Publications by authors named "Mariko Eguchi"

57 Publications

Active aneurysm thrombosis after Kawasaki disease in an adult: Insight into anticoagulation therapy.

J Cardiol Cases 2021 May 21;23(5):206-209. Epub 2020 Nov 21.

Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.

The management of systemic artery aneurysms secondary to Kawasaki disease (KD) in adults remains a therapeutic challenge. KD guidelines recommend the use of anticoagulation therapy with warfarin in addition to antiplatelet therapy when a giant coronary aneurysm or a history of thrombosis is documented. However, long-term use of warfarin presents several concerns. This case reports acute thrombotic occlusion due to the giant arterial aneurysm in an adult KD. A surgical resection of the aneurysm was performed because of recurrent thrombotic events, despite anticoagulant therapy with warfarin. Pathological examinations revealed a layered thrombus with inflammation in the aneurysm and Factor Xa expression mainly in newly formed thrombus. This study provides an insight into the anticoagulation therapy for cardiovascular sequelae after KD. < This study, along with pathological evidence, illustrates that Factor Xa might contribute to thrombotic events after Kawasaki disease.>.
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http://dx.doi.org/10.1016/j.jccase.2020.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103331PMC
May 2021

A Catheter-Related Bloodstream Infection by in a Child with Acute Myeloid Leukemia: Case Report and Literature Review.

Case Rep Pediatr 2021 9;2021:6691569. Epub 2021 Apr 9.

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

The most common organisms isolated from pediatric catheter-related bloodstream infections (CRBSIs) are Gram-positive cocci, such as coagulase-negative staphylococci and . There are few formal reports of infection and even fewer reports of CRBSI due to this Gram-positive rod. Here we report the first case of CRBSI due to in an 8-year-old girl with acute myeloid leukemia in Japan. The isolate exhibited decreased susceptibility to -lactam antibiotics. Antimicrobial therapy with meropenem and vancomycin, in addition to the removal of central venous catheter line, consequently led to a significant clinical improvement of the patient's symptoms. A literature review found available clinical courses in 16 cases (4 pediatric cases including our case) of infection. Our case and those in literature suggested that infection often occurs in patients with indwelling central venous catheters; the literature review further suggested that removal of central venous catheters is required in most cases. Special attention should be paid to the detection of opportunistic infections due to spp. in immunocompromized children who are using a central venous catheter.
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http://dx.doi.org/10.1155/2021/6691569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052168PMC
April 2021

Targeting critical kinases and anti-apoptotic molecules overcomes steroid resistance in MLL-rearranged leukaemia.

EBioMedicine 2021 Feb 10;64:103235. Epub 2021 Feb 10.

Laboratory for Human Disease Models, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. Electronic address:

Background: Acute lymphoblastic leukaemia with mixed lineage leukaemia gene rearrangement (MLL-ALL) frequently affects infants and is associated with a poor prognosis. Primary refractory and relapsed disease due to resistance to glucocorticoids (GCs) remains a substantial hurdle to improving clinical outcomes. In this study, we aimed to overcome GC resistance of MLL-ALL.

Methods: Using leukaemia patient specimens, we performed bioinformatic analyses to identify target genes/pathways. To test inhibition of target pathways in vivo, we created pre-clinical therapeutic mouse patient-derived xenograft (PDX)-models by transplanting human MLL-ALL leukaemia initiating cells (LIC) into immune-deficient NSG mice. Finally, we conducted B-cell lymphoma-2 (BCL-2) homology domain 3 (BH3) profiling to identify BH3 peptides responsible for treatment resistance in MLL-leukaemia.

Findings: Src family kinases (SFKs) and Fms-like tyrosine kinase 3 (FLT3) signaling pathway were over-represented in MLL-ALL cells. PDX-models of infant MLL- ALL recapitulated GC-resistance in vivo but RK-20449, an inhibitor of SFKs and FLT3 eliminated human MLL-ALL cells in vivo, overcoming GC-resistance. Further, we identified BCL-2 dependence as a mechanism of treatment resistance in MLL-ALL through BH3 profiling. Furthermore, MLL-ALL cells resistant to RK-20449 treatment were dependent on the anti-apoptotic BCL-2 protein for their survival. Combined inhibition of SFKs/FLT3 by RK-20449 and of BCL-2 by ABT-199 led to substantial elimination of MLL-ALL cells in vitro and in vivo. Triple treatment combining GCs, RK-20449 and ABT-199 resulted in complete elimination of MLL-ALL cells in vivo.

Interpretation: SFKs/FLT3 signaling pathways are promising targets for treatment of treatment-resistant MLL-ALL. Combined inhibition of these kinase pathways and anti-apoptotic BCL-2 successfully eliminated highly resistant MLL-ALL and demonstrated a new treatment strategy for treatment-resistant poor-outcome MLL-ALL.

Funding: This study was supported by RIKEN (RIKEN President's Discretionary Grant) for FI, Japan Agency for Medical Research and Development (the Basic Science and Platform Technology Program for Innovative Biological Medicine for FI and by NIH CA034196 for LDS. The funders had no role in the study design, data collection, data analysis, interpretation nor writing of the report.
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http://dx.doi.org/10.1016/j.ebiom.2021.103235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878180PMC
February 2021

Noninvasive ultrasound technique for assessment of liver fibrosis and cardiac function in Fontan-associated liver disease: diagnosis based on elastography and hepatic vein waveform type.

J Med Ultrason (2001) 2021 Apr 8;48(2):235-244. Epub 2021 Jan 8.

Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon City, Ehime, 791-0295, Japan.

Purpose: Patients with a Fontan circulation tend to develop liver fibrosis, liver cirrhosis and even hepatocellular carcinoma. A noninvasive ultrasound technique for liver fibrosis and cardiac function assessment in Fontan-associated liver disease (FALD) is needed to evaluate disease progression in real time. This study aimed to evaluate whether hepatic vein (HV) waveform analysis and elastography could be alternative markers to cardiac index (CI) in patients with FALD and assess factors influencing elastography measurements in FALD cases.

Methods: All patients underwent cardiac catheterization, B-mode ultrasound and ultrasound elastography measurement. Moreover, we measured serum markers related to fibrosis and examined HV blood flow using duplex Doppler ultrasonography.

Results: Forty-three patients (median age, 17 years; interquartile range, 12-25 years; 29 men, 6 with liver biopsy) were enrolled. The real-time tissue elastography (RTE) value was significantly higher in patients who underwent surgery > 7 years prior, suggesting that this value probably reflects the liver fibrosis due to FALD from the early fibrosis stage. The ultrasound elastography did not significantly correlate with hemodynamic parameters. The area under the receiver operating curve for the diagnosis of CI < 2.2 L/min/m using HV waveform was superior to the results from elastography and calculated fibrosis indices.

Conclusion: HV waveform can be used as a noninvasive measurable surrogate marker for CI. The RTE value increased overtime after the operation and would reflect liver fibrosis. The combination of RTE and HV waveform type could be useful noninvasive tools to evaluate clinical conditions in FALD patients in real time.
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http://dx.doi.org/10.1007/s10396-020-01078-8DOI Listing
April 2021

Metaplastic carcinoma of the breast and BRCA1 germline mutation: a case report and review.

Hered Cancer Clin Pract 2021 Jan 6;19(1). Epub 2021 Jan 6.

Department of Hepato-Biliary-Pancreatic Surgery and Breast Surgery, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan.

Background: Metaplastic carcinoma of the breast consists of both invasive ductal carcinoma and metaplastic carcinoma. This rare subtype of cancer has a poor prognosis. The development of metaplastic breast cancer and relationship with BRCA1 are not well known. Here, we report a rare case of germline BRCA1 mutation-positive breast cancer with chondroid metaplasia.

Case Presentation: A 39-year-old Japanese woman with a family history of breast cancer in her mother and ovarian cancer in her maternal grandmother consulted at our hospital with a left breast mass. Needle biopsy for the mass was performed, leading to a diagnosis of invasive breast cancer with chondroid metaplasia. We performed left mastectomy + sentinel lymph node biopsy + tissue expander insertion and replaced with a silicone implant later. Pathological examination revealed that the patient had triple-negative breast cancer. Four courses of doxorubicin+ cyclophosphamide therapy were performed as adjuvant therapy after surgery. We performed genetic counseling and genetic testing, and the results suggested the germline BRCA1 mutation 307 T> A (L63*). She has currently lived without a relapse for 2 years post-surgery.

Conclusions: There have been only 6 cases of metaplastic breast carcinoma with germline BRCA1 mutations including our case. Patients with BRCA1 mutations may develop basal-like subtypes or M type of triple-negative breast cancer besides metaplastic breast cancers.
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http://dx.doi.org/10.1186/s13053-020-00162-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789215PMC
January 2021

Re-irradiation using proton therapy for radiation-induced secondary cancer with Li-Fraumeni syndrome: A case report and review of literature.

J Cancer Res Ther 2020 Oct-Dec;16(6):1524-1527

Department of Radiation Oncology, Proton Medical Research Center, University of Tsukuba Hospital, Tsukuba, Ibaraki, Japan.

Li-Fraumeni syndrome (LFS) is a genetic disease that is hypersensitive to radiotherapy. Proton therapy (PT) was strongly recommended for pediatric and radiation-sensitive tumors. However, there is little information on PT for LFS. The patient was a 7-year-old girl with LFS who was diagnosed with radiation-induced right shoulder blade osteosarcoma and left chest wall malignant fibrous histiocytoma. Both tumors were in the area that had previously been irradiated (36-45 Gy by photon radiotherapy). Sixty-six GyE in 30 fractions was planned for both tumors. We set the clinical target to the minimum gross tumor volume. To comprehensively assess any adverse events, PT was conducted under hospital administration. Cisplatin was used as simultaneous combination chemotherapy. Although administration of granulocyte-colony stimulating factor was necessary for myelosuppression by chemotherapy, PT was completed without interruption. Acute radiation toxicity was observed as Grade 1 dermatitis. The dermatitis became exacerbated 2 weeks after PT but subsequently improved with conservation treatment alone. Twenty-three months after PT, magnetic resonance imaging showed an increase in the tumor on the right shoulder. A histological examination was not conducted as the family declined, but secondary cancer was suggested rather than recurrent osteosarcoma, as the tumor developed mainly from the soft tissue. Additional surgical treatment and radiotherapy were not indicated, and the patient died of tumor progression and sepsis caused by myelosuppression 27 months after undergoing PT. Up to 23 months after PT, there were no signs of Grade 2 or more late toxicities. This represents the first reported case of PT for a patient with LF to treat radiation-induced secondary cancer.
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http://dx.doi.org/10.4103/jcrt.JCRT_449_19DOI Listing
December 2020

Surgical Unroofing for Intramural Aortic Course of Left Main Coronary Artery Leading Reverse Vessel Remodeling.

Circ Cardiovasc Imaging 2020 11 10;13(11):e010740. Epub 2020 Nov 10.

Department of Regional Pediatrics and Perinatology (Y.A., T.C., T.H., M.E.), Ehime University Graduate School of Medicine, Toon, Japan.

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http://dx.doi.org/10.1161/CIRCIMAGING.120.010740DOI Listing
November 2020

A novel variant in a Japanese girl with Waardenburg syndrome type 4C and Kallmann syndrome.

Hum Genome Var 2020 28;7:30. Epub 2020 Sep 28.

Department of Pediatrics, Ehime University Graduate School of Medicine, Ehime, Japan.

We report the first case of Waardenburg syndrome type 4C and Kallmann syndrome in the same person. The patient, a Japanese girl, presented with bilateral iris depigmentation, bilateral sensorineural hearing loss, Hirschsprung disease, hypogonadotropic hypogonadism, and anosmia. We identified a novel variant, c.124delC, p.Leu42Cysfs*67.
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http://dx.doi.org/10.1038/s41439-020-00118-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522263PMC
September 2020

Lister hooded rats as a novel animal model of attention-deficit/hyperactivity disorder.

Neurochem Int 2020 12 30;141:104857. Epub 2020 Sep 30.

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

Appropriate animal models are necessary to determine the molecular and cellular mechanisms underlying attention-deficit/hyperactivity disorder (ADHD). This study used a battery of behavioral tests to compare Lister hooded rats (LHRs), an old outbred strain frequently used for autistic epilepsy research, with Wistar rats and spontaneously hypertensive rats (SHRs), a commonly used ADHD model. The open field, elevated plus maze, light/dark box, and drop tests demonstrated that LHRs were the most hyperactive animals and displayed the most inattentive- and impulsive-like behaviors, which are characteristics of ADHD. The radial arm maze, social interaction, and Morris water maze tests showed that LHRs did not display deficits characteristic of autism or intellectual disability. Although LHRs did not show different monoamine contents, the mRNA expression levels of various genes linked to ADHD (Cdh13, Drd5, Foxp2, Maoa, Sema6d, Slc9a9, and St3gal3) and tyrosine hydroxylase protein expression levels were lower in the prefrontal cortex of LHRs compared with that of Wistar rats or SHRs. c-Fos, synapsin I, and tau protein expression levels in the prelimbic region of the medial prefrontal cortex were also increased in LHRs compared with Wistar rats. Atomoxetine and guanfacine, commonly used non-stimulant treatments for ADHD, ameliorated ADHD-like behaviors in LHRs. These results suggest that LHRs can serve as a better ADHD model to develop novel pharmacological interventions.
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http://dx.doi.org/10.1016/j.neuint.2020.104857DOI Listing
December 2020

Development of Human CBF1-Targeting Single-Stranded DNA Aptamers with Antiangiogenic Activity .

Nucleic Acid Ther 2020 12 2;30(6):365-378. Epub 2020 Sep 2.

Department of Biochemistry and Molecular Genetics and Ehime University Graduate School of Medicine, Toon, Japan.

C promoter binding factor 1 (CBF1) (alias RBPJ) is a critical transcription factor involved in Notch signaling. The activation of Notch signaling through CBF1 maintains the angiostatic state of endothelial cells suppressing angiogenesis, that is, the formation of new blood vessels. Vascular endothelial growth factor (VEGF) induces angiogenesis by promoting the proteasomal degradation of CBF1, in addition to endothelial cell proliferation. To date, angiogenic inhibitors targeting VEGF have been successfully used in clinics for cancer and age-related macular degeneration. Most antiangiogenic drugs, however, only target VEGF or VEGF receptors. In this study, to expand the repertoire of antiangiogenic therapeutics, we developed 15 single-stranded deoxyribonucleic acid (ssDNA) aptamers capable of binding to CBF1 with high affinity (; 10-300 nM). To this end, systematic evolution of ligands by the exponential enrichment (SELEX) method was applied. One of the CBF1-binding ssDNA aptamers, Apt-3, inhibited angiogenesis through the activation of Notch signaling . We found that Apt-3 directly interacted with the LAG1 domain of CBF1. We suggest that the Apt-3 ssDNA aptamer may contribute to the development of a novel angiogenic inhibitor, which does not target VEGF.
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http://dx.doi.org/10.1089/nat.2020.0875DOI Listing
December 2020

Intraluminal duodenal diverticulum with repeated vomiting and acute pancreatitis.

Pediatr Int 2020 Sep 18;62(9):1109-1110. Epub 2020 Aug 18.

Department of Pediatrics, Ehime University Graduate School of Medicine, Ehime, Japan.

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http://dx.doi.org/10.1111/ped.14247DOI Listing
September 2020

Survey of patients with spinal muscular atrophy on the island of Shikoku, Japan.

Brain Dev 2020 Sep 3;42(8):594-602. Epub 2020 Jun 3.

Department of Pediatrics, Ehime University Graduate School of Medicine, Ehime, Japan.

Background: Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder associated with spinal motor neuron loss and characterized by generalized muscle weakness. Only a few reports exist on SMA epidemiology in Japan. Additionally, nusinersen recently became available as a treatment for this condition. We estimated the prevalence of each type of SMA on Shikoku, Japan's fourth-largest major island.

Methods: We sent a questionnaire to all 131 hospitals in Shikoku that have pediatrics or neurology departments from March to September 2019, asking whether each hospital had SMA patients at that time. If so, we sent a second questionnaire to obtain more detailed information on the clinical data and treatment of each patient.

Results: A total of 117 hospitals (89.3%) responded to our first questionnaire, and 21 SMA patients were reported, 16 of whom had homozygous deletion of SMN1. Of the 21, nine had SMA type 1, five were type 2, five were type 3, one was type 4, and one was unidentified. The estimated prevalence for all instances of SMA and 5q-SMA was 0.56 and 0.43 per 100,000 people, respectively. Thirteen patients had received nusinersen therapy. Its outcomes varied from no obvious effects and being unable to sit to being able to sit independently.

Conclusion: Our data showed the prevalence of SMA types 2 and 3 was relatively low on Shikoku compared with previous reports from other countries, suggesting delayed diagnosis may affect the results. Remaining motor function may be one predicting factor. Greater awareness of SMA among clinicians and patients seems necessary for more accurate epidemiological studies.
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http://dx.doi.org/10.1016/j.braindev.2020.05.004DOI Listing
September 2020

Malignant Ovarian Steroid Cell Tumor, Not Otherwise Specified, Causes Virilization in a 4-Year-Old Girl: A Case Report and Literature Review.

Case Rep Oncol 2020 Jan-Apr;13(1):358-364. Epub 2020 Apr 2.

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

We report a case of a 4-year-old girl with an ovarian steroid cell tumor, not otherwise specified (SCT-NOS). She was admitted to the hospital with progressing virilization and Cushing's syndrome, which included abnormality of the perineum, hirsutism, hypertrichosis, flushing of face, hoarseness, and weight gain. Blood testing showed a significantly increased testosterone level and slightly increased cortisol level. Computed tomography scan revealed an 8.0 × 5.0 × 5.0 cm tumor of the right ovary. The patient underwent right salpingo-oophorectomy, and pathological examination showed malignant potential. Three courses of bleomycin, etoposide, and cisplatin were administered as postoperative chemotherapy. After tumor resection, her testosterone decreased to undetectable levels. However, during the course of the treatment, the patient suffered from adrenal insufficiency resulting in the need for hydrocortisone replacement therapy. Although SCT-NOS in childhood are typically benign, pathological findings should be carefully observed for potential malignancy. In cases of cortisol-producing SCT-NOS, serum levels should be monitored, and hydrocortisone replacement therapy should be considered before resection.
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http://dx.doi.org/10.1159/000506044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184839PMC
April 2020

Brain Abscess Associated with Polymicrobial Infection after Intraoral Laceration: A Pediatric Case Report.

Case Rep Pediatr 2020 9;2020:8304302. Epub 2020 Mar 9.

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

Brain abscesses, infections within the brain parenchyma, can arise as complications of various conditions including infections, trauma, and surgery. However, brain abscesses due to polymicrobial organisms have rarely been reported in children. We herein report a case of a 9-year-old girl with unresolved congenital cyanotic heart disease (CCHD) presenting with right hemiplegia who was diagnosed with brain abscess caused by , , and after oropharyngeal injury. She was treated with intravenous antimicrobial therapy, drainage under craniotomy, and antiedema therapy with glycerol and goreisan, which led to the improvement of right hemiplegia to baseline; she was discharged following eight weeks of intravenous antimicrobial therapy. The clinical diagnosis of the brain abscess was difficult due to the nonspecific presentation, highlighting the importance of cranial imaging without haste in patients at increased risk for brain abscesses such as those with CCHD, presenting with fever in the absence of localizing symptoms or fever, accompanied with abnormal neurological findings.
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http://dx.doi.org/10.1155/2020/8304302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085370PMC
March 2020

Early Surgery Is Feasible for a Very Large Congenital Infantile Fibrosarcoma Associated With Life Threatening Coagulopathy: A Case Report and Literature Review.

Front Pediatr 2019 19;7:529. Epub 2019 Dec 19.

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

Congenital infantile fibrosarcoma (CIF) is a rare malignant soft tissue tumor that predominantly occurs in children under 1 year of age. CIF is frequently misdiagnosed with other conditions like hemangioma of infancy, infantile fibromatosis, or kaposiform hemangioendothelioma. Disseminated intravascular coagulopathy (DIVC) is rarely reported to be associated with CIF. We describe an infant who presented with a large mass over the right arm. She was initially treated conservatively as hemangioma but was later confirmed by tissue histopathological examination to have CIF as the mass rapidly increased in size. She developed massive intra-tumoral bleed with DIVC whilst receiving neoadjuvant chemotherapy requiring multiple blood products transfusion. An urgent near-total resection of the tumor was performed in view of life threatening bleeding despite multiple blood transfusions. Post-operatively, she received further adjuvant chemotherapy. Subsequently, she remained in complete remission 32 months off-treatment and has full function of the affected limb. CIF is an important condition to be considered in infant who has large mass over the extremity. DIVC could be associated with large CIF and when it occurs can be life-threatening. Whenever feasible early surgery should be performed in very young patients with large CIF to prevent mortality from bleeding.
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http://dx.doi.org/10.3389/fped.2019.00529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6951396PMC
December 2019

Renal dysfunction can occur in advanced-stage Duchenne muscular dystrophy.

Muscle Nerve 2020 02 28;61(2):192-197. Epub 2019 Nov 28.

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

Introduction: With improved treatments, patients with Duchenne muscular dystrophy (DMD) can survive far beyond adolescence. However, advanced-stage DMD patients are at risk of developing renal dysfunction. In this study, long-term renal function outcomes and associated risk factors in advanced stage DMD were analyzed.

Methods: Fifty-one patients were classified into three different age groups (<20, 20-29, and ≥30 years of age), and cystatin C (CysC) levels were compared among groups.

Results: Median serum CysC levels were 0.74 mg/L, 0.63 mg/L, and 0.76 mg/L in the age groups of <20, 20-29, and ≥30 years, respectively (P = .003). Five of the nine patients in the ≥30 years age group showed elevated serum CysC and decreased cardiac function compared with the other four in the group (P = .014).

Discussion: Our results indicate an association between cardiac and renal dysfunction in patients with advanced-stage DMD.
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http://dx.doi.org/10.1002/mus.26757DOI Listing
February 2020

Mesenchymal Stem Cell Therapy Overcomes Steroid Resistance in Severe Gastrointestinal Acute Graft-Versus-Host Disease.

Case Rep Transplant 2019 21;2019:7890673. Epub 2019 May 21.

Department of Pediatrics, Ehime University Graduate School of Medicine, Ehime, Japan.

The authors describe the high effectiveness of human mesenchymal stem cell (hMSC) therapy to treat steroid-refractory gastrointestinal acute graft-versus-host Disease (aGVHD) in a 15-year-old boy with acute lymphoblastic leukemia (ALL). He received allogeneic hematopoietic stem cell transplantation due to high-risk hypodiploid ALL. Around the time of engraftment, he developed severe diarrhea following high-grade fever and erythema. Although methylprednisolone pulse therapy was added to tacrolimus and mycophenolate mofetil, diarrhea progressed up to 5000~6000 ml/day and brought about hypocalcemia, hypoalbuminemia, and edema. Daily fresh frozen plasma (FFP), albumin, and calcium replacements were required to maintain blood circulation. After aGVHD was confirmed by colonoscopic biopsy, MSC therapy was administered. The patient received 8 biweekly intravenous infusions of 2×10 hMSCs/kg for 4 weeks, after which additional 4 weekly infusions were performed. A few weeks after initiation, diarrhea gradually resolved, and at the eighth dose of hMSC, lab data improved without replacements. MSC therapy successfully treated steroid-refractory gastrointestinal GVHD without complications. Despite life-threatening diarrhea, the regeneration potential of children and adolescents undergoing SMC therapy successfully supports restoration of gastrointestinal damage. Even with its high treatment costs, SMC therapy should be proactively considered in cases where young patients suffer from severe gastrointestinal GVHD.
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http://dx.doi.org/10.1155/2019/7890673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556259PMC
May 2019

Nonocclusive Mesenteric Ischemia Rescued by Immediate Surgical Exploration in a Boy with Severe Neurodevelopmental Disability.

Case Rep Pediatr 2019 19;2019:5354074. Epub 2019 Feb 19.

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

Background: Nonocclusive mesenteric ischemia (NOMI) defines acute mesenteric ischemia without occlusion of the mesenteric arteries. The most common cause of NOMI is vasoconstriction or vasospasm of a mesenteric artery. NOMI generally affects patients >50 years of age, and few cases have been reported in children.

Case Presentation: A 15-year-old boy with severe neurodevelopmental disability developed sudden-onset fever, abdominal distention, and dyspnea. Laboratory and radiological findings indicated acute intestinal obstruction and prerenal failure. He developed transient cardiopulmonary arrest and hypovolemic shock. Emergent laparotomy was performed, which revealed segmentally necrotic intestine from the jejunum to the ascending colon with pulsation of peripheral intestinal arteries, leading to a diagnosis of NOMI. The necrotic intestine was resected, and stomas were created. He was discharged on postoperative day 334 with short bowel syndrome as a complication.

Conclusions: NOMI should be considered a differential diagnosis for intestinal symptoms with severe general conditions in both adults and children with underlying disease. Immediate surgical exploration is essential with NOMI to save a patient's life.
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http://dx.doi.org/10.1155/2019/5354074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399550PMC
February 2019

Early detection of the PAX3-FOXO1 fusion gene in circulating tumor-derived DNA in a case of alveolar rhabdomyosarcoma.

Genes Chromosomes Cancer 2019 08 10;58(8):521-529. Epub 2019 Feb 10.

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

Cell-free DNA (cfDNA), which are small DNA fragments in blood derived from dead cells including tumor cells, could serve as useful biomarkers and provide valuable genetic information about the tumors. cfDNA is now used for the genetic analysis of several types of cancers, as a surrogate for tumor biopsy, designated as "liquid biopsy." Rhabdomyosarcoma (RMS), the most frequent soft tissue tumor in childhood, can arise in any part of the body, and radiological imaging is the only available method for estimating the tumor burden, because no useful specific biological markers are present in the blood. Because tumor volume is one of the determinants of treatment response and outcome, early detection at diagnosis as well as relapse is essential for improving the treatment outcome. A 15-year-old male patient was diagnosed with alveolar RMS of prostate origin with bone marrow invasion. The PAX3-FOXO1 fusion was identified in the tumor cells in the bone marrow. After the diagnosis, cfDNA was serially collected to detect the PAX3-FOXO1 fusion sequence as a tumor marker. cfDNA could be an appropriate source for detecting the fusion gene; assays using cfDNA have proved to be useful for the early detection of tumor progression/recurrence. Additionally, the fusion gene dosage estimated by quantitative polymerase chain reaction reflected the tumor volume during the course of the treatment. We suggest that for fusion gene-positive RMSs, and other soft tissue tumors, the fusion sequence should be used for monitoring the tumor burden in the body to determine the diagnosis and treatment options for the patients.
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http://dx.doi.org/10.1002/gcc.22734DOI Listing
August 2019

Exon skipping in CYBB mRNA and skewed inactivation of X chromosome cause late-onset chronic granulomatous disease.

Pediatr Hematol Oncol 2018 Aug - Sep;35(5-6):341-349. Epub 2019 Jan 11.

a Department of Pediatrics , Ehime University Graduate School of Medicine , Toon , Ehime , Japan.

Chronic granulomatous disease (CGD) is a hereditary immunodeficiency syndrome caused by a defect in the NADPH oxidase complex, which is essential for bactericidal function of phagocytes. Approximately 70% of patients with CGD have a mutation in the CYBB gene on the X chromosome, resulting in defective expression of gp91, one of the membrane-bound subunits of NADPH oxidase. Although most patients with X-linked CGD are males, owing to transmission of this disease as an X-linked recessive trait, there are female patients with X-linked CGD. Here, we report the case of a teenage girl with X-linked CGD associated with a heterozygous mutation in exon 5 of the CYBB gene (c.389G > C; R130P), which causes skipping of exon 5, resulting in a premature stop codon in exon 6 of CYBB. Accurate pro-mRNA splicing for mature mRNA formation is regulated by several splicing mechanisms that are essential for appropriate recognition of exonic sequences. The c.389G > C mutation disrupts exonic-splicing regulator sequences, thereby resulting in the aberrant skipping of exon 5 in the CYBB transcript of the patient. The patient showed an extremely skewed (≥96%) X inactivation pattern of the HUMARA locus; this inactivation is thought to be responsible for the development of CGD not only in neutrophils but also in monocytic, T-cell, and B-cell lineages and in CD34-positive immature hematopoietic cells. Our case and other reports indicate that the onset of X-linked CGD in female patients tends to occur later in life, and that the symptoms tend to be milder as compared to male patients.
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http://dx.doi.org/10.1080/08880018.2018.1522402DOI Listing
March 2019

Prolonged adrenal insufficiency after high-dose glucocorticoid in infants with leukemia.

Pediatr Hematol Oncol 2018 Aug - Sep;35(5-6):355-361. Epub 2018 Nov 20.

a Department of Pediatrics , Ehime University Graduate School of Medicine , Ehime , Japan.

Although outcomes for infant leukemia have improved recently, transient adrenal insufficiency is commonly observed during treatment, especially after glucocorticoid administration. We identified three infants with acute leukemia who suffered from prolonged adrenal insufficiency requiring long-term (from 15 to 66 months) hydrocortisone replacement. All infants showed life-threatening symptoms associated with adrenal crisis after viral infections or other stress. Severe and prolonged damage of hypothalamo-pituitary-adrenal (HPA) axis is likely to occur in early infants with leukemia, therefore routine tolerance testing to evaluate HPA axis and hydrocortisone replacement therapy are recommended for infants with leukemia to avoid life-threatening complications caused by adrenal crisis.
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http://dx.doi.org/10.1080/08880018.2018.1539148DOI Listing
March 2019

Usefulness of positron emission tomography-CT for diagnosis of primary bone marrow lymphoma in children.

Pediatr Hematol Oncol 2018 Mar 12;35(2):125-130. Epub 2018 Apr 12.

a Department of Pediatrics , Ehime University Graduate School of Medicine , Ehime , Japan.

Primary bone marrow lymphoma (PBML) is hard to diagnose in children, due to the difficult identification of malignant cells in bone marrow. The first case, a 5-year-old boy, showed knee swelling with an intermittent fever. The second case, a 12-year-old girl, showed fever of unknown origin without lymphadenopathy or hepatosplenomegaly. In both cases, the diagnosis was not confirmed despite the repeated bone marrow aspirations. Finally, bone marrow aspiration and biopsy at the positive site by positron emission tomography (PET)-CT contributed to definitive diagnosis of PBML. The PET-CT is useful for the accurate diagnosis of PBML in children with non-specific symptoms.
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http://dx.doi.org/10.1080/08880018.2018.1459984DOI Listing
March 2018

Manifestation of recessive combined D-2-, L-2-hydroxyglutaric aciduria in combination with 22q11.2 deletion syndrome.

Am J Med Genet A 2018 02 19;176(2):351-358. Epub 2017 Dec 19.

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

22q11.2 deletion syndrome is one of the most common human microdeletion syndromes. The clinical phenotype of 22q11.2 deletion syndrome is variable, ranging from mild to life-threatening symptoms, depending mainly on the extent of the deleted region. Brain malformations described in association with 22q11.2 deletion syndrome include polymicrogyria, cerebellar hypoplasia, megacisterna magna, and agenesis of the corpus callosum (ACC), although these are rare. We report here for the first time a patient who manifested combined D-2- and L-2-hydroxyglutaric aciduria as a result of a hemizygous mutation in SLC25A1 in combination with 22q11.2 deletion. The girl was diagnosed to have ACC shortly after birth and a deletion of 22q11.2 was identified by genetic analysis. Although the patient showed cardiac anomalies, which is one of the typical symptoms of 22q11.2 deletion syndrome, her rather severe phenotype and atypical face prompted us to search for additional pathogenic mutations. Three genes present in the deleted 22q11.2 region, SLC25A1, TUBA8, and SNAP29, which have been reported to be associated with brain malformation, were analyzed for the presence of pathogenic mutations. A frameshift mutation, c.18_24dup (p.Ala9Profs*82), was identified in the first exon of the remaining SLC25A1 allele, resulting in the complete loss of normal SLC25A1 function in the patient's cells. Our results support the notion that the existence of another genetic abnormality involving the retained allele on 22q11.2 should be considered when atypical or rare phenotypes are observed.
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http://dx.doi.org/10.1002/ajmg.a.38578DOI Listing
February 2018

Azacitidine successfully maintained the second remission in an infant with KMT2A-rearranged acute lymphoblastic leukemia who relapsed after unrelated cord blood transplantation.

Pediatr Blood Cancer 2017 Dec 4;64(12). Epub 2017 Jul 4.

Department of Pediatrics, Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital, Hiroshima, Japan.

The outcome for infants with KMT2A (MLL)-rearranged acute lymphoblastic leukemia (MLL-r ALL) is dismal despite intensive therapy, including hematopoietic stem cell transplantation (HSCT). Epigenetic dysregulation is considered a key driver of MLL-r leukemogenesis, which theoretically supports the use of epigenetic modifiers as a treatment option. We report an infant MLL-r ALL case with post-HSCT relapse. After achieving a second remission, which was maintained for 10 months using only the DNA methyltransferase inhibitor, azacitidine, the patient successfully received the second HSCT. This report describes the clinical effectiveness of azacitidine for the treatment of infant MLL-r ALL.
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http://dx.doi.org/10.1002/pbc.26697DOI Listing
December 2017

Reemergence of translocation t(11;19)(q23;p13.1) in the absence of clinically overt leukemia.

Int J Hematol 2017 Dec 1;106(6):847-851. Epub 2017 Jul 1.

Department of Hematology and Oncology, Children's Cancer Center, Kobe Children's Hospital, Minatojima-Minamimachi 1-6-7, Chuo-ku, Kobe, 650-0047, Japan.

We report the case of a 10-year-old female with acute myeloid leukemia (AML) FAB M0 carrying a novel t(11;19)(q23;p13.1) MLL-ELL variant, in which intron 8 of MLL is fused to exon 6 of ELL. Complete remission, judged by morphology and cytogenetic analysis, was achieved after the conventional chemotherapy. Eight months after completion of therapy, the level of WT-1 in peripheral blood and the number of cells with the MLL-ELL fusion transcript resurged. However, the patient remained overtly healthy and the morphology in the bone-marrow smear was innocuous, with no sign of relapse or secondary leukemia. Without any evidence of relapse, the patient has been closely observed without any therapeutic intervention. For approximately 2 years after the completion of therapy, despite clonal proliferation of pre-leukemic cells with an MLL-ELL fusion gene, she has maintained complete remission. In this case, the rare variant form of MLL-ELL fusion that has been identified may be related to diminished leukemogenic capacity, resulting in the persistence of pre-leukemic status; an additional genetic abnormality may thus be necessary for full transformation of pre-leukemic cells.
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http://dx.doi.org/10.1007/s12185-017-2289-yDOI Listing
December 2017

[Leukemia].

Gan To Kagaku Ryoho 2016 Nov;43(11):1341-1345

Dept. of Pediatrics, Ehime University Graduate School of Medicine.

Leukemia is derived from hematopoietic stem/progenitor cells that have acquired genetic abnormalities, leading to malignant transformation. The basis of therapyfor leukemia is a combination of anti-cancer drugs based on risk stratification. The overall 5-year survival rate in leukemia patients of all ages is still 40%, although it has improved in pediatric patients. Leuke- mia itself is a heterogeneous disease that includes various entities/subtypes with different pathogenic gene aberrations. Selection of the treatment strategylargelydepends on risk stratification, and this in turn is mainlybased on specific recurrent chromosome aberrations. However, in acute myeloid leukemia(AML), a significant proportion of patients present with a normal karyotype according to conventional cytogenetic analysis and are classified into an intermediate-risk group, which actuallyconsists of various subtypes with different prognoses. In addition, leukemic cells usuallyharbor one or more driver mutations among their various genetic aberrations, and these driver mutations could affect prognosis. The discoveryof additional mutations in genes such as NPM1, CEBPA and FLT3, which are frequent in AML patients with a normal karyotype, have improved the precision of risk stratification in AML. In this regard, array-based gene expression analysis and whole exome/ transcriptome sequencing could be useful tools for identifying the whole spectrum of genetic aberrations, or for compiling a complete list of mutated genes within leukemic cells. Genetic profiling information obtained using these newlydeveloped methods could provide more accurate information for molecular subtyping and risk stratification in leukemia.
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November 2016

Histological characterisation of visceral changes in a patient with type 2 Gaucher disease treated with enzyme replacement therapy.

Blood Cells Mol Dis 2018 02 12;68:194-199. Epub 2016 Nov 12.

Department of Genome Pathology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan.

Gaucher disease is a lysosomal storage disease caused by deficiency of glucocerebrosidase and accumulation of glucocerebroside. Three major sub-types have been described, type 2 is an acute neurological form that exhibits serious general symptoms and poor prognosis, compared with the other types. This case was a girl diagnosed with type 2 Gaucher disease at 12months of age who presented with poor weight gain from infancy, stridor, hypertonia, hepatosplenomegaly, trismus and an eye movement disorder. Enzyme replacement therapy (ERT) was administered, but she had frequent myoclonus and developmental regression. She needed artificial ventilation because of respiratory failure. She died at 11years of age. An autopsy demonstrated infiltrating CD68-positive large cells containing abundant lipids in alveoli, while in the liver, kidney and bone marrow CD68-positive cells were small and round. In the bone marrow, myelodysplastic changes were present without Gaucher cells. The infiltration of Gaucher cells in alveoli was marked, suggesting that ERT was relatively ineffective in pulmonary involvement, particularly intra-alveolar. Additional treatments are necessary to improve the neurological and pulmonary prognosis of type 2Gaucher disease.
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http://dx.doi.org/10.1016/j.bcmd.2016.11.006DOI Listing
February 2018

Installation of multiple automated external defibrillators to prevent sudden death in school-aged children.

Pediatr Int 2016 Dec 10;58(12):1261-1265. Epub 2016 Nov 10.

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

Background: Recently, a student died of idiopathic ventricular fibrillation in a school where an automated external defibrillator (AED) had been installed. The tragedy could not be prevented because the only AED in the school was installed in the teachers' office, far from the school ground where the accident took place. This prompted establishment of a multiple AED system in schools. The aim of this study was to analyze the efficacy of the multiple AED system to prevent sudden death in school-aged children.

Methods: Assumed accident sites consisted of the school ground, gymnasium, Judo and Kendo hall, swimming pool, and classrooms on the first and the fourth floor. Multiple AED were installed in the teachers' office, gymnasium, some classrooms, and also provided as a portable AED in a rucksack. The time from the accident site to the teachers' office for single AED, and from the accident site to the nearest AED for multiple AED, was calculated.

Results: The AED retrieval time was significantly shorter in 55 elementary schools and in 29 junior high schools when multiple AED were installed compared with single AED. Except for the classroom on the fourth floor, the number of people who took >120 s to bring the AED to the accident site was lower when multiple AED were installed compared with the single AED.

Conclusion: Multiple AED provided in appropriate sites can reduce the time to reach the casualty and hence prevent sudden death in school-aged children.
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http://dx.doi.org/10.1111/ped.13143DOI Listing
December 2016

[Recent progress in leukemic stem cell research for childhood leukemia].

Rinsho Ketsueki 2015 Oct;56(10):1871-81

Department of Pediatrics, Ehime University Graduate School of Medicine.

Leukemic stem cells (LSCs) were originally identified in acute myeloid leukemia (AML) cases by using xenograft models, as a distinct cell population that can initiate leukemia in immunodeficient mice. Since then, many efforts have been made to clarify the identities of LSCs and other cancer stem cells in various cancer types, to both understand their biology and determine the most suitable targets for anti-cancer therapies. LSCs were identified as existing in the immature CD34+CD38- leukemic population in most AML cases, and these cells were found to share some features with normal hematopoietic stem cells. On the other hand, recent studies have shown that in childhood acute lymphoblastic leukemia (ALL), LSCs exist among B-lineage-committed progenitors expressing CD19. In contrast to AML, in which LSCs generate leukemic cells in a hierarchical order with LSCs at the top, leukemia propagation in childhood ALL is better explained by a stochastic model. In B-precursor ALL, LSCs form via acquisition of additional genetic change(s) in CD19+ B-lineage progenitor cells with self-renewing capacity. These LSCs possess a growth advantage and the capacity to produce progeny with the same ability as the LSCs. Identification of genetic and cellular targets in leukemic transformation is necessary to develop improved anti-cancer therapies.
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http://dx.doi.org/10.11406/rinketsu.56.1871DOI Listing
October 2015

HMGA2 as a potential molecular target in KMT2A-AFF1-positive infant acute lymphoblastic leukaemia.

Br J Haematol 2015 Dec 25;171(5):818-29. Epub 2015 Sep 25.

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

Acute lymphoblastic leukaemia (ALL) in infants is an intractable cancer in childhood. Although recent intensive chemotherapy progress has considerably improved ALL treatment outcome, disease cure is often accompanied by undesirable long-term side effects, and efficient, less toxic molecular targeting therapies have been anticipated. In infant ALL cells with KMT2A (MLL) fusion, the microRNA let-7b (MIRLET7B) is significantly downregulated by DNA hypermethylation of its promoter region. We show here that the expression of HMGA2, one of the oncogenes repressed by MIRLET7B, is reversely upregulated in infant ALL leukaemic cells, particularly in KMT2A-AFF1 (MLL-AF4) positive ALL. In addition to the suppression of MIRLET7B, KMT2A fusion proteins positively regulate the expression of HMGA2. HMGA2 is one of the negative regulators of CDKN2A gene, which encodes the cyclin-dependent kinase inhibitor p16(INK4A) . The HMGA2 inhibitor netropsin, when combined with demethylating agent 5-azacytidine, upregulated and sustained the expression of CDKN2A, which resulted in growth suppression of KMT2A-AFF1-expressing cell lines. This effect was more apparent compared to treatment with 5-azacytidine alone. These results indicate that the MIRLET7B-HMGA2-CDKN2A axis plays an important role in cell proliferation of leukaemic cells and could be a possible molecular target for the therapy of infant ALL with KMT2A-AFF1.
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http://dx.doi.org/10.1111/bjh.13763DOI Listing
December 2015