Publications by authors named "Shoji Saito"

75 Publications

Investigation of risk factors associated with erythrocyte engraftment after ABO-incompatible hematopoietic stem cell transplantation.

Clin Transplant 2021 Mar 27:e14300. Epub 2021 Mar 27.

Center for Advanced Cell Therapy, Shinshu University Hospital, Matsumoto, Japan.

ABO-incompatible hematopoietic stem cell transplantations (HSCTs) are widely practiced; however, the delay in erythrocyte engraftment can be problematic. While erythrocyte engraftment is usually indicated by an increase in reticulocyte levels without the need for erythrocyte transfusions, the disappearance of recipient-derived anti-A/B isoagglutinin and detection of donor-derived A/B antigens can also be used as other parameters. We conducted a retrospective analysis of 68 ABO-incompatible HSCTs, focusing on major and bidirectional mismatch. We analyzed known clinical risk factors associated with delayed erythrocyte engraftment using the three parameters (disappearance of anti-A/B isoagglutinin in recipient, detection of donor derived A/B antigen, and reticulocyte levels >1%). Although the three parameters were well correlated, the results showed heterogeneity when analyzing the associated risk factors for delayed erythrocyte engraftment. In the analysis of all cases, the requirement for an HLA-matched platelet transfusion was a common risk factor. Furthermore, erythrocyte engraftment was slower in adults than in children. In adults, cytomegalovirus antigenemia was a risk factor for two parameters; however, in children, underlying disease was a common risk factor for all parameters. There is a complex relationship between erythrocyte engraftment and various factors related to HSCTs. Our results suggest that greater accuracy is possible by using analysis methods other than the measurement of reticulocyte levels.
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http://dx.doi.org/10.1111/ctr.14300DOI Listing
March 2021

Hemodynamic features of an intracranial aneurysm rupture predicted by perianeurysmal edema: A case report.

Surg Neurol Int 2021 10;12:49. Epub 2021 Feb 10.

Department of Neurosurgery, Niigata University, Brain Research Institute, Niigata, Japan.

Background: Perianeurysmal edema (PAE) has been suggested as an indicator of potential aneurysm rupture; however, the hemodynamic features of these aneurysms are still unknown. A computational fluid dynamic (CFD) analysis was performed to evaluate the hemodynamic features of a very rare case of a ruptured middle cerebral artery (MCA) aneurysm with PAE.

Case Description: A 65-year-old woman presented with disturbed consciousness. A subarachnoid hemorrhage due to an azygos anterior cerebral artery (ACA) aneurysm rupture was suspected. An unruptured MCA aneurysm with PAE was identified in the left temporal lobe. Although the ACA aneurysm was clipped to prevent re-bleeding, the MCA aneurysm subsequently ruptured 6 days later. Clipping of the MCA aneurysm was performed, and hemosiderin deposits suggestive of sentinel bleeding were found on the surface of the aneurysm dome. CFD analysis revealed unstable hemodynamic stress at the expanded bleb area after rupture, localized to the rupture site. Moreover, this analysis revealed flow impingement with pressure elevation and low wall shear stress, which indicated increased inflammation and aneurysm wall thinning that likely led to rupture.

Conclusion: Hemosiderin deposits at the aneurysm wall and PAE indicates leakage from a cerebral aneurysm. Hemodynamic stress at the aneurysm may promote an inflammatory response and lead to wall weakening accompanied by PAE. Based on our findings, we recommend that surgical intervention should be considered as the first line of treatment for such aneurysms to prevent rupture.
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http://dx.doi.org/10.25259/SNI_780_2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911146PMC
February 2021

Delayed Bleeding of Unruptured Intracranial Aneurysms After Coil Embolization: A Retrospective Case Series.

World Neurosurg 2021 Feb 20. Epub 2021 Feb 20.

Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata, Japan.

Objective: Delayed bleeding of unruptured intracranial aneurysms (UIAs) after coil embolization is rare; this study aimed to analyze the occurrence of delayed bleeding of UIAs after coil embolization.

Methods: We retrospectively analyzed patients with UIAs after coil embolization between January 2002 and December 2018 and assessed the features of UIAs with delayed bleeding after coil embolization.

Results: Analysis included 307 patients with 335 UIAs. Mean follow-up was 7.1 ± 4.9 years, and total follow-up was 2365 aneurysm-years. There were 271 (80.9%) aneurysms located in the anterior circulation and 64 (19.1%) aneurysms located in the posterior circulation. Significant differences were observed between the 2 groups in terms of maximum size of the aneurysm (P < 0.01), width of the aneurysm neck (P < 0.01), and number of retreatment cases (P < 0.01). During the follow-up period, delayed bleeding occurred in 4 aneurysms (annual bleeding rate of 0.17%); all were located in the posterior circulation. The original size was not relatively large (mean 8.6 ± 2.4 mm). All aneurysms bled within 5 years (mean 35 ± 9.6 months) after the initial treatment. Two were de novo aneurysms that developed adjacent to the coiled aneurysms and were not detected on follow-up magnetic resonance angiography.

Conclusions: Cautious follow-up of UIAs with digital subtraction angiography is important, articularly within the first 5 years after the procedure. If there are changes in the anatomic outcomes, short-term reassessment or additional treatment should be actively considered, particularly for aneurysms in the posterior circulation.
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http://dx.doi.org/10.1016/j.wneu.2021.02.061DOI Listing
February 2021

Refractory Hypotension Caused by Selenium Deficiency in a Patient on Peritoneal Dialysis.

Intern Med 2021 Feb 15. Epub 2021 Feb 15.

Department of Nephrology, Nagoya University Graduate School of Medicine, Japan.

Selenium is essential for human health; its deficiency leads to cardiac dysfunction. We herein report a 79-year-old man on peritoneal dialysis who presented with refractory hypotension caused by selenium deficiency. He was admitted to our hospital with bacterial pneumonia and hypotension and abnormal electrocardiogram (ECG) findings. Despite improvement of pneumonia, his hypotension continued, and intravenous noradrenalin could not be discontinued. His serum selenium level was extremely low, and he was started on intravenous selenium. His hypotension and ECG findings gradually improved, and noradrenalin was discontinued. Physicians should consider selenium deficiency when patients on PD show refractory hypotension.
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http://dx.doi.org/10.2169/internalmedicine.6632-20DOI Listing
February 2021

Possibility of Worsening Flow Diversion Effect Due to Morphological Changes of a Stented Artery With Multiple Overlapping Stents for Partially Thrombosed Vertebral Artery Aneurysms.

Front Neurol 2020 15;11:611124. Epub 2020 Dec 15.

Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata, Japan.

Morphological changes of a stented artery can cause a flow diversion effect to reduce intra-aneurysmal flow; however, there is a potential for the negative effect of increased intra-aneurysmal flow. We present cases with multiple overlapping stents for a partially thrombosed vertebral artery aneurysm and characterize the hemodynamic properties of a recurrent case by focusing on the morphological changes of the stented artery. Between October 2017 and April 2019, four consecutive cases of symptomatic unruptured large and giant partially thrombosed vertebral artery aneurysms were treated with multiple overlapping low-profile visualized intraluminal support stents and no coils. Both angiographic and clinical outcomes were assessed. Computational fluid dynamics analysis was performed to clarify hemodynamic features. The degree of pressure elevation was calculated as the pressure difference (Pd). Wall shear stress (WSS) was also calculated. In three of the four cases, successful flow reduction was achieved with no morphological change of the stented arteries. The patients' symptoms were gradually improved. The remaining case required additional stents after the initial treatment. In the recurrent case, Pd was noticeably elevated at the aneurysm neck after treatment, and WSS was generally increased in the area due to altered blood flow into the aneurysm dome caused by morphological changes of the stented artery. Overlapping stents can be used for the treatment of large and giant thrombosed vertebral artery aneurysms with flow diversion effect; however, morphological changes of the stented artery requires careful attention as it may lead to an increase in the intra-aneurysmal flow, causing negative outcomes.
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http://dx.doi.org/10.3389/fneur.2020.611124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770215PMC
December 2020

Autologous non-human primate model for safety assessment of transposon-mediated chimeric antigen receptor T cells on granulocyte-macrophage colony-stimulating factor receptor.

Clin Transl Immunology 2020 22;9(11):e1207. Epub 2020 Nov 22.

Department of Pediatrics Shinshu University School of Medicine Matsumoto Japan.

Objectives: Chimeric antigen receptor (CAR)-T cell therapy redirected to specific antigens on tumor cells is a promising immunotherapy strategy for various cancers. Most target antigens are also expressed on normal tissues at varying levels, and therefore, a considerable challenge in the field is determining safety profiles, including life-threatening off-tumor and off-target toxicities. The granulocyte-macrophage colony-stimulating factor receptor (hGMR) is a promising target for CAR T-cell therapy for a subset of acute myelocytic leukaemia, although it is also expressed on normal cells including monocytes, macrophages, CD34-positive haematopoietic cells and vascular endothelial cells. hGMR and other immune-related proteins are highly conserved between humans and cynomolgus macaques (). Therefore, in this study, we engineered cynomolgus T cells to express CAR molecules redirected to hGMR by (PB) transposon-based gene transfer and adoptively transferred autologous hGMR-CAR T cells into cynomolgus macaques.

Methods: We established PB-mediated human GMR (hGMR)-specific CAR T cells using cynomolgus peripheral blood mononuclear cells and transferred them into autologous individuals, and evaluated the potential toxicity related to hGMR-CAR T cells.

Results: hGMR-CAR T cells did not exert overt organ toxicities such as bone marrow suppression, monocytopenia and vasculitis, although they recognised and killed cynomolgus monocytes and macrophages .

Conclusion: Although our model did not simulate a tumor-bearing model, it supports the safety of hGMR-CAR T cells and demonstrates the usefulness of a non-human primate model to evaluate the safety of T-cell products by assessing off-tumor/off-target toxicity before clinical trials.
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http://dx.doi.org/10.1002/cti2.1207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680920PMC
November 2020

Unilateral oculomotor nerve palsy caused by arterial compression accompanying subarachnoid hemorrhage: a case report.

Acta Neurochir (Wien) 2021 03 5;163(3):813-816. Epub 2020 Nov 5.

Department of Neurosurgery, Brain Research Institute, Niigata University, 1-757 Asahimachidori, Chuo-ku, Niigata, Niigata, 951-8585, Japan.

Unilateral oculomotor nerve palsy, often caused by aneurysmal compression, is one of the decisive findings for confirming the site of a ruptured aneurysm. However, arterial compression can also cause unilateral oculomotor nerve palsy. Here, we present the case of a 59-year-old woman with a ruptured right internal carotid-posterior communicating artery aneurysm accompanied by contralateral oculomotor nerve palsy. The nerve was found to be compressed by the posterior cerebral artery and was isolated from the ruptured aneurysm. When confirming a ruptured aneurysm based on the evidence of unilateral oculomotor palsy, the arteries surrounding the nerve must be thoroughly assessed.
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http://dx.doi.org/10.1007/s00701-020-04633-xDOI Listing
March 2021

Assessment of kidney function using inulin-based and estimated glomerular filtration rates before and after allogeneic hematopoietic stem cell transplantation in pediatric patients.

Pediatr Blood Cancer 2020 12 1;67(12):e28733. Epub 2020 Oct 1.

Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan.

Background: Accurate evaluation of kidney function before and after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is important for both informed decision making and detection of chronic kidney disease. However, to the best of our knowledge, no report has evaluated the glomerular filtration rate (GFR) in pediatric patients who underwent HSCT using the gold standard GFR measurement, as well as inulin-based GFR (iGFR).

Methods: We assessed iGFR before and after allo-HSCT to evaluate the impact of allo-HSCT on GFR in a prospective cohort study of 17 pediatric patients. We also assessed the accuracy and bias of the values of estimated GFR (eGFR) calculated using serum creatinine (Cr), cystatin C (CysC), beta-2 microglobulin (β MG), 24-h creatinine clearance (24hCcr), and the full chronic kidney disease in children (CKiD) index that combines Cr, CysC, and blood urea nitrogen-based equations with iGFR as a reference to identify the most reliable equation for GFR.

Results: There was no significant difference between the values before and after allo-HSCT. CKiD CysC-, 24hCcr-, and full CKiD-based values showed good within 30% (P30) accuracy (80.6%, 79.3%, and 80.6%, respectively), but only 24hCcr and full CKiD had good mean bias (8.5% and 8.9%, respectively) and narrow 95% limits of agreement (-32.2 to 52.7 mL/min/1.73 m and -29.3 to 47.4 mL/min/1.73 m , respectively) compared with the corresponding iGFR.

Conclusion: There was no significant impact of allo-HSCT on GFR in our cohort. The most reliable equations for pediatric patients with allo-HSCT were eGFR-24hCcr and eGFR-full CKiD.
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http://dx.doi.org/10.1002/pbc.28733DOI Listing
December 2020

Acquired Fanconi Syndrome in a Patient with Nontyphoidal Salmonella Bacteremia.

Intern Med 2021 Mar 30;60(5):761-764. Epub 2020 Sep 30.

Department of Nephrology, Nagoya University Graduate School of Medicine, Japan.

Nontyphoidal Salmonella is a common cause of bacterial gastroenteritis, occasionally causing bacteremia. We herein report the case of an 80-year-old man who presented with bacteremia and pre-renal acute kidney injury (AKI) secondary to diarrhea caused by nontyphoidal Salmonella. Despite AKI improvement on fluid administration, some serological abnormalities, such as hypokalemia, hypophosphatemia, and hypouricemia, and abnormal urinary findings emerged, including renal glycosuria and aminoaciduria. Fractional excretion of phosphate and uric acid was increased, suggesting that the serological and urinary abnormalities may have arisen from Fanconi syndrome. Physicians should consider acquired Fanconi syndrome when patients with nontyphoidal Salmonella bacteremia present with electrolyte disorders.
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http://dx.doi.org/10.2169/internalmedicine.5932-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990623PMC
March 2021

Efficacy of favipiravir for an end stage renal disease patient on maintenance hemodialysis infected with novel coronavirus disease 2019.

CEN Case Rep 2021 02 17;10(1):126-131. Epub 2020 Sep 17.

Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

Background: Novel coronavirus disease 2019 (COVID-19) refers to infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogen, and has spread to pandemic levels since its inception in December 2019. While several risk factors for severe presentation have been identified, the clinical course for end-stage renal disease (ESRD) patients on maintenance hemodialysis with COVID-19 has been unclear. Previous studies have revealed that some antiviral agents may be effective against COVID-19 in the general population, but the pharmacokinetics and pharmacodynamics of these agents in ESRD patients remain under investigation. Favipiravir, an antiviral agent developed for treatment of influenza, is one candidate treatment for COVID-19, but suitable dosages for patients with renal insufficiency are unknown. Here we provide a first report on the efficacy of favipiravir in a patient with ESRD undergoing hemodialysis.

Case Presentation: The case involved a 52-year-old woman with COVID-19 who had been undergoing maintenance hemodialysis three times a week for 3 years due to diabetic nephropathy. She had initially been treated with lopinavir/ritonavir and ciclesonide for 5 days, but developed severe pneumonia requiring invasive positive-pressure ventilation. Those antiviral agents were subsequently switched to favipiravir. She recovered gradually, and after 2 weeks was extubated once the viral load of SARS-CoV-2 fell below the limit of detection. Although concentrations of several biliary enzymes were elevated, no major adverse events were observed.

Conclusion: Favipiravir may be an effective option for the treatment of COVID-19-infected patients with ESRD.
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http://dx.doi.org/10.1007/s13730-020-00534-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494976PMC
February 2021

[Endovascular Revascularization for Acute Ischemic Stroke Related to Blunt Carotid Injury:A Case Report].

No Shinkei Geka 2020 Jun;48(6):527-532

Department of Neurosurgery, Brain Research Institute, Niigata University.

Although blunt carotid artery injury is known as an important cause of ischemic stroke, the role of the endovascular treatment for acute ischemic stroke related to blunt carotid injuries remains unclear. We report the case of a patient with acute ischemic stroke secondary to blunt carotid artery injury who was treated with endovascular revascularization. A 46-year-old man suffered from sudden left-sided hemiparesis a day after a strike from a Japanese fencing staff on his right neck. 3D-CT angiography revealed tandem internal carotid artery occlusions of the cervical and C1 portions. We performed endovascular revascularization with carotid artery stenting and direct aspiration of the thrombus and achieved complete recanalization. The patient recovered almost completely. We conclude that endovascular revascularization should not be withheld from patients with acute ischemic stroke related to blunt carotid injury.
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http://dx.doi.org/10.11477/mf.1436204223DOI Listing
June 2020

Transfusion outcome for volume- and plasma-reduced platelet concentrates for pediatric patients.

Transfus Apher Sci 2020 Aug 18;59(4):102776. Epub 2020 May 18.

Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan.

Background And Objectives: Plasma reduction in platelet concentrate (PC) products has been reported to prevent large volume load and transfusion-related adverse reactions (TRARs). However, volume reduction might be associated with a poor transfusion response because of a deterioration in platelet (PLT) quality. Because PLT quality control and transfusion responses for recently washed PCs using PLT additive solutions are superior, we investigated the clinical safety and transfusion efficacy of volume-reduced washed PCs in pediatric patients.

Materials And Methods: We prepared a simplified resuspended PC product (RPC) as a washed PC. Regular RPC (R-RPC) included equivalent volumes of bicarbonate Ringer's solution and anticoagulant citrate dextrose solution A (BRS-A) as the resuspension solution. Half RPC (H-RPC) was prepared by adding a half volume of BRS-A. Twenty-four pediatric patients were scheduled for transfusions with R-RPC and H-RPC up to 4 times. R-RPC was transfused 42 times into 24 patients. H-RPC was transfused 41 times into 23 patients.

Results: Neither product was observed to cause TRARs. Although the calculated PLT recovery for H-RPC was significantly reduced, the posttransfusion corrected count increment (24 h) did not differ. Moreover, similar results were observed for vital signs during transfusion.

Conclusion: Volume-reduced washed PC can be transfused without causing TRARs, differences in vital signs, or inferior transfusion responses. Volume-reduced washed PC also provides the advantages of shortened transfusion times and reduced volume loads. Although a standard technique for stable resuspension is necessary, volume-reduced washed PC may be a beneficial option for children, including neonates, or individuals with cardiovascular or renal problems.
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http://dx.doi.org/10.1016/j.transci.2020.102776DOI Listing
August 2020

Inactivation of REV7 enhances chemosensitivity and overcomes acquired chemoresistance in testicular germ cell tumors.

Cancer Lett 2020 10 15;489:100-110. Epub 2020 Jun 15.

Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan. Electronic address:

REV7 is a multitasking protein involved in replication past DNA lesions, cell cycle regulation, and gene expression. REV7 is highly expressed in the adult testis and plays an essential role in primordial germ cell maintenance in mice. In this study, we analyzed whether REV7 can be a molecular target for the treatment of testicular germ cell tumors (TGCTs), in which acquired chemoresistance is a major cause of treatment failure. Strong expression of REV7 was detected in human TGCT tissues by immunohistochemistry. REV7 depletion in the TGCT cell lines suppressed cell proliferation and increased sensitivity to cisplatin and doxorubicin. cDNA microarray analysis revealed that REV7 depletion downregulated genes in the DNA repair gene set and upregulated genes in the apoptosis gene set. REV7 depletion-provoked chemosensitivity was associated with DNA double-strand break accumulation and apoptosis activation. In addition, inactivation of REV7 in cisplatin-resistant TGCT cells recovered chemosensitivity at almost equal levels as parental cells in vitro and in vivo. Our results indicate that inactivation of REV7 enhances chemosensitivity and overcomes chemoresistance in TGCT cells, suggesting REV7 as a potential therapeutic target in chemoresistant TGCTs.
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http://dx.doi.org/10.1016/j.canlet.2020.06.001DOI Listing
October 2020

Safety and feasibility of the distal transradial approach: A novel technique for diagnostic cerebral angiography.

Interv Neuroradiol 2020 Dec 13;26(6):713-718. Epub 2020 May 13.

Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata, Japan.

Purpose: We aimed to evaluate the safety and feasibility of the distal transradial approach (DTRA) as a novel technique for cerebral angiography based on our institutional initial experience.

Methods: We retrospectively analyzed our institutional database of consecutive diagnostic cerebral angiographies performed with DTRA from December 2018 to August 2019. Patient demographics and clinical and procedural data were recorded.

Results: In total, 51 diagnostic cerebral angiographies in 51 patients (age, 15-83 years; mean age, 59.4 years, SD 13.5; 35 (69%) females) were performed or attempted with DTRA. Ultrasound evaluation showed that the mean inner distal radial artery diameter was significantly smaller than the mean inner forearm radial artery diameter (2.19 mm vs. 2.56 mm, P < 0.001). Cannulation via the distal radial artery was successful in 47 (92%) procedures. In the four procedures that failed, operators converted to the ipsilateral transradial approach without repositioning or redraping. Selective catheterization of the intended vessel was achieved in 64 (91%) of 70 vessels. In the remaining six, operators achieved the objective of the examination with angiography injecting from proximal and conversion to another approach was not required. One patient experienced temporary numbness around the puncture site after the procedure. No radial artery occlusion was identified in the patients who underwent ultrasound evaluation.

Conclusion: Our results demonstrate that DTRA could become a standard approach for diagnostic cerebral angiography owing to the low complication rate and the high cannulation success rate.
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http://dx.doi.org/10.1177/1591019920925709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724605PMC
December 2020

Successful Introduction of Peritoneal Dialysis in an End-stage Renal Failure Patient with Idiopathic Aplastic Anemia.

Intern Med 2020 1;59(5):683-687. Epub 2020 Mar 1.

Department of Nephrology and Rheumatology, Aichi Medical University, Japan.

A 45-year-old man with idiopathic aplastic anemia required renal replacement therapy (RRT) due to end-stage renal disease (ESRD). We succeeded in inserting the peritoneal dialysis (PD) catheter under cover of frequent red blood cell and platelet infusions because of severe pancytopenia. During the one-year period after starting PD using an ultraviolet-ray sterilization device, he developed severe leukopenia but no PD-related peritonitis or exit site/tunnel infection until he died of pneumonia. This case suggests that PD might be a suitable choice as RRT in ESRD patients with aplastic anemia, even in those with severe pancytopenia.
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http://dx.doi.org/10.2169/internalmedicine.3775-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086332PMC
August 2020

Thyroid tumor surveillance using ultrasound in childhood cancer survivors.

Pediatr Int 2020 May;62(5):562-568

Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan.

Background: The optimal method for thyroid cancer screening in childhood cancer survivors (CCSs) who received radiation involving the thyroid gland is still debated. We describe a case series of ultrasound surveillance for thyroid tumor in CCSs in our institute.

Methods: We conducted thyroid tumor surveillance for CCSs with a history of radiation therapy involving the thyroid. The basic screening method was palpation. Thyroid ultrasound was also performed for patients who agreed after its benefits and risks were explained to them. We surveyed CCSs who visited the long-term follow-up outpatient clinic in our institution between October 2014 and September 2018.

Results: Of 82 CCSs who visited our institution during the study period, 44 were eligible for inclusion. None had a mass identified by palpation. Thyroid ultrasound was performed in 39 CCSs, and we identified thyroid nodules in 27. Four patients had a nodule with malignant echo features. Two of these cases received biopsies, and one patient was ultimately diagnosed with an early stage thyroid carcinoma.

Conclusions: Childhood cancer survivors irradiated in the thyroid had a higher prevalence of thyroid nodules than the general population. Ultrasound screening contributed to early detection of impalpable thyroid cancer and enabled us to perform minimal surgery. Thus, ultrasound appears to be a useful option for secondary thyroid cancer screening. The thyroid tumor surveillance modality should be considered according to the individual case, and the patient must receive a clear explanation of the benefits and risks. These results could help doctors consider how to screen for secondary thyroid cancer.
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http://dx.doi.org/10.1111/ped.14179DOI Listing
May 2020

Comparative analysis of graft-versus-host disease prophylaxis with tacrolimus in combination with methylprednisolone or methotrexate after umbilical cord blood transplantation.

Int J Hematol 2020 May 18;111(5):702-710. Epub 2020 Jan 18.

Department of Pediatrics, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan.

Post-transplant early immune disorders and engraftment failure/delay are major issues in unrelated umbilical cord blood transplantation (UCBT). We evaluated graft-versus-host disease (GVHD) prophylaxis approaches after UCBT by comparing UCBT outcomes with GVHD prophylaxis using tacrolimus plus methylprednisolone (Tac/mPSL, n = 32) to that with Tac plus methotrexate (Tac/MTX, n = 31) at a single pediatric transplantation center. The 30-day cumulative incidence rates of neutrophil engraftment and median neutrophil engraftment times in the Tac/mPSL and Tac/MTX groups were 70.1% and 90.3% and 19 and 17 days, respectively (p = 0.09). Pre-engraftment immune reactions (PIR) and acute GVHD were improved with Tac/MTX; PIR incidence (p = 0.020) and cumulative incidence of 100-day acute GVHD (grade II-IV, 38.7% vs 68.8%, p = 0.045; grade III-IV, 9.7% vs 34.4%, p = 0.021) were significantly lower in the Tac/MTX group than in the Tac/mPSL group. However, the incidence rates of relapse (p = 0.921) and cytomegalovirus reactivation (p = 0.908), and the estimated overall (p = 0.87) and event-free survival (p = 0.88) were comparable between the two groups. These data indicate that GVHD prophylaxis with Tac/MTX is associated with favorable results, including reduced PIR and acute GVHD incidence after UCBT, without adverse effects.
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http://dx.doi.org/10.1007/s12185-020-02826-9DOI Listing
May 2020

Prophylactic piperacillin administration in pediatric patients with solid tumors following different intensities of chemotherapy.

Pediatr Int 2020 Feb;62(2):158-168

Department of Hematology and Oncology, Nagano Children's Hospital, Azumino, Japan.

Background: Prophylactic antibiotics decrease mortality and morbidity in patients with hematological malignancies following intensive chemotherapy. However, the efficacy of prophylactic antibiotics for pediatric patients with solid tumors remains unclear.

Methods: We retrospectively assessed 103 neutropenic periods from 26 patients with neuroblastoma or brain tumors following three different intensity chemotherapy regimens (05A3, A, and B). While piperacillin was intravenously administered as prophylaxis (PIPC prophylaxis group), the historical control group received no prophylaxis. As patients exhibited a variable degree of myelosuppression based on the intensity of the chemotherapy regimen, we separately evaluated the frequency and severity of febrile neutropenia (FN) in each regimen.

Results: Following intensive chemotherapy, we observed a significantly lower frequency of FN in the PIPC prophylaxis group compared with the historical control group in both regimen 05A3 (20% vs 65%; P = 0.01) and regimen A (56% vs 93%; P = 0.02). We also observed a shorter duration of fever, lower maximum fever, and lower C-reactive protein levels in the PIPC prophylaxis group compared with the historical control group after regimens 05A3 and A. Conversely, the frequency and severity of FN were not different between the two groups after moderate-intensity chemotherapy (regimen B). However, a longitudinal routine surveillance study of Pseudomonas aeruginosa also indicated a reduction in the susceptibility to PIPC throughout the study period.

Conclusions: Although PIPC prophylaxis might provide an advantage for severe neutropenia in pediatric patients with solid tumors, there is concern regarding bacterial resistance to antibiotics. Therefore, further careful examination is necessary for adaptation.
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http://dx.doi.org/10.1111/ped.14103DOI Listing
February 2020

Multiple heterogeneous bone invasions of B lymphoblastic lymphoma with the TCF3/PBX1 fusion gene: a case report.

Int J Hematol 2020 Feb 11;111(2):163-165. Epub 2019 Dec 11.

Department of Pediatrics, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan.

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http://dx.doi.org/10.1007/s12185-019-02794-9DOI Listing
February 2020

Dramatic response of BRAF V600E-mutant epithelioid glioblastoma to combination therapy with BRAF and MEK inhibitor: establishment and xenograft of a cell line to predict clinical efficacy.

Acta Neuropathol Commun 2019 07 25;7(1):119. Epub 2019 Jul 25.

From the Departments of Neurosurgery, Niigata University, 1-757 Asahimachidori, Chuo-ku, Niigata, Japan.

Epithelioid glioblastoma is a rare aggressive variant of glioblastoma (GBM) characterized by a dismal prognosis of about 6 months and frequent leptomeningeal dissemination. A recent study has revealed that 50% of epithelioid GBMs harbor three genetic alterations - BRAF V600E mutation, TERT promoter mutations, and homozygous deletions of CDKN2A/2B. Emerging evidence support the effectiveness of targeted therapies for brain tumors with BRAF V600E mutation. Here we describe a dramatic radiographical response to combined therapy with BRAF and MEK inhibitors in a patient with epithelioid GBM harboring BRAF V600E mutation, characterized by thick spinal dissemination. From relapsed tumor procured at autopsy, we established a cell line retaining the BRAF V600E mutation, TERT promoter mutation and CDKN2A/2B loss. Intracranial implantation of these cells into mice resulted in tumors closely resembling the original, characterized by epithelioid tumor cells and dissemination, and invasion into the perivascular spaces. We then confirmed the efficacy of treatment with BRAF and MEK inhibitor both in vitro and in vivo. Epithelioid GBM with BRAF V600E mutation can be considered a good treatment indication for precision medicine, and this patient-derived cell line should be useful for prediction of the tumor response and clarification of its biological characteristics.
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http://dx.doi.org/10.1186/s40478-019-0774-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659204PMC
July 2019

Relationships between docosahexaenoic acid compositions of maternal and umbilical cord erythrocytes in pregnant Japanese women.

Prostaglandins Leukot Essent Fatty Acids 2019 08 12;147:1-5. Epub 2019 Apr 12.

Department of Development and Environmental Medicine, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.

Previous reports have shown that the transfer of docosahexaenoic acid (DHA) from mother to fetus during pregnancy is important for development of the child's nervous and visual functions. The amount of DHA passing through the placenta varies depending on the relative DHA compositions of the erythrocytes in the maternal blood and the umbilical cord. Prior research has reported that if the DHA composition of the maternal erythrocytes is over 5.6 g%, DHA in the erythrocytes of the child undergoes bioattenuation, whereas it undergoes biomagnification if the maternal erythrocyte composition is lower than 5.6 g%. The relationship between DHA levels in maternal erythrocytes during pregnancy and in umbilical cord erythrocytes at delivery was assessed in Japanese pregnant women. This study was performed as an adjunct study of the Japan Environment and Children's Study. DHA compositions of maternal erythrocytes at 24-30 weeks of pregnancy and of umbilical cord erythrocytes at delivery were determined in 1368 mother-infant pairs. Median DHA values were 7.41% in the maternal erythrocytes and 6.84% in the umbilical cord erythrocytes, indicating significantly lower levels in the umbilical cord. When DHA composition in maternal erythrocytes was lower than 6.6%, DHA was theoretically higher in umbilical cord erythrocytes than in maternal erythrocytes. Conversely, when DHA composition in maternal erythrocytes was higher than 6.6%, DHA in umbilical cord erythrocytes was theoretically lower than in maternal erythrocytes. We therefore consider that there is a turning point of around 6% in the DHA composition of maternal and umbilical cord blood that is exchanged between mother and fetus: if the composition in the maternal blood is higher, then bioattenuation in DHA transfer from the maternal circulation to the umbilical cord occurs, while if it is lower, then biomagnification occurs. This corroborates the findings of previous research.
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http://dx.doi.org/10.1016/j.plefa.2019.04.004DOI Listing
August 2019

Treatment Strategies for Infectious Intracranial Aneurysms: Report of Three Cases and Review of the Literature.

Neurol Med Chir (Tokyo) 2019 Sep 4;59(9):344-350. Epub 2019 Jul 4.

Department of Neurosurgery, Brain Research Institute, Niigata University.

We retrospectively reviewed the cases of three patients with infectious intracranial aneurysms (IIAs), and discuss the indications for surgical and endovascular treatments. We treated two men and one woman with a total of six aneurysms. The mean age was 43.3 years, ranging from 36 to 51 years. One patient presented initially with an intraparenchymal hemorrhage, one with mass effect, and the other one had four aneurysms (one causing subarachnoid hemorrhages and the other causing delayed intraparenchymal hemorrhages). The average size of all aneurysms was 12.2 mm (range, 2-50 mm). They were preferentially located in the distal posterior cerebral artery, and then, in the middle cerebral artery. All cases were caused by infective endocarditis. We selected endovascular treatments for five aneurysms and treated all but one within 24 h from detection. One aneurysm was treated by combined therapy with endovascular intervention and surgery. After treatment, none of the IIAs presented angiographical recurrence or re-bleeding. If feasible, endovascular treatment is probably the first choice, but a combined surgical and endovascular approach should be considered if surgery or endovascular treatment alone are not feasible. The method of treatment should be individualized. For cases with high risk of aneurysm rupture, treatment should be performed as soon as possible.
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http://dx.doi.org/10.2176/nmc.oa.2019-0051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753255PMC
September 2019

Roles of the Mesenchymal Stromal/Stem Cell Marker Meflin in Cardiac Tissue Repair and the Development of Diastolic Dysfunction.

Circ Res 2019 08 21;125(4):414-430. Epub 2019 Jun 21.

From the Department of Pathology (A.H., H.K., N.A., Y. Mizutani, Y. Miyai, S. Mii, M. Takahashi, A.E.), Nagoya University Graduate School of Medicine, Japan.

Rationale: Myofibroblasts have roles in tissue repair following damage associated with ischemia, aging, and inflammation and also promote fibrosis and tissue stiffening, causing organ dysfunction. One source of myofibroblasts is mesenchymal stromal/stem cells that exist as resident fibroblasts in multiple tissues. We previously identified meflin (mesenchymal stromal cell- and fibroblast-expressing Linx paralogue), a glycosylphosphatidylinositol-anchored membrane protein, as a specific marker of mesenchymal stromal/stem cells and a regulator of their undifferentiated state. The roles of meflin in the development of heart disease, however, have not been investigated.

Objective: We examined the expression of meflin in the heart and its involvement in cardiac repair after ischemia, fibrosis, and the development of heart failure.

Methods And Results: We found that meflin has an inhibitory role in myofibroblast differentiation of cultured mesenchymal stromal/stem cells. Meflin expression was downregulated by stimulation with TGF (transforming growth factor)-β, substrate stiffness, hypoxia, and aging. Histological analysis revealed that meflin-positive fibroblastic cells and their lineage cells proliferated in the hearts after acute myocardial infarction and pressure-overload heart failure mouse models. Analysis of meflin knockout mice revealed that meflin is essential for the increase in the number of cells that highly express type I collagen in the heart walls after myocardial infarction induction. When subjected to pressure overload by transverse aortic constriction, meflin knockout mice developed marked cardiac interstitial fibrosis with defective compensation mechanisms. Analysis with atomic force microscopy and hemodynamic catheterization revealed that meflin knockout mice developed stiff failing hearts with diastolic dysfunction. Mechanistically, we found that meflin interacts with bone morphogenetic protein 7, an antifibrotic cytokine that counteracts the action of TGF-β and augments its intracellular signaling.

Conclusions: These data suggested that meflin is involved in cardiac tissue repair after injury and has an inhibitory role in myofibroblast differentiation of cardiac fibroblastic cells and the development of cardiac fibrosis.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.314806DOI Listing
August 2019

Ovarian function after allogeneic hematopoietic stem cell transplantation in children and young adults given 8-Gy total body irradiation-based reduced-toxicity myeloablative conditioning.

Pediatr Transplant 2019 05 3;23(3):e13372. Epub 2019 Feb 3.

Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan.

Background: The spectrum of late sequelae after hematopoietic stem cell transplantation (HSCT) includes infertility, which is the most frequent complication. Some reports suggested that ovarian function may be better preserved in females undergoing HSCT with reduced-intensity conditioning (RIC) than with conventional myeloablative conditioning (MAC). However, the impact of HSCT after 8-Gy TBI-based reduced-toxicity MAC (RTMAC), whose efficacy is between those of conventional MAC and RIC, on ovarian function remains unclear.

Procedure: A single-center retrospective analysis of data derived from patient information for all the children who underwent transplantation at the Shinshu University Hospital was carried out. Patients who underwent 8-Gy total body irradiation (TBI)-based RTMAC before HSCT were analyzed.

Results: A total of 36% (five of 14) of the patients developed primary ovarian insufficiency (POI) during the observation period, but serum follicle-stimulating hormone levels reduced to normal range with spontaneous menstruation in two, implying the reversal of POI. Furthermore, only one (10%) of the 10 prepubertal patients (71%; 10/14) at the time of HSCT suffered from POI at the last observation, but all three post-pubertal patients developed POI (100%), and two (67%) continued to suffer from POI at the last observation.

Conclusions: Taken together, 8-Gy TBI-based RTMAC before HSCT may decrease the possibility of POI compared with conventional MAC, especially in prepubertal patients. A longer follow-up will be required to ascertain whether a normal pregnancy and delivery can occur in such patients.
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http://dx.doi.org/10.1111/petr.13372DOI Listing
May 2019

Lymphadenopathy with coexisting normal architecture in malignant lymphoma.

Int J Hematol 2018 11 6;108(5):463-464. Epub 2018 Sep 6.

Department of Hematology and Oncology, Nagano Children's Hospital, 3100 Toyoshina, Azumino, 399-8288, Japan.

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http://dx.doi.org/10.1007/s12185-018-2530-3DOI Listing
November 2018

High-fidelity CRISPR/Cas9- based gene-specific hydroxymethylation rescues gene expression and attenuates renal fibrosis.

Nat Commun 2018 08 29;9(1):3509. Epub 2018 Aug 29.

German Center for Cardiovascular Research (DZHK) Partner Site, Göttingen, Germany.

While suppression of specific genes through aberrant promoter methylation contributes to different diseases including organ fibrosis, gene-specific reactivation technology is not yet available for therapy. TET enzymes catalyze hydroxymethylation of methylated DNA, reactivating gene expression. We here report generation of a high-fidelity CRISPR/Cas9-based gene-specific dioxygenase by fusing an endonuclease deactivated high-fidelity Cas9 (dHFCas9) to TET3 catalytic domain (TET3CD), targeted to specific genes by guiding RNAs (sgRNA). We demonstrate use of this technology in four different anti-fibrotic genes in different cell types in vitro, among them RASAL1 and Klotho, both hypermethylated in kidney fibrosis. Furthermore, in vivo lentiviral delivery of the Rasal1-targeted fusion protein to interstitial cells and of the Klotho-targeted fusion protein to tubular epithelial cells each results in specific gene reactivation and attenuation of fibrosis, providing gene-specific demethylating technology in a disease model.
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http://dx.doi.org/10.1038/s41467-018-05766-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115451PMC
August 2018

Therapeutic efficacy of rituximab for the management of adult-onset steroid-dependent nephrotic syndrome: a retrospective study.

Clin Exp Nephrol 2019 Feb 18;23(2):207-214. Epub 2018 Aug 18.

Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background: Recent reports have described the efficacy of rituximab in treating steroid-dependent nephrotic syndrome (SDNS) in pediatric patients. However, few reports describe data regarding adult-onset SDNS. We investigated the efficacy of rituximab for the management of adult-onset SDNS.

Methods: We performed a retrospective cohort study investigating eight patients with adult-onset SDNS who were treated with rituximab. Clinical data were obtained at the initiation of rituximab therapy. The primary outcomes evaluated were successful suppression of relapses and CD19+ cells after rituximab treatment. The corticosteroid- and immunosuppressant-sparing effect and adverse events were additionally evaluated.

Results: All eight patients were diagnosed with minimal change nephrotic syndrome and received immunosuppressants in addition to corticosteroid. Total number of relapses was 10.5 times as a median value. Rituximab administration was repeated in two patients, whereas six received single-dose rituximab. Three of eight (37.5%) patients showed relapse after rituximab therapy. A rituximab-induced depletion in CD19+ cells noted initially was followed by their reappearance in all patients. There were cases with no relapse after the reappearance of CD19+ cells. The median relapse time pre- and post-rituximab therapy showed a decrease from 1 time/year (interquartile range [IQR] 1-3 times/year) to 0 time/year (IQR 0-1 time/year). Rituximab treatment induced a significant reduction in the required doses of corticosteroid and cyclosporine (P < 0.01). No serious adverse events were observed.

Conclusion: Rituximab treatment was effective not only in childhood-onset but also in adult-onset SDNS. Further studies are needed to establish optimal treatment regimens.
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http://dx.doi.org/10.1007/s10157-018-1630-yDOI Listing
February 2019