Publications by authors named "Hiroshi Kobayashi"

612 Publications

Proposal for developing treatment algorithms of women with symptomatic adenomyosis: A single-center experience.

J Obstet Gynaecol Res 2021 Jun 21. Epub 2021 Jun 21.

Department of Obstetrics and Gynecology, Nara Medical University, Nara, Japan.

Aims: The most common symptoms of adenomyosis include heavy menstrual bleeding and dysmenorrhea. A variety of medical or surgical techniques are utilized for the treatment of adenomyosis, but there are currently no specific treatment guidelines and best practice recommendations for management. The aim of this study is to summarize current treatment strategies for women with symptomatic adenomyosis in a single-center university hospital in order to provide reliable information for developing treatment algorithms.

Methods: We conducted an observational cross-sectional study using data from the adenomyosis cohort study from January 2008 to December 2020. Detailed information, including demographic, clinicopathological, and imaging data, were collected from 220 pathologically confirmed patients with adenomyosis.

Results: First, we identified clinical and imaging characteristics in women who underwent surgery or hormone therapy, especially dienogest (DNG) treatment, as first-line treatment. Surgery was generally recommended for multiparous women over the age of 43, especially for patients with intrinsic adenomyosis. Next, we identified the parameters that allowed the continuation of DNG treatment. Oral DNG was given to certain patients with a myometrium thickness of 35 mm or greater and coexisting with endometriosis and/or uterine fibroids. To prevent serious bleeding, DNG treatment can be limited to women with extrinsic adenomyosis with a uterine length of 125 mm or less.

Discussion: Our findings may provide useful information in developing an evidence-based treatment guideline for patients with symptomatic adenomyosis, nevertheless, further investigation is needed for the validation of treatment algorithms.
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http://dx.doi.org/10.1111/jog.14904DOI Listing
June 2021

Aortic Angiosarcoma in Association with Endovascular Aneurysm Repair: Case Report and Review of the Literature.

Am J Case Rep 2021 Jun 12;22:e931740. Epub 2021 Jun 12.

Division of Clinical Pathology, Niigata University Faculty of Medicine, Niigata, Japan.

BACKGROUND Primary aortic sarcoma often poses diagnostic challenges for pathologists and clinicians because of a very low incidence and controversy over nomenclature and definition. We report a case of aortic angiosarcoma in association with a graft. We also conducted a clinicopathological review of cases of primary aortic sarcomas associated with implanted grafts. CASE REPORT The patient was an 82-year-old woman. She underwent thoracic endovascular aneurysm repair (TEVAR) at age 78 because of an aneurysm in the descending aorta. Approximately 4 years after the TEVAR, computed tomography revealed a type II endoleak and expansion of the aneurysm. Her c-reactive protein level rose to 34 mg/dL, and Ga scintigraphy showed 67Ga accumulation at the aneurysm. She had fever up to 39°C, and a stent graft infection was suspected. Despite administration of antibiotics, her condition deteriorated, and she died. Postmortem examination identified epithelioid aortic angiosarcoma at the aorta with aneurysm repair and the graft, and the aortic angiosarcoma invaded the left lower lobe of the lung. CONCLUSIONS Our clinicopathological review revealed that the proper clinical diagnosis was very difficult owing to confusion of aortic sarcoma after the implantation with the infected graft, atypical endoleak, or pseudoaneurysm. The histological diagnosis was ambiguous because immunohistochemical and genetic studies were not adequately conducted. Overall prognosis of aortic sarcoma is poor as most patients die within a year, with no effective treatments. It is hoped that recent projects for genomic medicine will provide useful insights about the diagnosis and treatment of these cancers.
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http://dx.doi.org/10.12659/AJCR.931740DOI Listing
June 2021

Fat-forming solitary fibrous tumor of the sacrum: A case report and literature review.

Radiol Case Rep 2021 Jul 25;16(7):1874-1877. Epub 2021 May 25.

Department of Radiology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan.

Fat-forming variant of solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm. Here we report the case of a 33-year-old woman who developed pain and muscle weakness from the posterior aspect of the right hip to lower extremity. Imaging examinations revealed a mass with fatty components and hypervascular solid components filling the sacral spinal canal and sacral foramen. The sacral mass was resected and histological examination of the specimens revealed patternless proliferation of short spindle-shaped cells with staghorn blood vessels. A number of mature adipocyte-like cells were also observed. The tumor cells were positive for STAT6 and the nuclei of the adipocytes were also positive, which was diagnostic for fat-forming SFT.
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http://dx.doi.org/10.1016/j.radcr.2021.04.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170013PMC
July 2021

Prevalence of patients with lysosomal storage disorders and peroxisomal disorders: A nationwide survey in Japan.

Mol Genet Metab 2021 Jul 12;133(3):277-288. Epub 2021 May 12.

Advanced Clinical Research Center, Southern Tohoku Research Center for Neuroscience, Kanagawa, Japan.

Introduction: Lysosomal storage disorders and peroxisomal disorders are rare diseases caused by the accumulation of substrates of the metabolic pathway within lysosomes and peroxisomes, respectively. Owing to the rarity of these diseases, the prevalence of lysosomal storage disorders and peroxisomal disorders in Japan is unknown. Therefore, we conducted a nationwide survey to estimate the number of patients with lysosomal storage disorders and peroxisomal disorders in Japan.

Methods: A nationwide survey was conducted following the "Manual of nationwide epidemiological survey for understanding patient number and clinical epidemiology of rare diseases (3rd version)". A questionnaire asking for detailed information, such as disease phenotypes and medical history, was created and sent to 504 institutions with doctors who have experience in treating patients with lysosomal storage disorders and peroxisomal disorders. Result A total of 303 completed questionnaires were collected from 504 institutions (response rate: 60.1%). The number of patients was estimated by calculating the rate/frequency of overlap. The estimated number of patients was 1658 (±264.8) for Fabry disease, 72 (±11.3) for mucopolysaccharidosis I, 275 (±49.9) for mucopolysaccharidosis II, 211 (±31.3) for Gaucher disease, 124 (±25.8) for Pompe disease, 83 (±44.3) for metachromatic leukodystrophy, 57 (±9.4) for Niemann-Pick type C, and 262 (±42.3) for adrenoleukodystrophy. In addition the birth prevalence was calculated using the estimated number of patients and birth year data for each disease, and was 1.25 for Fabry disease, 0.09 for mucopolysaccharidosis I, 0.38 for mucopolysaccharidosis II, 0.19 for Gaucher disease, 0.14 for Pompe disease, 0.16 for metachromatic leukodystrophy, 0.16 for Niemann-Pick type C, and 0.20 for adrenoleukodystrophy.

Discussion: Among the diseases analyzed, the disease with the highest prevalence was Fabry disease, followed by mucopolysaccharidosis II, adrenoleukodystrophy, Gaucher disease and metachromatic leukodystrophy. In particular, the high prevalence of mucopolysaccharidosis II and Gaucher disease type II was a feature characteristic of Japan.

Conclusion: We estimated the number of patients with lysosomal storage disorders and peroxisomal disorders in Japan. The details of the age at diagnosis and treatment methods for each disease were clarified, and will be useful for the early diagnosis of these patients and to provide appropriate treatments. Furthermore, our results suggest that supportive care and the development of an environment that can provide optimal medical care is important in the future.
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http://dx.doi.org/10.1016/j.ymgme.2021.05.004DOI Listing
July 2021

Validation of magnetic resonance relaxometry R2 value and cyst fluid iron level for diagnosis of ovarian endometrioma.

Redox Rep 2021 Dec;26(1):105-110

Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Japan.

Objectives: Magnetic resonance (MR) R2 relaxometry is a safe, noninvasive diagnostic modality for the evaluation of iron levels in the contents of ovarian cysts. The study aims to investigate the sensitivity and specificity of the two methods, R2 value and iron level, in diagnosing OMA patients in the validation set.

Methods: A prospective cohort study was conducted from 2013 to 2019. We investigated how R2 value was affected by iron-related compounds, antioxidants and bioelements in the cysts.

Results: The sensitivity and specificity of CF iron-based diagnosis of OMA was 96.6% and 95.4%, respectively. The sensitivity and specificity for R2 value in diagnosing OMA were 86.2% and 70.7%, respectively. The outcomes of the two tests were highly correlated (r = 0.758; P <0.001). The R2 value was positively correlated with CF levels of iron-related compounds and antioxidants. The R2 value was affected not only by iron ions but also by calcium ions.

Conclusion: Preoperative MR relaxometry may provide a noninvasive alternative to CF iron test in diagnosing OMA. The presence of paramagnetic cations in the cyst may be associated with reduced specificity.
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http://dx.doi.org/10.1080/13510002.2021.1937456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183507PMC
December 2021

Is a Putative Therapeutic Target for -Mutated Ovarian Clear Cell Carcinoma.

Int J Mol Sci 2021 May 30;22(11). Epub 2021 May 30.

Department of Obstetrics and Gynecology, Nara Medical University, Nara 634-8521, Japan.

Background: Ovarian clear cell carcinoma (OCCC) is resistant to platinum chemotherapy and is characterized by poor prognosis. Today, the use of poly (ADP-ribose) polymerase (PARP) inhibitor, which is based on synthetic lethality strategy and characterized by cancer selectivity, is widely used for new types of molecular-targeted treatment of relapsed platinum-sensitive ovarian cancer. However, it is less effective against OCCC.

Methods: We conducted siRNA screening to identify synthetic lethal candidates for the mutation; as a result, we identified Cyclin-E1 () as a potential target that affects cell viability. To further clarify the effects of , human OCCC cell lines, namely TOV-21G and KOC7c ( mutant lines), and RMG-I and ES2 ( wild type lines) were transfected with siRNA targeting or a control vector.

Results: Loss of reduced proliferation of the TOV-21G and KOC7c cells but not of the RMG-I and ES2 cells. Furthermore, in vivo interference of effectively inhibited tumor cell proliferation in a xenograft mouse model.

Conclusion: This study showed for the first time that is a synthetic lethal target gene to -mutated OCCC. Targeting this gene may represent a putative, novel, anticancer strategy in OCCC treatment.
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http://dx.doi.org/10.3390/ijms22115869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198755PMC
May 2021

A Culture Method to Maintain Quiescent Human Hematopoietic Stem Cells.

J Vis Exp 2021 May 17(171). Epub 2021 May 17.

Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine;

Human hematopoietic stem cells (HSCs), like other mammalian HSCs, maintain lifelong hematopoiesis in the bone marrow. HSCs remain quiescent in vivo, unlike more differentiated progenitors, and enter the cell cycle rapidly after chemotherapy or irradiation to treat bone marrow injury or in vitro culture. By mimicking the bone marrow microenvironment in the presence of abundant fatty acids, cholesterol, low concentration of cytokines, and hypoxia, human HSCs maintain quiescence in vitro. Here, a detailed protocol for maintaining functional HSCs in the quiescent state in vitro is described. This method will enable studies of the behavior of human HSCs under physiological conditions.
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http://dx.doi.org/10.3791/61938DOI Listing
May 2021

Validation of tissue factor pathway inhibitor 2 as a specific biomarker for preoperative prediction of clear cell carcinoma of the ovary.

Int J Clin Oncol 2021 Jul 19;26(7):1336-1344. Epub 2021 May 19.

Department of Obstetrics and Gynecology, Nara Medical University, Nara, Japan.

Background: Tissue factor pathway inhibitor 2 (TFPI2) is a novel serum biomarker that discriminates ovarian clear cell carcinoma (CCC) from borderline ovarian tumors (BOTs) and non-clear cell epithelial ovarian cancers (EOCs). Here, we examined the performance of TFPI2 for preoperative diagnosis of CCC.

Methods: Serum samples were obtained preoperatively from patients with ovarian masses, who needed surgical treatment at five hospitals in Japan. The diagnostic powers of TFPI2 and cancer antigen 125 (CA125) serum levels to discriminate CCC from BOTs, other EOCs, and benign lesions were compared.

Results: A total of 351 patients including 69 CCCs were analyzed. Serum TFPI2 levels were significantly higher in CCC patients (mean ± SD, 508.2 ± 812.0 pg/mL) than in patients with benign lesions (154.7 ± 46.5), BOTs (181 ± 95.5) and other EOCs (265.4 ± 289.1). TFPI2 had a high diagnostic specificity for CCC (79.5%). In patients with benign ovarian endometriosis, no patient was positive for TFPI2, but 71.4% (15/21) were CA125 positive. TFPI2 showed good performance in discriminating stage II-IV CCC from BOTs and other EOCs (AUC 0.815 for TFPI2 versus 0.505 for CA125) or endometriosis (AUC 0.957 for TFPI2 versus 0.748 for CA125). The diagnostic sensitivity of TFPI2 to discriminate CCC from BOTs and other EOCs was improved from 43.5 to 71.0% when combined with CA125.

Conclusions: High specificity of TFPI2 for preoperative detection of CCC was verified with the defined cutoff level of TFPI2 in clinical practice. TFPI2 and CA125 may contribute substantially to precise prediction of intractable CCC.
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http://dx.doi.org/10.1007/s10147-021-01914-yDOI Listing
July 2021

Prognostic value of pre-treatment systemic immune-inflammation index in patients with endometrial cancer.

PLoS One 2021 14;16(5):e0248871. Epub 2021 May 14.

Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Nara, Japan.

Background: The systemic immune-inflammation index (SII), which is calculated using absolute platelet, neutrophil, and lymphocyte counts, has recently attracted attentions as a prognostic indicator in patients with solid malignancies. In the current study, we retrospectively investigated the prognostic significance of pre-treatment SII among patients with endometrial cancer.

Method: Endometrial cancer patients treated at Nara medical university hospital between 2008 and 2018 were included in the current study. Receiver operating characteristic (ROC) curve was used to find the optimal SII cut-off values for 3-years progression free survival (PFS) and overall survival (OS). Then, the predictive abilities of SII and its superiority over neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) were investigated. Kaplan-Meier method was used to calculate the OS and PFS rates, and log-rank test was used to compare the survival rate between two groups. Univariate and multivariate Cox regression analysis were performed to identify risk factors for PFS and OS.

Result: A total of 442 patients were included in the current study. The cut-off value of SII for predicting PFS and OS were defined by ROC analysis as 931 and 910, respectively. Univariate analyses showed that elevated SII was associated with significantly shorter survival (p <0.001 for both PFS and OS). Cox regression analyses revealed that an advanced FIGO stage (p <0.001 for both PFS and OS) and an elevated SII (p = 0.014 for PFS, p = 0.011 for OS) are the independent prognostic factors for survival. When SII was compared with NLR and PLR, SII showed greater area under curve for predicting survival.

Conclusion: The SII is an independent prognostic factor in endometrial cancer patients, allowing more precise survival estimation than PLR or NLR.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248871PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121307PMC
May 2021

Incidence of complications in 25 adult patients with X-linked hypophosphatemia.

J Clin Endocrinol Metab 2021 Apr 29. Epub 2021 Apr 29.

Division of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo, Japan.

Context: Adults with X-linked hypophosphatemia (XLH) present complications other than osteomalacia.

Objective: To describe the incidence and severity of comorbidities in adults with XLH.

Design: Observational retrospective study.

Patients: A total of 25 adults with XLH with thorough investigations, including spinal computed tomography scans, X-rays of hip/knee joints and Achilles tendons, abdominal ultrasounds and audiograms.

Main Outcome Measures: The index of ossification of the anterior/posterior longitudinal ligament and yellow ligament (OA/OP/OY index) and the sum of OA/OP/OY index (OS index) were utilized to evaluate the severity of spinal ligament ossification. The Kellgren-Lawrence (KL) classification was adopted to evaluate the severity of the hip/knee osteophytes.

Results: The participants consisted of 13 male patients and 12 female patients from 21 families, with a median age of 43 (range, 18-72) years. In all, 20 patients (80%) showed spinal ligament ossification. The median OA/OP/OY/OS indices were 2 (0-22), 0 (0-15), 6 (0-13) and 12 (0-41), respectively. Hip/knee osteophytes were reported in 24 (96%) and 17 cases (68%). The median KL grade was 3 in the hip joint and 2 in the knee joint, and 18 cases (72%) developed enthesopathy in the Achilles tendon. Nephrocalcinosis and hearing impairment were observed in 18 (72%) and eight (32%) cases.

Conclusion: This study revealed a high prevalence and severity of ectopic ossification and disclosed the incidence of nephrocalcinosis and hearing impairment in adults with XLH. In cases with severe spinal ligament ossification or noticeable osteophytes around the hip/knee joints, undiagnosed XLH should be considered as a possible underlying condition.
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http://dx.doi.org/10.1210/clinem/dgab282DOI Listing
April 2021

Relationship between magnetic resonance imaging-based classification of adenomyosis and disease severity.

J Obstet Gynaecol Res 2021 Apr 27. Epub 2021 Apr 27.

Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Nara, Japan.

Aims: The purpose of this study is to first investigate the correlation between image features and histological findings and the clinical severity of adenomyosis; second, search for imaging features to assess the type and locoregional extension of the disease; and finally, discuss the notation of image-based classification.

Methods: This paper combines a review of the literature on adenomyosis with a series of cases who underwent surgery at Nara Medical University Hospital.

Results: Currently, there has been a lack of clear, clinically relevant, and internationally acceptable definition and histological classification due to its diverse phenotype. A number of researchers have attempted to standardize the magnetic resonance imaging (MRI) features of adenomyosis. Some researchers have begun studies that relate the subtype classification using MRI to disease severity. There is evidence suggesting that diffuse adenomyosis and intrinsic adenomyosis are correlated with menstrual bleeding, while extrinsic adenomyosis and coexistence of deep infiltrating endometriosis (DIE) are related to pelvic pain. MRI-based classifications that are simple for use in the clinical setting are beginning to be proposed. However, the reliability and validity of these classifications have not yet been verified. A simplified notation is required to discuss the association between the classification and severity of adenomyosis. We introduce case reports using the notation of four items necessary for classification of adenomyosis.

Conclusion: There is an urgent need to determine the definitions of terms used in subtype classification and to create and validate a globally unified notation that can predict the severity of adenomyosis symptoms.
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http://dx.doi.org/10.1111/jog.14803DOI Listing
April 2021

MEK/ERK Signaling in β-Cells Bifunctionally Regulates β-Cell Mass and Glucose-Stimulated Insulin Secretion Response to Maintain Glucose Homeostasis.

Diabetes 2021 Apr 27. Epub 2021 Apr 27.

Department of Molecular Diabetic Medicine, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan

In diabetic pathology, insufficiency in β-cell mass, unable to meet peripheral insulin demand, and functional defects of individual β-cells in production of insulin are often concurrently observed, collectively causing hyperglycemia. Here we show that the phosphorylation of ERK1/2 is significantly decreased in the islets of mice as well as in those of a cohort of subjects with type 2 diabetes. In mice with abrogation of ERK signaling in pancreatic β-cells through deletion of and , glucose intolerance aggravates under high-fat diet-feeding conditions due to insufficient insulin production with lower β-cell proliferation and reduced β-cell mass, while in individual β-cells dampening of the number of insulin exocytosis events is observed, with the molecules involved in insulin exocytosis being less phosphorylated. These data reveal bifunctional roles for MEK/ERK signaling in β-cells for glucose homeostasis, i.e., in regulating β-cell mass as well as in controlling insulin exocytosis in individual β-cells, thus providing not only a novel perspective for the understanding of diabetes pathophysiology but also a potential clue for new drug development for diabetes treatment.
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http://dx.doi.org/10.2337/db20-1295DOI Listing
April 2021

Comparison of ethanol concentrations after drinking in patients who underwent total gastrectomy versus healthy controls.

ANZ J Surg 2021 Apr 19. Epub 2021 Apr 19.

Department of Orthopaedic Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan.

Background: The safety of drinking in patients who have undergone total gastrectomy for gastric cancer has not been established. We conducted a clinical trial to investigate the trend in alcohol absorption in actual patients.

Methods: Patients who received total gastrectomy with lymph-node dissection and Roux-en-Y reconstruction six or more months ago were enrolled. Participants drank 1 unit (20 g) of ethanol within 1 h starting at least 1 h after a meal. The blood alcohol concentration (BAC) was then estimated by a measurement of the breath alcohol concentration. The peak and trend in the BAC in patients was compared with that in healthy volunteers who were matched with patients for the alcohol-sensitive genotype.

Results: Ten patients and 10 healthy people were enrolled in the BAC evaluation. The peak BAC (%) was 0.158 in patients after total gastrectomy versus 0.110 in control (P < 0.001). The mean half-life of BAC was 58.0 min in the patient group and 94.0 min in the control group, although the mean time to complete drinking was significantly longer in the patient group than in the control group at 40.8 versus 21.9 min (P = 0.009).

Conclusion: Drinking alcohol is likely to carry a risk of increasing the BAC in patients who have undergone total gastrectomy.
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http://dx.doi.org/10.1111/ans.16691DOI Listing
April 2021

A delicate redox balance between iron and heme oxygenase-1 as an essential biological feature of endometriosis.

Arch Med Res 2021 Apr 13. Epub 2021 Apr 13.

Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, 634-8522, Nara, Japan; Ms.Clinic MayOne, Kashihara, 634-0813, Nara, Japan. Electronic address:

Background: Recent studies have focused on the role of oxidative stress, which may be implicated in the development, progression, and pathophysiology of endometriosis.

Aim Of The Study: The aim of this study is to investigate the redox balance of endometriosis by simultaneously measuring iron-related compounds (total iron, heme iron, free iron, oxyhemoglobin [oxyHb], methemoglobin [metHb] and 8-hydroxy-2-deoxy guanosine [8-OHdG]) and antioxidants (bilirubin, heme oxygenase-1 [HO-1] and total antioxidant capacity [TAC]).

Methods: This study includes 236 histopathologically confirmed cases (178 cases of endometriosis and 58 cases of non-endometriosis). Cyst fluid samples were collected from patients admitted to the Department of Gynecology, Nara Medical University, Kashihara, Japan, for surgery.

Results: Age at diagnosis (p <0.001), the maximum diameter of the cyst (p <0.001) and CA125 levels (p <0.001) differed significantly between the two groups. Total iron, heme iron, free iron, metHb, and oxyHb were markedly higher in endometriosis compared to non-endometriosis. Bilirubin, HO-1 and TAC were significantly higher in endometriosis patients compared with those from non-endometriosis patients. In endometriosis, total iron showed a positive correlation with HO-1 (r, 0.518, p = 0.001), but there were no antioxidants that correlated with iron in non-endometriosis. Iron and HO-1 did not correlate with age or tumor size.

Conclusions: HO-1 may regulate the delicate balance of iron-induced oxidative stress in endometriotic cyst fluid.
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http://dx.doi.org/10.1016/j.arcmed.2021.03.006DOI Listing
April 2021

Relationship between Cyst Fluid Concentrations of Iron and Severity of Dysmenorrhea in Patients with Ovarian Endometrioma.

Gynecol Obstet Invest 2021 29;86(1-2):185-192. Epub 2021 Mar 29.

Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Japan.

Objectives And Design: Endometriosis-related pain can be caused by anatomical distortions as well as environmental factors such as inflammation and oxidative stress. The aim of this study is to investigate the relationship between the severity of dysmenorrhea in patients with ovarian endometrioma (OMA) and cyst fluid (CF) concentrations of irons, including total iron, heme iron, and free iron.

Method: Eighty-three patients who were histologically diagnosed with OMA were enrolled in the Department of Gynecology, Nara Medical University Hospital, between 2013 and 2019. The patients were divided into 4 groups according to the severity of dysmenorrhea: no pain, mild, moderate, and severe. Iron concentration was measured by the inductively coupled plasma optical emission spectrometry method.

Results: There were no significant differences among the 4 groups in variables such as age at diagnosis, preoperative CA125, preoperative CA19-9, cyst size, and tumor laterality (unilateral or bilateral). There was a positive correlation between the severity of dysmenorrhea and total iron (p < 0.001) and heme iron (p = 0.016) concentrations. Multiple regression analyses revealed that the CF concentration of total iron (hazard ratio 18.75, 95% confidence interval: 2.26-155.35, p = 0.007) was a significant independent variable associated with the severity of dysmenorrhea. A receiver operating characteristic curve analysis showed that a total iron exceeding 290.8 mg/L was associated with severe dysmenorrhea with a sensitivity of 90.9% and a specificity of 65.7%.

Limitations: This study excluded patients with adenomyosis, superficial endometriosis, or deep endometriosis, resulting in a smaller number of cases. Iron levels could not be compared to the endometriosis stage using the r-ASRM score.

Conclusions: There is no clear evidence that iron predicts the severity of endometriosis-related pain. However, iron may be closely associated with dysmenorrhea.
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http://dx.doi.org/10.1159/000514972DOI Listing
March 2021

Prognostic factors and impact of surgery in patients with metastatic soft tissue sarcoma at diagnosis: A population-based cohort study.

Jpn J Clin Oncol 2021 May;51(6):918-926

Department of Orthopedic Surgery, The University of Tokyo, Tokyo, Japan.

Background: Approximately 10% of the patients with soft tissue sarcoma show metastasis at initial diagnosis, and hence, poorer prognosis. However, the prognostic factors and whether definitive surgery for the primary lesion improves overall survival, especially when complete resection of metastasis is difficult, remain unclear.

Methods: This retrospective analysis was based on the Bone and Soft Tissue Tumor Registry in Japan. Patients with soft tissue sarcoma having metastasis at diagnosis were enrolled, excluding those with Ewing's sarcoma, rhabdomyosarcoma and several other sarcomas with unique behavior and treatment strategies. Overall survival was estimated using the Kaplan-Meier method and compared among the common histologic subtypes. Multivariate analysis with the Cox regression model was used to identify the prognostic factors.

Results: In total, 1184 patients were included, with a median follow-up duration of 10 months (range: 1-83). The median overall survival was 21 months (95% confidence interval: 18.2-23.8). The multivariate analyses indicated that tumor size, grade and histologic subtypes significantly correlated with overall survival. Moreover, surgery for the primary lesion, in addition to surgery for metastases and chemotherapy, showed significant association with better survival.

Conclusions: The prognostic factors in patients with metastatic soft tissue sarcoma at diagnosis are generally similar to those in patients with localized disease. The overall survival in patients differed significantly according to histologic subtype. Surgical resection of primary lesions, especially those with a wide margin, may be an independent prognostic factor. Further studies are needed identify which subgroup of patients would benefit the most from primary lesion surgery.
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http://dx.doi.org/10.1093/jjco/hyab033DOI Listing
May 2021

p38α plays differential roles in hematopoietic stem cell activity dependent on aging contexts.

J Biol Chem 2021 Mar 18:100563. Epub 2021 Mar 18.

Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan. Electronic address:

Hematopoietic stem cells (HSCs) and their progeny sustain lifetime hematopoiesis. Aging alters HSC function, number, and composition and increases risk of hematological malignancies, but how these changes occur in HSCs remains unclear. Signaling via p38MAPK has been proposed as a candidate mechanism underlying induction of HSC aging. Here, using genetic models of both chronological and premature aging, we describe a multimodal role for p38α, the major p38MAPK isozyme in hematopoiesis, in HSC aging. We report that p38α regulates differentiation bias and sustains transplantation capacity of HSCs in the early phase of chronological aging. However, p38α decreased HSC transplantation capacity in the late progression phase of chronological aging. Furthermore, co-deletion of p38α in mice deficient in Ataxia-telangiectasia mutated (Atm), a model of premature aging, exacerbated aging-related HSC phenotypes seen in Atm single mutant mice. Overall, these studies provide new insight into multiple functions of p38MAPK, which both promotes and suppresses HSC aging context-dependently.
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http://dx.doi.org/10.1016/j.jbc.2021.100563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065231PMC
March 2021

A case of neuronal ceroid lipofuscinosis type 8 associated with central precocious puberty.

Pediatr Int 2021 Mar 11;63(3):338-339. Epub 2021 Mar 11.

Department of Pediatrics, The Jikei University School of Medicine, Tokyo,, Japan.

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http://dx.doi.org/10.1111/ped.14421DOI Listing
March 2021

Reprogramming of glucose metabolism of cumulus cells and oocytes and its therapeutic significance.

Reprod Sci 2021 Mar 5. Epub 2021 Mar 5.

Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Japan.

The aim of this review is to summarize our current understanding of the molecular mechanism for the glucose metabolism, especially pyruvate dehydrogenase (PDH), during oocyte maturation, as well as future perspectives of therapeutic strategies for aging focusing on metabolic regulation between aerobic glycolysis and the tricarboxylic acid (TCA) cycle/oxidative phosphorylation (OXPHOS). Each keyword alone or in combination was used to search from PubMed. Glucose metabolism is a dynamic process involving "On" and "Off" switches by the pyruvate dehydrogenase kinase (PDK)-PDH axis, which is crucial for energy metabolism and mitochondrial efficiency in cumulus cell differentiation and oocyte maturation. Activation of PDK suppresses the conversion of pyruvate to acetyl-coenzyme A (acetyl-CoA) through the inactivation of PDH, which allows the cumulus cells to supply sufficient amounts of pyruvate, lactate, and nicotinamide adenine dinucleotide phosphate (NADPH) to the oocytes. On the other hand, inactivation of PDK in oocytes can produce adenosine triphosphate (ATP) through a metabolic shift from aerobic glycolysis to the TCA cycle/OXPHOS. The metabolic balance between aerobic glycolysis and TCA cycle/OXPHOS presents us with a number of enzymes, ligands, receptors, and antioxidants that are potential therapeutic targets, some of which have already been successfully pursued to improve fertility outcomes. However, there are also many reports that question their efficacy. In conclusion, understanding the molecular mechanisms involved in the PDK-PDH axis is a crucial step to advance in novel therapeutic strategies to improve oocyte quality.
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http://dx.doi.org/10.1007/s43032-021-00505-6DOI Listing
March 2021

Evaluation of microchannel plate gain drops caused by high ion fluxes in time-of-flight mass spectrometry: A novel evaluation method using a multi-turn time-of-flight mass spectrometer.

J Mass Spectrom 2021 Mar;56(3):e4706

Department of Physics, Graduate School of Science, Osaka University, Osaka, 560-0043, Japan.

Use of a two-stage microchannel plate (MCP) detector is common in time-of-flight (TOF) mass spectrometry because it shows excellent time resolution with sufficient gains. However, the gain drops significantly when the detector detects intense ion fluxes, such as matrix ions, by matrix-assisted laser desorption/ionization mass spectrometry. As a result, significant ion signals corresponding to analytes, such as proteins, are hidden, thereby hampering the mass spectral interpretation. However, details of this phenomenon have not previously been investigated using ions because of the lack of suitable measurement methods and apparatus. Thus, we herein report a novel method for controlling the TOF of two selected ions, as a function of time differences between each other using a multi-turn TOF mass spectrometer. This method involves the use of an isotope cluster of ions that fly in a figure-of-eight orbit and the extraction of an ion at a given lap number. A series of time differences (∆t) between two ions in a TOF spectrum can be generated using this method. We evaluated the time constants of gain recovery after high ion-flux detection for two sets of two-stage MCP detectors to obtain values of 1,600 and 180 μs for channel plate resistances of 500 and 71 MΩ, respectively. The obtained time constants from the gains determined at various values of ∆t were 0.48 and 0.38 fold (for 500 and 71 MΩ, respectively) of the values suggested from the channel plate resistance and capacitance.
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http://dx.doi.org/10.1002/jms.4706DOI Listing
March 2021

Characteristics of the Electrocardiogram in Japanese Fabry Patients Under Long-Term Enzyme Replacement Therapy.

Front Cardiovasc Med 2020 14;7:614129. Epub 2021 Jan 14.

Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.

An electrocardiogram (ECG) is an important tool for demonstrating cardiac manifestations in various heart diseases. The present study clarified the characteristics of ECG parameters in Japanese Fabry patients under long-term enzyme replacement therapy (ERT). We analyzed the ECGs of 40 Fabry patients (male, = 17; female, = 23) before and after treatment with ERT. To evaluate the atrio-ventricular conduction, the PQ interval, corrected PQ and PQ minus P-wave in lead II (Pend-Q) were calculated. The QRS duration, QTc, Sokolow-Lyon index, and strain pattern were also examined. At the baseline, the shortening of the PQ interval, corrected PQ and Pend-Q was identified in 7.5, 25.0, and 47.5% of cases, respectively. The prolongation of QRS duration and QTc was found in 7.5 and 40.0% of cases, respectively. The strain pattern was mainly identified in female patients, irrespective of left ventricular hypertrophy (LVH). During long-term ERT, the PQ interval, corrected PQ and Pend-Q did not change significantly. The QRS duration was significantly prolonged in both genders, whereas the QTc was significantly prolonged only in male patients. A subgroup analysis revealed that the prolongation of the QRS duration and QTc only occurred in male patients with LVH and only occurred in female patients with the classical type mutation. The prevalence of the strain was significantly increased only in male patients with LVH. These results suggest that the shortening of the Pend-Q is a specific finding in Japanese Fabry patients, and the strain pattern without LVH in female patients can be considered Fabry disease. During long-term ERT, prolongation of the QRS duration and QTc can indicate the progression of myocardial damage in male patients with LVH and in female patients with the classical type mutation.
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http://dx.doi.org/10.3389/fcvm.2020.614129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840582PMC
January 2021

Phenyl-bonded monolithic silica capillary column liquid chromatographic separation and detection of fluorogenic derivatized intact proteins.

Biomed Chromatogr 2021 Jun 12;35(6):e5078. Epub 2021 Feb 12.

Laboratory of Proteomics Analysis, Research Institute of Pharmaceutical Sciences, Musashino University, Tokyo, Japan.

Prior to the identification of proteins for proteomics analysis in human cells, separation of fluorogenic derivatized proteins with a fluorogenic reagent, 7-chloro-N-[2-(dimethylamino)ethyl]-2,1,3-benzoxadiazole-4-sulfonamide, has typically been performed by using a conventional reversed-phase HPLC column. However, the number of proteins in human cells (HepaRG) that are separated by this conventional approach is limited to approximately 500. In this study, a nanoflow liquid chromatography system with an evaluated phenyl-bonded monolithic silica capillary column (0.1 mm i.d., 700 mm length) was used to increase the number of separated fluorogenic derivatized proteins. This system was used to separate derivatized human cell proteins (K562) and yeast (Saccharomyces cerevisiae) proteins as model cell proteomes. More than 1,300 protein peaks were separated/detected from both cell proteomes. We present a straightforward comparison of multiple separation profiles using a novel chromatogram display approach, termed the "spiderweb" chromatogram. In addition, to validate that the detected peaks are derived from proteins, a mass spectrometer was connected to the capillary column and deconvolution of the obtained mass spectra was performed. Furthermore, different molecular weight distribution profiles of the expressed proteins were observed between the two cell proteomes.
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http://dx.doi.org/10.1002/bmc.5078DOI Listing
June 2021

Comprehensive molecular and clinicopathological profiling of desmoid tumours.

Eur J Cancer 2021 Mar 11;145:109-120. Epub 2021 Jan 11.

Division of Cellular Signaling, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. Electronic address:

Previous studies have not clearly identified a prognostic factor for desmoid tumours (DT). Whole-exome sequencing (WES) and/or RNA sequencing (RNA-seq) were performed in 64 cases of DT to investigate the molecular profiles in combination with the clinicopathological characteristics. CTNNB1 mutations with specific hotspots were identified in 56 cases (87.5%). A copy number loss in chromosome 6 (chr6) was identified in 14 cases (21.9%). Clustering based on the mRNA expression profiles was predictive of the patients' prognoses. The risk score generated by the expression of a three-gene set (IFI6, LGMN, and CKLF) was a strong prognostic marker for recurrence-free survival (RFS) in our cohort. In risk groups stratified by the expression of IFI6, the hazard ratio for recurrence-free survival in the high-risk group relative to the low-risk group was 12.12 (95% confidence interval: 1.56-94.2; p = 8.0 × 10). In conclusion, CTNNB1 mutations and a chr6 copy number loss are likely the causative mutations underlying the tumorigenesis of DT while the gene expression profiles may help to differentiate patients who would be good candidates for wait-and-see management and those who might benefit from additional systemic or radiation therapies.
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http://dx.doi.org/10.1016/j.ejca.2020.12.001DOI Listing
March 2021

Revisiting estrogen-dependent signaling pathways in endometriosis: Potential targets for non-hormonal therapeutics.

Eur J Obstet Gynecol Reprod Biol 2021 Mar 29;258:103-110. Epub 2020 Dec 29.

Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Japan; Ms.Clinic MayOne, Kashihara, Japan.

Endometriosis is an estrogen-dependent gynecologic disease. Endometriotic cells survive in oxidative stress and hypoxic environments. The aim of this review is to reconsider new therapeutic strategies for endometriosis by focusing on estrogen signaling, ROS production and scavenging, and mitochondrial metabolism. Each keyword alone or in combination was used to search from PubMed and Embase by applying the filters of the title and the publication years between January 2000 and May 2020. Abnormal epigenetic marks of estrogen receptors (ERs) in endometriosis cause overexpression of ERβ, progesterone resistance, inflammation, anti-apoptosis, and mitochondrial metabolic modification. In addition to hormonal action, estrogen is involved in various functions such as mitochondrial biosynthesis and energy metabolism. Estrogen works with its downstream target genes to modulate mitochondrial gene expression, regulate ROS production, and affect mitochondrial biology, including ATP production, antioxidant defenses, mitochondrial biosynthesis, quality control, and energy-transducing capacity. Endometriosis can shift mitochondrial metabolism from oxidative phosphorylation to aerobic glycolysis. This metabolic conversion suppresses ROS production and thus activates the survival signal of endometriotic cells. Therefore, molecules associated with aerobic glycolysis and mitochondrial metabolism are considered therapeutic targets for endometriosis. In conclusion, estrogen downstream target genes involved in mitochondrial metabolic biosynthesis may be potential targets for non-hormonal treatment of endometriosis.
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http://dx.doi.org/10.1016/j.ejogrb.2020.12.044DOI Listing
March 2021

OGT Regulates Hematopoietic Stem Cell Maintenance via PINK1-Dependent Mitophagy.

Cell Rep 2021 01;34(1):108579

Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan. Electronic address:

O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) is a unique enzyme introducing O-GlcNAc moiety on target proteins, and it critically regulates various cellular processes in diverse cell types. However, its roles in hematopoietic stem and progenitor cells (HSPCs) remain elusive. Here, using Ogt conditional knockout mice, we show that OGT is essential for HSPCs. Ogt is highly expressed in HSPCs, and its disruption induces rapid loss of HSPCs with increased reactive oxygen species and apoptosis. In particular, Ogt-deficient hematopoietic stem cells (HSCs) lose quiescence, cannot be maintained in vivo, and become vulnerable to regenerative and competitive stress. Interestingly, Ogt-deficient HSCs accumulate defective mitochondria due to impaired mitophagy with decreased key mitophagy regulator, Pink1, through dysregulation of H3K4me3. Furthermore, overexpression of PINK1 restores mitophagy and the number of Ogt-deficient HSCs. Collectively, our results reveal that OGT critically regulates maintenance and stress response of HSCs by ensuring mitochondrial quality through PINK1-dependent mitophagy.
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http://dx.doi.org/10.1016/j.celrep.2020.108579DOI Listing
January 2021

Nonhormonal Treatment for Endometriosis Focusing on Redox Imbalance.

Gynecol Obstet Invest 2021 4;86(1-2):1-12. Epub 2021 Jan 4.

Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Japan,

The aim of this review is to investigate the oxidant/antioxidant status and its regulatory mechanisms in patients with endometriosis and to summarize the antioxidant therapy as an alternative to hormonal therapy for endometriosis. Each keyword alone or in combination was used to search from PubMed and Embase by applying the filters of the title and the publication years between January 2000 and March 2020. Endometriosis is a chronic inflammatory disease characterized by repeated episodes of hemorrhage. Methemoglobin in repeated hemorrhage produces large amounts of superoxide anion via the autoxidation of hemoglobin. Excessive free-radical production causes redox imbalance, leading to inadequate antioxidant defenses and damage to endometrial cells, but may contribute to endometrial cell growth and survival through activation of various signaling pathways. In addition, to overcome excessive oxidative stress, estradiol participates in the induction of antioxidants such as superoxide dismutase in mitochondria. Several antioxidants that suppress free radicals may be effective in endometriosis-related pain. We searched for 23 compounds and natural substances that could reduce the pain caused by superoxide/reactive oxygen species in basic research and animal models. Next, we built a list of 16 drugs that were suggested to be effective against endometriosis other than hormone therapy in preclinical studies and clinical trials. Of the 23 and 16 drugs, 4 overlapping drugs could be potential candidates for clinically reducing endometriosis-related pain caused by superoxide anion/reactive oxygen species. These drugs include polyphenols (resveratrol and polydatin), dopamine agonists (cabergoline), and statins (simvastatin). However, no randomized controlled trials have evaluated the efficacy of these drugs. In conclusion, this review summarizes the following 2 points: superoxide anion generation by methemoglobin is enhanced in endometriosis, resulting in redox imbalance; and some compounds and natural substances that can suppress free radicals may be effective in endometriosis-related pain. Further randomized clinical trials based on larger series are mandatory to confirm the promising role of antioxidants in the nonhormonal management of endometriosis.
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http://dx.doi.org/10.1159/000512628DOI Listing
May 2021

Systemic inflammation response index (SIRI) as a predictive factor for overall survival in advanced soft tissue sarcoma treated with eribulin.

J Orthop Sci 2020 Dec 29. Epub 2020 Dec 29.

Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Background: Eribulin is a tubulin and microtubule-targeting drug that has clinical benefit in overall survival (OS) for patients with advanced soft tissue sarcoma. Eribulin's efficacy has been confirmed in several clinical trials, although no clinically useful biomarkers have been identified. We therefore sought to clarify the predictive factor of eribulin treatment, while focusing on systemic inflammation and immune response values.

Methods: This study included 33 advanced STS patients treated with eribulin between March 2016 and September 2019. We evaluated the associations of clinical factors influencing the efficacy of eribulin treatment and systemic inflammatory and immune response, including the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), the lymphocyte-to-monocyte ratio (LMR), the systemic inflammation response index (SIRI), and the prognostic nutrition index (PNI), with progression-free survival (PFS) and OS using the Kaplan-Meier method and log-rank test.

Results: NLR, LMR, PLR, SIRI, and PNI were unassociated with PFS. Compared with patients with SIRI <1.5, those with an SIRI ≥1.5 had a significantly shorter OS [median OS 15 months (95% confidence interval [CI] 8-not reached) vs. 7 months (95% CI 3-14), P = 0.04]. Moreover, the PFS tended to be shorter for patients with SIRI ≥1.5 who received chemotherapy after eribulin treatment than in those with SIRI >1.5 [median PFS 92.5 days (95% CI 27-204) vs. 133 days (95% CI 36-507), P = 0.08].

Conclusions: High SIRI values may predict poorer overall survival and the efficacy of subsequent drugs after eribulin treatment among patients with advanced soft tissue sarcoma.
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http://dx.doi.org/10.1016/j.jos.2020.11.006DOI Listing
December 2020

Bone marrow transplantation into Abcd1-deficient mice: Distribution of donor derived-cells and biological characterization of the brain of the recipient mice.

J Inherit Metab Dis 2021 May 4;44(3):718-727. Epub 2021 Jan 4.

Faculty of Pharmaceutical Sciences, Hiroshima International University, Hiroshima, Japan.

X-linked adrenoleukodystrophy (X-ALD) is a severe inherited metabolic disease with cerebral inflammatory demyelination and abnormal accumulation of very long chain fatty acid (VLCFA) in tissues, especially the brain. At present, bone marrow transplantation (BMT) at an early stage of the disease is the only effective treatment for halting disease progression, but the underlying mechanism of the treatment has remained unclear. Here, we transplanted GFP-expressing wild-type (WT) or Abcd1-deficient (KO) bone marrow cells into recipient KO mice, which enabled tracking of the donor GFP cells in the recipient mice. Both the WT and KO donor cells were equally distributed throughout the brain parenchyma, and displayed an Iba1-positive, GFAP- and Olig2-negative phenotype, indicating that most of the donor cells were engrafted as microglia-like cells. They constituted approximately 40% of the Iba1-positive cells. Unexpectedly, no decrease of VLCFA in the cerebrum was observed when WT bone marrow cells were transplanted into KO mice. Taken together, murine study suggests that bone marrow-derived microglia-like cells engrafted in the cerebrum of X-ALD patients suppress disease progression without evidently reducing the amount of VLCFA in the cerebrum.
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http://dx.doi.org/10.1002/jimd.12346DOI Listing
May 2021

An ascites grading system for predicting the prognosis of gastric cancer with peritoneum dissemination.

Ann Gastroenterol Surg 2020 Nov 16;4(6):660-666. Epub 2020 Aug 16.

Department of Surgery Tsuboi Hospital Koriyama Japan.

Aim: Gastric cancer with peritoneum dissemination is intractable with surgical resection. The evaluation of the degree of dissemination using computed tomography (CT) is difficult. We focused on the amount of ascites based on CT findings and established a scaling system to predict these patients' prognoses.

Methods: We extracted individual data from a population-based cohort. Patients diagnosed with histologically proven gastric adenocarcinoma with peritoneum dissemination were enrolled. Two raters evaluated the CT images and determined the grade of ascites in each patient: grade 0 indicated no ascites in all slices; grade 1 indicated ascites detected only in the upper or lower abdominal cavity; grade 2 indicated ascites detected in both the upper and lower abdominal cavities; and grade 3 indicated ascites extending continuously from the pelvic cavity to the upper abdominal cavity. We evaluated the relationship between the ascites grade and survival time. After adjusting for other clinical factors, we calculated hazard ratios of each ascites grade.

Results: A total of 718 patients were enrolled. The number of patients with grades 0, 1, 2, and 3 were 303, 223, 94, and 98, respectively. The median overall survival times were 16.0, 8.7, 5.4, and 3.0 months for ascites on CT grades 0, 1, 2, and 3, respectively ( < .001). The adjusted hazard ratios for the survival time were 1.74 (1.33-2.26,  < .001), 3.20 (2.25-4.57,  < .001), and 4.76 (3.16-7.17,  < .001) for grades 1, 2, and 3, respectively.

Conclusion: We established a new grading system of pretreatment ascites to better predict the prognosis of gastric cancer.
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http://dx.doi.org/10.1002/ags3.12386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726691PMC
November 2020

Genetic Testing Distinguishes Multiple Chondroid Chordomas with Neuraxial Bone Metastases from Multicentric Tumors.

Case Rep Genet 2020 28;2020:8877722. Epub 2020 Nov 28.

Department of Orthopaedic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background: Chordomas are rare malignant bone tumors preferentially forming in neuraxial bones. Chondroid chordoma is a subtype of chordoma. Chordomas reportedly present as synchronous multiple lesions upon initial diagnosis. However, it remains unknown whether these lesions are multicentric or metastatic multiple chordoma tumors. . Here, we present the case of a 57-year-old woman with multiple chordomas at the clivus, C6, and T12 upon initial presentation. Sequential surgeries and radiotherapy were performed for these lesions, and postoperative histological diagnosis revealed that all lesions were chondroid chordomas. Next-generation sequencing revealed that these lesions harbored a common somatic mutation in epidermal growth factor receptor (), c.3617A>C, which is not considered a pathogenic chordoma mutation, thus indicating that these lesions were not multicentric but rather multiple metastatic tumors. Subsequent multiple metastases to the lung and appendicular and axial bones were detected 15 months after the initial surgery. Recurrent lesions at the clivus progressed despite EGFR-targeted therapy, surgery, and radiotherapy.

Conclusion: The present evidence indicates that multiple chordomas in this case were caused by multiple metastases rather than multicentric lesions. Multiple presentations of chordoma imply systemic dissemination of tumor cells, and novel efficient systemic therapy is required to treat this disease.
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http://dx.doi.org/10.1155/2020/8877722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719490PMC
November 2020