Publications by authors named "Ryoji Kobayashi"

212 Publications

Cryopreservation of Unrelated Hematopoietic Stem Cells from a Blood and Marrow Donor Bank During the COVID-19 Pandemic: A Nationwide Survey by the Japan Marrow Donor Program.

Transplant Cell Ther 2021 May 5. Epub 2021 May 5.

Japan Marrow Donor Program, Aichi Medical University School of Medicine, Nagakute, Japan.

During the COVID-19 pandemic, donor hematopoietic stem cell grafts are frequently cryopreserved to ensure the availability of graft before starting a conditioning regimen. However, the safety of cryopreservation has been controversial in unrelated hematopoietic stem cell transplantation (HSCT), especially for bone marrow (BM) grafts. In addition, in unrelated HSCT, the effect of the time from harvest to cryopreservation of donor grafts required for the transportation of donor graft has not been fully clarified. In this study, we retrospectively analyzed the first 112 patients with available data who underwent cryopreserved unrelated blood and marrow transplantation through the Japan Marrow Donor Program during the COVID-19 pandemic. There were 112 patients, including 83 who received BM grafts and 29 who received peripheral blood stem cell (PBSC) grafts. The median time from stem cell harvest to cryopreservation was 9.9 hours (range, 2.6 to 44.0 hours), and the median time from cryopreservation to infusion was 231.2 hours. The incidence of neutrophil engraftment at day 28 after HSCT was 91.1%, and among 109 patients (excluding 3 patients with early death), all but 1 patient achieved neutrophil engraftment within 60 days after HSCT. The time to neutrophil engraftment and time to platelet engraftment were shorter in PBSC transplantation compared with BM transplantation (BMT), but the differences were not statistically significant (P = .064 and .18). Multivariate analysis among BM recipients revealed that a higher number of frozen nucleated cells and the absence of HLA mismatch were associated with faster neutrophil engraftment. The time to neutrophil engraftment after unrelated cryopreserved BMT was not different from that after unrelated BMT without cryopreservation. Our findings suggest that unrelated donor BM and PBSC grafts can be safely cryopreserved even after transit from the harvest center to the transplantation center. In the current COVID-19 pandemic, cryopreservation can be considered as an option while balancing the risks and benefits of the procedure.
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http://dx.doi.org/10.1016/j.jtct.2021.04.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098035PMC
May 2021

Paranasal sinusitis at the initiation of chemotherapy is a risk factor for invasive fungal disease in children and adolescents with cancer.

Support Care Cancer 2021 Mar 22. Epub 2021 Mar 22.

Department of Hematology/Oncology for Children and Adolescents, Sapporo Hokuyu Hospital, Higashi-Sapporo 6-6, Shiroishi-ku, Sapporo, Hokkaido, 003-0006, Japan.

Background: The impact of paranasal sinusitis on the clinical outcome of patients with cancer remains unknown. The aim of this study was to determine whether paranasal sinusitis at the initiation of chemotherapy (SAI) affects the development of infectious complications in children and adolescents with cancer.

Methods: A retrospective cohort analysis of patients aged 0-20 years with cancer who received chemotherapy was performed. SAI was defined as the presence of a fluid level or mucosal swelling or total opacity on sinus computed tomography examination before the initiation of chemotherapy. The primary outcome measures were the incidence of bacteremia, septic shock, and invasive fungal disease (IFD, including proven, probable, and possible cases).

Results: SAI was observed in 57 (44%) of 130 enrolled patients. There were no significant differences in age, sex, and disease distribution between the patients with SAI (SAI group) and those without (non-SAI group). There was no significant difference in the 1-year cumulative incidence of bacteremia or septic shock after treatment initiation between the two groups (bacteremia, SAI group 33% vs. non-SAI group 35%, P = 0.53; septic shock, SAI group 4% vs. non-SAI group 4%, P = 0.87). The 1-year cumulative incidence of IFD was higher in the SAI group than in the non-SAI group (22% vs. 6%, P = 0.012). Cumulative incidence analysis after inverse probability of treatment weighting adjustment showed that the SAI group was more likely to develop IFD (HR: 3.5, 95% CI: 1.1-11.2, P = 0.033).

Conclusions: Our findings suggest that patients with SAI may be at higher risk for IFD during chemotherapy.
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http://dx.doi.org/10.1007/s00520-021-06143-7DOI Listing
March 2021

Risk factors for delayed elimination of high-dose methotrexate in childhood acute lymphoblastic leukemia and lymphoma.

Int J Hematol 2021 May 3;113(5):744-750. Epub 2021 Jan 3.

Department of Hematology/Oncology for Children and Adolescents, Sapporo Hokuyu Hospital, Higashi-Sapporo 6-6, Shiroishi-ku, Sapporo, 003-0006, Japan.

High-dose methotrexate (HD-MTX) therapy is widely used in patients with acute lymphoblastic leukemia (ALL) and lymphoma. However, some patients experience delayed MTX elimination, which requires treatment suspension or dose reduction to avoid organ damage. This single-center retrospective analysis reviewed the clinical data of 88 children with ALL or non-Hodgkin lymphoma who received a total of 269 courses of HD-MTX therapy between April 2008 and April 2019. HD-MTX was defined as MTX administration at 2.0, 3.0, or 5.0 g/m over a 24-h period, and delayed MTX elimination was defined as a serum MTX concentration ≥ 1.0 µmol/L at 48 h after the start of HD-MTX. Clinical factors were compared between courses with and without delayed MTX elimination. MTX elimination was delayed in 21 of the 269 courses (7.8%). Multivariate analysis showed that first HD-MTX course (OR 4.04), lower urine volume per BSA on the first day of HD-MTX administration (< 2,675 mL/m, OR 5.10), higher total bilirubin (> 0.5 mg/dL, OR 5.11), lower eGFR (< 136 mL/min/1.73 m, OR 3.90), higher dose of MTX(> 3.0 g/m, OR 10.8), and lower urine volume per BSA on the next day of starting HD-MTX (< 2,107 mL/m, OR 3.43) were independent risk factors for delayed MTX elimination.
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http://dx.doi.org/10.1007/s12185-020-03071-wDOI Listing
May 2021

Meropenem versus piperacillin/tazobactam for febrile neutropenia in pediatric patients: efficacy of piperacillin/tazobactam as a 1-h drip infusion four times a day.

Int J Hematol 2021 Mar 10;113(3):430-435. Epub 2020 Nov 10.

Department of Hematology/Oncology for Children and Adolescents, Sapporo Hokuyu Hospital, 6-6 Higashi-Sapporo, Shiroishiku, Sapporo, 003-0006, Japan.

Although survival of children with hematological diseases and cancer has increased dramatically, febrile neutropenia (FN) is a frequently observed complication and is sometimes life-threatening in pediatric cancer patients. A prospective, randomized study was performed to clarify the usefulness of meropenem (MEPM) and piperacillin/tazobactam (PIPC/TAZ) for pediatric patients with FN. Ninety-nine patients with 394 episodes were randomly assigned to receive MEPM or PIPC/TAZ. MEPM was administered at 120 mg/kg/day as a 1-h drip infusion 3 times a day. On the other hand, PIPC/TAZ was administered at 360 mg/kg/day as a 1-h drip infusion 4 times a day. MEPM was effective in 69.5% of the 200 episodes, and PIPC/TAZ was effective in 77.2% of the 193 episodes. Compared with our previous study of MEPM 120 mg/kg/day as a 1-h drip infusion 3 times a day versus PIPC/TAZ 337.5 mg/kg/day as a 1-h drip infusion 3 times a day, the success rate of the MEPM group was not different. However, the success rate of the PIPC/TAZ group was higher than in the previous study (p = 0.001). In particular, the success rate in patients ≥ 15 years of age was improved in the PIPC/TAZ group of the present study compared with the previous study (p = 0.005).
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http://dx.doi.org/10.1007/s12185-020-03031-4DOI Listing
March 2021

A survey of hypercalciuria during chemotherapy in acute lymphoblastic leukemia.

Pediatr Int 2020 Oct 30. Epub 2020 Oct 30.

Department of Hematology/Oncology for Children and Adolescents, Sapporo Hokuyu Hospital, Sapporo, Japan.

Background: Urolithiasis is an extremely rare complication in childhood acute lymphoblastic leukemia (ALL), and some reports have implicated corticosteroids during chemotherapy as a risk factor for it. However, only a few reports have analyzed urinary electrolytes in this context.

Methods: We retrospectively analyzed 55 patients with ALL who underwent chemotherapy between October 2007 and January 2019. Median age was 9.3 years (range, 0.3 - 24.0 years) with 30 males and 25 females. Lineages were B-cell precursor ALL (BCP-ALL) in 42 patients, T-cell in 9 and others in 4 patients. All patients received chemotherapy based on the Berlin-Frankfurt-Münster (BFM) regimen.

Results: Forty-nine out of the 55 ALL patients exhibited hypercalciuria at least once during chemotherapy. Moreover, 36 patients with BCP-ALL who were receiving identical BFM-based regimens exhibited significantly high urinary calcium excretion immediately following high-dose glucocorticoid administration. Among the 55 ALL patients, urolithiasis was observed in one patient, a six-year-old boy with BCP-ALL who developed urolithiasis at reinduction chemotherapy just after cessation of high-dose dexamethasone administration.

Conclusions: Nearly 90% of the ALL patients studied developed hypercalciuria during chemotherapy in strong association with corticosteroid administration.
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http://dx.doi.org/10.1111/ped.14527DOI Listing
October 2020

Comparison of myelosuppression using the D-index between children and adolescents/young adults with acute lymphoblastic leukemia during induction chemotherapy.

Pediatr Blood Cancer 2021 02 13;68(2):e28763. Epub 2020 Oct 13.

Department of Hematology/Oncology for Children and Adolescents, Sapporo Hokuyu Hospital, Sapporo, Japan.

Background: Adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) are more likely to have chemotherapy-related complications than children. In addition, several reports have shown that infections account for most of the therapy-related mortality during cancer treatment in AYAs. Thus, we hypothesized that chemotherapy-induced myelosuppression is more severe in AYAs than in children, and the state of neutropenia was compared between children and AYAs using the D-index, a numerical value calculated from the duration and depth of neutropenia.

Procedure: This study retrospectively analyzed 95 patients newly diagnosed with ALL at our institution between 2007 and 2019. Of these, 81 were children (<15 years old) and 14 were AYAs (≥15 years old). The D-index and duration of neutropenia during induction chemotherapy for ALL were compared between children and AYAs.

Results: The median D-index of children was significantly higher than that of AYAs (8187 vs 6446, respectively, P = .017). Moreover, the median duration of neutropenia was also significantly longer in children than in AYAs (24.0 days vs 11.5 days, respectively, P = .007).

Conclusion: Contrary to our expectations, myelosuppressive toxicity during induction chemotherapy for ALL was more severe in children than in AYAs.
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http://dx.doi.org/10.1002/pbc.28763DOI Listing
February 2021

Efficacy of liposomal amphotericin against febrile neutropenia in pediatric patients receiving prophylactic voriconazole.

Pediatr Int 2021 May 27;63(5):550-555. Epub 2021 Mar 27.

Department of Hematology/Oncology for Children and Adolescents, Sapporo Hokuyu Hospital, Sapporo, Japan.

Background: The risk factors for invasive fungal infection have gradually become evident for pediatric patients with hematological diseases. Here we analyze the efficacy of liposomal amphotericin (L-AMB) for pediatric patients with febrile neutropenia using prophylactic voriconazole (VRCZ).

Method: We administered L-AMB (2.5 mg/kg/day) in patients with febrile neutropenia who were receiving prophylactic VRCZ (10 mg/kg/day, orally) and were resistant to second-line antibiotics therapy. Thirteen patients (5 males, 8 females) with 19 febrile neutropenia episodes were targeted in this analysis. The median age of the patients was 14 years (range, 1-19 years). Eighteen out of 19 episodes occurred in patients with acute myeloid leukemia, with the remaining episode occurring in a patient with acute unclassified leukemia.

Results: The median period from start of L-AMB administration to resolution of fever was 4 days (1-27 days). In 15 out of 19 episodes, fever resolved within 5 days from commencement of L-AMB administration. Using criteria proposed by T. J. Walsh et al., the success rate of L-AMB for febrile neutropenia was 89.5% in this study.

Conclusions: Although the sample size of our study was small, the extremely high efficacy of L-AMB warrants its administration in patients with febrile neutropenia who are receiving VRCZ.
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http://dx.doi.org/10.1111/ped.14450DOI Listing
May 2021

Analysis of antibiotics discontinuation during bone marrow suppression in childhood, adolescent and young adult patients with febrile neutropenia.

J Microbiol Immunol Infect 2020 Aug 6. Epub 2020 Aug 6.

Department of Hematology/Oncology for Children and Adolescents, Sapporo Hokuyu Hospital, Japan.

Background: Antibiotics have been widely and efficaciously used for febrile neutropenia in pediatric patients. However, reports are scant regarding the risk factors for recurrent fever after discontinuation of antibiotics in a neutropenic state. Here, we investigated these factors using data from our previously reported randomized study regarding meropenem and piperacillin/tazobactam for pediatric patients with febrile neutropenia.

Procedure: We analyzed a total of 170 febrile episodes where first line antibiotic treatment was effective and discontinued before neutrophil recovery.

Results: Recurrent fever was observed in 31 episodes (18%). The median interval from antibiotics discontinuation to recurrent fever was 5 days (0-27 days). Risk factors for recurrent fever were: incomplete remission of original disease; and high white blood cell count, neutrophil count, and C reactive protein levels at start of antibiotics. Moreover, lower neutrophil count at discontinuation of antibiotics, duration of neutropenia, and onset day of febrile neutropenia from start of neutropenia were also risk factors of recurrent fever. In multivariate analysis, neutrophil count at discontinuation of antibiotics <0.011 × 10/L, neutrophil count at start of antibiotics ≥0.061 × 10/L, febrile onset following <1 day after onset of neutropenia, and incomplete remission of original disease were independent risk factors for recurrent fever.

Conclusions: Discontinuation of antibiotics while pediatric patients were still neutropenic was almost safe. However, physicians should note the risk factors of recurrent fever.
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http://dx.doi.org/10.1016/j.jmii.2020.07.014DOI Listing
August 2020

Clinical utility of target capture-based panel sequencing in hematological malignancies: A multicenter feasibility study.

Cancer Sci 2020 Sep 17;111(9):3367-3378. Epub 2020 Jul 17.

Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.

Although next-generation sequencing-based panel testing is well practiced in the field of cancer medicine for the identification of target molecules in solid tumors, the clinical utility and clinical issues surrounding panel testing in hematological malignancies have yet to be fully evaluated. We conducted a multicenter prospective clinical sequencing study to verify the feasibility of a panel test for hematological tumors, including acute myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma, and diffuse large B-cell lymphoma. Out of 96 eligible patients, 79 patients (82%) showed potentially actionable findings, based on the clinical sequencing assays. We identified that genetic alterations with a strong clinical significance were found at a higher frequency in terms of diagnosis (n = 60; 63%) and prognosis (n = 61; 64%) than in terms of therapy (n = 8; 8%). Three patients who harbored a germline mutation in either DDX41 (n = 2) or BRCA2 (n = 1) were provided with genetic counseling. At 6 mo after sequencing, clinical actions based on the diagnostic (n = 5) or prognostic (n = 3) findings were reported, but no patients were enrolled in a clinical trial or received targeted therapies based on the sequencing results. These results suggest that panel testing for hematological malignancies would be feasible given the availability of useful diagnostic and prognostic information. This study is registered with the UMIN Clinical Trial Registry (UMIN000029879, multiple myeloma; UMIN000031343, adult acute myeloid leukemia; UMIN000033144, diffuse large B-cell lymphoma; and UMIN000034243, childhood leukemia).
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http://dx.doi.org/10.1111/cas.14552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469806PMC
September 2020

Conditioning regimen for allogeneic bone marrow transplantation in children with acquired bone marrow failure: fludarabine/melphalan vs. fludarabine/cyclophosphamide.

Bone Marrow Transplant 2020 07 23;55(7):1272-1281. Epub 2020 May 23.

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

Fludarabine/cyclophosphamide-based conditioning regimens are standard in bone marrow transplantation (BMT) for acquired bone marrow failure in children, however, graft failure may occur. Using the data from a nationwide transplantation registry, we compared the outcomes of children aged <16 years with acquired aplastic anemia and refractory cytopenia of childhood who underwent allogeneic BMT with either fludarabine/melphalan (n = 71) or fludarabine/cyclophosphamide (n = 296) between 2000 and 2016. The fludarabine/melphalan regimen provided excellent outcomes, with 3-year overall survival and failure-free survival rates of 98% and 97%, respectively. The 83% 3-year failure-free survival in the fludarabine/cyclophosphamide group was significantly inferior (P = 0.002), whereas the overall survival did not differ between the two groups. Late graft failure was the most common cause of treatment failure in the fludarabine/cyclophosphamide group, which experienced a significantly higher incidence of late graft failure than the fludarabine/melphalan group (11% vs. 3%; P = 0.035). Multivariate analyses showed that the fludarabine/melphalan regimen was associated with a better failure-free survival (hazard ratio [HR] 0.12; P = 0.005) and lower risk of late graft failure (HR 0.16; P = 0.037). Fludarabine/melphalan-based conditioning regimen can be a promising option for children with acquired bone marrow failure receiving BMT.
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http://dx.doi.org/10.1038/s41409-020-0948-8DOI Listing
July 2020

Autologous Stem Cell Transplantation for Children With Renal Tumors, and Adults With Wilms Tumor: Retrospective Analysis of the Japanese Transplant Registry Unified Management Program.

J Pediatr Hematol Oncol 2020 05;42(4):251-255

Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.

Background: Almost all pediatric patients with renal tumors are diagnosed with nephroblastoma (Wilms tumor), clear cell sarcoma, or malignant rhabdoid tumor. The choice of treatment is important for relapsed and refractory patients with nephroblastoma. Furthermore, clear cell sarcoma of the kidney (CCSK) and malignant rhabdoid tumor of the kidney (MRTK) have a poor prognosis compared with nephroblastoma. Thus, stem cell transplantation (SCT) is sometimes selected to treat these tumors.

Patients And Methods: The authors targeted a total of 84 patients with nephroblastoma, CCSK, and MRTK who underwent a first autologous SCT between 1992 and 2014, and were registered in the Japanese Transplant Registry Unified Management Program system. The authors retrospectively analyzed the SCT data for survival rate.

Results: Five-year overall survival rates for nephroblastoma, CCSK, and MRTK were 72.4%±6.3%, 46.8%±13.8%, and 36.4%±14.5%, respectively. The event-free survival rates at 5 years were 64.9%±6.7%, 35.7%±12.8%, and 27.3%±13.4%, respectively. The relapse rates at 5 years were 25.3%±11.4%, 46.2%±28.4%, and 60.0%±43.1%, respectively.

Conclusion: Although the survival rate for nephroblastoma was relatively high, those of CCSK and MRTK were poor.
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http://dx.doi.org/10.1097/MPH.0000000000001779DOI Listing
May 2020

Peripherally Inserted Central Venous Catheter for Pediatric and Young Adult Patients With Hematologic and Malignant Diseases.

J Pediatr Hematol Oncol 2020 10;42(7):429-432

Department of Hematology/Oncology for Children and Adolescents, Sapporo Hokuyu Hospital, Sapporo, Japan.

Background: Long-term venous access is essential when treating malignant diseases. As an alternative to conventional central venous catheters, peripherally inserted central venous catheter (PICC) are now widely used. The aim of this study is to evaluate the safety, efficacy, and reliability of PICCs in comparison with previous reports, and to describe significant complications associated with their use.

Patients And Methods: From June 2009 to November 2017, PICCs were inserted 258 times in a total of 160 pediatric and young adult patients at our institution. We retrospectively evaluated our data regarding catheter life, a note of caution during insertion, reasons for removal, infection, and other notable complications.

Results: The 258 PICCs were placed for a total of 30,901 catheter-days with a median catheter life of 102 days ranging from 2 to 471 days. The most suitable vein for the insertion was a basilic vein. The insertion depth from the cubital fossa to the point of the lower third superior vena cava was found to have a strong correlation with body surface area. Suspected catheter infection requiring catheter removal was observed 30 times (0.97/1000 catheter-days) and catheter-related bloodstream infection was observed 2 times (0.06/1000 catheter-days). All the responsible pathogens were Staphylococcus epidermidis. As notable complications, fibrin sheath formation were seen in 4 patients and catheter tip migration to the thorax in 1 patient.

Conclusions: Our data suggest that PICC is safe and effective in pediatric and young adult patients receiving long-term treatment. However, clinicians should be aware of the possible complications during PICC use.
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http://dx.doi.org/10.1097/MPH.0000000000001719DOI Listing
October 2020

A Multicenter, Open-label, Clinical Trial to Assess the Effectiveness and Safety of Allogeneic Hematopoietic Stem Cell Transplantation Using Reduced-intensity Conditioning in Relapsed/refractory Anaplastic Large-cell Lymphoma in Children.

Acta Med Okayama 2020 Feb;74(1):89-94

Department of Pediatrics and Adolescence, Sapporo Hokuyu Hospital, Sapporo 003-0006, Japan.

No standard treatment for relapsed or refractory anaplastic large-cell lymphoma (ALCL) has been established. This study is a multicenter, open-label trial to examine the effectiveness and safety of transplantation with reduced-intensity conditioning (RIC) for patients under 20 years old with relapsed or refractory ALCL. We defined RIC as the administration of fludarabine (30 mg/m2/day) for five days plus melphalan (70 mg/m2/day) for two days and total body irradiation at 4 Gy, followed by allogeneic hematopoietic stem cell transplantation.
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http://dx.doi.org/10.18926/AMO/57959DOI Listing
February 2020

Verification of blood volume for blood culture and detection rate in pediatrics.

J Infect Chemother 2020 May 31;26(5):471-474. Epub 2019 Dec 31.

Department of Pediatrics, National Hospital Organization Saitama Hospital, Saitama, Japan.

Purpose: This study was conducted to estimate the blood culture volume that should be collected from pediatric patients to improve diagnostic abilities.

Methods: Blood cultures from neonates and children aged up to 18 years were collected and the volume was measured for over a 1-year period. During the intervention period, examiners were instructed to draw 3 mL of blood for culture, if possible. The pre-intervention period was from June 1 to August 31, 2016. The post-intervention period was from September 1, 2016, to May 30, 2017. The rate of positive detections was calculated and compared between pre and post-intervention periods.

Results: We collected 1352 samples and measured 1327 bottles. During the pre-intervention period, 340 cases were collected with a median blood volume of 1.64 mL; 9 cases (2.7%) were true-positive. During the intervention period, 1012 cases were ordered with a median blood volume of 2.41 mL; 19 cases (1.9%) were true-positive. After intervention, blood volume was increased significantly (p < 0.01). However, there was no significant difference in the rate of positive detections during the study periods (p = 0.254).

Conclusions: In the pediatric clinical setting in a Japanese municipal hospital, the positive detection rate did not improve even when the collected blood volume was increased. One milliliter of blood volume may be adequate for the pediatric bottle in children.
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http://dx.doi.org/10.1016/j.jiac.2019.12.008DOI Listing
May 2020

The effect of graft-versus-host disease on outcomes after allogeneic stem cell transplantation for refractory lymphoblastic lymphoma in children and young adults.

Pediatr Blood Cancer 2020 04 26;67(4):e28129. Epub 2019 Dec 26.

Department of Pediatrics, Sapporo Hokuyu Hospital, Sapporo, Japan.

Background: Patients with relapsed or refractory lymphoblastic lymphoma (LBL) have a poor prognosis. The efficacy of allogeneic blood stem cell transplantation for treatment of this disease remains unclear in terms of transplantation-related toxicity. Acute and chronic graft-versus-host diseases (GVHD) are both harmful to patients after allogeneic transplantation, but may have some positive effects through a substitute graft-versus-lymphoma effect.

Methods: To investigate the effect of GVHD on the survival of patients with refractory LBL, we retrospectively studied the outcomes of 213 patients with LBL who underwent first allogeneic stem cell transplantation before the age of 18 years, between 1990 and 2015 in Japan.

Results: The five-year overall survival (OS) and event-free survival rates after stem cell transplantation were 50.3% (95% confidence interval [CI], 43.2-56.9) and 47.8% (95% CI, 40.8-54.4), respectively. In univariate landmark analyses, the probability of OS was significantly better in patients with aGVHD than in those without (P = 0.002, five-year OS 58.1% vs 39.0%). The probability of OS was also better in patients with cGVHD than in those without (P = 0.036, five-year OS 72.2% vs 54.7%). Multivariate analysis demonstrated that only aGVHD was associated with better OS (hazard ratio, 0.63; 95% CI, 0.42-0.94, P = 0.024). Progression and recurrence statuses at SCT were associated with poor prognosis. The patients with grade II aGVHD showed the best prognosis (five-year OS: 65.6%).

Conclusion: Our results suggest that the occurrence of aGVHD may be associated with better outcomes in patients with relapsed/refractory LBL who undergo allogeneic transplantation.
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http://dx.doi.org/10.1002/pbc.28129DOI Listing
April 2020

Successful outcome with reduced-intensity condition regimen followed by allogeneic hematopoietic stem cell transplantation for relapsed or refractory anaplastic large-cell lymphoma.

Int J Hematol 2019 Dec 16;110(6):723-728. Epub 2019 Oct 16.

Division of Pediatrics, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.

We report a retrospective analysis of 38 patients (age ≤ 30 years) who underwent allogeneic hematopoietic stem cell transplantation (allo-SCT) for relapsed or refractory anaplastic large-cell lymphoma (ALCL). Median follow-up for survivors after undergoing allo-SCT was 72 months (range, 35-96 months). Eight patients received reduced-intensity conditioning (RIC) regimens, including three patients with fludarabine plus melphalan-based regimens and five patients with fludarabine plus busulfan-based regimens. The remaining 30 patients received myeloablative conditioning (MAC) regimens. Median ages in the RIC and MAC groups were 24 and 15 years, respectively. The 5-year overall survival rates in the RIC and MAC groups were 100% and 49%, respectively (P = 0.018). The 5-year event-free survival rates in the RIC and MAC groups were 88% and 43%, respectively (P = 0.039). In the RIC group, four of the eight patients showed residual disease at allo-SCT, but all eight patients survived with complete remission (CR), including one patient with relapse. This result suggests that allo-SCT using the RIC regimen may be effective for relapsed or refractory ALCL in children, adolescents, and young adults, even in non-CR cases.
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http://dx.doi.org/10.1007/s12185-019-02748-1DOI Listing
December 2019

A deep intronic mutation of c.1166-285 T > G in SLC46A1 is shared by four unrelated Japanese patients with hereditary folate malabsorption (HFM).

Clin Immunol 2019 11 5;208:108256. Epub 2019 Sep 5.

Department of Pediatrics, Faculty of Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan. Electronic address:

Hereditary folate malabsorption (HFM) is an autosomal recessive disease caused by mutations in SLC46A1 encoding the proton-coupled folate transporter (PCFT). HFM patients present with various clinical features including megaloblastic anemia, thrombocytopenia, combined immunodeficiency and neurodevelopmental disorders. In this study, we report the same deep intronic mutation of c.1166-285 T > G shared by four unrelated Japanese patients with HFM. This mutation was shown to generate a cryptic splice donor site for a 168-bp insertion of intron 3 sequences, leading to premature termination in the middle of this insertion. This mutation could be a founder mutation in the Japanese population, but also could be a hot-spot and could be present in undiagnosed HFM patients worldwide because of the difficulty to detect this mutation.
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http://dx.doi.org/10.1016/j.clim.2019.108256DOI Listing
November 2019

The effectiveness of busulfan-based conditioning regimens for stem cell transplantation against lymphomas in children, adolescents, and young adults in Japan.

Pediatr Blood Cancer 2019 10 12;66(10):e27918. Epub 2019 Jul 12.

Department of Pediatrics, Yamagata University Hospital, Yamagata, Yamagata Prefecture, Japan.

Conditioning regimens for stem cell transplantation (SCT) involving total body irradiation (TBI) are generally preferred over busulfan (BU)-based ones for lymphoid malignancies. However, reports of favorable results using BU against lymphomas have recently emerged. This study sought to compare the effectiveness of BU and TBI regimens for SCT against lymphomas. We retrospectively analyzed 893 lymphoma patients who underwent primary SCT in Japan between 1980 and 2015. The median age of all patients was 18 years (range, 0-30 years) with 589 males, 303 females, and 1 patient whose sex was unknown. Overall survival (OS) was not different between those receiving BU and TBI (P = 0.672). OS in patients receiving autologous SCT was significantly better with BU over TBI regimens (P = 0.038), particularly in children (0-15 years) (P = 0.024). Conversely, OS in adolescents and young adults (AYAs; 16-30 years) receiving allogeneic SCT was significantly worse with BU over TBI regimens (P = 0.035). Overall, BU regiments had comparable effectiveness to TBI conditioning regimens, and, although less effective for AYAs with allogeneic SCT, were particularly more effective than TBI regimens for children who received autologous SCT.
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http://dx.doi.org/10.1002/pbc.27918DOI Listing
October 2019

Erlotinib and bevacizumab combination therapy for afatinib-refractory leptomeningeal carcinomatosis from EGFR-mutated lung cancer.

Int Cancer Conf J 2019 Apr 18;8(2):81-85. Epub 2019 Jan 18.

Department of Thoracic and Breast Surgery, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama, Yufu, Oita 879-5593 Japan.

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors remains the main hurdle in treating EGFR-mutated lung cancer. Besides, when leptomeningeal carcinomatosis occurs during treatment, it often leads to treatment failure. We herein report a case of lung adenocarcinoma involving a patient with an EGFR exon 19 deletion mutation who developed leptomeningeal carcinomatosis after afatinib treatment for post-operative recurrence. He received right lower lobectomy, followed by four cycles of cisplatin and pemetrexed treatment. Follow-up CT/MRI revealed multiple pulmonary metastases and brain metastases at 7 months after surgery, and afatinib (40 mg/day) was administered after stereotactic radiotherapy for brain metastasis. At 28 months after surgery, follow-up MRI revealed asymptomatic leptomeningeal carcinomatosis, which was cytologically proven from the cerebrospinal fluid. Because EGFR T790M was not detected in plasma cell-free DNA or cerebrospinal fluid, erlotinib and bevacizumab combination treatment was administered. He remained asymptomatic and was radiographically clear of LM at 2 months after treatment. In comparison to other EGFR-TKIs, erlotinib shows penetrance into the cerebrospinal fluid. Furthermore, the addition of bevacizumab might enhance the treatment effect, because it is known to relieve brain edema from metastatic brain tumors by normalizing immature vascularity and improving drug penetrance into the cerebrospinal fluid by reducing interstitial fluid pressure.
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http://dx.doi.org/10.1007/s13691-019-00358-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498220PMC
April 2019

Pathogenic mutations identified by a multimodality approach in 117 Japanese Fanconi anemia patients.

Haematologica 2019 10 21;104(10):1962-1973. Epub 2019 Feb 21.

Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Kyoto, Japan

Fanconi anemia is a rare recessive disease characterized by multiple congenital abnormalities, progressive bone marrow failure, and a predisposition to malignancies. It results from mutations in one of the 22 known genes. The number of Japanese Fanconi anemia patients with a defined genetic diagnosis was relatively limited. In this study, we reveal the genetic subtyping and the characteristics of mutated genes in Japan and clarify the genotype-phenotype correlations. We studied 117 Japanese patients and successfully subtyped 97% of the cases. and pathogenic variants accounted for the disease in 58% and 25% of Fanconi anemia patients, respectively. We identified one and two hot spot mutations, which are found at low percentages (0.04-0.1%) in the whole-genome reference panel of 3,554 Japanese individuals (Tohoku Medical Megabank). was the third most common complementation group and only one case was identified in our series. Based on the data from the Tohoku Medical Megabank, we estimate that approximately 2.6% of Japanese are carriers of disease-causing gene variants, excluding missense mutations. This is the largest series of subtyped Japanese Fanconi anemia patients to date and the results will be useful for future clinical management.
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http://dx.doi.org/10.3324/haematol.2018.207241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886416PMC
October 2019

Interaction of S100A6 with Target Proteins In Vitro and in Living Cells.

Methods Mol Biol 2019 ;1929:367-377

Applied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Kita-ku, Okayama, Japan.

S100A6 is a member of the EF-hand Ca-binding protein family, which plays important roles in a wide variety of Ca signaling in the cells, as well as in pathophysiological conditions. Herein, we describe analytical protocols for evaluating the interaction of S100A6 with multiple target proteins in vitro, including biotinylated S100A6 overlay, glutathione-S-transferase (GST)-precipitation, surface plasmon resonance, and a GST-precipitation assay in living cells. These methods will elucidate the detailed molecular mechanisms of S100A6/target interactions and further improve our understanding of the physiological significance of S100A6-mediated Ca signaling. Moreover, they may be used to evaluate other physical S100/target interactions.
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http://dx.doi.org/10.1007/978-1-4939-9030-6_23DOI Listing
July 2019

Hematopoietic stem cell transplantation in children and adolescents with relapsed or refractory B-cell non-Hodgkin lymphoma.

Int J Hematol 2019 Apr 30;109(4):483-490. Epub 2019 Jan 30.

Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan.

We undertook a retrospective study using the national registry data of hematopoietic stem cell transplantation (HSCT) in Japan to investigate the effect of graft source, particularly autologous or allogeneic tissue, on the treatment outcome in patients aged less than 18 years with relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL). Survival analysis was conducted on 31 autologous HSCT (auto-HSCT) and 48 allogeneic HSCT (allo-HSCT) recipients between 1990 and 2013. The 5-year survival rates were significantly lower for allo-HSCT compared to auto-HSCT recipients (32% vs. 55%; P = 0.036). Multivariate analysis of survival rates identified allogeneic graft, Burkitt histology, and lack of response to chemotherapy as poor prognostic factors for survival. The cumulative incidence of treatment-related mortality (TRM) was significantly higher in allo-HSCT compared to auto-HSCT recipients (P = 0.017), explaining the difference in survival rates. In patients with Burkitt lymphoma (BL), overall survival was significantly inferior in the group of patients undergoing HSCT within 12 months from the initial diagnosis (P = 0.039). These data indicate that treatment outcomes for HSCT in children and adolescents with B-NHL were better in autograft recipients, suggesting that greater attention should be paid to the risk of TRM, especially after allografts, for patients with BL.
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http://dx.doi.org/10.1007/s12185-019-02608-yDOI Listing
April 2019

Lower gamma globulin level before conditioning is a risk factor for cytomegalovirus antigenemia after pediatric allogeneic stem cell transplantation.

Pediatr Blood Cancer 2019 04 17;66(4):e27586. Epub 2018 Dec 17.

Department of Hematology/Oncology for Children and Adolescents, Sapporo Hokuyu Hospital, Hokkaido, Japan.

Background: Despite the development of early detection methods and new antiviral drugs, cytomegalovirus (CMV) infection remains a persistent and sometimes severe complication of stem cell transplantation (SCT). CMV antigenemia has become widely used for early detection of CMV infection after SCT.

Procedure: We retrospectively analyzed risk factors for CMV antigenemia in pediatric patients following allogeneic SCT. We analyzed 74 pediatric patients who received allogeneic SCT at Sapporo Hokuyu Hospital between April 2007 and March 2018 and were alive over three months after SCT.

Results: Of the 74 patients, 22 (29.7%) were CMV antigenemia positive. On univariate analyses, many patients with CMV antigenemia tested positive for CMV antibody before SCT (P < 0.001), and had lower gamma globulin levels before conditioning (P = 0.014). Multivariate analysis additionally confirmed that pre-SCT CMV antibody positivity (P < 0.001) and preconditioning gamma globulin levels under 655 mg/dL (P = 0.004) were independent risk factors for post-SCT CMV antigenemia.

Conclusions: These results indicate the importance of assessing gamma globulin levels in pediatric patients prior to SCT.
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http://dx.doi.org/10.1002/pbc.27586DOI Listing
April 2019

Risk Factors for Invasive Fungal Infection in Children and Adolescents With Hematologic and Malignant Diseases: A 10-year Analysis in a Single Institute in Japan.

Pediatr Infect Dis J 2018 12;37(12):1282-1285

From the Department of Hematology/Oncology for Children and Adolescents, Sapporo Hokuyu Hospital, Shiroishiku, Sapporo, Japan.

Infection, especially invasive fungal infection (IFI), is an important complication of chemotherapy and stem cell transplantation. It is also a well-known risk factor in pediatric hematologic malignancy, acute myelogenous leukemia, recurrent disease and allogeneic stem cell transplantation. We previously revealed that a diagnosis of acute myelogenous leukemia, recurrent disease and >10 years of age were risk factors for IFI in patients with pediatric hematologic malignancies. We examined and compared the incidence, risk factors and mortality rate from IFI between 276 patients from 2007 to 2016 and patients in our past report. The cumulative incidence of IFI was 10.5%; this comprised cases of probable and possible IFI at rates of 5.1% and 5.4%, respectively. Univariate analysis showed that age >9 years at admission, recurrent disease and acute myelogenous leukemia diagnosis were risk factors for IFI. Similar to the results of the previous study, multivariate analysis showed that each of these 3 variables was an independent predictor of IFI. The survival rate was lower in patients with IFI than in those without IFI (38.8% versus 69.9%; P < 0.001). However, IFI was a direct cause of death in only 2 patients. Although 11 patients received stem cell transplantation after IFI treatment, only 2 patients have survived, and the other 9 patients died of other complications.
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http://dx.doi.org/10.1097/INF.0000000000002010DOI Listing
December 2018

Long-term outcome of renal function in children after stem cell transplantation measured by estimated glomerular filtration rate.

Pediatr Blood Cancer 2019 02 23;66(2):e27478. Epub 2018 Oct 23.

Department of Hematology/Oncology for Children and Adolescents, Sapporo Hokuyu Hospital, Sapporo, Japan.

Background: Stem cell transplantation (SCT) outcomes have improved over the last three decades, with many patients being rescued with this treatment. However, improved outcomes have led to issues with long-term sequelae. One of these sequelae in children is renal dysfunction, an index of which is estimated using glomerular filtration rate (eGFR).

Procedure: We retrospectively analyzed eGFR in 83 pediatric patients who received SCT. Data from all patients extended up to 12 months or more post SCT. The median follow-up time was 127.7 months (range 12.0-268.8 months).

Results: Eighteen patients (21.7%) had low eGFR (<90 ml/min/1.73 m ) post SCT. Cumulative incidence of low eGFR was 25.8 ± 2.0%. Nine (10.6%) patients had a low eGFR pre-SCT. However, pre- and post-SCT incidence of low eGFR were not correlated. Meanwhile, only two patients (2.4%) exhibited severe renal dysfunction, with eGFRs < 60 ml/min/1.73 m . Independent risk factors for low eGFR were solid tumor and use of fludarabine. Moreover, age at SCT ≥ 7 years was also a long-term post-SCT risk factor for low eGFR in all patients.

Conclusion: Independent post-SCT long-term risk factors for low eGFR in children were solid tumor and use of fludarabine. Moreover, age at SCT ≥ 7 years was a post-SCT long-term risk factor for low eGFR across all patients.
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http://dx.doi.org/10.1002/pbc.27478DOI Listing
February 2019

Intratumoral heterogeneity of copy number variation in lung cancer harboring L858R via immunohistochemical heterogeneous staining.

Lung Cancer 2018 10 13;124:241-247. Epub 2018 Aug 13.

Department of Thoracic and Breast Surgery, Oita University, Faculty of Medicine, Yufu, Oita, 879-5593 Japan. Electronic address:

Background: Although intratumoral heterogeneity is commonly observed in several cancers, few studies have shown its presence in EGFR-mutated lung cancer. We performed immunohistochemistry to analyze the intratumoral heterogeneity in EGFR-mutated (L858R) lung cancer and performed targeted sequencing in specific cases. We discuss the effects of intratumoral heterogeneity and acquired resistance to EGFR-TKI.

Methods: Twenty resected primary lung cancers known to harbor EGFR L858R were analyzed. IHC was performed using an L858R mutant-specific rabbit monoclonal antibody and the samples were scored by staining intensity (0-3) and proportion. For cases with heterogeneous L858R protein expression, the nucleic acids were extracted from each differently stained lesion, and targeted sequencing was performed. Single nucleotide variations (SNVs) and copy number variations (CNVs) were then analyzed. The cell proliferation and apoptosis were also evaluated by the ki-67 labeling index and TUNEL staining.

Results: Among 20 cases, 3 showed heterogeneous staining. Genetic analyses for cases with heterogeneous staining revealed an increase in the copy number of EGFR in the IHC-positive part compared to the negative part, and an increase in the copy number of CCNE1 was observed in the IHC-positive part compared to the negative part in one case (case 1). In another case (case 2), an increase in the copy number of EGFR was observed in the IHC-positive part compared to the negative part, and an increase in the copy number of MDM2 was observed in the IHC-positive part compared to the negative part. In three cases, no SNV changes were observed. An increase in the ki-67 labeling index in the L858R-positive part in case 1 and increased apoptosis in the L858R-positive part in case 2 were observed, suggesting the functional significance of CNV changes.

Conclusion: These cases exhibiting L858R IHC intratumoral heterogeneity suggest a heterogeneous effect on the cell activity due to CNV heterogeneity.
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http://dx.doi.org/10.1016/j.lungcan.2018.08.013DOI Listing
October 2018

The Effect of Interim FDG-PET-guided Response-Adapted Therapy in Pediatric Patients with Hodgkin's Lymphoma (HL-14) : Protocol for a Phase II Study.

Acta Med Okayama 2018 Aug;72(4):437-440

Department of Pediatrics, Graduate School of Medical Sciences Kyushu University, Fukuoka 812-8582,

This trial enrolls patients with untreated Hodgkin's lymphoma aged<20 years at diagnosis and examines the effects of omitting radiation therapy if the FDG-positron emission tomography (PET) findings after two completed cycles of combination chemotherapy are negative. It thereby aims to determine whether patients who truly require radiation therapy can be identified by FDG-PET. If so, this modality could be used to omit radiation therapy for all other patients, decreasing the risk of serious long-term complications without affecting survival rates. The outcomes of patients for whom FDG-PET is used to assess early treatment response will also be determined.
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http://dx.doi.org/10.18926/AMO/56185DOI Listing
August 2018

Secondary bone/soft tissue sarcoma in childhood cancer survivors: a nationwide hospital-based case-series study in Japan.

Jpn J Clin Oncol 2018 Sep;48(9):806-814

Department of Pediatric Surgery, Keio University School of Medicine, Tokyo, Japan.

Background: Secondary cancer is the most life-threatening late effect of childhood cancer. We investigated the clinical features of secondary bone/soft tissue sarcoma among childhood cancer survivors (CCSs).

Methods: We conducted a retrospective case-series study of 10 069 CCSs newly diagnosed with cancer between 1980 and 2009 across 15 Japanese hospitals. Twenty-one cases of pathologically diagnosed secondary bone/soft tissue sarcoma were selected, and the respective clinical courses were determined using additional questionnaires.

Results: The primary cancers included retinoblastoma (n = 7), acute lymphoblastic leukemia (n = 5), lymphoma (n = 5), osteosarcoma (n = 1), rhabdomyosarcoma (n = 1), brain tumor (n = 1) and Langerhans cell histiocytosis (n = 1). The median age at the primary cancer diagnosis was 2.9 years, and the male-to-female ratio was 16:5. The histological classifications of the secondary sarcoma included osteosarcoma (n = 10), malignant peripheral nerve sheath tumor (n = 4), rhabdomyosarcoma (n = 3), Ewing's sarcoma (n = 3) and primitive neuroectodermal tumor (n = 1). The median latency period to the secondary sarcoma was 10.2 years. Significant risk factors for secondary sarcoma in the multivariate Cox regression model included a history of retinoblastoma as the primary cancer (hazard ratio [HR], 20.9; 95% confidence interval [CI], 5.70-76.5) and autologous stem cell transplantation (SCT) (HR, 2.56; 95% CI, 1.08-6.03). Seventeen CCSs with secondary sarcoma underwent radiation, and nine, hematopoietic SCT. Twelve CCSs with secondary sarcoma achieved disease-free survival, while CCSs with hematological cancer or relapsed primary cancer who developed secondary sarcoma had the worst prognoses.

Conclusion: The prognoses of CCSs with secondary sarcoma may depend on the primary cancer or prior relapse of primary cancer.
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http://dx.doi.org/10.1093/jjco/hyy102DOI Listing
September 2018