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Tomoki Nakamura,1 Jun Sugaya,2 Norifumi Naka,3 Hiroshi Kobayashi,4 Tomotake Okuma,5 Toshiyuki Kunisada,6 Kunihiro Asanuma,1 Hedetatsu Outani,7 Shunji Nishimura,8 Hiroyuki Kawashima,9 Toru Akiyama,10 Taketoshi Yasuda,11 Shinji Miwa,12 Akihiro Sudo,1 Takafumi Ueda13 1Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, Tsu 514-8507, Japan; 2Department of Musculoskeletal Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo 104-0045, Japan; 3Musculoskeletal Oncology Service, Osaka International Cancer Institute, Chuo-ku, Osaka 541-8567, Japan; 4Department of Orthopaedic Surgery, The University of Tokyo Hospital, Bunkyo-ku, Tokyo 113-8655, Japan; 5Department of Musculoskeletal Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Bunkyo-ku, Tokyo 113-8677, Japan; 6Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan; 7Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan; 8Department of Orthopaedic Surgery, Kindai University Hospital, Osaka-Sayama, Osaka 589-8511, Japan; 9Division of Orthopaedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata 951-8510, Japan; 10Department of Orthopaedic Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Saitama 330-8503, Japan; 11Department of Orthopaedic Surgery, University of Toyama, Toyama 930-0194, Japan; 12Department of Orthopaedic Surgery, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-8641, Japan; 13Department of Orthopaedic Surgery, Osaka National Hospital, Chuo-ku, Osaka 540-0006, JapanCorrespondence: Tomoki NakamuraDepartment of Orthopedic Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, JapanTel +81-592315022Fax +81-592315211Email tomoki66@clin.medic.mie-u.ac.jpBackground: The outcomes of unplanned surgery for bone sarcomas have not been frequently discussed. However, it is important to recognize patterns, treatment, and clinical outcomes of unplanned surgeries for patients with bone sarcomas. This multicenter study aimed to characterize the clinical outcomes of patients with bone sarcomas who underwent unplanned surgeries.Patients and Methods: Data of 43 patients with bone sarcomas who underwent unplanned surgery between 2006 and 2017 were obtained from 23 hospitals in Japan. These included 18 cases of osteosarcoma, 9 of Ewing sarcoma, 8 of chondrosarcoma, and 6 of undifferentiated pleomorphic sarcoma. The study included 28 men and 15 women, with a mean age of 46 years. The mean follow-up duration was 59 months.Results: The main primary tumor sites were the femur (n = 19), spine (n = 6), pelvis (n = 5), tibia (n = 3), and humerus (n = 3). The primary diagnoses were benign bone tumor (n = 24), trauma (n = 7), bone metastasis (n = 5), osteomyelitis (n = 4), degeneration (n=2), and unknown (n = 1). As unplanned surgeries, curettage, with or without bone graft, was performed in 26 patients; internal fixation was performed in 7; spinal surgery in 5; arthroplasty in 4; and arthroscopy in one. Thirty-eight patients received additional standard treatments. Thirty-four of these patients underwent surgical tumor resections, including amputation (n = 10), and the remaining 4 received radiotherapy or carbon ion radiotherapy as additional standard treatments. The 5-year disease-specific survival (DSS) rates in patients with osteosarcoma, Ewing sarcoma, and chondrosarcoma were 65.5%, 58.3%, and 72.9%, respectively. Twelve (27.9%) patients developed local recurrences (LR); among the total 43 patients studied, the 5-year DSS rates were significantly worse for those who developed LR compared to those who did not (p = 0.03). The 5-year DSS rates in patients with and without LR were 44% and 73.8%, respectively.Conclusion: We recommend that patients who have undergone unplanned surgery be administered standard treatment, including the option of amputation because herein, LR was shown to be a risk factor for decreased DSS.Keywords: bone sarcoma, unplanned surgery, local recurrence, osteosarcoma, Ewing sarcoma, chondrosarcoma

Background. In children, hypernatraemia occurs most commonly in infants (younger than 1 year). Although hypernatraemia is associated with high mortality and morbidity rates, it is variably defined in the paediatric literature as either serum sodium ≥150 mmol/L or serum sodium >145 mmol/L. In hospitalised adults, a serum sodium level >145 mmol/L but <150 mmol/L (called borderline hypernatraemia) has recently been identified as an independent risk factor for mortality. There are limited data about a potential association between borderline hypernatraemia and mortality in infants. Objectives. To determine whether borderline hypernatraemia is associated with increased mortality in hospitalised infants. Methods. We conducted a single-centre, retrospective observational study of 8 343 infants admitted to a tertiary-level academic hospital in Johannesburg, South Africa, of whom 254 had borderline hypernatraemia, 376 had hypernatraemia (serum sodium ≥150 mmol/L), and 7 713 did not have hypernatraemia. Mortality rates were reported as odds ratios (ORs) with 95% confidence intervals (CIs). Results. In 254 infants with borderline hypernatraemia, 115 (45.3%) were neonates (≤28 days old) and 140 (55.1%) were male. In 139 infants >28 days old with borderline hypernatraemia, the mortality rate (n=9/139; 6.5%) was significantly higher than the mortality rate observed in infants without hypernatraemia (n=194/5 857; 3.3%) (OR 2.02; 95% CI 1.03 - 3.98). Conclusion. Borderline hypernatraemia may be a risk factor associated with higher mortality in hospitalised infants. Prospective studies are required to determine whether borderline hypernatraemia contributes independently to mortality risk in hospitalised infants. [ABSTRACT FROM AUTHOR]

A 76-year-old woman was referred to our hospital for evaluation of markedly high intraocular pressures (IOPs): ≥40 mmHg in both eyes. No intraocular inflammation, pseudoexfoliation, or glaucomatous optic neuropathy was observed on ophthalmological examination. The 24-hour IOP fluctuations, measured with a Goldmann tonometer in the sitting position at 8, 12, 16, 20, and 24 o' clock, were 22/17, 33/28, 41/33, 30/22, and 30/24 mmHg, respectively, and showed a peak in the afternoon. The patient was diagnosed with ocular hypertension, and microhook trabeculotomy (μLOT) (right eye with lens reconstruction, left eye initially pseudophakic) was performed. After μLOT surgery in both eyes (4 days postoperatively in the right eye and 1 day postoperatively in the left eye), IOP decreased in both eyes to 12/15, 11/14, 12/15, 10/11, and 10/10 mmHg, and the fluctuation range was suppressed. At 3 months postoperatively (measured at 8, 12, 16, 20, 24, and 4 o' clock), the effect was maintained at 14/15, 15/19, 14/19, 11/12, 13/14, and 13/13 mmHg, respectively, but was slightly attenuated. In a patient with marked 24-hour IOP fluctuation, μLOT was effective in reducing IOP values and fluctuation.

Background and Objectives : Proximal junctional kyphosis (PJK) and failure (PJF), the most prevalent complications following long-segment thoracolumbar fusions for adult spinal deformity (ASD), remain lacking in defined preventive measures. We studied whether one of the previously reported strategies with successful results-a prophylactic augmentation of the uppermost instrumented vertebra (UIV) and supra-adjacent vertebra to the UIV (UIV + 1) with polymethylmethacrylate (PMMA)-could also serve as a preventive measure of PJK/PJF in minimally invasive surgery (MIS). Materials and Methods : The study included 29 ASD patients who underwent a combination of minimally invasive lateral lumbar interbody fusion (MIS-LLIF) at L1-2 through L4-5, all-pedicle-screw instrumentation from the lower thoracic spine to the sacrum, S2-alar-iliac fixation, and two-level balloon-assisted PMMA vertebroplasty at the UIV and UIV + 1. Results : With a minimum 3-year follow-up, non-PJK/PJF group accounted for fifteen patients (52%), PJK for eight patients (28%), and PJF requiring surgical revision for six patients (21%). We had a total of seven patients with proximal junctional fracture, even though no patients showed implant/bone interface failure with screw pullout, probably through the effect of PMMA. In contrast to the PJK cohort, six PJF patients all had varying degrees of neurologic deficits from modified Frankel grade C to D3, which recovered to grades D3 and to grade D2 in three patients each, after a revision operation of proximal extension of instrumented fusion with or without neural decompression. None of the possible demographic and radiologic risk factors showed statistical differences between the non-PJK/PJF, PJK, and PJF groups. Conclusions : Compared with the traditional open surgical approach used in the previous studies with a positive result for the prophylactic two-level cement augmentation, the MIS procedures with substantial benefits to patients in terms of less access-related morbidity and less blood loss also provide a greater segmental stability, which, however, may have a negative effect on the development of PJK/PJF.

BACKGROUND Fulminant type 1 diabetes is characterized by a low prevalence of autoantibodies, and was originally described as a nonautoimmune subtype of type 1 diabetes. Herein, we report a case in which we observed the process of extremely rapid onset of diabetes and early decline in anti-glutamic acid decarboxylase (GAD) antibody titers during the inpatient stay. CASE REPORT A 61-year-old man was brought to our hospital with marked hyperglycemia (1327 mg/dL), ketonemia (3-hydroxybutyrate: 14 012 µmol/L), and moderately elevated HbA1c (7.2%) and glycoalbumin (22.3%). C-peptide levels were undetectable. He had suffered from thirst, polyuria, and fatigue for 2 days. Abrupt onset was proven by the clinical data when he visited the hospital with respiratory symptoms 6 days before his admission; plasma glucose, glycoalbumin, C-peptide, and insulin levels were 117 mg/dL, 13.0%, 5.07 ng/mL, and 24.4 µIU/mL, respectively. The anti-GAD antibody titer measured by enzyme-linked immunosorbent assay was 111 U/mL at admission, 22.8 U/mL 2 weeks after admission, and negative 1 year later. He had a susceptible haplotype DRB1*09: 01-DQB1*03: 03, which is significantly more common in anti-GAD antibody-positive patients with fulminant type 1 diabetes. CONCLUSIONS The early decline of anti-GAD antibody titer likely reflected rapid and complete beta cell loss. The sequential metabolic and immunological observation in this case may provide insight into the pathogenesis of fulminant type 1 diabetes.

A 7-year-old female sugar glider showed a well-defined, homogeneous, hypoechoic mass in the caudal abdominal cavity on ultrasound. Exploratory laparotomy revealed both uteri were severely dilated by viscous, purulent exudate. The patient underwent ovariohysterectomy with removal of bilateral vaginal canals. Antibiotic therapy was initiated postoperatively. Histopathological findings were consistent with suppurative metritis, leading to a clinical diagnosis of pyometra. Despite abscess formation in the uterine stump or central vaginal canal and bilateral renal pelvic/ureter dilations postoperatively, the sugar glider survived more than 270 days. Unfortunately, surgical and medical treatments performed in this case did not prove curative. The outcome of this case highlights the importance of further accumulation of cases to define more appropriate therapies for pyometra in sugar gliders.

Background: Congenital diaphragmatic hernia (CDH) is associated with high neonatal mortality. We performed this study to test the hypothesis that left ventricular (LV) and right ventricular (RV) volumes assessed by three-dimensional echocardiography may be associated with mortality in CDH., Methods: This study was a single-center retrospective cohort study involving 35 infants with CDH. RV and LV end-diastolic volume (RVEDV and LVEDV, respectively) were measured by three-dimensional echocardiography and were corrected by birth body weight (BBW) on day 1. RVEDV/BBW, LVEDV/BBW, and LVEDV/RVEDV were compared between CDH survivors and non-survivors. Receiver-operating characteristic curve analysis was performed to assess the predictive ability for mortality of the echocardiographic parameters., Results: Comparing CDH non-survivors (n = 6) with survivors (n = 29), respectively, RVEDV/BBW was significantly larger (2.54 ± 0.33 vs 1.86 ± 0.35 ml/kg; P < 0.01), LVEDV/BBW was significantly smaller (0.86 ± 0.21 vs 1.22 ± 0.33 ml/kg; P < 0.001), and LVEDV/RVEDV was significantly lower (0.34 ± 0.06 vs 0.66 ± 0.18; P < 0.001). The area under the curve for LVEDV/RVEDV was the largest (0.98)., Conclusions: Three-dimensional echocardiographic volume imbalance between the RV and LV was remarkable in CDH non-survivors. The LVEDV/RVEDV ratio may be associated with mortality in CDH., Impact: Mortality with congenital diaphragmatic hernia (CDH) is high, and evaluating left and right ventricular structures and functions may be helpful in assessing the prognosis. Three-dimensional (3D) echocardiography indicated that the left ventricular end-diastolic volume/right ventricular end-diastolic volume ratio within 24 h after birth was associated with mortality in CDH infants. The usefulness of this ratio should be validated in prospective multicenter studies involving larger numbers of patients., (© 2023. The Author(s).)

Background: The purpose of this meta-analysis was to comprehensively investigate the diagnostic ability of 1.5 T and 3.0 T whole heart coronary angiography (WHCA) to detect significant coronary artery disease (CAD) on X-ray coronary angiography., Methods: A literature search of electronic databases, including PubMed, Web of Science Core Collection, Cochrane advanced search, and EMBASE, was performed to retrieve and integrate articles showing significant CAD detectability of 1.5 and 3.0 T WHCA., Results: Data from 1899 patients from 34 studies were included in the meta-analysis. 1.5 T WHCA had a summary area under ROC of 0.88 in the patient-based analysis, 0.90 in the vessel-based analysis, and 0.92 in the segment-based analysis. These values for 3.0 T WHCA were 0.94, 0.95, 0.96, respectively. Contrast-enhanced 3.0 T WHCA had significantly higher specificity than non-contrast-enhanced 1.5 T WHCA on a patient-based analysis (0.87, 95% CI 0.80-0.92 vs. 0.74, 95% CI 0.64-0.82, P = 0.02). There were no differences in diagnostic performance on a patient-based analysis by use of vasodilators, beta-blockers or between Asian and Western countries., Conclusions: The diagnostic performance of WHCA was deemed satisfactory, with contrast-enhanced 3.0 T WHCA exhibiting higher specificity compared to non-contrast-enhanced 1.5 T WHCA in a patient-based analysis. There were no significant differences in diagnostic performance on a patient-based analysis in terms of vasodilator or beta-blocker use, nor between Asian and Western countries. However, further large-scale multicentre studies are crucial for the widespread global adoption of WHCA., (© 2023. The Author(s).)

Background: We herein report the anesthetic management for extracardiac conduit-total cavopulmonary connection (EC-TCPC) for weaning from an extracorporeal right ventricular assist device (RVAD) in a patient with an implantable left ventricular assist device (LVAD) for fulminant cardiomyopathy., Case Presentation: A 24-year-old man developed fulminant cardiomyopathy and was placed on a biventricular assist device (BiVAD) comprising an implantable LVAD and an extracorporeal RVAD. The Fontan procedure was performed to wean the patient from the RVAD and allow him to be discharged home. Atrial septal defect creation, right ventricular suture, and tricuspid valve closure were then simultaneously performed to ensure sufficient left ventricular preload to drive the LVAD. Furthermore, to keep the central venous pressure lower, the inflow cannula of the LVAD was oriented in the correct direction., Conclusion: This is the first report of anesthetic management of the Fontan procedure in a patient with a BiVAD., (© 2023. The Author(s).)

The morphology of 58 apocrine tumors from 31 domestic Richardson's ground squirrels ( Urocitellus richardsonii ) was examined, comparing tumor subtypes with clinical information and histological findings. The squirrels included 23 males (74%) and 8 females (26%). Of the 58 tumors, 36 (62%) were located from the cervical skin to the dorsal skin, 17 (29%) were from the perioral region to the cheek, and the location was unrecorded for the remaining 5 squirrels (9%). Histologically, 49 tumors (84%) were apocrine adenocarcinomas, 6 were apocrine adenomas (10%), and 3 were apocrine cysts (5%). The 49 apocrine adenocarcinomas were subclassified as 16 (33%) cystic papillary type, 16 (33%) tubulopapillary type, 12 (24%) solid type, and 5 (10%) micropapillary invasive type. Fisher's exact test revealed correlations between tumor subtypes and tumor diameters, nuclear atypia, tumor margins, vascular invasion, and periodic acid-Schiff (PAS) positivity. This study showed a predominance of apocrine adenocarcinomas with various histological subtypes. In addition, subclassification of these tumors was useful for predicting the biological behavior of apocrine gland tumors in Richardson's ground squirrels.

No standard treatment has been established for most rare cancers. Here, we report a clinical trial of a biweekly WT1 tri-peptide-based vaccine for recurrent or advanced rare cancers. Due to the insufficient number of patients available for a traditional clinical trial, the trial was designed for rare cancers expressing shared target molecule WT1. The recruitment criteria included WT1-expressing tumors as well as HLA-A*24:02 or 02:01. The primary endpoints were immunoglobulin G (IgG) antibody (Ab) production against the WT1-235 cytotoxic T lymphocyte (CTL) epitope and delayed-type hypersensitivity (DTH) skin reactions to targeted WT1 CTL epitopes. The secondary endpoints were safety and clinical efficacy. Forty-five patients received WT1 Trio, and 25 (55.6%) completed the 3-month protocol treatment. WT1-235 IgG Ab was positive in 88.0% of patients treated with WT1 Trio at 3 months, significantly higher than 62.5% of the weekly WT1-235 CTL peptide vaccine. The DTH positivity rate in WT1 Trio was 62.9%, which was not significantly different from 60.7% in the WT1-235 CTL peptide vaccine. The WT1 Trio safety was confirmed without severe treatment-related adverse events, except grade 3 myasthenia gravis-like symptoms observed in a patient with thymic cancer. Fifteen (33.3%) patients achieved stable disease after 3 months of treatment. In conclusion, the biweekly WT1 Trio vaccine containing the WT1-332 helper T lymphocyte peptide induced more robust immune responses targeting WT1 than the weekly WT1-235 CTL peptide vaccine. Therefore, WT1-targeted immunotherapy may be a potential therapeutic strategy for rare cancers.

Purpose: To objectively evaluate surgically induced astigmatism (SIA) after trabeculectomy with mitomycin C and investigate the relationships between SIA and various factors., Patients and Methods: This retrospective study included the right eyes of 66 consecutive patients who underwent standard trabeculectomy performed in the superior temporal quadrant for the first time by a single surgeon. Keratometry recordings made before surgery and 3 months after surgery were collected to calculate the SIA in each patient. The arithmetic mean of SIA (M-SIA) and the centroid of SIA (C-SIA) were determined using vector analysis. The relationships between the magnitude of SIA and the following possible related factors were assessed: age, sex, pre-operative corneal astigmatism, pre-operative intraocular pressure (IOP), 3-month postoperative IOP, pre-operative best-corrected visual acuity (BCVA), 3-month postoperative BCVA, the number of total scleral flap sutures (T-SFS), the number of leftover scleral flap sutures without laser suture lysis at 3 months postoperatively (L-SFS), shape of the scleral flap (triangle or trapezoid), and incision type of the conjunctival flap (fornix- or limbal-based)., Results: The mean (± standard deviation) M-SIA was 1.00 ± 0.85 D, and the mean C-SIA was 0.34 ± 1.28 D at 104°. The direction of C-SIA showed a trend of corneal steepening to the superior temporal location, in the direction of the scleral flap location. There were significant correlations of the magnitudes of SIA with the number of T-SFS (P = 0.001) and the number of L-SFS (P < 0.001)., Conclusion: Trabeculectomy induced SIA in the direction of the scleral flap location, and scleral sutures are significantly associated with the SIA. The scleral suture may play a key role in steepening the cornea toward the scleral flap direction in post-trabeculectomy patients., Competing Interests: The authors report no conflicts of interest in this work., (© 2022 Shiratori et al.)

Pigmentary mosaicism of the Ito type, also known as hypomelanosis of Ito, is a neurocutaneous syndrome considered to be predominantly caused by somatic chromosomal mosaicism. However, a few monogenic causes of pigmentary mosaicism have been recently reported. Eleven unrelated individuals with pigmentary mosaicism (mostly hypopigmented skin) were recruited for this study. Skin punch biopsies of the probands and trio-based blood samples (from probands and both biological parents) were collected, and genomic DNA was extracted and analyzed by exome sequencing. In all patients, plausible monogenic causes were detected with somatic and germline variants identified in five and six patients, respectively. Among the somatic variants, four patients had MTOR variant (36%) and another had an RHOA variant. De novo germline variants in USP9X, TFE3, and KCNQ5 were detected in two, one, and one patients, respectively. A maternally inherited PHF6 variant was detected in one patient with hyperpigmented skin. Compound heterozygous GTF3C5 variants were highlighted as strong candidates in the remaining patient. Exome sequencing, using patients' blood and skin samples is highly recommended as the first choice for detecting causative genetic variants of pigmentary mosaicism., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Intimal smooth muscle cells (SMCs) play an important role in the vasculitis caused by Kawasaki disease (KD). Lipoprotein receptor 11 (LR11) is a member of the low-density lipoprotein receptor family, which is expressed markedly in intimal vascular SMCs and secreted in a soluble form (sLR11). sLR11 has been recently identified as a potential vascular lesion biomarker. sLR11 is reportedly elevated in patients with coronary artery lesions long after KD, but there is no description of sLR11 in acute KD. Our aim was to determine the sLR11 dynamics in acute KD and to assess its usefulness as a biomarker.Methods and Results: 106 acute KD patients and 18 age-matched afebrile controls were enrolled. KD patients were classified into the following subgroups: intravenous immunoglobulin (IVIG) responders (n=85) and non-responders (n=21). Serum sLR11 levels before IVIG therapy were higher in non-responders (median, 19.6 ng/mL; interquartile range [IQR], 13.0-24.9 ng/mL) than in controls (11.9 ng/mL, 10.4-14.9 ng/mL, P<0.01) or responders (14.3 ng/mL, 11.7-16.5 ng/mL, P<0.01). Using a cutoff of >17.5 ng/mL, non-responders to initial IVIG therapy were identified with 66.7% sensitivity and 78.8% specificity., Conclusions: sLR11 can reflect the state of acute KD and might be a biomarker for patient response to IVIG therapy.

Background: These clinical practice guidelines are intended to provide recommendations based on the best evidence obtained to date on key issues in clinical practice to improve the prognosis, diagnostic and therapeutic processes for patients with soft tissue tumors., Methods: The Guidelines Development Committee and Systematic Review Committee were composed of a multidisciplinary team of specialists who play an important role in soft tissue tumor care. Clinical questions (CQs) were determined by choosing key decision-making points based on Algorithms for the diagnosis and treatment of soft tissue tumors. The guidelines were developed according to the "Medical Information Network Distribution Service (Minds) Handbook for Clinical Practice Guideline Development 2014" and "Minds Manual for Clinical Practice Guideline Development 2017." Recommendation strength was rated on two levels and the strength of evidence was rated on four levels. The recommendations were decided based on agreement by 70% or more voters., Results: Twenty-two CQs were chosen by the Guidelines Development Committee. The Systematic Review Committee reviewed the evidence concerning each CQ, a clinical value judgment was added by experts, and the text of each recommendation was determined., Conclusion: We established 22 CQs and recommendations for key decision-making points in the diagnosis and treatment of soft tissue tumors according to the Minds Clinical Practice Guideline development methods. We hope that these guidelines will assist the decision-making of all medical staff engaged in the treatment and diagnosis of soft tissue tumors, and eventually lead to improved soft tissue tumor care in the country., Competing Interests: Declaration of competing Interest Akira Kawai reports research grants from Daiichi-Sankyo, Eli-Lilly, Taiho, Takara-Bio and Japanese Orthopaedic Association. Hirotaka Kawano reports honoraria from Daiichi Sankyo and Hisamitsu, and research grants from Japanese Orthopaedic Association, Nakatomi Foundation, Daiichi-Sankyo, Kyocera, Shionogi, Teijin, Zimmer Biomet, Johnson and Johnson, Smith and Nephew, Peter Blehm Japan and Stryker Japan. Toshiyuki Kunisada reports a research grant from Kuraray, and the Department of Medical Materials for Musculoskeletal Reconstruction is an endowment department, supported with an unrestricted grant from Kyocera. Shunji Takahashi reports honoraria from Eisai, Novartis, Taiho, Astrazeneca, Chugai, Bayer, Daiichi-Sankyo, and research grants from EISAI, Novartis, Taiho, Astrazeneca, Chugai, Bayer, Daiichi-Sankyo, Ono pharmaceutical, IQVIA and Bristol-Myers-Squib. Kazuhiro Tanaka belongs to an endowment department supported with grants from Teijin Nakashima Medical Co., Ltd. and Meditec Co., Ltd. Norio Yamamoto belongs to an endowed department supported with grants from Zimmer Biomet G.K. and Hisamitsu Pharmaceutical Co., Inc., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

The Wilms' tumor gene WT1 is highly expressed in various malignancies and may be a common target antigen for cancer immunotherapy. In our group, peptide-based cancer vaccines targeting WT1 CTL epitopes were developed as an immunotherapy for these malignancies. In the present study, WT1 epitope-specific immune responses were analyzed in 31 patients with advanced sarcoma with human leukocyte antigen-A*24:02- and WT1-expressing tumors who received the WT1-235 peptide vaccine as monotherapy. The serum levels of IgG and IgM antibodies against the target epitope WT1-235 and the non-target epitopes WT1-332 and WT1-271 were measured using ELISA. IgM antibodies against WT1-235, WT1-332 and WT1-271 were detected in three (9.6%), four (12.9%) and 20 patients (64.5%), respectively, prior to vaccine administration, indicating immune recognition of the WT1 antigen prior to administering the vaccine. Of 15 patients who had completed the 3-month treatment protocol, WT1-235 IgG was positive in five (33.3%) patients. An enzyme-linked immunospot assay revealed that WT1-235 epitope-specific IL-10 production/secretion in peripheral blood mononuclear cells declined in the first month of vaccine administration in all three patients with positivity for WT1-235 IgM at the start of the vaccine. Furthermore, positivity for both WT1-235 and WT1-271 IgM antibodies at the start of treatment was associated with unfavorable tumor control at 3 months after vaccine administration. These results suggested that WT1 epitope-specific IgG and IgM antibodies may be utilized as immune-monitoring markers for WT1 peptide cancer vaccine immunotherapy. The trials were entered in the University hospital Medical Information Network (UMIN) Clinical Trials Registry (https://www.umin.ac.jp/ctr; no. UMIN000002001 on May 24, 2009 and no. UMIN000015997 on December 20, 2014)., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Alzaaqi et al.)

A 5-y-old, male degu ( Octodon degus ) was presented with a subcutaneous mass in the ventral aspect of the cervical area. The mass was removed surgically. Histologically, the mass was a densely cellular, expansile neoplasm, with compression of thymic tissue to the periphery. The neoplasm consisted of solid sheets of polygonal cells, mixed with fewer small lymphocytes. Rare Hassall bodies were scattered throughout the mass. Polygonal cells were positive for anti-keratin/cytokeratin AE1/AE3 antibody, and small lymphocytes were positive for anti-CD3 antibody. The histopathologic and immunohistochemical findings were consistent with a thymoma. In addition, an autopsy revealed myxosarcoma of the right thoracic wall with metastasis to the lung. To our knowledge, thymoma originating from the cervical component of the thymus has not been documented previously in a rodent species.

Decreased vision and cystoid macular edema (CME) developed in phakic eyes of a patient who underwent laser iridotomy after changing the glaucoma eye drops from carteolol 2% long-acting ophthalmic solution to omidenepag isopropyl 0.002%. CME completely disappeared at approximately 2 months after discontinuation of omidenepag isopropyl in conjunction with the use of bromfenac sodium 0.1%.

Skin lesions possibly caused by Papillomavirus infections in two four-toed hedgehogs are described. In case 1, there was a papillary mass on the right hind limb. Histologically, the mass was consistent with a viral papilloma. In the other case, multifocal papillary masses with erosions and ulcers were found throughout the body, mainly on the extremities. Histology showed continuative lesions composed of acanthosis, Bowenoid in situ carcinoma, and squamous cell carcinoma, with abrupt transitions between the lesions. In both cases, keratinocytes in the granular layer infrequently had features of koilocytes and intranuclear inclusion bodies, and immunohistochemical staining was positive for anti-human papillomavirus antibody. To the best of the authors' knowledge, this is the first pathological documentation of possibly papillomavirus-associated skin lesions in four-toed hedgehogs.

The relationship between hippocampal subfield volumetry and verbal list-learning test outcomes have mostly been studied in clinical and elderly populations, and remain controversial. For the first time, we characterized a relationship between verbal list-learning test outcomes and hippocampal subfield volumetry on two large separate datasets of 447 and 1,442 healthy young and middle-aged adults, and explored the processes that could explain this relationship. We observed a replicable positive linear correlation between verbal list-learning test free recall scores and CA1 volume, specific to verbal list learning as demonstrated by the hippocampal subfield volumetry independence from verbal intelligence. Learning meaningless items was also positively correlated with CA1 volume, pointing to the role of the test design rather than word meaning. Accordingly, we found that association-based mnemonics mediated the relationship between verbal list-learning test outcomes and CA1 volume. This mediation suggests that integrating items into associative representations during verbal list-learning tests explains CA1 volume variations: this new explanation is consistent with the associative functions of the human CA1., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: As percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) gains wider acceptance as a therapeutic option for coronary artery disease, the importance of appropriate patient selection has increased. Although cardiovascular magnetic resonance imaging (MRI) allows segmental and quantitative analyses of myocardial ischemia and scar transmurality, it has limitations, including contraindications, cost, and accessibility. This study established a non-invasive method to evaluate patients undergoing CTO-PCI using two-dimensional speckle-tracking echocardiography (2D-STE)., Methods: Overall, we studied 55 patients who underwent successful CTO-PCI. Cardiovascular MRI and 2D-STE were performed before and 8 ± 2 months after CTO-PCI. Segmental findings of strain parameters were compared with those obtained with late gadolinium enhancement and stress-perfusion MRI., Results: With a cutoff of -10.7, pre-procedural circumferential strain (CS) showed reasonable sensitivity (71%) and specificity (73%) for detecting segments with transmural scar. The discriminatory ability of longitudinal strain (LS) for segments with transmural scar significantly improved during follow-up after successful CTO-PCI in the territory of the recanalized artery (area under the curve (AUC) 0.70 vs. 0.80, p < 0.001). LS accuracy was lower than that of CS at baseline (AUC 0.70 vs. 0.79, p = 0.048), and was increased at follow-up (AUC 0.80 vs. 0.82, p = 0.81). Changes in myocardial perfusion reserve from baseline to follow-up were significantly associated with those in LS but not in CS., Conclusions: Use of 2D-STE may allow the non-invasive evaluation of patients undergoing CTO-PCI to assess the indication before the procedure and treatment effects at follow-up.

Purpose: To clarify the intraocular pressure (IOP)-lowering effect of a selective prostanoid EP2 receptor agonist, omidenepag isopropyl (OMDI) during a 24-hour period., Patients and Methods: Subjects aged ≥20 years and with diagnosed, untreated primary open-angle glaucoma or ocular hypertension were enrolled. IOP measurements were performed every 4 hours over a 24-hour period using a Goldmann applanation tonometer (GAT) and Icare PRO tonometer (PRO). The baseline 24-hour IOP was measured in untreated subjects. After the baseline measurements, participants were given OMDI 1 drop once daily at night for 4 weeks. At week 4, the IOP measurement was repeated under the same conditions. Diurnal (9 am, 1 pm, 5 pm) and nocturnal (9 pm, 1 am, 5 am) IOP measurements were compared between baseline and treatment with OMDI. Safety measures included adverse events, slit-lamp biomicroscopy, visual acuity, heart rate and blood pressure., Results: Of 27 participants enrolled, 25 patients (20 males and 5 females, average age 52.2 ± 8.5 years) completed the study. In the sitting position, the baseline diurnal and nocturnal mean IOPs (GAT) were 19.1 ± 2.1 mmHg and 18.2 ± 2.6 mmHg, respectively, the diurnal and nocturnal mean IOP reduction from baseline were -2.8 ± 2.6 mmHg (p < 0.0001) and -3.3 ± 2.9 mmHg (p < 0.0001), respectively, mean 24-hour IOP (GAT) was significantly lower with the OMDI treatment (-3.1 ± 2.5 mmHg, p < 0.0001). In the supine position, the baseline nocturnal mean IOP (PRO) was 17.99 ± 2.22 mmHg, and the nocturnal mean IOP reduction from baseline was -1.78 ± 2.37 mmHg (p = 0.0009) after 4 weeks of the treatment. Nine adverse events were observed in 8 patients including mild conjunctival hyperemia (n = 8) and mild iritis (n=1). There were no significant effects on systemic safety., Conclusion: Once daily OMDI treatment was able to produce stable 24-hour IOP reduction., Competing Interests: The authors have made the following disclosure: NS, YN, AT, SS and KT received non-financial research support from Santen Pharmaceutical Co., Ltd. during the conduct of study; NO, NI, DS, and KH were employees of Santen Pharmaceutical Co., Ltd.; KN had a consulting relationship with Santen Pharmaceutical Co., Ltd and reports personal fees from Shinanozaka Clinic. The authors report no other conflicts of interest in this work., (© 2021 Shiratori et al.)

Human brain white matter undergoes a protracted maturation that continues well into adulthood. Recent advances in diffusion-weighted imaging (DWI) methods allow detailed characterizations of the microstructural architecture of white matter, and they are increasingly utilized to study white matter changes during development and aging. However, relatively little is known about the late maturational changes in the microstructural architecture of white matter during post-adolescence. Here we report on regional changes in white matter volume and microstructure in young adults undergoing university-level education. As part of the MRi-Share multi-modal brain MRI database, multi-shell, high angular resolution DWI data were acquired in a unique sample of 1,713 university students aged 18-26. We assessed the age and sex dependence of diffusion metrics derived from diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) in the white matter regions as defined in the John Hopkins University (JHU) white matter labels atlas. We demonstrate that while regional white matter volume is relatively stable over the age range of our sample, the white matter microstructural properties show clear age-related variations. Globally, it is characterized by a robust increase in neurite density index (NDI), and to a lesser extent, orientation dispersion index (ODI). These changes are accompanied by a decrease in diffusivity. In contrast, there is minimal age-related variation in fractional anisotropy. There are regional variations in these microstructural changes: some tracts, most notably cingulum bundles, show a strong age-related increase in NDI coupled with decreases in radial and mean diffusivity, while others, mainly cortico-spinal projection tracts, primarily show an ODI increase and axial diffusivity decrease. These age-related variations are not different between males and females, but males show higher NDI and ODI and lower diffusivity than females across many tracts. These findings emphasize the complexity of changes in white matter structure occurring in this critical period of late maturation in early adulthood., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tsuchida, Laurent, Crivello, Petit, Pepe, Beguedou, Debette, Tzourio and Mazoyer.)

We demonstrate that broadband sum frequency generation (SFG) spectroscopy based on a partially incoherent supercontinuum light source can elucidate dark p-series excitons in monolayer WSe 2 encapsulated between hexagonal boron nitride (hBN) slabs. The observed 2p exciton peak energy is a few meV higher than that predicted by the Rytova-Keldysh potential model, which is originated from the Berry phase effect. Interestingly, although the radiative relaxation of the 2p exciton is weaker, the 2p exciton peak is broader than the 1s and 2s peaks, which indicates its faster dephasing than the 1s and 2s excitons. Measuring the excitation intensity and temperature dependence, we clarified that this broader linewidth is not caused by excitation- or phonon-induced dephasing, but rather by exciton-electron scattering.

Purpose: The relationship between endometrial polyps (EPs), chronic endometritis (CE), hysteroscopic findings, and antimicrobial in infertility patients was determined., Methods: We retrospectively enrolled 115 infertility patients with suspected EPs who underwent office hysteroscopy. Patients were divided into 3 groups: 38 with increased plasma cells in EPs (group 1); 31 without increased plasma cells in EPs (group 2); and 46 without EPs (group 3). The 3 groups underwent hysteroscopy with or without polypectomies, and immediately thereafter, an endometrial aspiration biopsy (EAB) was performed. CE was diagnosed based on plasma cell infiltration in the non-polypoid endometrium obtained by EAB., Results: The percentage of CE was 68.4%, 32.2%, and 28.3% in groups 1, 2, and 3, respectively. CE was more frequent in group 1 than group 2 or 3 ( P  = .01 and P  = .002, respectively). The number of polyps was higher in group 1 than group 2. After adjustment for age and assisted reproductive technology, antibiotic therapy was not associated with pregnancy (adjusted odds ratio, 0.44; 95% confidence interval, 0.05-3.57) in patients with EPs and CE., Conclusions: Group 1 was associated with CE, and hysteroscopic findings were different from group 2. Antibiotic therapy after polypectomy for EPs with CE may not always be necessary., Competing Interests: Conflict of interest: The authors declare no conflicts of interest. Human rights statements and informed consent: All of the procedures were followed in accordance with the ethical standards of the responsible committees on human experimentation (institutional and national) and with the principles of the 1964 Helsinki Declaration and subsequent amendments. This study was approved by the Institutional Review Board of Takagi Hospital. This was a retrospective study involving patients who submitted informed consent for undergoing fertility treatment in our Department. Animal studies: This article did not involve animal experimentation by any of the authors., (© 2021 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine.)

Background and Objectives: Young adults represent an increasingly large proportion of healthy volunteers in brain imaging research, but descriptions of incidental findings (IFs) in this age group are scarce. We aimed to assess the prevalence and severity of IFs on brain MRIs of healthy young research participants aged 18-35 years, and to describe the protocol implemented to handle them. Methods: The study population comprised 1,867 participants aged 22.1 ± 2.3 years (72% women) from MRi-Share, the cross-sectional brain MRI substudy of the i-Share student cohort. IFs were flagged during the MRI quality control. We estimated the proportion of participants with IFs [any, requiring medical referral, potentially serious (PSIFs) as defined in the UK biobank]: overall, by type and severity of the final diagnosis, as well as the number of IFs. Results: 78/1,867 participants had at least one IF [4.2%, 95% Confidence Interval (CI) 3.4-5.2%]. IFs requiring medical referral ( n = 38) were observed in 36/1,867 participants (1.9%, 1.4-2.7%), and represented 47.5% of the 80 IFs initially flagged. Referred IFs were retrospectively classified as PSIFs in 25/1,867 participants (1.3%, 0.9-2.0%), accounting for 68.4% of anomalies referred (26/38). The most common final diagnosis was cysts or ventricular abnormalities in all participants (9/1,867; 0.5%, 0.2-0.9%) and in those with referred IFs (9/36; 25.0%, 13.6-41.3%), while it was multiple sclerosis or radiologically isolated syndrome in participants with PSIFs (5/19; 26.3%, 11.5-49.1%) who represented 0.1% (0.0-0.4%) and 0.2% (0.03-0.5%) of all participants, respectively. Final diagnoses were considered serious in 11/1,867 participants (0.6%, 0.3-1.1%). Among participants with referred IFs, 13.9% (5/36) required active intervention, while 50.0% (18/36) were put on clinical surveillance. Conclusions: In a large brain imaging study of young healthy adults participating in research we observed a non-negligible frequency of IFs. The etiological pattern differed from what has been described in older adults., Competing Interests: SD is currently a guest editor for the Research Topic this work will be submitted to, and has collaborated/is collaborating on research projects or publications with the other two editors of this topic. Outside the submitted work, BB served on the scientific advisory board of Biogen, BMS, Novartis, Roche, Merck, and Jansen, received speaker honoraria from Biogen, BMS, and Roche, served as an editorial board member of Multiple Sclerosis International (2019–2020), received research support from Roche, Biogen, Bayer, Sanofi, and Caridian. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Soumaré, Beguedou, Laurent, Brochet, Bordes, Mournet, Mellet, Pereira, Pollet, Lachaize, Mougin, Tsuchida, Loiseau, Tourdias, Tzourio, Mazoyer and Debette.)

A 45-year-old woman was referred to our hospital for the evaluation of proximal muscle weakness and serum creatine kinase elevation [corrected]. She had atrial fibrillation and left ventricular asynergy. She was diagnosed with myopathy, accompanied by cardiomyopathy of unknown etiology. She was treated with prednisolone. After long-term follow-up and a detailed examination, the patient was diagnosed with antimitochondrial antibody (AMA)-associated myopathy with cardiac involvement. Although the patient received medical treatment, including beta-blockers and prednisolone, her cardiac function deteriorated progressively. Physicians should consider AMA-associated myopathy when diagnosing myopathies of unknown etiology. The presence of cardiac involvement should be proactively investigated in AMA-associated myopathy.

We report an unusual case of acute myocardial infarction in a high school girl. The patient was 17 years of age and had multiple coronary risk factors, including marked obesity with a body mass index (BMI) of 42.7 kg/m 2 , dyslipidemia and glucose intolerance. She had been an on and off smoker since she was 13 years of age. Due to the recent Westernization of the lifestyle, the prevalence of metabolic syndrome in the young generation has been increasing in Japan. Cardiovascular disease based on lifestyle-related diseases may become more common in young people.

We describe the case of a primary open-angle glaucoma patient with re-elevated nocturnal sitting intraocular pressure (IOP) after restarting medical therapy due to a failing bleb. IOP was markedly higher than diurnal IOP during multiple-drug therapy in both eyes, but it did not increase in the left eye with a functional bleb without medical therapy after trabeculectomy with adjuvant mitomycin. However, nocturnal sitting IOP was re-elevated after restarting multiple-drug therapy due to a failing bleb, while diurnal IOP was maintained at a low level.

Competing Interests: Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Angiosarcoma (AS) is a rare and aggressive tumor with high rates of local recurrence and distant metastasis. Stewart-Treves syndrome (STS) is defined as AS arising in the setting of chronic lymphedema, and is extremely uncommon in the lower abdominal wall. Eribulin mesylate (eribulin) is a non-taxane microtubule inhibitor that has been approved in Japan for treating soft tissue sarcoma. The current study reports the case of a 76 year-old woman with STS in the lower abdominal wall who exhibited an excellent response to eribulin. Having undergone surgery and postoperative radiation therapy (RT) for cervical cancer 12 years earlier, the patient presented with a mass in her left lower abdominal wall, where chronic lymphedema had developed. Contrast-enhanced computed tomography revealed multiple enhancing nodules in the left lower abdominal wall and edema of the subcutaneous tissues in the whole lower abdomen. A histologic analysis of the specimens revealed AS, and she was diagnosed as STS. A total of 3 cycles of combination chemotherapy with gemcitabine and docetaxel were administered, but the patient discontinued treatment owing to severe adverse events. RT was performed for the tumor, but multiple reddish nodules appeared in the whole lower abdominal wall 3 months later. At this point, eribulin administration was offered. After 4 cycles of treatment, there was a clear reduction in the size of the nodules. All lesions were stable, no new lesions had developed, and the side effects of treatment were minor over the course of 1 year. The results reveal that eribulin may serve as a potential therapeutic option for the treatment of STS., (Copyright: © Imura et al.)

We describe a case of primary localized histiocytic sarcoma of the lumbar vertebrae in a four-toed hedgehog. The case showed aggressive osteolysis of lumbar vertebrae on radiography, and a soft-tissue mass effacing this region was noted, suggesting a neoplastic lesion. No metastatic lesions were apparent. Antemortem diagnosis was challenging, and necropsy was performed. Histopathological and immunohistochemical findings were consistent with localized histiocytic sarcoma. This report provides documentation of the clinical and pathologic features of an unusual form of histiocytic sarcoma localizing to lumbar vertebrae in a four-toed hedgehog.