were 25 patients in the planned holiday group and 21 in the daily group. Median age was 73 years (range 43-84) and 62 years (range 42-75), and histologic subtype of papillary/follicular was 21/4 cases and 15/6 cases, respectively. Time to treatment failure (TTF) and overall survival (OS) were significantly longer in the planned holiday group than the daily group (not reached [NR] vs. 14.9 months, hazard ratio [HR] 0.25, 95% confidence interval [Cl] 0.11-0.58, p

BackgroundPersistent opioid use frequently leads to substantial negative impacts on quality of life, and as the outlook for numerous cancer types continues to improve, these complications become increasingly crucial. It is essential to acknowledge that extended or excessive opioid use may result in adverse effects in patients who completed radiation therapy (RT).MethodsIn this time-series analysis, we compared the outcomes of patients who participated in the pharmacist-led opioid de-escalation (PLODE) program after completing concurrent radiotherapy (CRT) between June 2018 and February 2019 against patients who completed CRT between June 2017 and March 2018 and did not participate in the program.ResultsAmong 61 patients, 16 (26%) used opioids after completing CRT and participated in the PLODE program. Before starting the program, 93 patients completed CRT between June 2017 and March 2018 and 32 (34%) used opioids at CRT completion. These patients were deemed the control group. In the PLODE group, outpatient pharmacist intervention was performed, with 29 total interventions related to opioid use, of which 16 (55%) recommended tapering or discontinuing opioids according to the definition of this program. Patients who participated in the PLODE program discontinued opioids significantly earlier than those in the control group (median time to opioid discontinuation 11 days vs. 24.5 days, p < 0.001). None of the patients in the PLODE group resumed opioid use following discontinuation or escalated opioid dosing due to worsening pain.ConclusionThis study showed the utility of pharmacist-initiated interventions for opioid use in patients with head and neck cancer who had completed CRT.

Background: Safety and efficacy data for dupilumab beyond 1 year are lacking for patients from Japan with moderate-to-severe asthma. Methods: The TRAVERSE open-label extension (OLE) study (NCT02134028) assessed the safety and efficacy of dupilumab 300 mg every 2 weeks up to 96 weeks in 2282 patients who completed a previous dupilumab asthma study. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Secondary endpoints included annualized severe exacerbation rate and change from parent study baseline in pre-bronchodilator forced expiratory volume in 1 second (FEV1), asthma control, quality of life, and blood eosinophil levels. Anti-drug antibodies (ADA) were evaluated. We report results in 160 (7.8% of exposed population) patients recruited from Japanese centers with non-oral corticosteroid (OCS)-dependent asthma rolled over from two parent studies, and in subgroups with a type 2 inflammatory phenotype. Results: TEAEs were consistent with the parent studies and the known safety profile of dupilumab. One patient permanently discontinued treatment due to TEAEs. Exacerbation rates remained low and were sustained to Week 96, as were improvements in pre-bronchodilator FEV1. Rapid, sustained improvements were observed in dupilumab-treated patients who previously received placebo in a parent study, while further improvements in exacerbation rates, asthma control, and asthma-related quality of life were observed in those continuing dupilumab. Blood eosinophil levels decreased progressively while on treatment. Treatment-emergent ADA responses were highest in patients who had previously received placebo. Efficacy results were consistent in patients with a type 2 phenotype. Conclusions: Long-term dupilumab treatment was well tolerated and efficacious in patients with non–OCS-dependent, moderate-to-severe asthma recruited from Japan.(Funded by Sanofi and Regeneron Pharmaceuticals, Inc.; ClinicalTrials.gov identifier, NCT02134028)

Abstract Background Previous clinical trials have demonstrated the potential efficacy of poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) in patients with cancer involving homologous recombination repair (HRR) gene-mutation. Moreover, HRR gene-mutated cancers are effectively treated with immune checkpoint inhibitors (ICIs) with the increase in tumor mutation burden. We have proposed to conduct a multicenter, single-arm phase II trial (IMAGENE trial) for evaluating the efficacy and safety of niraparib (PARPi) plus programmed cell death-1 inhibitor combination therapy in patients with HRR gene-mutated cancers who are refractory to ICIs therapy using a next generation sequencing-based circulating tumor DNA (ctDNA) and tumor tissue analysis. Methods Key eligibility criteria for this trial includes HRR gene-mutated tumor determined by any cancer gene tests; progression after previous ICI treatment; and Eastern Cooperative Oncology Group Performance Status ≤ 1. The primary endpoint is the confirmed objective response rate (ORR) in all patients. The secondary endpoints include the confirmed ORR in patients with HRR gene-mutation of ctDNA using the Caris Assure (CARIS, USA). The target sample size of the IMAGENE trial is 57 patients. Biomarker analyses will be performed in parallel using the Caris Assure, proteome analysis, and T cell repertoire analysis to reveal tumor immunosurveillance in peripheral blood. Expected outcome Our trial aims to confirm the clinical benefit of PARPi plus ICI combination therapy in ICI-resistant patients. Furthermore, through translational research, our trial will shed light on which patients would benefit from the targeted combination therapy for patients with HRR gene-mutated tumor even after the failure of ICIs. Trial registration The IMAGENE trial: jRCT, Clinical trial no.: jRCT2051210120, Registered date: November 9, 2021.

This is an abridged edition of English version of the Clinical Practice Guidelines for the Management of Atopic Dermatitis 2021. Atopic dermatitis (AD) is a disease characterized by relapsing eczema with pruritus as a primary lesion. In Japan, from the perspective of evidence-based medicine, the current strategies for the treatment of AD consist of three primary measures: (i) use of topical corticosteroids, tacrolimus ointment, and delgocitinib ointment as the main treatment of the inflammation; (ii) topical application of emollients to treat the cutaneous barrier dysfunction; and (iii) avoidance of apparent exacerbating factors, psychological counseling, and advice about daily life. In the present revised guidelines, the description about three new drugs, namely, dupilumab, delgocitinib, and baricitinib, has been added. The guidelines present recommendations to review clinical research articles, evaluate the balance between the advantages and disadvantages of medical activities, and optimize medical activity-related patient outcomes with respect to several important points requiring decision-making in clinical practice.

This article covers the salient and updated themes of the Japanese Pediatric Guidelines for the Treatment and Management of Asthma (JPGL) 2020 published by the Japanese Society of Pediatric Allergy and Clinical Immunology. In the 2020 guidelines, five new clinical questions (CQs) have been added to address the 12 CQs regarding the treatment of childhood asthma. “Infant and preschool asthma” is diagnosed when young children (

BackgroundDespite advances in precision medicine, most patients with recurrent or metastatic salivary gland carcinoma still need conventional chemotherapies, such as the combination of taxane and platinum. However, evidence for these standardized regimens is limited.MethodsWe retrospectively reviewed patients with salivary gland carcinoma treated with a taxane and platinum, which contained docetaxel at a dose of 60 mg/m2 plus cisplatin at a dose of 70 mg/m2 on day 1, or paclitaxel at a dose of 100 mg/m2 plus carboplatin at a dose of area under the plasma concentration-time curve = 2.5 on days 1 and 8 (both on 21-day cycles), between January 2000 and September 2021.ResultForty patients with ten adenoid cystic carcinomas and thirty other pathologies were identified. Of these, 29 patients were treated with docetaxel plus cisplatin and 11 with paclitaxel plus carboplatin. For the total population, the objective response rate (ORR) and median progression-free survival (mPFS) were 37.5% and 5.4 months (95% confidence interval: 3.6–7.4 months), respectively. On subgroup analysis, docetaxel plus cisplatin provided favorable efficacy compared with paclitaxel plus carboplatin (ORR: 46.5% vs. 20.0%, mPFS: 7.2 vs. 2.8 months), and the findings were well retained in patients with adenoid cystic carcinoma (ORR: 60.0% vs. 0%, mPFS: 17.7 vs. 2.8 months). Grade 3/4 neutropenia was relatively frequent in the docetaxel plus cisplatin (59% vs.27%), although febrile neutropenia was uncommon (3%) in the cohort. No treatment-related death was seen in any case.ConclusionThe combination of taxane and platinum is generally effective and well-tolerated for recurrent or metastatic salivary gland carcinoma. In contrast, paclitaxel plus carboplatin appears unfavorable in terms of efficacy in certain patients, such as those with adenoid cystic carcinoma.

Abstract Mutations within Superoxide dismutase 1 (SOD1) cause amyotrophic lateral sclerosis (ALS), accounting for approximately 20% of familial cases. The pathological feature is a loss of motor neurons with enhanced formation of intracellular misfolded SOD1. Homozygous SOD1-D90A in familial ALS has been reported to show slow disease progression. Here, we reported a rare case of a slowly progressive ALS patient harboring a novel SOD1 homozygous mutation D92G (homD92G). The neuronal cell line overexpressing SOD1-D92G showed a lower ratio of the insoluble/soluble fraction of SOD1 with fine aggregates of the misfolded SOD1 and lower cellular toxicity than those overexpressing SOD1-G93A, a mutation that generally causes rapid disease progression. Next, we analyzed spinal motor neurons derived from induced pluripotent stem cells (iPSC) of a healthy control subject and ALS patients carrying SOD1-homD92G or heterozygous SOD1-L144FVX mutation. Lower levels of misfolded SOD1 and cell loss were observed in the motor neurons differentiated from patient-derived iPSCs carrying SOD1-homD92G than in those carrying SOD1-L144FVX. Taken together, SOD1-homD92G has a lower propensity to aggregate and induce cellular toxicity than SOD1-G93A or SOD1-L144FVX, and these cellular phenotypes could be associated with the clinical course of slowly progressive ALS.

BackgroundProteinuria is the most frequent adverse event of lenvatinib use. However, the association between lenvatinib-induced proteinuria and renal dysfunction remains unclear.MethodsWe retrospectively reviewed medical records of patients with thyroid cancer without proteinuria treated with lenvatinib as a first-line systemic therapy at the initiation of treatment to assess the association between lenvatinib-induced proteinuria and renal function and the risk factors for the development of ≥3+ proteinuria on a dipstick test. Proteinuria was assessed by the dipstick test throughout the treatment in all cases.ResultsOf the 76 patients, 39 developed ≤2+ proteinuria (low proteinuria group) and 37 developed ≥3+ proteinuria (high proteinuria group). There was no significant difference in estimated glomerular filtration rate (eGFR) between high and low proteinuria groups at each time point, but there was a trend toward a significant decrease in eGFR of -9.3 ml/min/1.73 m2 in all patients after 2 years of treatment. The percentage of change in eGFR (ΔeGFR) significantly decreased in the high proteinuria group compared to that in the low proteinuria group (ΔeGFR: -6.8% vs. -17.2%, p=0.04). However, there was no significant difference in development of severe renal dysfunction with eGFR

Colorectal cancer (CRC) is one of the most common malignant diseases. Generally, stoma construction is performed following surgery for the resection of the primary tumor in patients with CRC. The association of CRC with the gut microbiota has been widely reported, and the gut microbiota is known to play an important role in the carcinogenesis, progression, and treatment of CRC. In this study, we compared the microbiota of patients with CRC between with and without a stoma using fecal metagenomic sequencing data from SCRUM-Japan MONSTAR-SCREEN, a joint industry-academia cancer research project in Japan. We found that the composition of anaerobes was reduced in patients with a stoma. In particular, the abundance of Alistipes, Akkermansia, Intestinimonas, and methane-producing archaea decreased. We also compared gene function (e.g., KEGG Orthology and KEGG pathway) and found that gene function for methane and short-chain fatty acids (SCFAs) production was underrepresented in patients with a stoma. Furthermore, a stoma decreased Shannon diversity based on taxonomic composition but increased that of the KEGG pathway. These results suggest that the feces of patients with a stoma have a reduced abundance of favorable microbes for cancer immunotherapy. In conclusion, we showed that a stoma alters the taxonomic and functional profiles in feces and may be a confounding factor in fecal microbiota analysis.

BackgroundThe addition of induction chemotherapy (IC) before chemoradiotherapy (CRT) has improved survival over CRT alone in locoregionally advanced nasopharyngeal cancer (LA-NPC). Nevertheless, this population would benefit from further development of a novel IC regimen with satisfactory efficacy and a more favorable safety profile.MethodsWe retrospectively assessed 29 LA-NPC patients who received the combination of paclitaxel (PTX), carboplatin (CBDCA), and cetuximab (Cmab) (PCE) as IC (IC-PCE) at the National Cancer Center Hospital East between March 2017 and April 2021. IC-PCE consisted of CBDCA area under the plasma concentration-time curve (AUC) = 1.5, PTX 80 mg/m2, and Cmab with an initial dose of 400 mg/m2 followed by 250 mg/m2 administered weekly for a maximum of eight weeks.ResultsPatient characteristics were as follows: median age, 59 years (range 24–75); 0, 1 performance status (PS), 25, 4 patients; and clinical stage III/IVA/IVB, 6/10/13. The median number of PCE cycles was 8(1-8). After IC-PCE, 26 patients received concurrent cisplatin and radiotherapy (CDDP-RT), one received concurrent carboplatin/5-fluorouracil and radiotherapy (CBDCA/5-FU-RT), and two received RT alone. The % completion of CDDP-RT was 88.5%. The response rate was 75.9% by IC and 100% at completion of CRT. The 3-year recurrence-free survival, locoregional failure-free survival, distant recurrence-free survival, and overall survival were 75.9%, 79.3%, 84.3%, and 96.3%, respectively. The incidence of adverse events of grade 3/4 was 34.5% during IC and 44.8% during CRT.ConclusionIC-PCE is feasible and effective for LA-NPC and may be a treatment option for this disease.

To prevent invasive pneumococcal disease (IPD), pneumococcal conjugate vaccines (PCVs) have been implemented in many countries; however, many cases of IPD still occur and can be attributable to nonvaccine serotypes of Streptococcus pneumoniae. In Japan, the number of IPD cases attributable to serotype 12F increased from 4.4% in 2015 to 24.6% in 2017 after 13-valent PCV was introduced. To clarify the associated genetic characteristics, we conducted whole-genome sequencing of 75 serotype 12F isolates. We identified 2 sequence types (STs) among the isolates: ST4846, which was the major type, and ST6945. Bayesian analysis suggested that these types diverged in »1942. Among serotype 12F-ST4846, we identified a major cluster, PC-JP12F, whose time of most recent common ancestor was estimated to be »2012. A phylogeographic analysis demonstrated that PC-JP12F isolates spread from the Kanto region, the most populated region in Japan, to other local regions.

Background: In the LIBERTY ASTHMA QUEST (ClinicalTrials.gov: NCT02414854) study, dupilumab 200 mg and 300 mg every 2 weeks vs matched-volume placebo reduced severe asthma exacerbations and improved lung function (FEV1), asthma control, and quality of life in patients with uncontrolled, moderate-to-severe asthma (N = 1902). Here, we examine the safety and efficacy of dupilumab in the subpopulation of Japanese patients who participated in QUEST (n = 114; 6%). Methods: Endpoints assessed were annualized severe exacerbation rates and the effect of treatment over the 52-week treatment period on FEV1, asthma control, asthma-related quality of life, and markers of type 2 inflammation. Results: In Japanese patients, dupilumab 200 and 300 mg every 2 weeks vs matched placebo reduced severe asthma exacerbation rates by 44% (P = 0.33) and 75% (P = 0.03), respectively, and improved FEV1 at Week 12 by 0.20 L (P = 0.05) and 0.17 L (P = 0.12). FEV1 improvements were rapid (by Week 2) and sustained throughout treatment. Significant and/or numerical improvements vs placebo in asthma control and quality of life were also observed throughout treatment. For each endpoint, greater efficacy was observed in patients with elevated baseline levels of type 2 inflammatory biomarkers (blood eosinophils or FeNO). Dupilumab treatment significantly reduced levels of FeNO and total IgE, but not blood eosinophils. Conclusions: In this subanalysis of QUEST, the efficacy and safety of dupilumab in Japanese patients was comparable to that observed in the overall intention-to-treat population, suggesting no variability in efficacy on the basis of Japanese ethnicity.(Funded by Sanofi and Regeneron Pharmaceuticals, Inc.; ClinicalTrials.gov number: NCT02414854)

The Japanese Guideline for Childhood Asthma (JGCA) 2020 is a translation of the Japanese Pediatric Guideline for the Treatment and Management of Asthma (JPGL) 2017 into English, which was published by the Japanese Society of Pediatric Allergy and Clinical Immunology. It makes recommendations for best practices in the management of childhood asthma, including management of acute exacerbations and non-pharmacological and pharmacological management. These guidelines will be of interest to non-specialist physicians involved in the care of children with asthma. In JPGL, JPGL2017 is the first evidence-based guidelines updated according to the GRADE system and Minds approach, and it addresses eight clinical questions about the treatment of childhood asthma. In children aged ≤5 years, infant and preschool asthma is diagnosed according to the response to short acting beta2 agonists or the effect of a therapeutic trial during 1 month with controller treatment and worsening after treatment cessation. Long-term management both promotes pharmacological therapy and measures against risk factors that induce exacerbation, better patient education and a partnership with trinity. In addition, long-term management should not be carried out without review but rather be based on a cycle of evaluation, adjustment and treatment. In JPGL2017, the transdermal patch and oral beta2 agonists are positioned as drugs within the concept of “short-term additional treatment” to be used until the symptoms are stabilized when the control state transiently deteriorates.

Atopic dermatitis (AD) is a disease characterized by relapsing eczema with pruritus as a primary lesion, which is frequently encountered in clinical practice. Skin barrier dysfunction leads to enhanced skin irritability to non-specific stimuli and epicutaneous sensitization. In the lesion site, a further inflammation-related reduction in skin barrier function, enhanced irritability and scratching-related stimuli deteriorate eczema, leading to vicious cycle of inflammation. The current strategies to treat AD in Japan from the perspective of evidence-based medicine consist of three primary measures: (i) the use of topical corticosteroids and tacrolimus ointment as the main treatment for the inflammation; (ii) topical application of emollients to treat the cutaneous barrier dysfunction; and (iii) avoidance of apparent exacerbating factors, psychological counseling and advice about daily life. The guidelines present recommendations to review clinical research articles, evaluate the balance between the advantages and disadvantages of medical activities, and optimize medical activity-related patient outcomes with respect to several important points requiring decision-making in clinical practice.

Five years have passed since the Japanese Pediatric Guideline for Food Allergy (JPGFA) was first revised in 2011 from its original version. As many scientific papers related to food allergy have been published during the last 5 years, the second major revision of the JPGFA was carried out in 2016. In this guideline, food allergies are generally classified into four clinical types: (1) neonatal and infantile gastrointestinal allergy, (2) infantile atopic dermatitis associated with food allergy, (3) immediate-type of food allergy (urticaria, anaphylaxis, etc.), and (4) special forms of immediate-type of food allergy such as food-dependent exercise-induced anaphylaxis and oral allergy syndrome (OAS). Much of this guideline covers the immediate-type of food allergy that is seen during childhood to adolescence. Infantile atopic dermatitis associated with food allergy type is especially important as the onset of most food allergies occurs during infancy. We have discussed the neonatal and infantile gastrointestinal allergy and special forms of immediate type food allergy types separately. Diagnostic procedures are highlighted, such as probability curves and component-resolved diagnosis, including the recent advancement utilizing antigen-specific IgE. The oral food challenge using a stepwise approach is recommended to avoid complete elimination of causative foods. Although oral immunotherapy (OIT) has not been approved as a routine treatment by nationwide insurance, we included a chapter for OIT, focusing on efficacy and problems. Prevention of food allergy is currently the focus of interest, and many changes were made based on recent evidence. Finally, the contraindication between adrenaline and antipsychotic drugs in Japan was discussed among related medical societies, and we reached an agreement that the use of adrenaline can be allowed based on the physician's discretion. In conclusion, this guideline encourages physicians to follow the principle to let patients consume causative foods in any way and as early as possible.

Abstract Background Several epidemiological studies have examined the possibility of a relationship between season of birth and atopic dermatitis (AD) and food allergy (FA), yet their results are contradictory. We investigated the association between season of birth and risk of AD and FA in Japanese infants. Methods Study subjects were 612 newborn infants born at a single obstetric/pediatric clinic without perinatal diseases. Season of birth was classified as spring (March–May), summer (June–August), autumn (September–November) or winter (December–February). AD was diagnosed according to the United Kingdom Working Party’s criteria. FA was defined as present if there was a history of immediate allergic symptoms within 2 h after ingestion of a food. Specific IgE to the corresponding food was also assessed to support the diagnosis. We assessed the association between season of birth and risk of AD and FA using Cox proportional hazard models. Results We identified a total of 365 cases of AD occurring during 3659 person-months of follow-up. Compared with summer birth, autumn, winter, and spring birth were significantly positively associated with the risk of AD: adjusted HRs (95% CIs) were 2.67 (1.96–3.63), 1.42 (1.03–1.95), and 1.43 (1.04–1.98), respectively. We identified a total of 23 cases of physician-diagnosed FA occurring during 6815 person-months of follow-up. Conclusions Being born in the summer is associated with a lower risk of AD compared to other seasons of birth. The low incidence of FA in our cohort group made it difficult to establish a valid association between FA and season of birth as the statistical power was low.

Abstract Background Induction chemotherapy (IC) in locally advanced squamous cell carcinoma of the head and neck (LA‐SCCHN) often compromises compliance with subsequent chemoradiotherapy (CRT), which negatively affects outcomes. Here, we assessed the combination of paclitaxel (PTX), carboplatin (CBDCA), and cetuximab (Cmab) as IC for unresectable LA‐SCCHN. Methods Induction chemotherapy consisted of weekly CBDCA area under the plasma concentration‐time curve = 1.5, PTX 80 mg/m2 and Cmab with an initial dose of 400 mg/m2 followed by 250 mg/m2 for 8 weeks. Following IC, CDDP (20 mg/m2, 4 days × 3 cycles) and concurrent radiotherapy (70 Gy/35 fr) were started. Primary endpoint was the proportion of CRT completion (%CRT completion). PCE was planned to be deemed effective if the Bayesian posterior probability (PP), defined as the probability that %CRT completion was larger than the threshold value of 65%, exceeded 84%. Results Thirty‐five patients were enrolled. Cases were hypopharynx/oropharynx/larynx in 17/17/1 patients, all at Stage IV. Of 35 patients, 34 (97%) completed IC and 32 received CRT and met the criteria of full analysis set (FAS). In FAS, the %CRT completion was 96.9%, and PP was 99.9%, exceeding the prespecified boundary of 84%. Mean cumulative dose and relative to dose intensity of CDDP in CRT was 232.5 mg/m2 and 100%, respectively. Response rate was 88.6% by IC and 93.8% in the CRT phase. Three year overall survival was 83.5%. Main grade 3 toxicities included neutropenia (11.4%) and skin rash (5.7%) during IC; and oral mucositis (31.3%) and neutropenia (12.5%) during CRT. No grade 4 toxicity or treatment‐related death was seen. Conclusions PCE as IC was feasible, with promising efficacy and no effect on compliance with subsequent CRT in unresectable LA‐SCCHN.

Food allergy is one of the major existing health problems, but no effective treatment is available. In the current work, a murine model that closely mimics pathogenesis of human food allergy and its quantifiable diagnostic parameter design, even for mild hypersensitivity reactions, were established. BALB/c mice were epicutaneously sensitized with 1 mg chicken egg ovomucoid (OVM) or cow’s milk casein, free of adjuvants, five times a week for two consecutive weeks. Eleven days later, allergen-specific IgG1 and IgE in serum were measured by ELISA. On day 25, 20 mg OVM or 12 mg α-casein was administered orally, and allergic reactions such as the fall in rectal temperature, symptom scores during 90–120 min, serum mast cell protease-1 and cytokine levels were monitored. The detection of mild allergic reactions due to adjuvant-free allergen sensitization and oral allergen challenge routes was amplified by the combination of oral allergen and aspirin administration simultaneously or aspirin administration within 15–30 min before an allergen challenge. Quantification of the maximum symptom score and the frequency of symptoms during the monitoring period improved evaluation accuracy of food allergy signals. Based on these results, efficacy of casein oral immunotherapy for cow’s milk allergies, which are generally difficult to detect, was monitored adequately.

Background: Recent studies indicate that the timing of introduction of potentially allergenic food is crucial for the development of food allergy in children. This cross-sectional study aimed to clarify the reality of allergen food intake in a general population of young children in Japan. Methods: A questionnaire survey of caregivers was conducted at health checkups for 1.5-year (18-month)-old and 3-year-old children in the fall of 2020. The caregivers were asked about (1) the presence/absence of allergic disease symptoms based on the ISAAC questionnaire, and (2) foods that caregivers avoided giving their children. Ordinal logistic regression analyses were periformed to determine factors associated with food avoidance. Results: Questionnaires were distributed to 1720 caregivers, and 1603 (93%) responded. The responders consisted of 771 and 832 caregivers who participated in 1.5-year-old and 3-year-old checkups, respectively. The prevalence of allergic diseases was comparable to recent epidemiological studies in Japan, indicating that the population may be representative. At 1.5 years old, more than 50% of the children were not exposed to peanuts, tree nuts, fish eggs, shellfish, and buckwheat. At 3 years old, the avoidance rates of the foods had decreased but were still between 18.8% and 32.0%. On the other hand, the avoidance rates of chicken egg and cow’s milk, the top 2 common allergenic foods in Japan, were much lower at 2.8% and 1.5% at 1.5 years, and they decreased to 1.4% and 0.7% at 3 years old, respectively. Ordinal logistic analysis showed that avoidance of chicken egg, cow’s milk, and wheat was associated with food allergy diagnosis and chicken egg avoidance with eczema, but avoidance of other foods showed no associations with any risk factors for food allergy. Conclusion: Caregivers avoided giving various foods, independent of allergy risk factors, to their young children. Since delayed introduction of an allergenic food has been reported to increase the risk of developing an allergy to the food, the results warrant future investigation of the development of food allergies in relation to current eating habits and recommendations.

Abstract We report the first Japanese case of primary ciliary dyskinesia caused by DNAH9 variations. The patient, a 5-year-old girl, had repeated episodes of productive cough after contracting the common cold at the age of 1 year and 6 months. She did not have a situs abnormality or congenital heart defect. We identified two novel DNAH9 variants, NM_001372.3: c. [1298C>G];[5547_5550delTGAC], (p.[Ser433Cys];[Asp1850fs]).

Background: Childhood asthma is a major risk for low lung function in later adulthood, but what factors in asthma are associated with the poor lung function during childhood is not known. Objective: To identify clinical factors in children with asthma associated with low or declining lung function during the treatment. Methods: We enrolled children with asthma who had been treated throughout three age periods, i.e., 6–9, 10–12, and 13–15 years old, at seven specialized hospitals in Japan. Clinical information and lung function measurements were retrieved from the electronic chart systems. To characterize the lung function trajectories during each age period, we evaluated the forced expiratory volume 1 (FEV1) with % predicted values and individual changes by the slope (S) from linear regression. We defined four trajectory patterns: normal (Group N) and low (Group L), showing %FEV1 ≥80% or n = 150)/U (n = 47), while 76 (28%) were in Group D (n = 66)/L (n = 10). A history of poor asthma control, long-acting beta2 agonist use, and a lower height Z-score during 13–15 years were associated with an unfavorable outcome (Group D/L). Conversely, inhaled corticosteroid (ICS) use during 10–12 years and high-dose ICS use during 13–15 years were associated with a favorable outcome (Group N/U). Conclusion: We identified several factors that are associated with unfavorable lung function changes in pediatric asthma. Attention should be paid to the possible relationship between yearly changes in lung function and poor asthma control, use of ICS (and its dose) and use of LABA.

Background: Although the guidelines in most countries do not recommend continuous inhalation of l-isoproterenol to treat pediatric patients with acute severe exacerbation of asthma, lower dose of l-isoproterenol has been widely used in Japan. To determine whether the efficacy of low-dose l-isoproterenol was superior to that of salbutamol, we conducted a double-blind, randomized controlled trial. Methods: Hospitalized patients aged 1–17 years were eligible if they had severe asthma exacerbation defined by the modified pulmonary index score (MPIS). Patients were randomly assigned (1:1) to receive inhalation of l-isoproterenol (10 μg/kg/h) or salbutamol (500 μg/kg/h) for 12 hours via a large-volume nebulizer with oxygen. The primary outcome was the change in MPIS from baseline to 3 hours after starting inhalation. Trial registration number UMIN000001991. Results: From December 2009 to October 2013, 83 patients (42 in the l-isoproterenol group and 41 in the salbutamol group) were enrolled into the study. Of these, one patient in the l-isoproterenol group did not receive the study drug and was excluded from the analysis. Compared with salbutamol, l-isoproterenol reduced MPIS more rapidly. Mean (SD) changes in MPIS at 3 hours were −2.9 (2.5) in the l-isoproterenol group and −0.9 (2.3) in the salbutamol group (difference −2.0, 95% confidence interval −3.1 to −0.9; P

Background: Allergen-specific immunotherapy is currently the only disease-modifying treatment for allergic asthma, and it has been shown to improve control of asthma while reducing both drug use and asthma exacerbations. However, its effects on lung function—especially its long-term effects—remain controversial. We aimed to identify factors associated with a possible beneficial effect of allergen-specific immunotherapy on lung function in asthma by retrospectively evaluating the long-term changes in lung function in children with asthma who received house dust mite subcutaneous immunotherapy (HDM-SCIT). Methods: We enrolled children with asthma who had undergone HDM-SCIT for more than 1 year. Clinical information and lung function measurements were retrieved from the electronic chart system. To characterize the trajectory of lung function change, we performed linear regression analysis to evaluate the maximal expiratory flow at 50% of the forced vital capacity during two periods: before and during HDM-SCIT. Slopes from a least-squares regression line for the two periods, i.e., S1 before HDM-SCIT and S2 during HDM-SCIT, were compared. The subjects were then classified into two groups: an improving group (Group I) defined as S2 − S1 > 0, and a declining group (Group D) defined as S2 − S1 < 0. The clinical factors at the start of HDM-SCIT were compared between the two groups. Results: A total of 16 patients were analyzed. Eight patients were classified into each of Group I and Group D. The mean ages were 10.5 and 11.8 years, and the mean treatment periods were 4.1 and 3.9 years. Group I had a significantly lower blood eosinophil count and a significantly higher HDM-specific IgE level than Group D. Logistic regression showed a strong relationship between those two markers and the lung function trajectory. Conclusion: Control of the blood eosinophil count in highly HDM-sensitized patients may increase the beneficial effect of HDM-SCIT on lung function.

Background: Platinum-containing doublet chemotherapy regimens are generally considered the standard first-line systemic therapy for recurrent or metastatic (R/M) nasopharyngeal cancer (NPC). Gemcitabine (GEM) plus cisplatin (CDDP) has become a standard therapy based on a phase 3 study in several countries, yet this regimen sometimes affects quality of life due to nausea or appetite loss. Here, we present the manageable toxicity and promising activity of paclitaxel + carboplatin + cetuximab (PCE) therapy for R/M NPC.Materials and Methods: We conducted a retrospective review of patients with R/M NPC who were treated with PCE from 2013 to 2019 at the National Cancer Center East, Kashiwa, Japan. PCE consisted of PTX 100 mg/m2 on days 1 and 8; CBDCA area under the blood concentration–time curve (AUC) 2.5 on days 1 and 8, repeated every 3 weeks; and cetuximab at an initial dose of 400 mg/m2, followed by 250 mg/m2 weekly, as reported in the paper.Results: Fourteen patients were identified, consisting of 10 males and 4 females with a median age 59.6 years (range, 43–74). Among the 12 of 14 patients assessed for efficacy, overall response rate was 58.3%, with 2 complete responses and 5 partial responses. On median follow-up of 23.8 months, median overall survival was not reached with observed death events of 2. Median PFS was 4.1 months (95% CI, 2.6–5.6 months). Two patients experienced disease progression during cetuximab maintenance and restarted PCE treatment, then achieved partial response again. The most common grade 3 or 4 adverse events were neutropenia (21.4%) and skin reaction (14.3%). No treatment-related death was observed.Conclusion: Although the number of study population was small, our results suggest that PCE is feasible and potentially effective for R/M NPC, with a 58.3% response rate and 4.1-month PFS. Further prospective evaluation is warranted.

Background: Generally, oral immunotherapy (OIT) aims for daily administration. Recently, the efficacy of treatment with OIT at a low dose has been reported. However, the optimal dose and the evaluation of dose-dependent OIT outcome have not been described. Methods: A multicenter, parallel, open-labeled, prospective, non-placebo controlled, randomized study enrolled 101 Japanese patients for treatment with OIT. We hypothesized that target dose OIT would induce short-term unresponsiveness (StU) earlier than reduced dose OIT. StU was defined as no response to 6200 mg whole egg, 3400 mg milk, and 2600 mg wheat protein, as evaluated by oral food challenge after 2-week ingestion cessation. To compare the two doses of OIT efficacy, the maximum ingestion doses during the maintenance phase of OIT were divided into 100%-dose or 25%-dose groups against their target StU dose, respectively. A total of 51 patients were assigned to the 100%-dose group [hen's egg (HE) = 26, cow's milk (CM) = 13, wheat = 12] and 50 to the 25%-dose group (HE = 25, CM = 13, wheat = 12). Primary outcome was established by comparing StU at 1 year. Secondary outcome was StU at 2 years and established by comparing allergic symptoms and immunological changes. Results: The year 1 StU rates (%) for the 100%- and 25%-dose groups were 26.9 vs. 20.0 (HE), 7.7 vs. 15.4 (CM), and 50.0 vs. 16.7 (wheat), respectively. The year 2 StU rates were 30.8 vs. 36.0 (HE), 7.7 vs. 23.1 (CM), and 58.3 vs. 58.3 (wheat), respectively. There were no statistically significant differences in StU between years 1 and 2. The total allergic symptom rate in the 25%-dose group was lower than that in the 100%-dose group for egg, milk, and wheat. Antigen-specific IgE levels for egg-white, milk, and wheat decreased at 12 months. Conclusions: Reduced maintenance dose of egg OIT showed similar therapeutic efficacy to the target dose. However, we were not able to clearly demonstrate the efficacy, particularly for milk and wheat. Reducing the maintenance dose for eggs, milk, and wheat may effectively lower the symptoms associated with their consumption compared to the target OIT dose. Furthermore, aggressive reduction of the maintenance dose might be important for milk and wheat, compared to the 25%-dose OIT. Trial registration: UMIN000009373, Multicenter Oral Immunotherapy for Hen's Egg, Cow's Milk, and Wheat-Allergic Children at Outpatient Clinic.

Objectives: Nivolumab, a fully IgG4-programmed death-1 inhibitor antibody, led to improved overall survival compared with single-agent therapy in patients with platinum-refractory recurrent head and neck cancers. In general, nivolumab is used in inoperable patients. To the best of our knowledge, there have been no reports of salvage surgery during nivolumab therapy for patients with head and neck cancer. We report the case of a woman treated with salvage reconstructive surgery during nivolumab therapy. Method: Case report and literature review. Results: The patient underwent nivolumab therapy for recurrent primary and neck disease after induction chemotherapy, followed by concurrent chemoradiation therapy. The neck disease shrunk, whereas the primary disease temporarily shrunk but later progressed again. Recurrent primary disease led to a narrowing of her airway, and she required airway management. We performed total pharyngolaryngectomy with free jejunal reconstruction, and her quality of life improved. The surgery was performed without complications and the postoperative course was uneventful. She was discharged postoperative day 18 with oral intake function and a safer airway. Conclusion: As far as we know, this is the first report of salvage surgery during nivolumab therapy for patients with head and neck cancer. The salvage reconstructive surgery in this case proceeded uneventfully.

Abstract Background Primary ciliary dyskinesia (PCD) is a rare genetic disorder caused by functional impairment of cilia throughout the body. The involvement of copy number variation (CNV) in the development of PCD is largely unknown. Methods We examined 93 Japanese patients with clinically suspected PCD from 84 unrelated families. CNV was examined either by exome sequencing of a PCD gene panel or by whole‐exome sequencing (WES). The identified alterations were validated by PCR and Sanger sequencing. Nasal ciliary ultrastructure was examined by electron microscopy. Results Analysis of CNV by the panel or WES revealed a biallelic deletion in the dynein regulatory complex subunit 1 (DRC1) gene in 21 patients, which accounted for 49% of the PCD patients in whom a disease‐causing gene was found. Sanger sequencing of the PCR product revealed a 27,748‐bp biallelic deletion including exons 1–4 of DRC1 with identical breakpoints in all 21 patients. The ciliary ultrastructure of the patients with this CNV showed axonemal disorganization and the loss or gain of central microtubules. Conclusion The deletion of DRC1 is the major cause of PCD in Japan and this alteration can cause various ciliary ultrastructural abnormalities.

Amyotrophic lateral sclerosis (ALS) is a neurological disease that leads to loss of voluntary muscle movement. Here, the authors screen for molecules that disrupt interaction between SOD1, a protein linked to ALS, and Derlin-1, and find an inhibitor that reduces pathology in an ALS mouse model.

Background: Clinical trials on oral immunotherapy (OIT) have been increasing for nearly a decade; however, several national guidelines do not recommend OIT as a standardized procedure. The aim of this study was to obtain insights into the current use and practice of OIT in Japan. Methods: A first questionnaire was mailed to 524 training and teaching facilities of the Japan Pediatric Society. The first survey requested information on the implementation of OIT, whereas the second survey aimed to gather more detailed information on OIT, such as its safety. Results: In total, 360 facilities (69%) responded to the survey; among them, 102 (28%) provided OIT to 7973 patients [1544 received OIT while hospitalized (inpatient OIT), whereas 6429 received OIT without hospitalization (outpatient OIT)]. Approval for OIT was obtained from an ethics committee or institutional review board in 89% and 31% of facilities for inpatient and outpatient OIT, respectively. In inpatient OIT, immediate allergic reactions requiring treatment occurred in 68% of patients while hospitalized, and in another 56%, following discharge. In contrast, 11% of patients developed immediate allergic reactions in outpatient OIT. Adrenaline injections at home were required in 2%. Sixteen patients developed adverse reactions other than immediate allergic reactions, among which eosinophilic gastroenteritis was most common. Conclusions: OIT is widely provided not only as clinical research but also as general practice in Japan. However, because there is a high risk of developing anaphylaxis at home, OIT should be conducted carefully as in a clinical research setting taking safety into consideration. Keywords: Anaphylaxis, Desensitization, Food hypersensitivity, Oral immunotherapy, Questionnaires

Background: To evaluate the long-term safety of subcutaneous immunotherapy with TO-204, a standardized house dust mite (HDM) allergen extracts, we conducted a multicenter, open label clinical trial. Methods: Japanese patients aged 5–65 years were eligible for the study, if they had HDM-induced allergic rhinitis (AR), allergic bronchial asthma (BA), or both. TO-204 was administered in a dose titration scheme, and the maintenance dose was determined according to the predefined criteria. The treatment period was 52 weeks, and patients who were willing to continue the treatment received TO-204 beyond 52 weeks. This clinical trial is registered at the Japan Pharmaceutical Information Center (Japic CTI-121900). Results: Between July 2012 and May 2015, 44 patients (28 with AR and 16 with allergic BA) were enrolled into the study. All patients were included in the analysis. The duration of treatment ranged from 23 to 142 weeks and the median maintenance dose was 200 Japanese allergy units (JAU). Adverse events occurred in 22 patients (50%). The most common adverse event was local reactions related to the injection sites. Four patients experienced anaphylactic reactions when they were treated with the dose of 500 JAU. Two patients experienced anaphylactic shock with the doses of 1000 JAU at onset. These 6 patients could continue the study with dose reduction. Conclusions: Safety profile of TO-204 was acceptable in Japanese patients with HDM-induced AR or allergic BA. Higher doses should be administered carefully, because the risk of anaphylaxis increased at doses of 500 or 1000 JAU. Keywords: Allergen immunotherapy, Allergic bronchial asthma, Allergic rhinitis, Clinical trial, House dust mite

Background: Patients with food allergies and their families have a significantly reduced health-related quality of life (QOL). Methods: We performed a multicenter, randomized, parallel-group, delayed-start design study to clarify the efficacy and safety of rush oral immunotherapy (rOIT) and its impact on the participants' daily life and their guardians (UMIN000003943).Forty-five participants were randomly divided into an early-start group and a late-start group. The early-start group received rOIT for 3 months, while the late-start group continued the egg elimination diet (control). In the next stage, both groups received OIT until all participants had finished 12 months of maintenance OIT. Results: The ratio of the participants in whom an increase of the TD was achieved in the first stage was significantly higher in the early-start group (87.0%), than in the late-start group (22.7%). The QOL of the guardians in the early-start group significantly improved after the first stage (65.2%), in comparison to the late-start group (31.8%). During 12 months of rOIT, the serum ovomucoid-specific IgE levels, the percentage of CD203c+ basophils upon stimulation with egg white, and the wheal size to egg white were decreased, while the serum ovomucoid-specific IgG4 levels were increased. However, approximately 80% of the participants in the early-start group showed an allergic reaction during the first stage of the study, whereas none of the patients in the late-start group experienced an allergic reaction. Conclusions: rOIT induced desensitization to egg and thus improved the QOL of guardians; however, the participants experienced frequent allergic reactions due to the treatment. Keywords: Desensitization, Food allergy, Guardians, Oral immunotherapy, Quality of life

After the introduction of pneumococcal conjugate vaccines, the incidence of pneumococcal infections due to meropenem-resistant serotype 15A-ST63 strains increased in Japan. By using whole-genome sequencing and comparing sequences with those of clones from the United Kingdom, the United States, and Canada, we clarified the traits of the serotype 15A-ST63 clone. Our analysis revealed that the meropenem-resistant serotype 15A-ST63 strains from Japan originated from meropenem-susceptible strains from Japan. Recombination site prediction analysis showed that the meropenem-resistant strain-specific recombination regions included the pbp1a and pbp2b regions. A detailed analysis of the composition of these genes indicated that resistance seems to be caused by pbp1a recombination. The pbp1a gene in meropenem-resistant isolates was identical to that in multidrug (including meropenem)–resistant serotype 19A-ST320 pneumococci, which have spread in the United States. The global spread of pneumococci of this lineage is noteworthy because serotype 15A is not included in the currently used 13-valent pneumococcal conjugate vaccine.

Background: While Japanese guideline recommends initial control treatment for preschool children with asthma symptoms more than once a month, Western guidelines do not. To determine whether control treatment with montelukast was more effective than as-needed β2-agonists in this population, we conducted a randomized controlled trial. Methods: Eligible patients were children aged 1–5 years who had asthma symptoms more than once a month but less than once a week. Patients were randomly assigned in a 1:1 ratio to receive montelukast 4 mg daily for 48 weeks or as-needed β2-agonists. The primary endpoint was the number of acute asthma exacerbations before starting step-up treatment with inhaled corticosteroids. This study is registered with the University Hospital Medical Information Network clinical trials registry, number UMIN000002219. Results: From September 2009 to November 2012, 93 patients (47 in the montelukast group and 46 in the no-controller group) were enrolled into the study. All patients were included in the analysis. During the study, 13 patients (28%) in the montelukast group and 23 patients (50%) in the no-controller group had acute exacerbations with the mean numbers of 0.9 and 1.9/year, respectively (P = 0.027). In addition, 10 (21%) and 19 (41%) patients received step-up treatment, respectively. Cumulative incidence of step-up treatment was significantly lower in the montelukast group (hazard ratio 0.45, 95% confidence interval 0.21 to 0.92; P = 0.033). Conclusions: Montelukast is an effective control treatment for preschool children who had asthma symptoms more than once a month but less than once a week.

Background: In September 2015, Japan experienced an unusual increase in acute asthma hospitalizations of children that coincided with an enterovirus D68 (EV-D68) epidemic. The objective of this study is to investigate whether EV-D68 had a causal relationship with the spike in asthma hospitalizations. Methods: A nation-wide retrospective survey of asthma hospitalizations of children was performed for the period from January 2010 through October 2015. The Japanese Society of Pediatric Allergy and Clinical Immunology asked its affiliated hospitals to report monthly numbers of hospitalizations, ICU admissions and mechanical ventilations due to acute asthma exacerbation. The data were retrieved from medical databases using predefined search criteria: diagnosis of asthma or asthmatic bronchitis, admission, and age

Background: Eosinophils play important roles in asthma, especially airway remodeling, by producing various granule proteins, chemical mediators, cytokines, chemokines and proteases. However, protease production by eosinophils is not fully understood. In the present study, we investigated the production of eosinophil-specific proteases/proteinases by transcriptome analysis. Methods: Human eosinophils and other cells were purified from peripheral blood by density gradient sedimentation and negative/positive selections using immunomagnetic beads. Protease/proteinase expression in eosinophils and release into the supernatant were evaluated by microarray analysis, qPCR, ELISA, flow cytometry and immunofluorescence staining before and after stimulation with eosinophil-activating cytokines and secretagogues. mRNAs for extracellular matrix proteins in human normal fibroblasts were measured by qPCR after exposure to recombinant protease serine 33 (PRSS33) protein (rPRSS33), created with a baculovirus system. Results: Human eosinophils expressed relatively high levels of mRNA for metalloproteinase 25 (MMP25), a disintegrin and metalloprotease 8 (ADAM8), ADAM10, ADAM19 and PRSS33. Expression of PRSS33 was the highest and eosinophil-specific. PRSS33 mRNA expression was not affected by eosinophil-activating cytokines. Immunofluorescence staining showed that PRSS33 was co-localized with an eosinophil granule protein. PRSS33 was not detected in the culture supernatant of eosinophils even after stimulation with secretagogues, but its cell surface expression was increased. rPRSS33 stimulation of human fibroblasts increased expression of collagen and fibronectin mRNAs, at least in part via protease-activated receptor-2 activation. Conclusions: Activated eosinophils may induce fibroblast extracellular matrix protein synthesis via cell surface expression of PRSS33, which would at least partly explain eosinophils' role(s) in airway remodeling.

Abstract Background Epithelial-mesenchymal transition is currently recognized as an important mechanism for the increased number of myofibroblasts in cancer and fibrotic diseases. We have already reported that epithelial-mesenchymal transition is involved in airway remodeling induced by eosinophils. Procaterol is a selective and full β2 adrenergic agonist that is used as a rescue of asthmatic attack inhaler form and orally as a controller. In this study, we evaluated whether procaterol can suppress epithelial-mesenchymal transition of airway epithelial cells induced by eosinophils. Methods Epithelial-mesenchymal transition was assessed using a co-culture system of human bronchial epithelial cells and primary human eosinophils or an eosinophilic leukemia cell line. Results Procaterol significantly inhibited co-culture associated morphological changes of bronchial epithelial cells, decreased the expression of vimentin, and increased the expression of E-cadherin compared to control. Butoxamine, a specific β2-adrenergic antagonist, significantly blocked changes induced by procaterol. In addition, procaterol inhibited the expression of adhesion molecules induced during the interaction between eosinophils and bronchial epithelial cells, suggesting the involvement of adhesion molecules in the process of epithelial-mesenchymal transition. Forskolin, a cyclic adenosine monophosphate-promoting agent, exhibits similar inhibitory activity of procaterol. Conclusions Overall, these observations support the beneficial effect of procaterol on airway remodeling frequently associated with chronic obstructive pulmonary diseases.

Background: Food allergy (FA) is a heavy burden for patients and their families and can significantly reduce the quality of life (QoL) of both. To provide adequate support, qualitative and quantitative evaluation of the parents' QoL may be helpful. The objective of this study is to develop and validate a Japanese version of the Food Allergy QoL Questionnaire–Parent Form (FAQLQ-PF-J), an internationally validated disease-specific QoL measurement of the parental burden of having a child with FA. Methods: The FAQLQ-PF and the Food Allergy Independent Measure (FAIM), an instrument to test the construct validity of the FAQLQ-PF-J, were translated into Japanese. After language validation, the questionnaires were administered to parents of FA children aged 0–12 years and those of age-matched healthy (without FA) children. Internal consistency (by Cronbach's α) and test-retest reliability were evaluated. Construct validity and discriminant validity were also examined. Results: One hundred twenty-seven parents of children with FA and 48 parents of healthy children filled out the questionnaire. The FAQLQ-PF-J showed excellent internal consistency (Cronbach's α > 0.77) and test-retest reliability. Good construct validity was demonstrated by significant correlations between the FAQLQ-PF-J and FAIM-J scores. It discriminated parents of children with FA from those without. The scores were significantly higher (lower QoL) for parents of FA children with a history of anaphylaxis than those without, for those with >6 FA-related symptoms experienced than those with less FA-related symptoms. Conclusions: The FAQLQ-PF-J is a reliable and valid measure of the parental burden of FA in children.