Publications by authors named "Hideaki Watanabe"

148 Publications

Legg-Calvé-Perthes disease following Ender nail fixation of a pediatric femoral fracture.

Int J Surg Case Rep 2021 Jul 17;85:106209. Epub 2021 Jul 17.

Department of Orthopaedic Surgery, Jichi Medical University, Tochigi, Japan.

Introduction And Importance: Legg-Calvé-Perthes disease (LCPD) sometimes occur in children, however it is difficult to diagnose it at the early stage especially in the cases there are no complaints of symptoms. Femoral shaft fractures in children cause various complications such as leg-length discrepancy, nonunion and malunion, refracture, and osteonecrosis of the femoral head. We presented a rare case in which a pediatric patient developed LCPD after femoral shaft fracture.

Case Presentation: A healthy 8-year-old boy sustained a left femoral diaphyseal fracture following a pedestrian car accident. Fixation was achieved using retrograde Ender nails; bone union was confirmed at 3 months postoperatively, and the Ender nails were removed at 8 months postoperatively without any problems. Unfortunately, the morphological change of the ipsilateral femoral head and subtle symptoms were missed until the femoral head collapsed. LCPD was successfully treated with intertrochanteric varus osteotomy, which achieved a good clinical result.

Clinical Discussion: Although the reason for the ipsilateral LCPD after the femoral shaft fracture is unclear, this case highlights the need for close postoperative follow-up of pediatric femoral fractures resulting from high-energy trauma to prevent the misdiagnosis of this coincidental complication.

Conclusion: This case report describes a missed ipsilateral LCPD after a femoral diaphyseal fracture caused by high-energy trauma. Close postoperative follow-up with a detailed assessment and vigilant interpretation of postoperative radiography is imperative to avoid delayed/missed diagnosis of conditions for which early management may provide better outcomes.
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http://dx.doi.org/10.1016/j.ijscr.2021.106209DOI Listing
July 2021

Chloride intracellular channel protein 2 is secreted and inhibits MMP14 activity, while preventing tumor cell invasion and metastasis.

Neoplasia 2021 Aug 3;23(8):754-765. Epub 2021 Jul 3.

Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Japan. Electronic address:

The abilities to invade surrounding tissues and metastasize to distant organs are the most outstanding features that distinguish malignant from benign tumors. However, the mechanisms preventing the invasion and metastasis of benign tumor cells remain unclear. By using our own rat distant metastasis model, gene expression of cells in primary tumors was compared with that in metastasized tumors. Among many distinct gene expressions, we have focused on chloride intracellular channel protein 2 (CLIC2), an ion channel protein of as-yet unknown function, which was predominantly expressed in the primary tumors. We created CLIC2 overexpressing rat glioma cell line and utilized benign human meningioma cells with naturally high CLIC2 expression. CLIC2 was expressed at higher levels in benign human brain tumors than in their malignant counterparts. Moreover, its high expression was associated with prolonged survival in the rat metastasis and brain tumor models as well as with progression-free survival in patients with brain tumors. CLIC2 was also correlated with the decreased blood vessel permeability likely by increased contents of cell adhesion molecules. We found that CLIC2 was secreted extracellularly, and bound to matrix metalloproteinase (MMP) 14. Furthermore, CLIC2 prevented the localization of MMP14 in the plasma membrane, and inhibited its enzymatic activity. Indeed, overexpressing CLIC2 and recombinant CLIC2 protein effectively suppressed malignant cell invasion, whereas CLIC2 knockdown reversed these effects. Thus, CLIC2 suppress invasion and metastasis of benign tumors at least partly by inhibiting MMP14 activity.
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http://dx.doi.org/10.1016/j.neo.2021.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260957PMC
August 2021

A rare case of neurosarcoidosis occurred only in the medulla oblongata mimicking malignant brain tumor.

Surg Neurol Int 2021 31;12:243. Epub 2021 May 31.

Department of Neurosurgery, Ehime University School of Medicine, Toon, Ehime, Japan.

Background: Sarcoidosis is a multisystem disorder characterized by noncaseating epithelioid granulomas. However, neurosarcoidosis occurring only in the medulla oblongata is very rare and lacks specific imaging and clinical features. We report a rare case of neurosarcoidosis arising from the medulla oblongata alone, suggesting the significance of pathological findings for accurate diagnosis.

Case Description: A 78-year-old woman with a history of rheumatoid arthritis was admitted to our hospital with a 3-month history of progressive numbness in bilateral lower extremities and gait disturbance. Neurological examination on admission showed mild bilateral paired paralysis of the lower limbs (manual muscle test: right 2/V; left 4/V) and marked numbness in the right lower limb. Neuroimaging revealed a solid mass with clear boundaries in the dorsal medulla oblongata appearing hypointense on T1-weighted imaging (WI), hyperintense on T2-WI, and hypointense on diffusion WI (DWI), with strong enhancement on gadolinium-enhanced T1-WI. Cerebrospinal fluid analysis showed moderately elevated levels of protein and lymphocytic cells. Biopsy to determine the exact diagnosis revealed histological findings of noncaseating epithelioid granulomas and inflammatory infiltration, consistent with sarcoidosis. Postoperatively, corticosteroid therapy with prednisolone was initiated as soon as possible, resulting in marked reductions in lesion size. Follow-up neuroimaging after 12 months showed no signs of recurrence.

Conclusion: Neurosarcoidosis is difficult to diagnose from routine neuroimaging and laboratory findings. Accurate diagnosis requires careful identification of clinical signs, hypointensity on DWI, and morphological findings from surgical biopsy.
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http://dx.doi.org/10.25259/SNI_195_2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247731PMC
May 2021

Clinical Results of Corrective Cast and Brace Treatment for Early-onset Scoliosis: The Effectiveness of Long-term Cast Treatment That Extends into Children's Schooldays.

J Pediatr Orthop 2021 Jun 29. Epub 2021 Jun 29.

Department of Orthopedic Surgery, Jichi Medical University Department of Pediatric Orthopedics, Jichi Children's Medical Center Tochigi, Shimotsuke, Tochigi, Japan.

Background: Cast and brace treatment is a conservative treatment for early-onset scoliosis (EOS). We analyzed the clinical results of this treatment when extended into patients' schooldays.

Methods: Twenty-two children with EOS underwent alternatively repetitive cast and brace treatment (ARCBT). Cast was applied under general anesthesia and remained for some weeks, and the brace was continuously worn, which was repeatedly applied when scoliosis progressed. The change in the major curve angle, requirement for surgical intervention, and complications of ARCBT were analyzed.

Results: Six patients had idiopathic scoliosis (IS), 9 had syndromic scoliosis (SS), and 7 had neuromuscular scoliosis. Cast treatment started at 4.9±2.1 years of age, and the patients were followed up for 8.3 years. The average total number of cast applications was 5.5 per patient. The mean major scoliosis angle was 45.4±12.5 degrees at the first visit; this was corrected to 26.5±8.7 degrees at the first cast application and progressed to 75.4±22.1 degrees at the final visit. Nine patients whose scoliosis progressed finally underwent surgery. The mean age at surgery was 11.0 years (range, 8.8 to 13.1 y), and the mean period from first cast application to surgery was 6.1 years (range, 5.0 to 8.9 y). Four patients' IS rapidly progressed after 9 years of age, and all of them underwent final fusion surgery with a correction rate of 56.9%. Among patients with SS, 1 final fusion, and 2 growth-friendly surgeries were performed at a mean age of 9.2 years; the correction rate was 21.5%. Among patients with neuromuscular scoliosis, 2 final fusion surgeries were performed at a mean age of 11.3 years; the correction rate was 30.7%. The cast-related complication rate was 5.0%, and most complications were skin problems.

Conclusions: Long-term ARCBT extended into schooldays might be effective for IS. This should be considered as a time-saving treatment option for EOS.

Level Of Evidence: Level IV-case series.
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http://dx.doi.org/10.1097/BPO.0000000000001888DOI Listing
June 2021

Prediction of Glioma Stemlike Cell Infiltration in the Non-Contrast-Enhancing Area by Quantitative Measurement of Lactate on Magnetic Resonance Spectroscopy in Glioblastoma.

World Neurosurg 2021 Jun 16. Epub 2021 Jun 16.

Department of Neurosurgery, Ehime University School of Medicine, Toon, Ehime, Japan.

Background: We previously reported that glioma stemlike cells (GSCs) exist in the area of the tumor periphery showing no gadolinium enhancement on magnetic resonance imaging. In the present work, we analyzed glucose metabolism to investigate whether lactate could be predictive of tumor invasiveness and of use in detection of the tumor invasion area in glioblastoma multiforme (GBM).

Methods: The expression of lactate dehydrogenase A (LDH-A) and pyruvate dehydrogenase (PDH) was investigated in 20 patients. In GSC lines, LDH-A and PDH expression also was examined in parallel to assessments of mitochondrial respiration. We then investigated the relationship between lactate/creatine ratios in the tumor periphery measured by magnetic resonance spectroscopy, using learning-compression-model algorithms and phenotypes of GBMs.

Results: In 20 GBMs, high-invasive GBM expressed LDH-A at significantly higher expression than did low-invasive GBM, whereas low-invasive GBM showed significantly higher expression of PDH than did high-invasive GBM. The highly invasive GSC line showed higher expression of LDH-A and lower expression of PDH compared with low-invasive GSC lines. The highly invasive GSC line also showed the lowest consumption of oxygen and the lowest production of adenosine triphosphate. Lactate levels, as measured by magnetic resonance spectroscopy, showed a significant positive correlation with LDH-A transcript levels, permitting classification of the GBMs into high-invasive and low-invasive phenotypes based on a cutoff value of 0.66 in the lactate/creatine ratio.

Conclusions: In the tumor periphery area of the highly invasive GBM, aerobic glycolysis was the predominant pathway for glucose metabolism, resulting in the accumulation of lactate. The level of lactate may facilitate prediction of the tumor-infiltrating area on GBM.
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http://dx.doi.org/10.1016/j.wneu.2021.06.044DOI Listing
June 2021

Reduced expression of programmed cell death 1 and programmed cell death ligand 1 in infiltrating inflammatory cells of lichen planus without administration of immune checkpoint inhibitors.

J Dermatol 2021 Jun 7. Epub 2021 Jun 7.

Department of Dermatology, School of Medicine, Showa University, Tokyo, Japan.

Keratinocytes are the main targets of infiltrating T cells in the pathogenesis of lichen planus. However, the mechanisms of dense inflammatory infiltrates beneath the epidermis remain unknown. The aim of the present study was to clarify the roles of programmed cell death 1 (PD-1) and its ligand (PD-L1) in the pathogenesis of lichen planus. Immunohistochemistry of PD-1 and PD-L1 in 12 cases each of lichen planus and dermal-type erythema multiforme was performed. The expression of PD-1 and PD-L1 on infiltrating inflammatory cells, predominantly lymphocytes in lichen planus, was significantly less compared to that in dermal-type erythema multiforme. By dual immunofluorescence, the overlap between PD-1 and leukocyte common antigen, CD4, CD8, CD68, and factor XIIIa was limited and found in only a very small portion of lichen planus cells. Our data suggest that decreased expression of PD-1 and PD-L1 could play a role in accelerating inflammatory cell infiltration targeting the epidermis in the pathogenesis of lichen planus.
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http://dx.doi.org/10.1111/1346-8138.15977DOI Listing
June 2021

Unilateral premature osteoarthritis of the hip with excessive anteversion of the femoral neck developing in the early second decade: two surgical cases.

BMC Musculoskelet Disord 2021 Jun 5;22(1):517. Epub 2021 Jun 5.

Department of Paediatric Orthopaedics and Orthopaedic Surgery, Jichi Children's Medical Center Tochigi, Tochigi Prefecture, Shimotsuke, Japan.

Background: Osteoarthritis (OA) of the hip rarely develops in the early second decade. As the incidence of this disease is low, no treatment method has been established. We report two patients with unilateral OA in their early teens in whom the anteversion angle of the femoral neck on the affected side was greater than that on the unaffected side.

Case Presentation: Case 1 was an 11-year-old girl with left coxalgia and limited range of motion. There was no history of femoroacetabular impingement (FAI) or developmental dysplasia of the hip (DDH). Plain X-rays revealed the disappearance of the Y cartilage, joint space narrowing of the left hip, and acetabular/femoral head osteosclerosis. In CT images, the anteversion angle of the femoral neck (lt/rt) was 45/35 degrees. As osteoarthritis was severe, proximal femoral flexional derotational varus osteotomy (PFFDVO) and triple pelvic osteotomy (TPO) were performed. Case 2 was a 13-year-old girl with left coxalgia and limited range of motion. There was no history of FAI or DDH. Plain X-ray revealed irregularity of the left anterolateral femoral head, and a subcartilaginous cyst. In CT images, the anteversion angle of the femoral neck (lt/rt) was 30/20 degrees. As osteoarthritis was severe, PFFDVO was performed. In addition, we resected bone spurs on the femoral head because flexion was limited owing to the presence of osteophytes. In both patients, coxalgia and claudication/gait disorder resolved postoperatively, and joint space narrowing and osteosclerosis improved. However, in Case 1, there was a 3-cm difference in the leg length, and in Case 2, range-of-motion limits remained.

Conclusions: We present the findings in two patients with unilateral OA in their early second decade in whom the femoral anteversion angle on the affected side was greater than that on the unaffected side. PFFDVO + TPO was performed in Case 1, and PFFDVO + bone spur resection on the femoral head was performed in Case 2. Coxalgia resolved, and plain X-ray demonstrated improvements in OA; however, a difference in the leg length and range-of-motion limits remained.
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http://dx.doi.org/10.1186/s12891-021-04386-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8180035PMC
June 2021

Hypoxia-induced phenotypic transition from highly invasive to less invasive tumors in glioma stem-like cells: Significance of CD44 and osteopontin as therapeutic targets in glioblastoma.

Transl Oncol 2021 Aug 27;14(8):101137. Epub 2021 May 27.

Department of Neurosurgery, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan.

The poor prognosis of glioblastoma multiforme (GBM) is primarily due to highly invasive glioma stem-like cells (GSCs) in tumors. Upon GBM recurrence, GSCs with highly invasive and highly migratory activities must assume a less-motile state and proliferate to regenerate tumor mass. Elucidating the molecular mechanism underlying this transition from a highly invasive phenotype to a less-invasive, proliferative tumor could facilitate the identification of effective molecular targets for treating GBM. Here, we demonstrate that severe hypoxia (1% O) upregulates CD44 expression via activation of hypoxia-inducible factor (HIF-1α), inducing GSCs to assume a highly invasive tumor. In contrast, moderate hypoxia (5% O) upregulates osteopontin expression via activation of HIF-2α. The upregulated osteopontin inhibits CD44-promoted GSC migration and invasion and stimulates GSC proliferation, inducing GSCs to assume a less-invasive, highly proliferative tumor. These data indicate that the GSC phenotype is determined by interaction between CD44 and osteopontin. The expression of both CD44 and osteopontin is regulated by differential hypoxia levels. We found that CD44 knockdown significantly inhibited GSC migration and invasion both in vitro and in vivo. Mouse brain tumors generated from CD44-knockdown GSCs exhibited diminished invasiveness, and the mice survived significantly longer than control mice. In contrast, siRNA-mediated silencing of the osteopontin gene decreased GSC proliferation. These results suggest that interaction between CD44 and osteopontin plays a key role in tumor progression in GBM; inhibition of both CD44 and osteopontin may represent an effective therapeutic approach for suppressing tumor progression, thus resulting in a better prognosis for patients with GBM.
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http://dx.doi.org/10.1016/j.tranon.2021.101137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175402PMC
August 2021

CD44 expression in the tumor periphery predicts the responsiveness to bevacizumab in the treatment of recurrent glioblastoma.

Cancer Med 2021 03 5;10(6):2013-2025. Epub 2021 Feb 5.

Department of Neurosurgery, Ehime University School of Medicine, Toon, Japan.

Antiangiogenic therapy with bevacizumab (Bev), a monoclonal antibody targeting vascular endothelial growth factor (VEGF), is a common treatment for recurrent glioblastoma (GBM), but its survival benefit is limited. Resistance to Bev is thought to be a major cause of ineffectiveness on Bev therapy. To optimize Bev therapy, identification of a predictive biomarker for responsiveness to Bev is required. Based on our previous study, we focused on the expression and functions of CD44 and VEGF in the Bev therapy. Here, we analyze a relationship between CD44 expression and responsiveness to Bev and elucidate the role of CD44 in anti-VEGF therapy. CD44 and VEGF expression in the tumor core and periphery of 22 GBMs was examined, and the relationship between expression of these molecules and progression-free time on Bev therapy was analyzed. The degree of CD44 expression in the tumor periphery was evaluated by the ratio of the mRNA expression in the tumor periphery to that in the tumor core (P/C ratio). VEGF expression was evaluated by the amount of the mRNA expression in the tumor periphery. To elucidate the roles of CD44 in the Bev therapy, in vitro and in vivo studies were performed using glioma stem-like cells (GSCs) and a GSC-transplanted mouse xenograft model, respectively. GBMs expressing high P/C ratio of CD44 were much more refractory to Bev than those expressing low P/C ratio of CD44, and the survival time of the former was much shorter than that of the latter. In vitro inhibition of VEGF with siRNA or Bev-activated CD44 expression and increased invasion of GSCs. Bev showed no antitumor effects in mice transplanted with CD44-overexpressing GSCs. The P/C ratio of CD44 expression may become a useful biomarker predicting responsiveness to Bev in GBM. CD44 reduces the antitumor effect of Bev, resulting in much more highly invasive tumors.
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http://dx.doi.org/10.1002/cam4.3767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957167PMC
March 2021

Ventricular tachycardia in patients undergoing 24-h Holter monitoring as preoperative evaluation for noncardiac surgery.

Heart Vessels 2021 Jul 21;36(7):1047-1055. Epub 2021 Jan 21.

Clinical Laboratory Department, National Hospital Organization Miyakonojo Medical Center, 5033-1 Iwayoshi-cho, Miyakonojo, 885-0014, Japan.

The incidence of ventricular tachycardia (VT) in preoperative evaluation for noncardiac surgery in general hospitals has not been established. The aim of this study was to determine the incidence of VT, characteristics of patients with VT, characteristics of VT, and significance of VT in patients undergoing 24-h Holter monitoring as preoperative evaluation for noncardiac surgery. In 601 patients, VT was detected in 46 patients (7.7%). In patients with VT, left ventricular ejection fraction (LVEF) was lower (62.6 ± 9.3% vs. 66.6 ± 8.9%, p = 0.003), and B-type natriuretic peptide (BNP) was higher compared with patients without VT (median, 52.5 pg/mL vs. 32.8 pg/mL, p = 0.02). The maximum number of consecutive beats of VT was more frequent in the patients with LVEF < 50% than in the patients with LVEF ≥ 50% (median, 11.5 beats vs. 3.0 beats, p = 0.01). Forty patients (87%) underwent scheduled surgery without major complications.
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http://dx.doi.org/10.1007/s00380-021-01779-1DOI Listing
July 2021

Relationship between Deep White Matter Hyperintensities on Magnetic Resonance Imaging and Postoperative Cognitive Function Following Clipping of Unruptured Intracranial Aneurysm.

Neurol Med Chir (Tokyo) 2021 Feb 30;61(2):152-161. Epub 2020 Dec 30.

Department of Neurosurgery, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.

To evaluate the effects on cognitive function of deep white matter hyperintensities (DWMHs) on magnetic resonance imaging (MRI) in patients treated surgically for unruptured intracranial aneurysms (UIAs). The subjects were 106 patients in whom a Wechsler adult intelligence scale-revised (WAIS-R) examination was performed 1 week before and 1 month after clipping surgery for asymptomatic UIAs. DWMH severity was evaluated on preoperative MR images by Fazekas scale, as follows: none (absence), mild (punctate foci), moderate (beginning confluence of foci), or severe (large confluent areas). A decrease of 7 or more points in intelligence quotient (IQ) postoperatively was considered deterioration. Fazekas score was none in 41 (none group), mild in 42 (mild group), moderate in 21, and severe in 2 patients (moderate/severe group). Patient characteristics, surgical factors, IQ change, and abnormal findings on postoperative MRI were compared among the groups. Although there was no statistically significant deterioration in IQ postoperatively in any group, the percentage of deteriorated patients was significantly higher in the moderate/severe group (34.8%) than in the other groups (4.9% in the none group, 7.1% in the mild group; p <0.01, p <0.05, respectively). Brain injury was observed more frequently on postoperative MR images in the moderate/severe group (17.4%) compared with the none group (2.4%; p = 0.052). The presence of moderate/severe DWMHs was an independent prognostic factor for postoperative cognitive dysfunction. In conclusion, the presence of moderate/severe DWMHs was a prognostic factor for postoperative cognitive dysfunction after surgery for UIAs.
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http://dx.doi.org/10.2176/nmc.oa.2020-0290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905299PMC
February 2021

Comparison of Hospitalization Incidence in Influenza Outpatients Treated With Baloxavir Marboxil or Neuraminidase Inhibitors: A Health Insurance Claims Database Study.

Clin Infect Dis 2020 Dec 23. Epub 2020 Dec 23.

Department of Infectious Diseases, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

Background: Baloxavir marboxil (baloxavir) is a single-dose, oral anti-influenza drug with a novel mechanism of action. We compared the incidence of hospitalization in patients treated with baloxavir versus neuraminidase inhibitors.

Methods: This was a retrospective observational cohort study using real-world patient data extracted from a Japanese health insurance claims database. The enrollment period was October 1, 2018 to April 17, 2019. On day 1, eligible patients (N = 339 007) received baloxavir, oseltamivir, zanamivir, or laninamivir. Baseline characteristics were standardized using the inverse probability of treatment weighting method. Primary end point was the incidence of hospitalization (days 2-14). Secondary end points included antibacterial use, secondary pneumonia, and additional anti-influenza drug use.

Results: Compared with the baloxavir group, the incidence of hospitalization was greater in the oseltamivir group (risk ratio [RR] and 95% confidence interval [CI], 1.41 [1.00-2.00]; risk difference [RD] and 95% CI, 0.06 [0.01-0.12]) and zanamivir group (RR, 1.85 [1.23-2.78]; RD, 0.11 [0.02-0.20]). Oseltamivir-treated patients were less likely to require antibacterials than baloxavir-treated patients (RR, 0.87 [0.82-0.91]). However, oseltamivir-treated patients were more likely to be hospitalized with antibacterials (RR, 1.70 [1.21-2.38]) or antibacterial injection (RR, 1.67 [1.17-2.38]) than baloxavir-treated patients (post hoc analysis). Compared with baloxavir-treated patients, additional anti-influenza drug use was greater in oseltamivir-, zanamivir-, and laninamivir-treated patients (RR, 1.51 [1.05-2.18], 2.84 [2.04-3.96], and 1.68 [1.35-2.10], respectively).

Conclusions: Baloxavir is an efficacious anti-influenza treatment that may reduce hospitalization compared with oseltamivir and zanamivir.
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http://dx.doi.org/10.1093/cid/ciaa1870DOI Listing
December 2020

Comparison of Household Transmission of Influenza Virus From Index Patients Treated With Baloxavir Marboxil or Neuraminidase Inhibitors: A Health Insurance Claims Database Study.

Clin Infect Dis 2021 06;72(11):e859-e867

Department of Respiratory Medicine, Nagasaki University Hospital, Nagasaki, Japan.

Background: Baloxavir marboxil (baloxavir) is expected to reduce influenza transmission by rapid reduction of viral load. The incidence of household transmission was compared between index patients (IPs) treated with baloxavir and those treated with neuraminidase inhibitors.

Methods: Using a Japanese claims database, the first family members with influenza diagnosis during the 2018-2019 influenza season were identified as IPs, and the diagnosis date was designated day 1. According to the anti-influenza drug dispensed to the IP, their families were classified into the oral baloxavir group and 3 controls: oral oseltamivir group (a primary control), inhaled zanamivir group, and inhaled laninamivir group. A household transmission was defined as influenza diagnosed for any non-IP family members during days 3-8. The incidence of household transmission was compared between groups using a logistic regression model adjusting backgrounds of IPs.

Results: The proportion of families with household transmission was 17.98% (15 226 of 84 672) in the baloxavir group and 24.16% (14 983 of 62 004) in the oseltamivir group. The covariate-adjusted odds ratio (oseltamivir/baloxavir) was 1.09 (95% confidence interval [95% CI], 1.05-1.12), which indicated significantly lower incidence in the baloxavir group. The adjusted odds ratios (controls/baloxavir) against zanamivir and laninamivir were 0.93 (95% CI, .89-.97) and 0.99 (95% CI, .96-1.02), respectively.

Conclusions: Baloxavir may contribute to reduction in household transmission compared with oseltamivir. In comparison between baloxavir and inhalants, a similar reduction was not shown and it might be due to unmeasured confounding by administration route differences.
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http://dx.doi.org/10.1093/cid/ciaa1622DOI Listing
June 2021

The nationwide epidemiological survey of Stevens-Johnson syndrome and toxic epidermal necrolysis in Japan, 2016-2018.

J Dermatol Sci 2020 Dec 28;100(3):175-182. Epub 2020 Sep 28.

Department of Hygiene, Public Health and Preventive Medicine, Showa University School of Medicine, Tokyo, Japan.

Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening severe cutaneous adverse reactions (SCARs). The first national epidemiological survey of SJS/TEN was carried out in 2008. We conducted a new survey to identify changes from the previous survey.

Objective: The present survey aimed to estimate the number of SJS/TEN patients in Japan between 2016 and 2018 (primary survey) and to clarify clinical epidemiological profiles (secondary survey).

Methods: A primary survey asking for numbers of SJS/TEN patients during the study period was sent to 1205 institutions nationwide. A secondary survey was sent to institutions reporting SJS/TEN patients, seeking detailed information.

Results: Yearly prevalence per million was 2.5 for SJS and 1 for TEN. The secondary survey allowed analysis of 315 SJS cases and 174 TEN cases from 160 institutions. Mean age was 53.9 years in SJS, and 61.8 years in TEN. Mortality rate was 4.1 % for SJS and 29.9 % for TEN. In TEN, mean age and mortality rates had increased from the previous survey. The ratio of expected to observed mortality calculated by SCORTEN score was lowest with high-dose steroid therapy (0.40), followed by steroid pulse therapy (0.52).

Conclusion: The present findings suggest that the mortality rate of TEN has increased because of increases in mean ages of patients and patients with malignant neoplasm as underlying disease. When comparing the ratio of expected mortality to actual mortality, high-dose steroid therapy achieved the greatest reduction in mortality.
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http://dx.doi.org/10.1016/j.jdermsci.2020.09.009DOI Listing
December 2020

Dupilumab treatment ameliorates clinical and hematological symptoms, including blood eosinophilia, in patients with atopic dermatitis.

Int J Dermatol 2021 Feb 29;60(2):190-195. Epub 2020 Sep 29.

Department of Dermatology, Showa University School of Medicine, Tokyo, Japan.

Background: Atopic dermatitis (AD) is an allergic disease that affects individuals of various ages. Recently, the IL-4/13 inhibitor dupilumab has gained regulatory approval for clinical use in AD patients. Dupilumab has been reported to reduce several markers of AD, including the serum levels of thymus and activation-regulated chemokine (TARC/CCL17), blood lactate dehydrogenase (LDH), and serum total immunoglobulin E (IgE).

Methods: We retrospectively reviewed data from 40 AD patients who were treated with dupilumab. Eczema Area and Severity Index (EASI), Investigator's Global Assessment (IGA), body surface area (BSA) scores, TARC, LDH, total IgE, and eosinophil count in peripheral blood were assessed for a total of 32 weeks.

Results: The EASI, IGA, and BSA scores improved significantly with treatment, indicating a reduction in AD severity. Serum TARC and LDH levels also significantly decreased with treatment. Serum IgE levels were unchanged at 2 weeks of treatment but decreased significantly between 4 and 32 weeks. The number of eosinophils in the peripheral blood decreased at 4, 16, and 32 weeks after treatment initiation.

Conclusions: Several studies have reported that serum TARC, LDH, and total IgE levels are reduced by dupilumab treatment. Our real-world data are the first to demonstrate a reduction in blood eosinophilia in patients who receive clinical treatment with dupilumab.
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http://dx.doi.org/10.1111/ijd.15183DOI Listing
February 2021

Tricks and traps of ICG endoscopy for effectively applying endoscopic transsphenoidal surgery to pituitary adenoma.

Neurosurg Rev 2020 Sep 5. Epub 2020 Sep 5.

Department of Neurosurgery, Ehime University School of Medicine, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan.

Differentiating tumor from normal pituitary gland is very important for achieving complete resection without complications in endoscopic endonasal transsphenoidal surgery (ETSS) for pituitary adenoma. To facilitate such surgery, we investigated the utility of indocyanine green (ICG) fluorescence endoscopy as a tool in ETSS. Twenty-four patients with pituitary adenoma were enrolled in the study and underwent ETSS using ICG endoscopy. After administering 12.5 mg of ICG twice an operation with an interval > 30 min, times from ICG administration to appearance of fluorescence on vital structures besides the tumor were measured. ICG endoscopy identified vital structures by the phasic appearance of fluorescent signals emitted at specific consecutive elapsed times. Elapsed times for internal carotid arteries did not differ according to tumor size. Conversely, as tumor size increased, elapsed times for normal pituitary gland were prolonged but those for the tumor were reduced. ICG endoscopy revealed a clear boundary between tumors and normal pituitary gland and enabled confirmation of no more tumor. ICG endoscopy could provide a useful tool for differentiating tumor from normal pituitary gland by evaluating elapsed times to fluorescence in each structure. This method enabled identification of the boundary between tumor and normal pituitary gland under conditions of a low-fluorescence background, resulting in complete tumor resection with ETSS. ICG endoscopy will contribute to improve the resection rate while preserving endocrinological functions in ETSS for pituitary adenoma.
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http://dx.doi.org/10.1007/s10143-020-01382-4DOI Listing
September 2020

Handgrip strength correlates with walking in lumbar spinal stenosis.

Eur Spine J 2020 09 10;29(9):2198-2204. Epub 2020 Jul 10.

Department of Orthopaedic Surgery, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Japan.

Purpose: To examine the relationship between handgrip strength and leg extension power, walking speed, and intermittent claudication for lumbar spinal stenosis (LSS) using computed tomography.

Methods: We examined patients who underwent laminectomy for LSS from June 2015 through March 2018. Before spine surgery, we evaluated walking distance, handgrip strength, leg extension power (LEP), 10-m walk test (time and steps), psoas muscle index (PMI), and the area of both total and multifidus muscle using plain computed tomography imaging at the third lumbar level. Handgrip strength was compared with comorbidities including anemia, diabetes, hypertension, marital status, etc. RESULTS: There were 183 patients (55 female, 128 male) with a mean age of 70.5 years. Handgrip strength significantly correlated with LEP (P < 0.001, r = 0.723), walking speed (P < 0.001, r = - 0.269), 10-m walking test (steps) (P < 0.001, r = - 0.352), area of skeletal muscle at L3 level (P < 0.001, r = 0.469), area of psoas muscle (P < 0.001, r = 0.380), PMI (P < 0.001, r = 0.253), and intermittent claudication. Age, height, and weight were correlated with handgrip strength, but BMI was not correlated. Handgrip strength was significantly reduced by anemia, hypertension, and single marital status.

Conclusions: The more handgrip strength patients with LSS have, the more LEP, the faster walking speed, the greater area of psoas and skeletal muscle, the fewer steps for a 10-m walk they have, and the longer walking distance. Age, height, and weight were associated with handgrip strength, but BMI has no association. Low handgrip strength was related to comorbidities including anemia, hypertension, and marital status.
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http://dx.doi.org/10.1007/s00586-020-06525-1DOI Listing
September 2020

Clinical features and endoscopic findings of granular cell tumor of the sellar region: A case report and review of the literature.

Surg Neurol Int 2020 9;11:101. Epub 2020 May 9.

Departments of Neurosurgery, Ehime University School of Medicine, Shitsukawa, Toon, Ehime, Japan.

Background: Granular cell tumor (GCT) of the sellar region is a rare tumor of the sellar and suprasellar regions that originate from the neurohypophysis. This tumor is very difficult to differentiate from other pituitary neoplasms, such as pituitary adenoma, pituicytoma, and spindle cell oncocytoma. We report a rare case of GCT arising from the posterior pituitary of the sellar region and suggest a useful indicator for accurate diagnosis and pitfalls for surgical procedures.

Case Description: A 42-year-old woman was admitted to our hospital with bitemporal hemianopsia. Neuroimaging showed a large pituitary tumor in the sellar and suprasellar regions with a hypointense part on T2-weighted magnetic resonance imaging, and the enhanced anterior pituitary gland was displaced anteriorly. Laboratory findings showed mild hyperprolactinemia. Subtotal resection of the tumor was achieved using an endoscopic endonasal transsphenoidal approach. Histological findings showed round or polygonal cells with abundant granular eosinophilic cytoplasm staining strongly for thyroid transcription factor 1. The tumor was, therefore, diagnosed as a GCT of the sellar region, belonging to tumors of the posterior pituitary. After surgery, visual impairment and anterior pituitary function were improved. Follow-up neuroimaging after 1 year showed no signs of recurrence.

Conclusion: GCT of the sellar region is difficult to diagnose on routine neuroimaging. Therefore, accurate diagnosis requires careful identification of clinical signs, magnetic resonance imaging including hypointensity on T2-weighted imaging, and analysis of combined morphological and immunohistochemical studies.
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http://dx.doi.org/10.25259/SNI_111_2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265469PMC
May 2020

Are Salt Tablets Effective in the Treatment of Euvolemic Hyponatremia?

South Med J 2020 Mar;113(3):125-129

From the Division of Nephrology, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, and the Department of Medicine, University of Hawaii John A. Burns School of Medicine, Honolulu.

Objectives: There is limited evidence for the use of salt tablets in the treatment of hyponatremia. This retrospective study evaluated the effectiveness of salt tablet administration in euvolemic hyponatremia.

Methods: This was a single-center, retrospective cohort study. Information on patients' demographics, clinical characteristics, and laboratory data were collected for retrospective review. Treatment for hyponatremia, including the amount of salt tablets, fluid restriction, and diuretics was collected. We compared hyponatremic patients with those who received salt tablets versus those who did not receive salt tablets. The primary outcome of interest was the change in serum sodium at 48 hours between the two groups.

Results: A total of 1258 medical records were initially screened with inclusion and exclusion criteria. After screening, there were 83 patients included in the study. Forty-two patients received salt tablets and 41 patients were in the group that did not receive salt tablets. Patients treated with salt tablets were older, more often female, and had lower body weight and lower initial serum sodium. The change in serum sodium after 48 hours was higher in the salt tablet group (5.2 mEq/L) than the non-salt tablet group (3.1 mEq/L; < 0.001). This difference in serum sodium between the two groups remained statistically significant when adjusted for age, sex, weight, and initial serum sodium.

Conclusions: The use of salt tablets in the treatment of euvolemic hyponatremia is associated with a small but significant improvement in serum sodium compared with patients who did not receive such therapy, even after adjusting for age, sex, weight, and initial serum sodium. This study supports the effectiveness of salt tablets in the treatment of euvolemic hyponatremia in medical patients.
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http://dx.doi.org/10.14423/SMJ.0000000000001075DOI Listing
March 2020

Clinical utility of new three-dimensional model using a zero-echo-time sequence in endoscopic endonasal transsphenoidal surgery.

Clin Neurol Neurosurg 2020 03 21;190:105743. Epub 2020 Feb 21.

Department of Neurosurgery, Ehime University School of Medicine, 454 Shitsukawa, Toon, Ehime 791-0295, Japan.

Objectives: Recognizing the anatomical orientation surrounding the sellar floor is crucial in endoscopic endonasal transsphenoidal surgery (ETSS). Zero-echo-time (ZTE) sequences were recently suggested for a new bone identification technique on magnetic resonance imaging (MRI). This study aimed to evaluate the clinical usefulness of three-dimensional (3D)-ZTE-based MRI models in providing anatomical guidance for ETSS.

Patients And Methods: ZTE-based MRI and magnetic resonance angiography (MRA) data from 15 consecutive patients with pituitary tumor treated between September 2018 and May 2019 were used to create 3D-MRI models. From these, the architecture surrounding the sellar floor, particularly anatomical relationships between tumors and internal carotid arteries (ICAs), was visualized to preoperatively plan surgical procedures. In addition, 3D-ZTE-based MRI models were compared to actual surgical views during ETSS to evaluate model applicability.

Results: These 3D-ZTE-based MRI models clearly demonstrated the morphology of the sellar floor and matched well with intraoperative views, including pituitary tumor, by successively eliminating sphenoidal structures. The models also permitted determination of the maximum marginal line of the opening of the sellar floor by presenting vital structures such as ICAs and tumors. With such 3D-MRI models, the surgeon could access the intracranial area through the sellar floor more safely, and resect the pituitary tumor maximally without complications.

Conclusion: Our 3D-MRI models based on ZTE sequences allowed distinct visualization of vital structures and pituitary tumor around the sellar floor. This new method using 3D-ZTE-based MRI models showed low invasiveness for patients and was useful in preoperative planning for ETSS, facilitating maximum tumor resection without complications.
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http://dx.doi.org/10.1016/j.clineuro.2020.105743DOI Listing
March 2020

Met-PET uptake index for total tumor resection: identification of C-methionine uptake index as a goal for total tumor resection including infiltrating tumor cells in glioblastoma.

Neurosurg Rev 2021 Feb 15;44(1):587-597. Epub 2020 Feb 15.

Department of Neurosurgery, Ehime University School of Medicine, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan.

Glioblastoma multiforme (GBM) is largely due to glioma stem cells (GSCs) that escape from total resection of gadolinium (Gd)-enhanced tumor on MRI. The aim of this study is to identify the imaging requirements for maximum resection of GBM with infiltrating GSCs. We investigated the relationship of tumor imaging volume between MRI and C-methionine (Met)-PET and also the relationship between Met uptake index and tumor activity. In ten patients, tumor-to-contralateral normal brain tissue ratio (TNR) was calculated to evaluate metabolic activity of Met uptake areas which were divided into five subareas by the degrees of TNR. In each GBM, tumor tissue was obtained from subareas showing the positive Met uptake. Immunohistochemistry was performed to examine the tumor proliferative activity and existence of GSCs. In all patients, the volume of Met uptake area at TNR ≦ 1.4 was larger than that of the Gd-enhanced area. The Met uptake area at TNR 1.4 beyond the Gd-enhanced tumor was much wider in high invasiveness-type GBMs than in those of low invasiveness type, and survival was much shorter in the former than the latter types. Immunohistochemistry revealed the existence of GSCs in the area showing Met uptake at TNR 1.4 and no Gd enhancement. Areas at TNR > 1.4 included active tumor cells with relatively high Ki-67 labeling index. In addition, it was demonstrated that GSCs could exist beyond the border of Gd-enhanced tumor. Therefore, to obtain maximum resection of GBMs, including infiltrating GSCs, aggressive surgical excision that includes the Met-positive area at TNR 1.4 should be considered.
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http://dx.doi.org/10.1007/s10143-020-01258-7DOI Listing
February 2021

Epithelioid glioblastoma presenting as multicentric glioma: A case report and review of the literature.

Surg Neurol Int 2020 17;11. Epub 2020 Jan 17.

Department of Neurosurgery, Ehime University School of Medicine.

Background: Epithelioid glioblastoma is a rare aggressive variant of glioblastoma multiforme (GBM), which was formally recognized by the World Health Organization classification of the central nervous system in 2016. Clinically, epithelioid GBMs are characterized by aggressive features, such as metastases and cerebrospinal fluid dissemination, and an extremely poor prognosis. A rare case of epithelioid GBM that was discovered as a multicentric glioma with different histopathology is reported.

Case Description: A 78-year-old man was admitted to our hospital with mild motor weakness of the right leg. Neuroimaging showed small masses in the left frontal and parietal lobes on magnetic resonance imaging. The abnormal lesion had been increasing rapidly for 3 weeks, and a new lesion appeared in the frontal lobe. 11C-methionine positron emission tomography (PET) showed abnormal uptake corresponding to the lesion. To reach a definitive diagnosis, surgical excision of the right frontal mass lesion was performed. Histological findings showed diffuse astrocytoma. Only radiotherapy was planned, but the left frontal and parietal tumors progressed further within a short period. Therefore, it was thought that these tumors were GBM, and a biopsy of the left parietal tumor was performed. The histological diagnosis was epithelioid GBM. Immunohistochemistry showed that most tumor cells were negatively stained for p53 and isocitrate dehydrogenase 1. V600E mutations were not identified, but promoter mutations were identified. Immediately after surgery, the patient was given chemotherapy using temozolomide, extended local radiotherapy and then bevacizumab. After 6 months, he showed no signs of recurrence.

Conclusion: Epithelioid GBM is one of the rarest morphologic subtypes of GBM and has a strongly infiltrative and aggressive nature. Therefore, careful identification of preoperative imaging studies and detailed evaluation of genetic studies are necessary to select the appropriate treatment for epithelioid GBM.
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http://dx.doi.org/10.25259/SNI_544_2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6969379PMC
January 2020

RIP3 as a diagnostic and severity marker for Stevens-Johnson syndrome and toxic epidermal necrolysis.

J Allergy Clin Immunol Pract 2020 05 15;8(5):1768-1771.e7. Epub 2020 Jan 15.

Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2020.01.006DOI Listing
May 2020

Prognostic significance of immunohistochemical subtypes based on the stage of B-cell differentiation in primary CNS lymphoma.

Int J Clin Exp Pathol 2019 1;12(4):1457-1467. Epub 2019 Apr 1.

Department of Neurosurgery, Ehime University School of Medicine 454 Shitsukawa, Toon, Ehime 791-0295, Japan.

Primary central nervous system lymphoma (PCNSL) has been immunohistochemically classified into two subtypes, germinal center (GC) B-cell and non-GC B-cell, but the prognostic impact of these subtypes remains debated. We investigated clinical features and prognostic significance of immunohistochemical subtypes that were identified by expression patterns of three B-cell differentiation markers in PCNSL. We also analyzed a factor related to responsiveness to high-dose methotrexate (HD-MTX) chemotherapy. Tumors from 32 PCNSL patients were immunohistochemically evaluated for expression of cluster of differentiation (CD) 10, B-cell lymphoma-6 (BCL-6), and multiple myeloma oncogene-1 (MUM-1) and classified into subtypes according to the expression patterns of these markers. Clinical features and prognostic outcome of these subtypes were investigated. Twenty-three patients were treated with HD-MTX-based chemotherapy followed by whole-brain radiation therapy (WBRT), and nine were treated with WBRT alone. Three immunohistochemical subtypes were identified, including A-type expressing CD10, BCL-6, and MUM-1 (12 patients), B-type expressing BCL-6 and MUM-1 (12 patients) and C-type expressing MUM-1 only (8 patients). Response rate in the HD-MTX therapy group was 57.1% (4/7) in A-type, 87.5% (7/8) in B-type, and 75% (6/8) in C-type. C-type with the lowest metabolic activity showed significantly longer overall survival than A-type with the higher uptake of methionine (71.6 versus 39.6 months) (P<0.05). Immunohistochemical identification of PCNSL based on the B-cell differentiation stage revealed three types of tumors, showing different metabolic activity and survival time. Refined immunohistochemical classification of PCNSL subtypes may become a useful tool for predicting more accurate prognosis and accessing sensitivity to HD-MTX therapy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947071PMC
April 2019

Confusion in determination of two types of cutaneous adverse reactions to drugs, maculopapular eruption and erythema multiforme, among the experts: A proposal of standardized terminology.

J Dermatol 2020 Feb 28;47(2):169-173. Epub 2019 Nov 28.

Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.

The clinical classification of cutaneous adverse reactions by drugs should be clearly distinguished to avoid conceptual confusion and inconsistency. Although dermatologists appear to have established a roughly common consensus for cutaneous adverse reactions, some types are more rigorously defined than other, possibly misleading classifications. To assess the consensus on the clinical classifications, we investigated the concordance rate of diagnosis by Japanese experts through a snap visual inspection of various clinical pictures exhibiting erythema multiforme and maculopapular eruption types of cutaneous adverse reactions. The experts were shown images on a screen and were then asked to decide whether to classify cases as maculopapular eruption or erythema multiforme type, and the concordance rates were calculated. Overall, the mean concordance rate was 71.6% (standard deviation, 17.3%), and only 33.8% of cases had a 90% or more concordance rate. Our study shows that the determinations of erythema multiforme and maculopapular eruption types by the existing classification criteria were confusing even among experts, which prompted us to standardize the terminology. We propose clinically defining erythema multiforme type as generalized macules mainly of 1 cm or more with a tendency of elevation and coalescence, and maculopapular eruption type as generalized erythema other than erythema multiforme type. Currently, the clinical definitions of cutaneous adverse reactions are poorly described, which may be problematic upon analyzing large volumes of data. Our proposal for a new terminology will enhance the accuracy and consistency of information for the correct analysis of cutaneous adverse reactions.
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http://dx.doi.org/10.1111/1346-8138.15164DOI Listing
February 2020

Severe Cutaneous Adverse Reactions during Tapering of High-Dose Systemic Steroid Therapy for Autoimmune Diseases: Implications for Non-HIV Immune Reconstitution Inflammatory Syndrome.

Case Rep Dermatol 2019 May-Aug;11(2):166-174. Epub 2019 Jun 13.

Department of Dermatology, School of Medicine, Showa University, Tokyo, Japan.

We present 2 cases of severe cutaneous adverse reactions (SCARs) during the tapering of corticosteroids, following several courses of high-dose pulse therapy for Vogt-Koyanagi-Harada disease. Their general symptoms and mucous membrane lesions, including those of the eye, were milder than those usually seen in Stevens-Johnson syndrome/toxic epidermal necrolysis. Based on their initial presentation, these cases were not initially identified as SCARs, but continued to progress over the course of a few days. The mechanism underlying the paradoxical response to steroid administration seen in these patients can be interpreted as immune reconstitution inflammatory syndrome in human immunodeficiency virus-negative patients.
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http://dx.doi.org/10.1159/000500945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600039PMC
June 2019