Kurzfassung: Mutations in the OTOF gene are a common cause of hereditary hearing loss and the main cause of auditory neuropathy spectrum disorder (ANSD). Although it is reported that most of the patients with OTOF mutations have stable, congenital or prelingual onset severe-to-profound hearing loss, some patients show atypical clinical phenotypes, and the genotype–phenotype correlation in patients with OTOF mutations is not yet fully understood. In this study, we aimed to reveal detailed clinical characteristics of OTOF -related hearing loss patients and the genotype–phenotype correlation. Detailed clinical information was available for 64 patients in our database who were diagnosed with OTOF -related hearing loss. As reported previously, most of the patients (90.6%) showed a “typical” phenotype; prelingual and severe-to-profound hearing loss. Forty-seven patients (73.4%) underwent cochlear implantation surgery and showed successful outcomes; approximately 85–90% of the patients showed a hearing level of 20–39 dB with cochlear implant and a Categories of Auditory Performance (CAP) scale level 6 or better. Although truncating mutations and p.Arg1939Gln were clearly related to severe phenotype, almost half of the patients with one or more non-truncating mutations showed mild-to-moderate hearing loss. Notably, patients with p.His513Arg, p.Ile1573Thr and p.Glu1910Lys showed “true” auditory neuropathy-like clinical characteristics. In this study, we have clarified genotype–phenotype correlation and efficacy of cochlear implantation for OTOF -related hearing loss patients in the biggest cohort studied to date. We believe that the clinical characteristics and genotype–phenotype correlation found in this study will support preoperative counseling and appropriate intervention for OTOF -related hearing loss patients.

Kurzfassung: To apply a deep learning model for automatic localisation of the scleral spur (SS) in anterior segment optical coherence tomography (AS-OCT) images and compare the reproducibility of anterior chamber angle (ACA) width between deep learning located SS (DLLSS) and manually plotted SS (MPSS). Methods In this multicentre, cross-sectional study, a test dataset comprising 5166 AS-OCT images from 287 eyes (116 healthy eyes with open angles and 171 eyes with primary angle-closure disease (PACD)) of 287 subjects were recruited from four ophthalmology clinics. Each eye was imaged twice by a swept-source AS-OCT (CASIA2, Tomey, Nagoya, Japan) in the same visit and one eye of each patient was randomly selected for measurements of ACA. The agreement between DLLSS and MPSS was assessed using the Euclidean distance (ED). The angle opening distance (AOD) of 750 µm (AOD750) and trabecular-iris space area (TISA) of 750 µm (TISA750) were calculated using the CASIA2 embedded software. The repeatability of ACA width was measured. Results The mean age was 60.8±12.3 years (range: 30–85 years) for the normal group and 63.4±10.6 years (range: 40–91 years) for the PACD group. The mean difference in ED for SS localisation between DLLSS and MPSS was 66.50±20.54 µm and 84.78±28.33 µm for the normal group and the PACD group, respectively. The span of 95% limits of agreement between DLLSS and MPSS was 0.064 mm for AOD750 and 0.034 mm 2 for TISA750. The respective repeatability coefficients of AOD750 and TISA750 were 0.049 mm and 0.026 mm 2 for DLLSS, and 0.058 mm and 0.030 mm 2 for MPSS. Conclusion DLLSS achieved comparable repeatability compared with MPSS for measurement of ACA.

Kurzfassung: Obesity is reported to be a risk factor for Clostridioides difficile infection. However, obesity rarely occurs in older Asian patients, and the effects of obesity on health and disease are different in Asian and Western countries. This study aimed to assess the association between body mass index and C. difficile infection risk among older patients with pneumonia in Japan. Methods This retrospective observational cohort study used data from the nationwide database of acute hospital inpatients' data in Japan between July 2014 and March 2016. All patients aged ≥65 years admitted with a primary diagnosis of pneumonia were enrolled. Risk factors for C. difficile infection were determined by logistic regression analysis, including known risks as covariates. Results Among 221 242 pneumonia patients, 611 developed C. difficile infection. Underweight patients (body mass index 〈 18.5 kg/m 2 ) showed higher odds for C. difficile infection (odds ratio 1.38, 95% confidence interval 1.17–1.62, P   〈  0.001) than normal weight patients (body mass index 18.5–24.9 kg/m 2 ), whereas overweight patients (body mass index ≥25 kg/m 2 ) showed lower odds (odds ratio 0.63, 95% confidence interval 0.45–0.89, P   〈  0.01). Conclusions Body mass index was associated with C. difficile infection in older pneumonia patients in Japan. Underweight was a risk factor, whereas overweight was a protective factor for C. difficile infection. Geriatr Gerontol Int 2022; 22: 63–67 .

Kurzfassung: : This study aimed to evaluate the changes in the rates of genetic counseling and genetic testing as well as the diagnosis rate of Lynch syndrome (LS)-associated colorectal cancer before and after multistep approach with multidisciplinary team in Japanese. Methods In September 2016, we started universal screening for LS by mismatch repair protein immunohistochemistry and prospectively collected the records. Following patient interviews, we started multistep approach with multidisciplinary team (MA) in January 2020. MA consists of six surgeons, one genetic counselor, one medical geneticist, and six pathologists. MA is set up to compensate for patients’ lack of knowledge about genetic diseases and make case selection for elderly colorectal cancer patients with deficient mismatch repair (dMMR). MA is designed as a system that could be performed by a small number of medical genetic specialists. A total of 522 patients were included during the study duration, 323 and 199 patients in the pre-MA (P-MA) and MA groups, respectively. Results The frequency of dMMR in all patients was 10.0%. The patient interview results indicated a significant lack of patient education regarding genetic diseases. The rates of genetic counseling and genetic testing was significantly higher in MA group than in P-MA group (genetic counseling: MA 34.6% vs. P-MA 7.7%, p = 0.04; genetic testing: MA 30.8% vs. P-MA 3.8%, p = 0.02). Moreover, the diagnosis rate of LS-associated colorectal cancer was significantly higher in MA group (2.5%) than in P-MA group (0.3%) ( P  = 0.03). In addition, MA could be performed without problems despite the small number of medical and human genetics specialists. Conclusions MA has achieved appropriate pickup of suspected hereditary colorectal cancer patients and complemented the lack of knowledge about genetic diseases. The introduction of MA increased LS-associated colorectal cancer after universal screening. MA is an appropriate LS screening protocol for Japanese patients who lag behind in medical and human genetics education.

Kurzfassung: In the nucleus, genomic DNA is wrapped around histone octamers to form nucleosomes. In principle, nucleosomes are substantial barriers to transcriptional activities. Nuclear non-coding RNAs (ncRNAs) are proposed to function in chromatin conformation modulation and transcriptional regulation. However, it remains unclear how ncRNAs affect the nucleosome structure. Eleanors are clusters of ncRNAs that accumulate around the estrogen receptor-α ( ESR1 ) gene locus in long-term estrogen deprivation (LTED) breast cancer cells, and markedly enhance the transcription of the ESR1 gene. Here we detected nucleosome depletion around the transcription site of Eleanor2, the most highly expressed Eleanor in the LTED cells. We found that the purified Eleanor2 RNA fragment drastically destabilized the nucleosome in vitro. This activity was also exerted by other ncRNAs, but not by poly(U) RNA or DNA. The RNA-mediated nucleosome destabilization may be a common feature among natural nuclear RNAs, and may function in transcription regulation in chromatin.

Kurzfassung: Background: E7777 is a recombinant cytotoxic fusion protein composed of diphtheria toxin fragments A, B and human interleukin-2. The amino acid sequence of E7777 is the same as that of denileukin diftitox, approved in the USA for treatment of persistent or recurrent CD25-positive cutaneous T-cell lymphoma in 1999, but the purity of E7777 is improved and then it has an increased percentage of active protein monomer species. Since the specific bioactivity of E7777 is 1.5-2 times higher than that of the prior less purified form, a phase 1 study of E7777 was conducted in Japanese patients (pts) with peripheral and cutaneous T-cell lymphoma (PTCL and CTCL). The maximum tolerated and recommended dose of E7777 was 9 μg/kg/day for 5 consecutive days per 21-day cycle. E7777 was well tolerated and preliminary, but clinically meaningful antitumor activity was observed (Ohmachi, et al.: Cancer Sci 2018). Therefore, a subsequent phase 2 study of E7777 was conducted. Methods: This multicenter, single-arm phase 2 study assessed the efficacy, safety, pharmacokinetics (PK) and immunogenicity (IM) of E7777 in pts with relapsed or refractory PTCL and CTCL. E7777 was administered by IV infusion over 60 min for 5 consecutive days of every 21-day cycle (up to 8 cycles) at dose of 9 μg/kg/day with premedication including systemic steroid. Primary endpoint was objective response rate (ORR) by the independent review assessment. Thirty-five patients were required to detect the lower limit of 2-sided 95% confidence interval (CI) to exceed the 5% threshold in ORR, with the expected ORR of 25% with a statistical power of 90%. Efficacy was evaluated based on integrated criteria of IWG2007 (Cheson, et al,: JCO 2007) for nodal/ex-nodal disease by CT or PET/CT assessment and ISCL2011 (Olsen, et al.: JCO 2011) for cutaneous and blood disease assessment, in both PTCL and CTCL. Tumor CD25 expression level (%) in archival tumor samples from all pts was examined by immunohistochemistry. Results: As of 26 Apr 2019, a total of 37 pts were enrolled. Based on the central pathological review, 17 pts had PTCL [PTCL-not otherwise specified (NOS), n=13; angioimmunoblastic T-cell lymphoma, n=3; anaplastic large cell lymphoma-ALK negative, n=1], 19 pts had CTCL [mycosis fungoides, n=12; Sézary syndrome, n=2; primary cutaneous CD30+ T-cell lymphoproliferative disorder, n=2; primary cutaneous γδ T-cell lymphoma, n=1; primary cutaneous aggresive epidermotropic CD8+ cytotoxic T-cell lymphoma, n=1; PTCL-NOS, n=1] and 1 pt had the other disease (extranodal NK/T cell lymphoma, nasal type). The median age was 65 years (range 27-82), and the median number of prior chemotherapy regimens (excluding PUVA, interferon, etretinate) was 2 (range 1-10). Among the 36 pts with PTCL and CTCL, the ORR as assessed by the independent review was 36% (13/36 pts: 95%CI, 21%-54%), including 1 pt with complete response. The ORR were 41% (7/17 pts: 95%CI, 18%-67%) in PTCL and 31% (6/19 pts: 95%CI, 13%-57%) in CTCL, respectively. Responses were observed regardless of the level of CD25 expression in lymphoma cells. With a median follow-up time of 26.3 months, the median progression-free survival (mPFS) of all 36 pts with PTCL and CTCL was 3.1 months (95% CI, 1.9-6.0). The mPFS were 2.1 months (95% CI, 1.1-4.5) in PTCL and 4.2 months (95% CI, 2.6-NE) in CTCL, respectively. Among all 37 treated pts, the common adverse events (AEs) in any grade were AST increased (89%), ALT increased (87%), hypoalbuminemia (70%), lymphopenia (70%), pyrexia (51%), γ-GTP increased (46%), constipation (38%), thrombocytopenia (35%) and malaise (32%). The common Grade 3 or higher AEs were ALT increased (57%), lymphopenia (57%) and AST increased (43%). The common serious AEs considered related to study drug were ALT increased (14%), AST increased (14%) and capillary leak syndrome (11%). One pt died from rhabdomyolysis, which was considered as treatment related. PK and IM data will be presented. Conclusions: The primary endpoint of the study was met with greater lower limit of 2-sided 95% CI in ORR than the predefined 5% threshold. The study results indicated the promising efficacy and acceptable safety profile of E7777 at the dose of 9 μg/kg/day in Japanese pts with relapsed or refractory PTCL and CTCL, regardless of the level of tumor CD25 expression. The common AEs were manageable, but ALT/AST increased, hypoalbuminemia and capillary leak syndrome should be carefully managed during the treatment. Disclosures Maruyama: Eisai: Honoraria, Research Funding. Ando:Eisai: Research Funding. Yamamoto:Chugai: Consultancy, Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Sanofi: Honoraria; Novartis: Honoraria, Research Funding; Kyowa Kirin: Honoraria; Gilead Sciences: Research Funding; Otsuka: Honoraria; SymBio: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Bayer: Research Funding; AbbVie: Consultancy, Research Funding; ARIAD: Research Funding; Solasia Pharma: Research Funding; Janssen: Honoraria; MSD: Consultancy, Honoraria; Astra-Zeneca: Consultancy, Research Funding; Sumitomo Dainippon: Honoraria; Pfizer: Honoraria; Eisai: Consultancy, Honoraria, Research Funding; HUYA/IQVIA Services Japan: Consultancy, Honoraria; Mundipharma: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Meiji Seika Pharma: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Kiyohara:Eisai: Research Funding. Terui:Bristol-Myers Squibb K.K.: Research Funding; Bristol-Myers Squibb, Celgene, Janssen, Takeda, MSD, Eisai, Ono, and Chugai-Roche Pharmaceuticals Co.,Ltd.: Honoraria. Fukuhara:Chugai Pharmaceutical Co., Ltd.: Honoraria; Celgene Corporation: Honoraria, Research Funding; Zenyaku: Honoraria; Janssen Pharma: Honoraria; Eisai: Honoraria, Research Funding; Kyowa-Hakko Kirin: Honoraria; Mochida: Honoraria; Mundi: Honoraria; Nippon Shinkyaku: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding; AbbVie: Research Funding; Bayer: Research Funding; Gilead: Research Funding; Solasia Pharma: Research Funding. Tokura:Eisai: Consultancy, Honoraria. Kuroda:Eisai: Research Funding. Uchida:Eisai: Honoraria. Nakanishi:Eisai: Employment. Nakai:Eisai: Employment. Matsunaga:Eisai: Employment. Tobinai:HUYA Bioscience: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria; Verastem: Honoraria; Takeda Pharmaceutical: Consultancy, Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Zenyaku Kogyo: Consultancy, Honoraria; AbbVie: Research Funding; Yakult: Honoraria; Janssen Pharmaceutical: Honoraria, Research Funding; Mundi Pharma: Consultancy, Honoraria, Research Funding; Solasia: Honoraria; Meiji Seika: Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Ono Pharmaceutical: Consultancy, Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding. OffLabel Disclosure: E7777 is investigational drug