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Wheat-dependent exercise-induced anaphylaxis (WDEIA) is a life-threatening food allergy triggered by wheat in combination with the second factor such as exercise. The identification of potential genetic risk factors for this allergy might help high-risk individuals before consuming wheat-containing food. We aimed to identify genetic variants associated with WDEIA. A genome-wide association study was conducted in a discovery set of 77 individuals with WDEIA and 924 control subjects via three genetic models. The associations were confirmed in a replication set of 91 affected individuals and 435 control individuals. Summary statistics from the combined set were analyzed by meta-analysis with a random-effect model. In the discovery set, a locus on chromosome 6, rs9277630, was associated with WDEIA in the dominant model (OR = 3.95 [95% CI, 2.31-6.73], p = 7.87 × 10 -8 ). The HLA-DPB1 ∗ 02:01:02 allele displayed the most significant association with WDEIA (OR = 4.51 [95% CI, 2.66-7.63], p = 2.28 × 10 -9 ), as determined via HLA imputation following targeted sequencing. The association of the allele with WDEIA was confirmed in replication samples (OR = 3.82 [95% CI, 2.33-6.26], p = 3.03 × 10 -8 ). A meta-analysis performed in the combined set revealed that the HLA-DPB1 ∗ 02:01:02 allele was significantly associated with an increased risk of WDEIA (OR = 4.13 [95% CI, 2.89-5.93], p = 1.06 × 10 -14 ). Individuals carrying the HLA-DPB1 ∗ 02:01:02 allele have a significantly increased risk of WDEIA. Further validation of these findings in independent multiethnic cohorts is needed., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Ovarian metastasis (OM) from breast cancer accounts for 3-38% of all ovarian neoplasms and is associated with various characteristic clinical presentations, such as pseudo-Meigs syndrome and Krukenberg tumor. Accurate diagnosis of OM may be challenging, as such lesions are frequently asymptomatic until they reach a large size. Occasionally, metastatic ovarian cancer is detected prior to the diagnosis of the primary tumor. Immunohistochemistry plays an important role in distinguishing primary ovarian tumors from extraovarian tumor metastases and may be helpful for identifying the primary tumor site. We herein report a case of OM from breast cancer masquerading as primary ovarian cancer. However, the correct diagnosis was made based on histopathological and immunohistochemical examinations. The patient had bilateral breast cancer, namely invasive lobular carcinoma of the left breast and ductal carcinoma of the right breast. Due to the presence of bilateral synchronous breast tumors, the possibility that the patient had hereditary breast and ovarian cancer syndrome or other relevant genetic factors was considered. Immunohistochemistry plays a key role in distinguishing between primary ovarian tumors and OM, and it was also important for confirming the metastatic nature of the ovarian lesion and diagnosing the primary tumor in the present study., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Akizawa et al.)

Murine models to elucidate the pathogenesis of pollen food allergy syndrome (PFAS), characterized by oral hypersensitivity symptoms induced by specific foods in patients previously sensitized with a pollen, are lacking. The study aimed to examine PFAS pathogenesis in a novel murine model. Birch pollen-immunized mice were orally administered apple extract, and oral symptoms were evaluated based on oral rubbing frequency following the challenge. The birch pollen-immunized mice orally challenged with apple extract exhibited PFAS-like symptoms, including oral rubbing and positive reaction of swelling by the prick test. The apple extract administered with a protease inhibitor reduced the oral rubbing frequency, which was also significantly reduced in the immunized Fcer1a -/- and mast cell-deficient mice compared with the immunized control mice. The oral rubbing frequency, serum IgE levels, and Th2-cytokine production by the cervical lymph node cells were significantly reduced in the immunized Il-33 -/- and thymic stromal lymphopoietin receptor-deficient ( Crlf2 -/- ) mice as compared with the immunized wild-type mice. IL-33 and thymic stromal lymphopoietin involve the pathogenesis of PFAS. The apple-extract stimulation did not lead to increased Th2-cytokine production in the oral mucosa or number of group 2 innate lymphoid cells or eosinophils. PFAS involves an early-phase response by mast cell degranulation via IgE signaling after the cross-reactivity of Bet v 1-specific IgE and the food allergen, and exacerbation of allergic symptom via proteases in food; PFAS does not involve a late phase with local Th2/eosinophilic inflammation in the oral mucosa. This novel murine model might be used for elucidating the pathogenesis and assessing new therapeutic strategies for PFAS., (Copyright © 2021 by The American Association of Immunologists, Inc.)

Purpose: Anaplastic lymphoma kinase ( ALK ) rearrangement is a well-known driver oncogene in non-small-cell lung cancer and has also been identified in other types of tumors. However, there is limited evidence on the clinical response to ALK tyrosine kinase inhibitors (TKIs), such as alectinib and crizotinib, in rare tumors with ALK fusion. We evaluated the therapeutic effect of ALK-TKIs in rare ALK -rearranged tumors., Patients and Methods: Between April 2012 and April 2019, clinical outcomes and characteristics of patients with ALK -rearranged nonlung solid tumors who received ALK-TKIs (alectinib and/or crizotinib) outside of clinical trials were reviewed. Expression and/or rearrangement of ALK was evaluated by immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing. The tumor response was assessed according to RECIST (version 1.1). Progression-free survival was estimated from initial ALK-TKI initiation until progression., Results: We identified seven patients (inflammatory myofibroblastic tumors, n = 3; ALK-positive histiocytosis, n = 1; histiocytic sarcoma, n = 1; osteosarcoma, n = 1; and parotid adenocarcinoma, n = 1), with a median age of 17 years. Two rare ALK fusions, namely, CTNNA1-AL K and ITSN2-ALK , were identified. As initial ALK-TKI therapy, five patients received alectinib and two received crizotinib. The objective response rate for the initial ALK-TKI therapy was 85.7% (95% CI, 44 to 97), including two patients who received alectinib and achieved complete response. The median progression-free survival was 8.1 months (range, 1.7 to not estimable). There were no treatment interruptions or dose reductions because of adverse events caused by alectinib., Conclusion: This study highlights the potential benefit of ALK-TKIs, especially alectinib, in patients with ALK -rearranged nonlung solid tumors., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Tadaaki Nishikawa Honoraria: AstraZeneca, Eisai Consulting or Advisory Role: Eisai Speakers' Bureau: AstraZeneca, EisaiKazuki Sudo Honoraria: AstraZeneca, PfizerEmi Noguchi Honoraria: Nippon Kayaku Speakers' Bureau: Sysmex, AstraZeneca, Pfizer, Eisai, Lilly Japan, Taiho Pharmaceutical, Chugai PharmaAyumu Arakawa Research Funding: Chugai Pharma Travel, Accommodations, Expenses: AmgenKuniko Sunami Honoraria: Sysmex, Chugai Pharma, AstraZeneca, Novartis, Eisai, Riken Genesis, LillyTakashi Kubo Consulting or Advisory Role: SysmexTakashi Kohno Consulting or Advisory Role: LOXO Oncology, Lilly Japan Research Funding: Daiichi Sankyo, SysmexNoboru Yamamoto Honoraria: AstraZeneca, Pfizer, Chugai Pharma, Bristol Myers Squibb Japan, Ono Pharmaceutical, Lilly Japan, Sysmex Consulting or Advisory Role: Eisai, Takeda, Otsuka, Boehringer Ingelheimm, CMIC, Chugai Pharma Research Funding: Chugai Pharma, Taiho Pharmaceutical, Eisai, Astellas Pharma, Novartis, Daiichi Sankyo, Lilly Japan, Boehringer Ingelheim, Takeda, Kyowa Hakko Kirin, Bayer, Pfizer, Ono Pharmaceutical, Janssen, IQVIA, Merck Sharp & Dohme, Abbvie, Bristol Myers Squibb, Merck Serono, GlaxoSmithKline, Sumitomo Dainippon, Chiome Bioscience, OtsukaKan Yonemori Honoraria: Eisai, Pfizer, AstraZeneca, Novartis, Taiho Pharmaceutical Consulting or Advisory Role: Chugai Pharma, Ono Pharmaceutical, Novartis, Eisai Research Funding: Ono Pharmaceutical No other potential conflicts of interest were reported.Tadaaki Nishikawa Honoraria: AstraZeneca, Eisai Consulting or Advisory Role: Eisai Speakers' Bureau: AstraZeneca, Eisai Kazuki Sudo Honoraria: AstraZeneca, Pfizer Emi Noguchi Honoraria: Nippon Kayaku Speakers' Bureau: Sysmex, AstraZeneca, Pfizer, Eisai, Lilly Japan, Taiho Pharmaceutical, Chugai Pharma Ayumu Arakawa Research Funding: Chugai Pharma Travel, Accommodations, Expenses: Amgen Kuniko Sunami Honoraria: Sysmex, Chugai Pharma, AstraZeneca, Novartis, Eisai, Riken Genesis, Lilly Takashi Kubo Consulting or Advisory Role: Sysmex Takashi Kohno Consulting or Advisory Role: LOXO Oncology, Lilly Japan Research Funding: Daiichi Sankyo, Sysmex Noboru Yamamoto Honoraria: AstraZeneca, Pfizer, Chugai Pharma, Bristol Myers Squibb Japan, Ono Pharmaceutical, Lilly Japan, Sysmex Consulting or Advisory Role: Eisai, Takeda, Otsuka, Boehringer Ingelheimm, CMIC, Chugai Pharma Research Funding: Chugai Pharma, Taiho Pharmaceutical, Eisai, Astellas Pharma, Novartis, Daiichi Sankyo, Lilly Japan, Boehringer Ingelheim, Takeda, Kyowa Hakko Kirin, Bayer, Pfizer, Ono Pharmaceutical, Janssen, IQVIA, Merck Sharp & Dohme, Abbvie, Bristol Myers Squibb, Merck Serono, GlaxoSmithKline, Sumitomo Dainippon, Chiome Bioscience, Otsuka Kan Yonemori Honoraria: Eisai, Pfizer, AstraZeneca, Novartis, Taiho Pharmaceutical Consulting or Advisory Role: Chugai Pharma, Ono Pharmaceutical, Novartis, Eisai Research Funding: Ono Pharmaceutical No other potential conflicts of interest were reported.Tadaaki Nishikawa Honoraria: AstraZeneca, Eisai Consulting or Advisory Role: Eisai Speakers' Bureau: AstraZeneca, Eisai Kazuki Sudo Honoraria: AstraZeneca, Pfizer Emi Noguchi Honoraria: Nippon Kayaku Speakers' Bureau: Sysmex, AstraZeneca, Pfizer, Eisai, Lilly Japan, Taiho Pharmaceutical, Chugai Pharma Ayumu Arakawa Research Funding: Chugai Pharma Travel, Accommodations, Expenses: Amgen Kuniko Sunami Honoraria: Sysmex, Chugai Pharma, AstraZeneca, Novartis, Eisai, Riken Genesis, Lilly Takashi Kubo Consulting or Advisory Role: Sysmex Takashi Kohno Consulting or Advisory Role: LOXO Oncology, Lilly Japan Research Funding: Daiichi Sankyo, Sysmex Noboru Yamamoto Honoraria: AstraZeneca, Pfizer, Chugai Pharma, Bristol Myers Squibb Japan, Ono Pharmaceutical, Lilly Japan, Sysmex Consulting or Advisory Role: Eisai, Takeda, Otsuka, Boehringer Ingelheimm, CMIC, Chugai Pharma Research Funding: Chugai Pharma, Taiho Pharmaceutical, Eisai, Astellas Pharma, Novartis, Daiichi Sankyo, Lilly Japan, Boehringer Ingelheim, Takeda, Kyowa Hakko Kirin, Bayer, Pfizer, Ono Pharmaceutical, Janssen, IQVIA, Merck Sharp & Dohme, Abbvie, Bristol Myers Squibb, Merck Serono, GlaxoSmithKline, Sumitomo Dainippon, Chiome Bioscience, Otsuka Kan Yonemori Honoraria: Eisai, Pfizer, AstraZeneca, Novartis, Taiho Pharmaceutical Consulting or Advisory Role: Chugai Pharma, Ono Pharmaceutical, Novartis, Eisai Research Funding: Ono Pharmaceutical No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

There are many differences between Asian regions in terms of the regulatory requirements and operational procedures in conducting international academic clinical trials for the approval of new drugs. The National Cancer Center Hospital in Japan has launched an international investigator-initiated registration-directed trial (IIRDT) in Japan, Korea, Taiwan, and Singapore, aiming at obtaining pharmaceutical approval in participating regions. Differences in regulatory and operational procedures were identified while coordinating the trial. In Japan, regulatory authority reviews should be performed after approval by institutional review boards for IIRDT, whereas in other regions these can be done in parallel. There were disparities in Good Manufacturing Practice-related documents between regions. Several differences were found regarding investigational product (IP) management, specifically concerning labeling, import/export procedures, and customs clearance costs. On the other hand, safety reporting procedures were relatively well-harmonized in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (ICH-E2A). Regions also differed in per-patient costs, due to varying regulations for academic registration-directed trials. In conclusion, the observed differences among Asian regions should be harmonized to facilitate international academic trials in Asia and thus resolve unmet patient needs worldwide. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? International clinical trials have become common because they make it possible to accrue patients faster and obtain new drug approval in wider areas. However, pharmaceutical regulatory differences hinder the efficient conduct of international clinical trials, especially in academia. WHAT QUESTION DID THIS STUDY ADDRESS? We conducted an academic international clinical trial on new drug applications in four Asian countries and clarified pharmaceutical regulatory differences and operational difficulties. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? The study identified differences between countries in terms of regulatory affairs, institutional review board (IRB) review processes, investigational new drug (IND) dossiers, investigational product (IP) management procedures, and clinical trial costs, while safety reporting procedures were relatively harmonized. Japan utilizes investigator-initiated registration-directed trials, an advanced regulatory system for new drug application by academia, but the other countries do not. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? Harmonization of pharmaceutical regulations and trial initiation procedures, and regulatory reform of clinical trial costs are important to accelerate academic international clinical trials for new drug applications., (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Background: Advance care planning (ACP) is a process that supports adults in understanding and sharing their personal values, life goals, and preferences regarding future medical care. We examined the current status of ACP and end-of-life (EOL) communication between oncologists and patients with metastatic breast cancer., Materials and Methods: We conducted a survey among 41 institutions that specialize in oncology by using an online tool in October 2019. Participants (118 physicians) from 38 institutions completed a 39-item questionnaire that measured facility type and function; physicians' background and clinical approach, education about EOL communication, and understanding about ACP; and the current situation of ACP and EOL discussions., Results: Ninety-eight responses concerning physicians' engagement in ACP with patients were obtained. Seventy-one (72%) answered that they had engaged in ACP. Among these, 23 (33%) physicians used a structured format to facilitate the conversation in their institutions, and only 6 (8%) settled triggers or sentinel events for the initiation of ACP. In the multivariable analysis, only the opportunity to learn communication skills was associated with physicians' engagement with ACP (odds ratio: 2.8, 95% confidence interval: 1.1-7.0). The frequency and timing of communication about ACP and EOL care with patients substantially varied among the oncologists. Communication about patients' life expectancy was less frequent compared with other topics., Conclusion: The opportunity to improve EOL communication skills promoted physicians' engagement with ACP among patients with metastatic/advanced breast cancer. However, there were still substantial variabilities in the method, frequency, and timing of ACP and EOL communication among the oncologists., Implications for Practice: This study found that the opportunity to improve end-of-life (EOL) communication skills promoted physicians' engagement in advance care planning (ACP) among patients with metastatic/advanced breast cancer. All oncologists who treat said patients are encouraged to participate in effective education programs concerning EOL communication skills. In clinical practice, there are substantial variabilities in the method, frequency, and timing of ACP and EOL communication among oncologists. As recommended in several clinical guidelines, the authors suggest a system that identifies patients who require conversations about their care goals, a structured format to facilitate the conversations, and continuous measurement for improving EOL care and treatment., (© 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Background: Standard treatment for malignant peritoneal mesothelioma has not been established, and systemic chemotherapy is administered according to malignant pleural mesothelioma. We previously reported the efficacy of cisplatin plus pemetrexed as first-line chemotherapy; however, the efficacy of second-line chemotherapy remains unknown., Methods: We retrospectively evaluated patients with malignant peritoneal mesothelioma who started first-line systemic chemotherapy with platinum plus pemetrexed between March 2007 and February 2019 at the National Cancer Center Hospital. Patients who received second-line chemotherapy after failure of platinum plus pemetrexed were identified. We evaluated the efficacy of first- and second-line chemotherapy, and explored the prognostic factors. Survival outcomes were estimated using the Kaplan-Meier method, and between-group differences were compared using the log-rank test. Univariate and multivariate analyses were performed using Cox proportional hazards models., Results: A total of 54 and 26 patients received platinum plus pemetrexed as first- and second-line chemotherapy, respectively (gemcitabine in 12 patients; taxane, six; nivolumab, three; and others, five). In all patients, the median overall survival and progression-free survival after first-line chemotherapy were 16.6 and 7.3 months, respectively. Among patients who received second-line chemotherapy, the median overall survival, progression-free survival, and second-line overall survival were 16.9, 3.2, and 9.9 months, respectively. Patients who received ≥6 cycles of platinum plus pemetrexed as first-line chemotherapy had longer overall survival after second-line chemotherapy than those who did not (hazard ratio, 0.23; 95% confidence interval: 0.06-0.82; p = 0.02)., Conclusions: Second-line chemotherapy may be an option for refractory malignant peritoneal mesothelioma, especially in patients who have completed 6 cycles of platinum plus pemetrexed as first-line chemotherapy.

Over the past 10 years, immunotherapy with immune checkpoint inhibitors has revolutionized the management of various cancers. However, immunotherapy in breast cancer has not been successful. Breast cancer has long been recognized as an immunologically 'cold' tumor, although a higher frequency of tumor-infiltrating lymphocytes present in certain subtypes and an association between tumor-infiltrating lymphocytes and favorable prognosis have been reported. In March 2019, the combination of atezolizumab and nanoparticle albumin-bound paclitaxel was granted accelerated approval in the United States for the treatment of programmed death-ligand 1-positive advanced or metastatic triple-negative breast cancer. This finally opened the door for immune checkpoint blockade therapy for breast cancer. Several clinical trials have been conducted using different combinations of immune checkpoint inhibitors and chemotherapy or targeted agents in various treatment settings for metastatic breast cancer and early-stage breast cancer. In this review, we summarize recent advances in immune checkpoint blockade therapy and predictive biomarkers in breast cancer., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Breast cancer is the second most common origin of brain metastasis after lung cancer. Brain metastasis in breast cancer is commonly found in patients with advanced course disease and has a poor prognosis because the blood-brain barrier is thought to be a major obstacle to the delivery of many drugs in the central nervous system. Therefore, local treatments including surgery, stereotactic radiation therapy, and whole-brain radiation therapy are currently considered the gold standard treatments. Meanwhile, new targeted therapies based on subtype have recently been developed. Some drugs can exceed the blood-brain barrier and enter the central nervous system. New technology for early detection and personalized medicine for metastasis are warranted. In this review, we summarize the historical overview of treatment with a focus on local treatment, the latest drug treatment strategies, and future perspectives using novel therapeutic agents for breast cancer patients with brain metastasis, including ongoing clinical trials.

Purpose: In Japan, for pharmaceutical products to be covered by public medical insurance, their efficacy and safety must first be confirmed in clinical trials. To our knowledge, this study is the first investigation into the off-label use of pharmaceutical products at a high-volume cancer treatment center in Japan. The objective of this study is to explore the framework necessary for future pharmaceutical development and regulatory approval in the field of oncology by surveying the frequency of and indications for off-label use of pharmaceutical products at the National Cancer Center Hospital in Tokyo, Japan., Materials and Methods: The pharmaceutical products used off-label in daily practice from 2003 to 2015 at the National Cancer Center Hospital were retrospectively examined based on applications that had been submitted to an internal review committee requesting off-label use., Results: A total of 1,390 applications were submitted during the study period. The most frequently used supporting documents were the results of phase II trials, followed by case series and phase III trials. The cancer most frequently treated with off-label drugs was sarcoma (15.1%), followed by urologic cancer (9.2%) and GI cancer (7.6%)., Conclusion: As reported in previous studies, pharmaceutical products were generally used off-label for the treatment of rare cancers, for which large-scale clinical trials are difficult to conduct. Continued discussion of the types of frameworks that are needed to guide pharmaceutical development is necessary., Competing Interests: Conflicts of Interest Statement:The authors have declared that no competing interests exist.

A key to longevity assurance is the nutrient-sensing mTOR pathway. Inhibition of mTOR extends lifespan in a variety of organisms. However, the downstream effectors of the mTOR pathway for lifespan regulation are elusive. In a recent report, we described the role of Maf1 as a critical lifespan regulator downstream of the mTOR pathway in fission yeast. Maf1 is the master negative regulator of RNA polymerase III-directed transcription (e.g. tRNAs and 5S rRNAs) and is regulated by mTOR-mediated phosphorylation. We demonstrated that Maf1 is required for lifespan extension under calorie restriction or when mTOR is inhibited. We also showed that Maf1 prevents DNA damage at tRNA genes, which appears to contribute to lifespan maintenance by Maf1. Here we highlight these observations and present additional results to discuss the role of the mTOR-Maf1-Pol III axis in promoting genomic integrity in the face of DNA replication-transcription conflicts in order to maintain normal lifespan.

Two cases of pediatric lung cancer (in 23-month-old and 6-year-old boys) resulting from mother-to-infant transmission of uterine cervical tumors were incidentally detected during routine next-generation sequencing of paired samples of tumor and normal tissue. Spontaneous regression of some lesions in the first child and slow growth of the tumor mass in the second child suggested the existence of alloimmune responses against the transmitted tumors. Immune checkpoint inhibitor therapy with nivolumab led to a strong regression of all remaining tumors in the first child. (Funded by the Japan Agency for Medical Research and Development and others; TOP-GEAR UMIN Clinical Trials Registry number, UMIN000011141.)., (Copyright © 2021 Massachusetts Medical Society.)

Neoantigens have attracted attention as biomarkers or therapeutic targets. However, accurate prediction of neoantigens is still challenging, especially in terms of its accuracy and cost. Variant detection using RNA sequencing (RNA-seq) data has been reported to be a low-accuracy but cost-effective tool, but the feasibility of RNA-seq data for neoantigen prediction has not been fully examined. In the present study, we used whole-exome sequencing (WES) and RNA-seq data of tumor and matched normal samples from six breast cancer patients to evaluate the utility of RNA-seq data instead of WES data in variant calling to detect neoantigen candidates. Somatic variants were called in three protocols using: (i) tumor and normal WES data (DNA method, Dm); (ii) tumor and normal RNA-seq data (RNA method, Rm); and (iii) combination of tumor RNA-seq and normal WES data (Combination method, Cm). We found that the Rm had both high false-positive and high false-negative rates because this method depended greatly on the expression status of normal transcripts. When we compared the results of Dm with those of Cm, only 14% of the neoantigen candidates detected in Dm were identified in Cm, but the majority of the missed candidates lacked coverage or variant allele reads in the tumor RNA. In contrast, about 70% of the neoepitope candidates with higher expression and rich mutant transcripts could be detected in Cm. Our results showed that Cm could be an efficient and a cost-effective approach to predict highly expressed neoantigens in tumor samples., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: An orosomucoid-like 3 (ORMDL3)/gasdermin B (GSDMB) gene locus on chromosome 17q is consistently associated with childhood-onset asthma, which is highly atopic. As some evidence suggests the relationship between asthma and allergic sensitization reflects asthma patient susceptibility to augmented IgE responses driven by common environmental allergens rather than an increased asthma risk after allergen exposure, we aimed to determine any relationships between this locus region and childhood-onset adult asthma with regard to serum total IgE levels or allergic sensitization., Methods: We conducted a case-control association study using three independent Japanese populations (3869 total adults) and analyzed the ORs for association of rs7216389, an expression quantitative trait locus for ORMDL3/GSDMB, with adult asthma according to onset age. Additionally, associations between the rs7216389 genotype and total serum IgE levels or allergic sensitization was examined., Results: Rs7216389 was associated with both childhood-onset adult asthma (OR for asthmatic patients afflicted at the age of 10 years or younger = 1.61, p = 0.00021) and asthmatic patients with higher levels of total serum IgE (OR for asthmatic patients with IgE ≥1000IU/mL = 1.55, p = 0.0033). In both healthy controls and in the combined healthy and asthmatic individuals, rs7216389 was correlated with increased total serum IgE levels (p < 0.0005), but not allergic sensitization (p > 0.1)., Conclusions: ORMDL3/GSDMB is an important susceptibility gene for childhood-onset adult asthma in Japanese populations and this association is linked to elevated total serum IgE levels but not to allergic sensitization., (Copyright © 2020 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

HER3 (erbB3) signaling serves an important role in the development and chemoresistance of ovarian cancer, and is activated by chemotherapy. To evaluate the influence of neoadjuvant chemotherapy and other clinical factors on the expression of HER3, as well as to examine its role as a prognostic marker, the present study evaluated archived tissues from patients who underwent surgery for ovarian cancer between 2011 and 2018 at our hospital. Immunohistochemical staining for HER3 was performed using formalin-fixed paraffin-embedded surgical specimens and biopsy samples. In total, data from 111 patients with sufficient surgically resected tumor samples were extracted. A total of 28 patients with histology type high-grade serous carcinoma (HGSC) had specimens available from both pre-chemotherapy biopsies and post-chemotherapy surgery. High HER3 expression (HER3-high) was observed in 64 patients (58%), whereas low HER3 expression (HER3-low) was observed in 47 patients (42%). Multivariate logistic regression analysis identified neoadjuvant chemotherapy [odds ratio (OR), 7.49; 95% confidence interval (CI), 2.48-22.64; P<0.001) and non-HGSC histology (OR, 5.42; 95% CI, 1.99-14.78; P<0.001) as significant predictive factors for HER3-high. In pre-chemotherapy biopsy specimens, 15 patients were HER3-high and 13 were HER3-low. After chemotherapy, eight of 13 patients with HER3-low exhibited a change in status to HER3-high, with a trend toward poorer progression-free survival compared to that of patients whose status remained HER3-low. In conclusion, HER3 overexpression was revealed to be common among patients with ovarian cancer, especially in those with non-HGSC histology. In addition, HER3 expression may be promoted by chemotherapy. These findings suggested that patients with ovarian cancer are good candidates for emerging HER3-targeting therapies., (Copyright: © Mizuno et al.)

Patients with cervical adenocarcinoma (AC) and adenosquamous carcinoma (ASC) have a poorer prognosis than those with squamous cell carcinoma (SCC). Erb-b2 receptor tyrosine kinase 3 (HER3) is a member of the epidermal growth factor receptor family and its expression is associated with unfavorable prognosis in several cancer types, including SCC of the cervix. As there is limited information on the prognostic value of HER3 for AC and ASC of the cervix, the present study aimed to evaluate the expression of HER3 and its impact on post-operative recurrence in patients with AC and ASC of the cervix. This retrospective study included 39 patients with early-stage AC and ASC who underwent primary surgery between January 1997 and December 2017. Immunohistochemical staining for HER3 was performed on formalin-fixed paraffin-embedded surgical specimens. The possible influence of HER3 expression on disease-free survival (DFS) was studied by using multivariate Cox regression with adjustment for established risk factors of post-operative recurrence. High expression of HER3 (HER3-high) was detected in 85.1% of cases of AC (23/27) and in 58.3% of cases of ASC (7/12). The median follow-up duration was 63.1 months and Kaplan-Meier analysis indicated that the 5-year DFS rates of patients with AC and ASC of the cervix were 56.7% in patients with HER3-high and 77.8% in patients with HER3-low (log rank, P=0.20). On multivariate analysis, HER3-high [hazard ratio (HR)=6.32, 95% CI: 1.10-36.26, P=0.039), pelvic lymph node metastasis (HR=7.61, 95% CI: 2.07-28.00, P=0.002) and vascular invasion (HR=4.28, 95% CI: 1.12-16.31, P=0.033) were indicated to be independent predictors of DFS. To date, the present study is the most comprehensive analysis to evaluate the expression of HER3 in patients with early-stage AC and ASC of the cervix. The results suggested that HER3 overexpression may be an independent risk factor for post-operative recurrence. However, these results and the prognostic value of HER3 should be confirmed in a larger sample., (Copyright: © Mizuno et al.)

During alcohol consumption, the esophageal mucosa is directly exposed to high concentrations of ethanol (EtOH). We therefore investigated the response of normal human esophageal epithelial cell lines EPC1, EPC2 and EPC3 to acute EtOH exposure. While these cells were able to tolerate 2% EtOH for 8 h in both three-dimensional organoids and monolayer culture conditions, RNA sequencing suggested that EtOH induced mitochondrial dysfunction. With EtOH treatment, EPC1 and EPC2 cells also demonstrated decreased mitochondrial ATPB protein expression by immunofluorescence and swollen mitochondria lacking intact cristae by transmission electron microscopy. Mitochondrial membrane potential (ΔΨm) was decreased in a subset of EPC1 and EPC2 cells stained with ΔΨm-sensitive dye MitoTracker Deep Red. In EPC2, EtOH decreased ATP level while impairing mitochondrial respiration and electron transportation chain functions, as determined by ATP fluorometric assay, respirometry, and liquid chromatography-mass spectrometry. Additionally, EPC2 cells demonstrated enhanced oxidative stress by flow cytometry for mitochondrial superoxide (MitoSOX), which was antagonized by the mitochondria-specific antioxidant MitoCP. Concurrently, EPC1 and EPC2 cells underwent autophagy following EtOH exposure, as evidenced by flow cytometry for Cyto-ID, which detects autophagic vesicles, and immunoblots demonstrating induction of the lipidated and cleaved form of LC3B and downregulation of SQSTM1/p62. In EPC1 and EPC2, pharmacological inhibition of autophagy flux by chloroquine increased mitochondrial oxidative stress while decreasing cell viability. In EPC2, autophagy induction was coupled with phosphorylation of AMP activated protein kinase (AMPK), a cellular energy sensor responding to low ATP levels, and dephosphorylation of downstream substrates of mechanistic Target of Rapamycin Complex (mTORC)-1 signaling. Pharmacological AMPK activation by AICAR decreased EtOH-induced reduction of ΔΨm and ATP in EPC2. Taken together, acute EtOH exposure leads to mitochondrial dysfunction and oxidative stress in esophageal keratinocytes, where the AMPK-mTORC1 axis may serve as a regulatory mechanism to activate autophagy to provide cytoprotection against EtOH-induced cell injury., Competing Interests: The authors have declared that no competing interests exist.

Since 2013, trastuzumab emtansine (T-DM1) has been widely used in Japan to treat patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) who were previously administered trastuzumab and a taxane. However, there is no information about the treatment outcomes after exposure to T-DM1 in Japanese patients with HER2-positive MBC. In this study, we aimed to describe the survival outcomes of patients with HER2-positive MBC who received a treatment following T-DM1 and clarify the predictive factors of their prognosis.We retrospectively identified patients with HER2-positive MBC who received T-DM1 between April 1, 2014, and December 31, 2018, at the National Cancer Center Hospital, and focused on the population that received another line of therapy following T-DM1 discontinuation.Thirty patients were available for the outcome analysis. Median progression-free survival (PFS) of the first subsequent therapy was 6.0 months [95% confidence interval (95% CI) 4.1-6.4], whereas the median overall survival (OS) from the first subsequent therapy was 20.6 months (95% CI 13.5 months to not reached). We divided the patients into 2 groups according to their PFS with T-DM1 treatment and compared their PFS with the subsequent therapy. The results revealed a significant difference in the median PFS with the first subsequent treatment between patients with the PFS of less than and more than 3 months [5.1 (95% CI 1.7-6.2) vs 6.2 (95% CI 4.0-11.3) months, P = .03].This is the first study to evaluate the survival outcomes of post-T-DM1 therapy in Japanese patients with HER2-positive MBC. A short PFS with T-DM1 might affect the PFS with a treatment after T-DM1.

Background: Asthma is a complex chronic inflammatory disease of the airways. Association studies between HLA and asthma were first reported in the 1970s, and yet, the precise role of HLA alleles in asthma is not fully understood. Numerous genome-wide association studies were recently conducted on asthma, but were always limited to simple genetic markers (single nucleotide polymorphisms) and not complex HLA gene polymorphisms (alleles/haplotypes), therefore not capturing the biological relevance of this complex locus for asthma pathogenesis., Objective: To run the first HLA-centric association study with asthma and specific asthma-related phenotypes in a large cohort of African-ancestry individuals., Methods: We collected high-density genomics data for the Consortium on Asthma among African-ancestry Populations in the Americas (N = 4993) participants. Using computer-intensive machine-learning attribute bagging methods to infer HLA alleles, and Easy-HLA to infer HLA 5-gene haplotypes, we conducted a high-throughput HLA-centric association study of asthma susceptibility and total serum IgE (tIgE) levels in subjects with and without asthma., Results: Among the 1607 individuals with asthma, 972 had available tIgE levels, with a mean tIgE level of 198.7 IU/mL. We could not identify any association with asthma susceptibility. However, we showed that HLA-DRB1∗09:01 was associated with increased tIgE levels (P = 8.5 × 10 -4 ; weighted effect size, 0.51 [0.15-0.87])., Conclusions: We identified for the first time an HLA allele associated with tIgE levels in African-ancestry individuals with asthma. Our report emphasizes that by leveraging powerful computational machine-learning methods, specific/extreme phenotypes, and population diversity, we can explore HLA gene polymorphisms in depth and reveal the full extent of complex disease associations., (Copyright © 2020. Published by Elsevier Inc.)

Formaldehyde is a common environmental pollutant and is associated with adverse health effects. Formaldehyde is also considered to be a carcinogen because it can form DNA adducts, leading to genomic instability. How these adducts are prevented and removed is not fully understood. In this study, we used the fission yeast Schizosaccharomyces pombe as a model organism to investigate cellular tolerance pathways against formaldehyde exposure. We show that Fmd1 is a major formaldehyde dehydrogenase that functions to detoxify formaldehyde and that Fmd1 is critical to minimize formaldehyde-mediated DNA lesions. Our investigation revealed that nucleotide excision repair and homologous recombination have major roles in cellular tolerance to formaldehyde, while mutations in the Fanconi anemia, translesion synthesis, and base excision repair pathways also render cells sensitive to formaldehyde. We also demonstrate that loss of Wss1 or Wss2, proteases involved in the removal of DNA-protein crosslinks, sensitizes cells to formaldehyde and leads to replication defects. These results suggest that formaldehyde generates a variety of DNA lesions, including interstrand crosslinks, DNA-protein crosslinks, and base adducts. Thus, our genetic studies provide a framework for future investigation regarding health effects resulting from formaldehyde exposure.

Background: Despite recent findings that epithelial cell adhesion molecule (EPCAM) deletions can cause Lynch syndrome (LS), its clinical characteristics are still unknown. We present the first case of ileum cancer in a patient with germline EPCAM gene deletion, which was discovered during ovarian tumor surgery., Case Presentation: A 59-year-old woman presented with a history of colon cancer occurring at 38 and 55 years old. Five of her siblings had a history of colon cancer, and an elder sister had confirmed LS. As imaging examination revealed an ovarian tumor, and we performed hysterectomy and bilateral salpingo-oophorectomy. Careful observation during surgery revealed a cherry-sized tumor in the ileum, prompting partial ileal resection. Pathological examination showed the ovarian tumor to be a metastasis of ileum cancer. Genetic testing with blood-relative information using multiplex ligation-dependent probe amplification showed EPCAM exons 8 and 9 deletions, confirming LS. The patient received adjuvant chemotherapy with CAPOX (capecitabine and oxaliplatin) and has remained disease-free for 24 months., Conclusions: We were fortunate to identify ileum cancer that would have been difficult to find preoperatively through careful observation during ovarian tumor surgery and successfully treated the patient by using surgical resection and CAPOX chemotherapy. When treating patients with hereditary cancer syndromes including LS, we should keep all associated cancers in mind.

Type I allergy is an immunological disorder triggered by allergens and causes significant health problems. The major allergen of birch pollen is Bet v 1, which belongs to the pathogen-related protein 10 (PR-10) family. Here, we established a rapid and robust method for the production of Bet v 1 in Nicotiana benthamiana leaves, with binding activity to allergic patients' IgE. The Bet v 1 allergen was expressed in N. benthamiana using a strong agroinfiltration-based transient protein expression system, which consists of a deconstructed geminiviral vector system with a double terminator. Five days post-infiltration, the allergen concentration in N. benthamiana leaves was 1.2 mg/g of fresh mass, being this the maximum yield of Bet v 1 in plants reported up to now. A part of plant-derived Bet v 1 was glycosylated. Bet v 1 purified from N. benthamiana or Brevibacillus brevis was used to carry out enzyme-linked immunoassays; both recombinant allergens were found to have comparable binding properties to the IgE of allergic patients. These results suggest that our plant expression system allows rapid and robust production of the allergen, which keeps the immunogenicity., (Copyright © 2020 Yamada, Kidoguchi, Yata, Nakamura, Yoshida, Kato, Masuko, Hizawa, Fujieda, Noguchi and Miura.)

Maf1 is the master repressor of RNA polymerase III responsible for transcription of tRNAs and 5S rRNAs. Maf1 is negatively regulated via phosphorylation by the mTOR pathway, which governs protein synthesis, growth control, and lifespan regulation in response to nutrient availability. Inhibiting the mTOR pathway extends lifespan in various organisms. However, the downstream effectors for the regulation of cell homeostasis that are critical to lifespan extension remain elusive. Here we show that fission yeast Maf1 is required for lifespan extension. Maf1's function in tRNA repression is inhibited by mTOR-dependent phosphorylation, whereas Maf1 is activated via dephosphorylation by protein phosphatase complexes, PP4 and PP2A. Mutational analysis reveals that Maf1 phosphorylation status influences lifespan, which is correlated with elevated tRNA and protein synthesis levels in maf1∆ cells. However, mTOR downregulation, which negates protein synthesis, fails to rescue the short lifespan of maf1∆ cells, suggesting that elevated protein synthesis is not a cause of lifespan shortening in maf1∆ cells. Interestingly, maf1∆ cells accumulate DNA damage represented by formation of Rad52 DNA damage foci and Rad52 recruitment at tRNA genes. Loss of the Rad52 DNA repair protein further exacerbates the shortened lifespan of maf1∆ cells. Strikingly, PP4 deletion alleviates DNA damage and rescues the short lifespan of maf1∆ cells even though tRNA synthesis is increased in this condition, suggesting that elevated DNA damage is the major cause of lifespan shortening in maf1∆ cells. We propose that Maf1-dependent inhibition of tRNA synthesis controls fission yeast lifespan by preventing genomic instability that arises at tRNA genes., (© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Background and Purpose: Tapering immunosuppressants is desirable in patients with well-controlled myasthenia gravis (MG). However, the association between tapering of calcineurin inhibitor dosage and reduction-associated exacerbation is not known. The aim of this study was to clarify the frequency of reduction-associated exacerbation when tacrolimus is tapered in stable patients with anti-acetylcholine receptor antibody-positive MG, and to determine the factors that predict exacerbations., Methods: We retrospectively analyzed 115 patients in whom tacrolimus dosage was tapered. The reduction-associated exacerbation was defined as the appearance or worsening of one or more MG symptoms <3 months after the reduction., Results: Tacrolimus dosage was successfully tapered in 110 patients (96%) without any exacerbation. Five patients (4%) experienced an exacerbation, but symptoms were reversed in all patients when the tacrolimus dose was increased to the previous maintenance level. No patient developed an MG crisis. The age at onset was significantly earlier (30 vs. 56 years, P = 0.025) and the reduction in dosage was significantly larger (2.0 vs. 1.0 mg/day, P = 0.002) in patients with reduction-associated exacerbation than in those without exacerbation. The cut-off values determined in a receiver-operating characteristic curve analysis were 52 years (sensitivity, 57%; specificity, 100%) for the age at onset and 1.5 mg (sensitivity, 80%; specificity, 100%) for the dose reduction., Conclusion: Tapering of tacrolimus was possible in most patients with well-controlled anti-acetylcholine receptor antibody-positive MG. Early age at onset and a large reduction from maintenance dosage were associated with exacerbation. Reductions ≤1.5 mg/day from the maintenance dosage should be considered for patients with late-onset disease., (© European Academy of Neurology 2019.)

Background: Intimal sarcoma (InS) is an exceedingly rare neoplasm with an unfavorable prognosis, for which new potentially active treatments are under development. We report on the activity of anthracycline-based regimens, gemcitabine-based regimens, and pazopanib in patients with InS., Methods: Seventeen sarcoma reference centers in Europe, the United States, and Japan contributed data to this retrospective analysis. Patients with MDM2-positive InS who were treated with anthracycline-based regimens, gemcitabine-based regimens, or pazopanib between October 2001 and January 2018 were selected. Local pathological review was performed to confirm diagnosis. Response was assessed by RECIST1.1. Recurrence-free survival (RFS), progression-free survival (PFS) and overall survival were computed by Kaplan-Meier method., Results: Seventy-two patients were included (66 anthracycline-based regimens; 26 gemcitabine-based regimens; 12 pazopanib). In the anthracycline-based group, 24 (36%) patients were treated for localized disease, and 42 (64%) patients were treated for advanced disease. The real-world overall response rate (rwORR) was 38%. For patients with localized disease, the median RFS was 14.6 months. For patients with advanced disease, the median PFS was 7.7 months. No anthracycline-related cardiac toxicity was reported in patients with cardiac InS (n = 26). For gemcitabine and pazopanib, the rwORR was 8%, and the median PFS was 3.2 and 3.7 months, respectively., Conclusion: This retrospective series shows the activity of anthracycline-based regimens in InS. Of note, anthracyclines were used in patients with cardiac InS with no significant cardiac toxicity. The prognosis in patients with InS remains poor, and new active drugs and treatment strategies are needed., (© 2019 American Cancer Society.)

Introduction: Carcinosarcoma is a rare cancer, and its prognosis is poor. There are few reports on the prognostic factors of patients with carcinosarcoma who receive second-line chemotherapy., Objective: To investigate the outcome and prognostic factors of patients who received second-line chemotherapy for gynecologic carcinosarcoma., Methods: We retrospectively investigated patients with ovarian or uterine carcinosarcoma, who were treated at two institutions from July 2006 to March 2018. All patients who had received second-line chemotherapy for advanced or recurrent disease were eligible. The efficacy of second-line chemotherapy and prognostic factors were evaluated., Results: Forty-six patients were eligible. Combination chemotherapy was used in approximately half (52.2%) of the patients. The response rate and disease control rate of second-line chemotherapy were 32.6 and 60.9%, respectively. The median follow-up period was 11.0 (range, 8.8-107.5) months. The median progression-free survival and overall survival were 6.3 (95% CI, 3.2-7.5) months and 12.9 (95% CI, 7.8-16.0) months, respectively. In the multivariate analysis of overall survival, a treatment-free interval >180 days was a significant good prognostic factor. The median overall survival was 7.8 (95% CI, 5.1-10.5) months in the <180 days group and 16.4 (95% CI, 13.1-130.6) months in the >180 days group (p = 0.0052; hazard ratio, 0.26; 95% CI, 0.10-0.66), respectively., Conclusion: The outcome of gynecologic carcinosarcoma in the second-line setting is poor, especially in patients with a short treatment-free interval., (© 2020 S. Karger AG, Basel.)

House dust mite (HDM) is a major allergen that causes allergic diseases such as atopic dermatitis. However, the regulatory mechanisms of HDM-induced immune responses are incompletely understood. NC/Nga mice are an inbred strain that is more susceptible to HDM and develops more severe dermatitis than other strains. Using whole-exome sequencing, we found that NC/Nga mice carry a stop-gain mutation in Clec10a , which encodes a C-type lectin receptor, Clec10a (MGL1/CD301a). The repair of this gene mutation using the CRISPR-Cas9 system ameliorated HDM-induced dermatitis, indicating that the Clec10a mutation is responsible for hypersensitivity to HDM in NC/Nga mice. Similarly, Clec10a -/- mice on the C57BL/6J background showed exacerbated HDM-induced dermatitis. Clec10a expressed on skin macrophages inhibits HDM-induced Toll-like receptor 4 (TLR4)-mediated inflammatory cytokine production through the inhibitory immunoreceptor tyrosine activating motif in its cytoplasmic portion. We identified asialoglycoprotein receptor 1 (Asgr1) as a functional homolog of mouse Clec10a in humans. Moreover, we found that a mucin-like molecule in HDM is a ligand for mouse Clec10a and human Asgr1. Skin application of the ligand ameliorated a TLR4 ligand-induced dermatitis in mice. Our findings suggest that Clec10a in mice and Asgr1 in humans play an important role in skin homeostasis against inflammation associated with HDM-induced dermatitis., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Food allergy is a growing health problem worldwide because of its increasing prevalence, life-threatening potential, and shortage of effective preventive treatments. In an outbreak of wheat allergy in Japan, thousands of patients had allergic reactions to wheat after using soap containing hydrolyzed wheat protein (HWP)., Objectives: The aim of the present study was to investigate genetic variation that can contribute to susceptibility to HWP allergy., Methods: We conducted a genome-wide association study of HWP allergy in 452 cases and 2700 control subjects using 6.6 million genotyped or imputed single nucleotide polymorphisms. Replication was assessed by genotyping single nucleotide polymorphisms in independent samples comprising 45 patients with HWP allergy and 326 control subjects., Results: Through the genome-wide association study, we identified significant associations with the class II HLA region on 6p21 (P = 2.16 × 10 -24 for rs9271588 and P = 2.96 × 10 -24 for HLA-DQα1 amino acid position 34) and with the RBFOX1 locus at 16p13 (rs74575857, P = 8.4 × 10 -9 ). The associations were also confirmed in the replication data set. Both amino acid polymorphisms (HLA-DQβ1 amino acid positions 13 and 26) located in the P4 binding pockets on the HLA-DQ molecule achieved the genome-wide significance level (P < 5.0 × 10 -8 )., Conclusions: Our data provide the first demonstration of genetic risk for HWP allergy and show that this genetic risk is mainly represented by multiple combinations of HLA variants., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Aim: This study aimed to retrospectively evaluate the efficacy and safety of ifosfamide plus paclitaxel(IT)in Japanese patients with recurrent or metastatic uterine carcinosarcoma., Methods: This study included 15 patients who received IT(ifosfamide [1.6 g/m / 2 on days 1-3]and paclitaxel[135mg/m2 on day 1]every 3 weeks)for recurrent or metastatic uterine carcinosarcoma., Results: The overall response rate was 38.4%, and the disease control rate was 92.3%. The median progression- free survival was 7.0 months, and the median overall survival was 9.0 months after initiation of IT therapy. The most common hematological adverse event was Grade 1-2 neutropenia. Peripheral neuropathy of Grade 1 or 2 was observed in 33.3% of cases. There was no treatment-related death., Conclusion: IT therapy showed good efficacy and tolerability in Japanese patients with recurrent or metastatic uterine carcinosarcoma.

Atopic dermatitis (AD) is a chronic inflammatory skin disease, and skin barrier defects are often observed in patients with AD. So far, few association studies between FLG loss-of-function mutations and onset of AD in longitudinal studies of early childhood have been reported. In the present study, we aimed to investigate the effect of FLG loss-of-function mutations on the development of AD in a longitudinal birth cohort study. The status of AD diagnosis at each age until 6 years was collected from the Tokyo Children's Health, Illness, and Development (T-CHILD) study. We analyzed eight loss-of-function mutations in FLG in 712 participants. FLG loss-of-function mutations were significantly associated with AD onset in infancy (≤2 years) (P < 0.001, OR 3.54, 95% CI 1.88-6.65), but not with AD onset in childhood (≥3 years) (P = 0.981, OR 0.99, 95% CI 0.29-3.36), and none of the children in the present cohort who developed AD at 5 years of age or later carried FLG loss-of-function mutations. Our data support the notion that the effect of FLG loss-of-function mutations is prominent during a very early stage of life.

Background: Trastuzumab emtansine (T-DM1) has been approved since 2013 for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) who had received trastuzumab (Tmab) and taxane. However, no clinical trial has evaluated the efficacy of T-DM1 in those who have previously received pertuzumab (Pmab). This study aimed to compare the efficacy of T-DM1 between patients who had received Tmab and Pmab and those who had received Tmab only in Japanese population., Methods: We identified all patients with HER2-positive MBC who received T-DM1 between April 1, 2014 and February 28, 2017 in our institution. The patients were divided into the Tmab group (i.e., those who received only Tmab before T-DM1 treatment) and the Tmab/Pmab group (i.e., those who received Tmab and Pmab before T-DM1 treatment), and progression-free survival (PFS) and best response were compared between the two groups., Results: A total of 42 patients were enrolled for outcome analysis. The median follow-up period was 4.8 months, and the median number of prior chemotherapy regimens for metastatic disease before T-DM1 was 1 (range 1-2) in the Tmab/Pmab group and 2 (range 0-6) in the Tmab group. The median PFS was 2.8 months in the Tmab/Pmab group (95% confidence interval [CI] 1.7-4.8 months) and 7.8 months in the Tmab group (95% CI 5.5-15.9 months) (p = 0.0030). The best response was lower in the Tmab/Pmab group (11.1% vs. 25.0%)., Conclusions: Patients with HER2-positive MBC who received Tmab and Pmab treatment before T-DM1 have fewer benefits from T-DM1.

A sarcoplasmic serine proteinase (SSP) was purified from threadfin bream (Nemipterus virgatus) belly muscle by ammonium sulfate precipitation and a series of chromatographies including Q-Sepharose, Phenyl Sepharose and Superdex 200. The SSP was purified 1967 folds with a yield of 4.8%. The molecular weight of the SSP was estimated to be 43.5 kDa and 22.5 kDa on SDS-PAGE under non-reducing and reducing conditions, respectively. The N-terminal amino acid sequence of the two protein bands were determined as IVGGYEXQPYSQAHQVSLNSGY and corresponded. It is suggested that the SSP exists as a homodimer. Optimum pH and temperature were 9.5 and 50 °C, using Boc-Val-Pro-Arg-MCA as a substrate. Substrate specificity and effects of inhibitors indicated that the SSP was a trypsin-like serine proteinase. The SSP was responsible for hydrolyzing myosin heavy chain (MHC) and inducing modori phenomenon in the threadfin bream surimi gel. Thus, the SSP was considered as a modori-inducing proteinase., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Little is known about annual hazard rates of cancer mortality and recurrence for papillary thyroid cancer (PTC). This study investigated the time-varying pattern of cancer death and recurrence from PTC and independent prognostic factors for cause-specific mortality (CSM) and recurrence of PTC. Methods: This retrospective chart review enrolled 466 patients diagnosed with PTC who underwent curative initial surgery between April 1981 and December 1991 with a median follow-up of 18.4 years. Clinical characteristics, cancer mortality (primary endpoint), and recurrence (secondary endpoint) were ascertained. The failure rates of either death or recurrence were estimated using the Kaplan-Meier methods, and annual death/recurrence hazard was depicted using hazard function. Results: In this Japanese cohort where only 1.5% of patients received radioactive iodine therapy, the 10-, 20-, and 30-year CSM rates were 2.7%, 6.2%, and 8.6%, respectively. Eleven (44.0%) cases of death occurred within the first 10 years, whereas 10 (40.0%) and 4 (16.0%) cases occurred within 10-20 and 20-30 years after surgery, respectively. The 10-, 20-, and 30-year recurrence rates were 11.3%, 21.8%, and 29.4%, respectively. Forty-six (54.8%) cases of recurrence occurred within the first 10 years, predominantly within the first five years (31 cases; 36.9%), whereas 29 (34.5%), 7 (8.3%), and 2 (2.4%) cases occurred within 10-20, 20-30, and ≥30 years after surgery, respectively. Age ≥55 years was the only independent prognostic factor for CSM. Age ≥55 years, male, tumor size > 4 cm, extranodal extension, and positive pathological lymph node metastasis were independent prognostic factors for recurrence. The annual hazard curve of cancer mortality presented a double-peaked distribution, with a first peak at the 10th year, and the second peak reaching the maximum at the 20th year after surgery for the entire population. The annual hazard curve of recurrence showed a triple-peaked pattern, with surges at about 12, 22, and 29 years after surgery. Conclusions: Patients with PTC harboring at least one of the prognostic characteristics may be at persistent risk of cancer mortality and recurrence even 10 or more years after initial treatment. Understanding the hazard rate of PTC is key to creating more tailored treatment and surveillance.

Ewing sarcoma/peripheral primitive neuroectodermal tumor (ES/PNET) is an aggressive bone tumor. Bone marrow aspiration and biopsy (BMAB) has been recognized as the gold standard for assessing bone marrow status. While the latest guideline suggests the need to omit bone marrow aspiration in patients with no findings on 18 F-fluorodeoxyglucose positron emission tomography ( 18 F-FDG PET) based on one retrospective report, there is no study using 18 F-FDG PET/computed tomography (CT). We retrospectively reviewed 26 consecutive, previously untreated, ES/PNET patients. We compare the results of bone marrow aspiration and biopsy (BMAB) and those of 18 F-FDG PET/CT in ES/PNET patients. All of the 21 patients without metastases on 18 F-FDG PET/CT had negative BMAB. The sensitivity of bone marrow involvement in bone metastases positive patients on 18 F-FDG PET/CT was 75% (3/4), and the specificity was 100% (22/22). In addition to the metastatic findings on 18 F-FDG PET/CT, tumor diameter, lactate dehydrogenase level at diagnosis, and the presence or absence of bone metastasis were factors related to bone marrow involvement. It may be a reasonable option to omit BMAB in ES/PNET patients with no distant metastasis based on 18 F-FDG PET/CT findings.

Objective Few reports have analyzed the diagnostic process of carcinoma of unknown primary site (CUP) or have focused on the frequency of nonmalignant lesions among patients with suspected malignant diseases. The aim of this study was to investigate the incidence and characteristics of nonmalignant diseases that tend to be mistaken for malignant diseases. Patients We retrospectively analyzed the medical records of patients with suspected CUP who were referred to the National Cancer Center Hospital (Tokyo, Japan) between April 2007 and December 2014. All patients underwent a thorough history and physical examination as well as radiological and ultrasonography imaging tests for the CUP diagnostic work up. Results Among 830 patients with suspected CUP, 46 were diagnosed with nonmalignant diseases, and 780 were diagnosed with a malignant neoplasm (409 neoplasms with detected primary site and 371 CUP neoplasms). Four patients discontinued the diagnostic workup because they refused further examinations or had a poor general status. The final diagnosis of the 46 patients with nonmalignant disease comprised 10 benign tumors, 10 benign diseases, and 26 with no evidence of disease. The nonmalignant tumors comprised three hemangiomas, two schwannomas, two uterine myomas, two pseudomyxoma peritonei, one lymphangioma, one meningioma, and one poroma. Conclusion The incidence of nonmalignant diseases among patients with suspected CUP was 46 out of 830 patients in our institution. It is important to perform a thorough pathological examination in the CUP diagnostic workup. To confirm a diagnosis, some patients may need to visit specialized institutions, especially those with liver and bone lesions.

Background: Histone acetylation plays an important role in DNA replication and repair because replicating chromatin is subject to dynamic changes in its structures. However, its precise mechanism remains elusive. In this report, we describe roles of the NuA4 acetyltransferase and histone H4 acetylation in replication fork protection in the fission yeast Schizosaccharomyces pombe., Results: Downregulation of NuA4 subunits renders cells highly sensitive to camptothecin, a compound that induces replication fork breakage. Defects in NuA4 function or mutations in histone H4 acetylation sites lead to impaired recovery of collapsed replication forks and elevated levels of Rad52 DNA repair foci, indicating the role of histone H4 acetylation in DNA replication and fork repair. We also show that Vid21 interacts with the Swi1-Swi3 replication fork protection complex and that Swi1 stabilizes Vid21 and promotes efficient histone H4 acetylation. Furthermore, our genetic analysis demonstrates that loss of Swi1 further sensitizes NuA4 and histone H4 mutant cells to replication fork breakage., Conclusion: Considering that Swi1 plays a critical role in replication fork protection, our results indicate that NuA4 and histone H4 acetylation promote repair of broken DNA replication forks.

Background: The chitinase-like protein YKL-40 plays a major role in inhibiting the inflammasome. Deregulation of inflammasome activation is emerging as a key modulator of pathologic airway inflammation in patients with asthma. We determined whether cis-expression quantitative trait loci (eQTLs) of the gene that encodes YKL-40, chitinase 3-like 1 (CHI3L1), are involved in the onset of asthma or in specific asthma phenotypes., Methods: This case-control study, which was conducted at the University of Tsukuba, Japan, included a total of 2709 adults from the Tsukuba genome-wide association study (GWAS) cohort (734 healthy volunteers and 237 asthma patients), the Tsukuba replication cohort (375 healthy adult volunteers and 381 adult asthma patients), and the Hokkaido replication cohort (554 healthy adult volunteers and 428 adult asthma patients). Among 34 cis-eQTLs in CHI3L1 in the lung, rs946261 was associated with adult asthma in these Japanese cohorts. The genetic impact of rs946261 on asthma was also examined according to the age at onset and adult asthma clusters., Results: In the Tsukuba GWAS cohort, the C allele at rs946261 was significantly associated with reduced expression of CHI3L1 mRNA in the lung and with development of asthma (odds ratio (OR) 1.27; P = 0.036). The association was also observed following analysis of the three Japanese cohorts (OR 1.16; P = 0.013). A stronger association was found with late-onset asthma that developed at 41 years of age or later (OR 1.24; 95% confidence interval (CI) 1.07-1.45; P = 0.0058) and with a specific asthma phenotype characterized by late onset, less atopy, and mild airflow obstruction (OR 1.29; 95% CI 1.03-1.61; P = 0.027)., Conclusions: The genotype consisting of the cis-eQTL allele that reduces expression of CHI3L1 was specifically associated with late-onset adult asthma. Given the important role of YKL-40 in many pathophysiological processes, including cell growth, migration, chemotaxis, reorganization, and tissue remodeling, it may be involved in an important pathogenic role in the establishment of inflammation and remodeling in asthmatic airways. Our findings may indicate the presence of a specific endotype related to exaggerated activation of YKL-40 in the pathogenesis of late-onset adult asthma.

Background: Human and animal research indicates that oxytocin (OT) plays a key role in the cross-generational transmission of parental bonding, and human studies suggest that allelic variations on the oxytocin receptor gene (OXTR) and circulating OT levels interact with patterns of parental care to shape children's social-affiliative competencies. Yet, no study to date has tested the joint contribution of OT and parental care across three generations., Methods: The study included 345 participants comprising 115 family lines of grandmothers, mothers, and their infants. Salivary OT and allelic variations on the OXTR (rs53576 and rs2254298) and CD38 (rs3796863) single nucleotide polymorphisms (SNPs), which have been previously associated with parental bonding, were assessed in all participants. Parental care was measured from grandmothers to mothers and from mothers to their infants., Results: Mothers receiving parenting characterized by high overprotection from grandmothers showed more rejection toward their infants only when carrying the G allele on the OXTRrs53576 (AG/GG). These mothers of highly overprotective grandmothers also had lower oxytocin levels. Infants who were OXTRrs2254298 A carriers (AA/AG) and whose mothers reported more rejection toward their infants had higher oxytocin levels. Grandmothers receiving higher overprotection from great-grandmothers showed poorer parenting style compared to grandmothers experiencing lower parental overprotection only when carrying the OXTRrs2254298 GG genotype., Conclusions: Our findings are the first to demonstrate how genetic and peripheral markers on the oxytocin system interact with experienced parenting to shape bonding across three generations. Results have important implications for specifying the biological and behavioral determinants associated with the continuity of adaptive versus maladaptive patterns of attachment across generations., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: TYRO3 is a member of the TAM (TYRO3, AXL, MERTK) receptor tyrosine kinase family and functions to limit type 2 immune responses implicated in allergic sensitization. Recent studies have shown that multiple intronic variants of TYRO3 were associated with asthma, implying that genetic variation could contribute to errant immune activation. We therefore hypothesized that expression quantitative trait loci (eQTLs) of the TYRO3 gene influence the development of allergic diseases (including asthma and allergic rhinitis) in Japanese populations., Methods: We performed a candidate gene case-control association study of 8 eQTLs of TYRO3 on atopy, asthma, and allergic rhinitis using 1168 unrelated Japanese adults who had GWAS genotyping. We then examined the genetic impact of rs2297377 (TYRO3) on atopy and allergic rhinitis in 2 other independent Japanese populations., Results: A meta-analysis of 3 Japanese populations (a total of 2403 Japanese adults) revealed that rs2297377 was associated with atopy and allergic rhinitis (OR = 1.29 and 1.31; P = 0.00041 and 0.0010, respectively). The risk allele at rs2297377 correlated with decreased expression of TYRO3 mRNA. The gene-gene interaction between HLA-DPB1 and TYRO3 was not significant with regard to sensitization. The estimated proportion of atopy and allergic rhinitis cases attributable to the risk genotype was 14% and 16%, respectively., Conclusions: Our study identified TYRO3 as an important susceptibility gene to atopy and allergic rhinitis in Japanese., (Copyright © 2018 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Purpose: To investigate the safety, pharmacokinetics, and efficacy of trastuzumab emtansine (T-DM1) in combination with pertuzumab in Japanese patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer., Patients and Methods: Patients with HER2-positive advanced or recurrent breast cancer who had received trastuzumab and chemotherapy-containing therapies were eligible. Patients received T-DM1 (3.6 mg/kg) with full-dose pertuzumab (a loading dose of 840 mg and then 420 mg) intravenously every 3 weeks. This study was registered at the Japan Pharmaceutical Information Center-Clinical Trials Information (JapicCTI-101234)., Results: Six patients enrolled in this study. The median duration of treatment was 11 (range 1-32) cycles. The most common treatment-emergent adverse event (TEAE) for any grade was diarrhea. Grade 3 or greater TEAEs included aspartate aminotransferase increased, left ventricular ejection fraction (LVEF) decreased, and neutrophil count decreased. The dose-limiting toxicity of grade 3 LVEF decreased was observed in one patient during cycle 1; however, it resolved within 30 days. The pharmacokinetic parameters of T-DM1 and pertuzumab were not affected by co-administration of the drugs. The best overall response included a partial response (PR) in 3 patients (50%) and stable disease (SD) in 2 patients (33%)., Conclusions: The combination of T-DM1 and pertuzumab was tolerated and showed exploratory efficacy in Japanese patients with HER2-positive metastatic breast cancer.

Objective: Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare autosomal recessive primary immunodeficiency. Hypogammaglobulinemia is a major manifestation of ICF syndrome, but immunoglobulin replacement therapy does not seem to be effective for some ICF patients. Therefore, we aimed to reassess the immunological characteristics of this syndrome., Methods: Eleven Japanese patients with ICF syndrome were enrolled. We performed whole-exome sequencing in four cases and homozygosity mapping using SNP analysis in two. We evaluated their clinical manifestations and immunological status., Results: We newly diagnosed six ICF patients who had tentatively been diagnosed with common variable immunodeficiency. We identified two novel mutations in the DNMT3B gene and one novel mutation in the ZBTB24 gene. All patients showed low serum IgG and/or IgG 2 levels and were treated by periodic immunoglobulin replacement therapy. Three of the six patients showed worse results of the mitogen-induced lymphocyte proliferation test. Analyses of lymphocyte subpopulations revealed that CD19 + CD27 + memory B cells were low in seven of nine patients, CD3 + T cells were low in three patients, CD4/8 ratio was inverted in five patients, CD31 + recent thymic emigrant cells were low in two patients, and CD19 + B cells were low in four patients compared with those in the normal controls. ICF2 patients showed lower proportions of CD19 + B cells and CD16 + 56 + NK cells and significantly higher proportions of CD3 + T cells than ICF1 patients. T cell receptor excision circles were undetectable in two patients. Despite being treated by immunoglobulin replacement therapy, three patients died of influenza virus, fatal viral infection with persistent Epstein-Barr virus infection, or JC virus infection. One of three dead patients showed normal intelligence with mild facial anomaly. Two patients presented with autoimmune or inflammatory manifestations. Infectious episodes decreased in three patients who were started on trimethoprim-sulfamethoxazole and/or antifungal drugs in addition to immunoglobulin replacement therapy. These patients might have suffered from T cell immunodeficiency., Conclusion: These results indicate that patients with ICF syndrome have a phenotype of combined immunodeficiency. Thus, to achieve a better prognosis, these patients should be treated as having combined immunodeficiency in addition to receiving immunoglobulin replacement therapy.

In this study, we found Cystatin SN (CST1), a type 2 cystatin subfamily member, to be highly expressed in nasal polyps from patients with intractable chronic rhinosinusitis (CRS) with nasal polyps, using a whole-transcript analysis with next-generation sequencing. Eosinophilic CRS (ECRS) involves nasal polyps that are refractory and recur immediately after endoscopic sinus surgery. We hypothesized that CST1 may contribute to the pathogenesis of ECRS. We examined the expression of CST1 in nasal polyps from patients with ECRS by assessing mRNA expression levels using real-time PCR and immunohistochemistry. CST1 showed significantly greater expression in the epithelial cells of nasal polyps from patients with ECRS than in those from patients who did not have ECRS (non-ECRS). In particular, CST1 showed very strong expression in patients with severe ECRS. The expression of CST1 may be correlated with the recurrent and refractory nature of ECRS. We examined the function of CST1 using nasal epithelial cells and nasal fibroblasts. Stimulation by a combination of IL-4 plus double-stranded RNA plus CST1 significantly elevated mRNA expression levels and protein levels of TSLP in nasal epithelial cells. Stimulation by TSLP or IL-33 significantly elevated mRNA expression levels of CST1 in nasal epithelial cells. Stimulation of CST1 significantly elevated mRNA expression levels of CCL11 and POSTN in nasal fibroblasts. CST1 could amplify eosinophilic infiltration and T-helper cell type 2 inflammation by interacting with epithelial-derived cytokines and fibroblasts on nasal polyps. CST1 may be involved in the pathogenesis of ECRS, and may contribute to the severity and recurrence of CRS with nasal polyps after endoscopic sinus surgery.

Background Nasal polyps (NP) are characterized by pseudocysts derived from stromal tissue edema and cause persistent infections in patients with chronic rhinosinusitis (CRS). A low level of tissue-type plasminogen activator (gene name PLAT) is considered a cause of stromal tissue edema because of insufficient plasmin activation in NP; however, the mechanism regulating PLAT gene expression levels is still unclear. The epigenetic mechanism regulating the PLAT gene expression has been studied in other tissues. Objective We aimed to investigate the methylation levels in the proximal PLAT promoter and their effects on gene expression in NP tissue. Methods We investigated the methylation levels at 3 CpG sites in the proximal PLAT promoter regions (-618, -121, and -105 with respect to the transcription initiation site) by bisulfite pyrosequencing and their effects on the gene expression by quantitative real-time polymerase chain reaction (qPCR) in 20 paired samples of NP and inferior turbinate tissue (IT) from patients with CRS. Results The DNA methylation levels at all CpG sites were higher ( P < .01), and the PLAT expression was lower ( P < .001) in NP compared with IT. The methylation changes at the -618 site showed a negative correlation with the gene expression changes between NP and IT ( r = -.65, P < .01). Conclusions Hypermethylation of PLAT promoter may downregulate the gene expression in NP, leading to excessive fibrin deposition by aberrant coagulation cascade. DNA methylation of proximal PLAT promoter may contribute to NP growth and have a potential as a new therapeutic target.