Publications by authors named "Chitose Ogawa"

59 Publications

A quantification method of somatic mutations in normal tissues and their accumulation in pediatric patients with chemotherapy.

Proc Natl Acad Sci U S A 2022 Aug 27;119(31):e2123241119. Epub 2022 Jul 27.

Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan, 104-0045.

Somatic mutations are accumulated in normal human tissues with aging and exposure to carcinogens. If we can accurately count any passenger mutations in any single DNA molecule, since their quantity is much larger than driver mutations, we can sensitively detect mutation accumulation in polyclonal normal tissues. Duplex sequencing, which tags both DNA strands in one DNA molecule, enables accurate count of such mutations, but requires a very large number of sequencing reads for each single sample of human-genome size. Here, we reduced the genome size to 1/90 using the HI restriction enzyme and established a cost-effective pipeline. The enzymatically cleaved and optimal sequencing (EcoSeq) method was able to count somatic mutations in a single DNA molecule with a sensitivity of as low as 3 × 10 per base pair (bp), as assessed by measuring artificially prepared mutations. Taking advantages of EcoSeq, we analyzed normal peripheral blood cells of pediatric sarcoma patients who received chemotherapy ( = 10) and those who did not ( = 10). The former had a mutation frequency of 31.2 ± 13.4 × 10 per base pair while the latter had 9.0 ± 4.5 × 10 per base pair ( < 0.001). The increase in mutation frequency was confirmed by analysis of the same patients before and after chemotherapy, and increased mutation frequencies persisted 46 to 64 mo after chemotherapy, indicating that the mutation accumulation constitutes a risk of secondary leukemia. EcoSeq has the potential to reveal accumulation of somatic mutations and exposure to environmental factors in any DNA samples and will contribute to cancer risk estimation.
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http://dx.doi.org/10.1073/pnas.2123241119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9351471PMC
August 2022

The first Japanese biobank of patient-derived pediatric acute lymphoblastic leukemia xenograft models.

Cancer Sci 2022 Jul 25. Epub 2022 Jul 25.

Japan Children's Cancer Group, Relapsed ALL Committee.

A lack of practical resources in Japan has limited preclinical discovery and testing of therapies for pediatric relapsed and refractory acute lymphoblastic leukemia (ALL), which has poor outcomes. Here, we established 57 patient-derived xenografts (PDXs) in NOD.Cg-Prkdc ll2rg /ShiJic (NOG) mice and created a biobank by preserving PDX cells including 3 extramedullary relapsed ALL PDXs. We demonstrated that our PDX mice and PDX cells mimicked the biological features of relapsed ALL and that PDX models reproduced treatment-mediated clonal selection. Our PDX biobank is a useful scientific resource for capturing drug sensitivity features of pediatric patients with ALL, providing an essential tool for the development of targeted therapies.
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http://dx.doi.org/10.1111/cas.15506DOI Listing
July 2022

Safety and efficacy of blinatumomab in Japanese adult and pediatric patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia: final results from an expansion cohort.

Acta Haematol 2022 Jul 5. Epub 2022 Jul 5.

Background The safety and efficacy of blinatumomab, a CD19/CD3 BiTE® (bispecific T-cell engager) molecule, was evaluated in an expansion cohort of the phase 1b/2 study (NCT02412306) in Japanese adult (n=14) and pediatric (n=17) patients with relapsed/refractory Philadelphia-negative B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). Methods Globally recommended blinatumomab doses were administered to adult (9-28 μg/day) and pediatric (5-15 μg/m2/day) patients. Primary endpoint was the incidence of treatment-emergent adverse events (TEAEs) and treatment-related AEs. Results All adult and pediatric patients experienced ≥1 TEAE. Grade ≥3 TEAEs were observed in 11 (79%) adult and 15 (88%) pediatric patients. Blinatumomab was discontinued in one (6%) pediatric patient due to treatment-related grade 4 cytokine release syndrome. Fatal AEs such as disease progression and multiple organ dysfunction syndrome, which were not treatment-related, were reported in two (12%) pediatric patients. Eleven (79%) adults achieved complete remission (CR)/CR with partial hematological recovery (CRh) within the first two blinatumomab cycles. Nine of 10 adult patients with CR/CRh and evaluable minimal residual disease (MRD) achieved MRD response. CR/CRh was achieved by five (29%) pediatric patients, of which two had MRD response. Conclusion In conclusion, blinatumomab was safe and efficacious in Japanese patients with relapsed/refractory BCP ALL.
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http://dx.doi.org/10.1159/000525835DOI Listing
July 2022

A phase I study of inotuzumab ozogamicin as a single agent in pediatric patients in Japan with relapsed/refractory CD22-positive acute lymphoblastic leukemia (INO-Ped-ALL-1).

Int J Hematol 2022 May 30. Epub 2022 May 30.

Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.

Inotuzumab ozogamicin (InO) is a CD22-directed antibody conjugated with calicheamicin approved for adult relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL). This phase 1 study primarily aimed to determine the pediatric recommended doses of InO through the standard 3 + 3 design, and to evaluate the safety, tolerability, pharmacokinetic (PK) profile, immunogenicity and efficacy of InO. Dose level 1 (DL1) was 1.8 mg/m (days 1, 8, and 15: 0.8, 0.5, and 0.5 mg/m, respectively). Six of the seven registered patients were eligible [median age, 7.5 (2-17) years]. Although all six patients started DL1, only five completed the dose. No dose-limiting toxicity was observed. All patients experienced adverse events (AEs), including increased alanine aminotransferase and aspartate aminotransferase in four patients. Three patients experienced serious AEs, which were hepatic veno-occlusive disease (VOD), ALL, and fever. Five patients achieved complete remission (CR) or CR with incomplete blood cell recovery (CRi), among whom 3 (60%) were negative for minimal residual disease. PK findings were similar to those in adults. No patient had anti-drug antibodies to InO. In conclusion, InO was well tolerated in children and promoted similar antileukemic efficacy as in adults. Nonetheless, the risk for VOD requires attention.
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http://dx.doi.org/10.1007/s12185-022-03388-8DOI Listing
May 2022

First phase 1 clinical study of olaparib in pediatric patients with refractory solid tumors.

Cancer 2022 08 20;128(15):2949-2957. Epub 2022 May 20.

Medical Innovation Promotion Center, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.

Background: The survival of patients with high-risk, refractory, relapsed, or metastatic solid tumors remains dismal. A poly(ADP-ribose) polymerase (PARP) inhibitor could be effective for the treatment of pediatric solid tumors with defective homologous recombination.

Methods: This open-label, multicenter phase 1 clinical trial evaluated the safety, tolerability, and efficacy of olaparib, a PARP inhibitor, in pediatric patients with refractory solid tumors to recommend a dose for Phase 2 trials. Olaparib (62.5, 125, and 187.5 mg/m twice daily) was administered orally every day (1 cycle = 28 days) using a standard 3 + 3 dose-escalation design. Patients aged 3-18 years with recurrent pediatric solid tumors were eligible. Pharmacokinetic and pharmacodynamic analyses were performed.

Results: Fifteen patients were enrolled and received olaparib monotherapy, which was well tolerated. The recommended phase 2 dose for daily administration was 187.5 mg/m twice daily. Pharmacokinetics were dose proportional. The area under the concentration-time curve from 0 to 12 h and the peak plasma concentration for 187.5 mg/m twice daily in children were comparable to previous data obtained in a 200-mg, twice-daily cohort and lower than those in the 300-mg twice-daily cohort in adults. Pharmacodynamic studies demonstrated substantial inhibition of PARP activity. Two partial responses were observed in patients with Wilms tumor and neuroblastoma.

Conclusions: This report is the first clinical trial to describe the use of a PARP inhibitor as monotherapy in children. Olaparib was well tolerated, with preliminary antitumor responses observed in DNA damage response-defective pediatric tumors.

Lay Summary: This Phase 1 trial evaluated the efficacy and safety of olaparib in patients with refractory childhood solid tumors. Olaparib was well tolerated, achieving objective response in 2/15 patients. The DNA damage response was attenuated in nearly one-half of advanced neuroblastoma patients, demonstrating the utility of the PARP inhibitor. The results support further investigation of olaparib as a new treatment for DNA damage-response or repair-defective pediatric cancers.
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http://dx.doi.org/10.1002/cncr.34270DOI Listing
August 2022

Feasibility and clinical utility of comprehensive genomic profiling of hematological malignancies.

Cancer Sci 2022 Aug 17;113(8):2763-2777. Epub 2022 Jun 17.

Division of Molecular Oncology, National Cancer Center Research Institute, Tokyo, Japan.

Identification of genetic alterations through next-generation sequencing (NGS) can guide treatment decision-making by providing information on diagnosis, therapy selection, and prognostic stratification in patients with hematological malignancies. Although the utility of NGS-based genomic profiling assays was investigated in hematological malignancies, no assays sufficiently cover driver mutations, including recently discovered ones, as well as fusions and/or pathogenic germline variants. To address these issues, here we have devised an integrated DNA/RNA profiling assay to detect various types of somatic alterations and germline variants at once. Particularly, our assay can successfully identify copy number alterations and structural variations, including immunoglobulin heavy chain translocations, IKZF1 intragenic deletions, and rare fusions. Using this assay, we conducted a prospective study to investigate the feasibility and clinical usefulness of comprehensive genomic profiling for 452 recurrently altered genes in hematological malignancies. In total, 176 patients (with 188 specimens) were analyzed, in which at least one alteration was detected in 171 (97%) patients, with a median number of total alterations of 7 (0-55). Among them, 145 (82%), 86 (49%), and 102 (58%) patients harbored at least one clinically relevant alteration for diagnosis, treatment, and prognosis, respectively. The proportion of patients with clinically relevant alterations was the highest in acute myeloid leukemia, whereas this assay was less informative in T/natural killer-cell lymphoma. These results suggest the clinical utility of NGS-based genomic profiling, particularly for their diagnosis and prognostic prediction, thereby highlighting the promise of precision medicine in hematological malignancies.
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http://dx.doi.org/10.1111/cas.15427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9357666PMC
August 2022

Surgical Treatment for Pneumothorax and Tumor-bronchial Fistula Secondary to Pulmonary Metastasis of Osteosarcoma in Pediatric and Adolescent Patients.

J Pediatr Hematol Oncol 2022 Jan 28. Epub 2022 Jan 28.

Departments of Pediatric Surgical Oncology Pediatric Oncology Thoracic Surgery Musculoskeletal Oncology and Rehabilitation, National Cancer Center Hospital, Tokyo Department of Pediatric Surgery, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: Pneumothorax and tumor-bronchial fistula are rare complications of pulmonary metastasis of osteosarcoma.

Observations: We herein report the cases of 3 pediatric and adolescent patients who developed pneumothorax or tumor-bronchial fistula during treatment of pulmonary metastasis of osteosarcoma with chemotherapeutics or antiangiogenic agents. Two patients developed pneumothorax, and the other patient developed tumor-bronchial fistula. All of the patients finally underwent the surgery to treat their complications.

Conclusions: Although it is not a curative surgery, surgery for pneumothorax and tumor-bronchial fistula is acceptable. The operative procedure should be considered on the basis of the predicted prognosis of the patient.
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http://dx.doi.org/10.1097/MPH.0000000000002416DOI Listing
January 2022

Feasibility and usefulness of recommended screenings at long-term follow-up clinics for hematopoietic cell transplant survivors.

Support Care Cancer 2022 Mar 27;30(3):2767-2776. Epub 2021 Nov 27.

Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, 5-1-1 Tsukiji Chuo-ku, Tokyo, 104-0045, Japan.

Purpose: Advances in allogeneic hematopoietic cell transplantation (allo-HCT) have resulted in a growing number of transplant survivors; however, long-term survivors are at risk of developing late complications, and published guidelines recommend screening of this population. We conducted a single-center prospective study to evaluate the adherence to and usefulness of recommended screenings at a long-term follow-up (LTFU) clinic.

Methods: We included consecutive patients who received allo-HCT at our center from 2014, as well as post-HCT patients visiting our outpatient clinic. Visits and screenings were planned at 3 months, 6 months, and 1 year after allo-HCT, and annually thereafter. Outcomes were reported by physicians including the incidence of findings at each screening that led to interventions.

Results: Among the 216 participants, 95% visited the LTFU clinic, and 94% completed planned screenings. However, the rate of secondary cancer screenings targeting high-risk subjects was lower (38% to 68%). The overall percentage of screening results leading to interventions was 4.5%, with higher percentages (> 10%) for bone density testing, ophthalmological examinations, dental assessment, upper gastrointestinal endoscopy, and colonoscopy, with two patients diagnosed with secondary cancers.

Conclusions: Although the overall screening rate was high, it should be possible to improve the detection rate of late complications by decreasing screening failures, especially the screening for secondary cancers limited for high-risk survivors. A nationwide effort to educate HCT survivors and health practitioners using standardized nationwide LTFU tools may be effective, along with the development of institutional, local, and nationwide networks to maintain effective follow-up systems.
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http://dx.doi.org/10.1007/s00520-021-06698-5DOI Listing
March 2022

Prognostic Impact of Pretransplantation Quality of Life and Its Post-Transplantation Longitudinal Change after Allogeneic Hematopoietic Cell Transplantation: A Prospective Study That Administered the Short-Form Health Survey (SF-12) and EuroQol 5.

Transplant Cell Ther 2021 11 8;27(11):935.e1-935.e9. Epub 2021 Aug 8.

Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan.

In allogeneic hematopoietic cell transplantation (allo-HCT), investigator-based clinical variables have been used for pretransplantation prognostic prediction, risk adjustment, and post-transplantation long-term screenings. Although several studies have investigated the prognostic significance of pretransplantation patient-reported outcomes (PROs) and longitudinal trends in PROs after allo-HCT, few have assessed these outcomes using the Medical Outcomes Study 12-Item Short-Form Health Survey (SF-12) and EuroQol 5 Dimension (EQ-5D) index. The present study used 18 items from the SF-12 and EQ-5D index to evaluate the prognostic impact of pretransplantation quality of life (QOL) on allo-HCT outcomes and longitudinal changes in QOL in allo-HCT recipients. This single-center prospective study included consecutive patients who underwent allo-HCT at our center between October 2014 and September 2016. All participants were followed up until October 2017. The SF-12 and EQ-5D index were administered to assess patient-reported QOL before allo-HCT and at 3 months, 6 months, 1 year, and 2 years after allo-HCT when participants visited the long-term follow-up clinic. Longitudinal trends in the QOL-adjusted means were estimated using linear mixed-effects, adjusting for pretransplantation covariates and reasons for missing QOL data. Among 157 patients who underwent allo-HCT, 145 (92%) were registered in this study, and 143 with available QOL data were analyzed. The median pretransplantation scores were 45.3 for the SF-12 physical component score (PCS), 55.6 for the mental component score (MCS), 38.8 for the role/social component score (RCS), 70.0 for the visual analog scale (VAS), and 49.0 for the EQ-5D index. Overall survival (OS) was significantly improved in patients with higher pretransplantation scores on the PCS, RCS, and EQ-5D index, and multivariable analyses showed that the median pretransplantation RCS was significantly associated with OS after allo-HCT (hazard ratio, 3.66; P = .003). The longitudinal trends in the SF-12 score showed that the PCS was improved at 2 years after allo-HCT and was comparable to the normative score for the general population. The MCS remained comparable to or higher than the normative score after allo-HCT. The RCS improved significantly beginning at 6 months after allo-HCT but remained lower than the normative score at 2 years. The VAS and EQ-5D index values showed a drop at 3 months after allo-HCT. Patient-reported QOL assessed by 18 questions on the SF-12 and EQ-5D predicted prognosis, and may be used as a prognosticator to determine treatment strategies, including preparative regimens. Although we experienced a certain amount of patient attrition in the longitudinal follow-up of QOL data, we demonstrated characteristic trajectories of QOL in different domains after adjusting for background covariates and reasons for the lack of QOL data.
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http://dx.doi.org/10.1016/j.jtct.2021.07.026DOI Listing
November 2021

Use of Pegfilgrastim in Japanese Pediatric Patients With Solid Tumors: A Retrospective Analysis.

J Pediatr Hematol Oncol 2022 Mar;44(2):e386-e390

Division of Medical Support and Partnership, Center for Cancer Control and Information Services, National Cancer Center.

There are no detailed analyses of regarding pegfilgrastim usage in Japanese pediatric solid tumor patients. The approved dose of pegfilgrastim in Japan is 3.6 mg. We retrospectively evaluated the incidence of dose delays and dose reductions due to neutropenia in pediatric patients with solid tumors receiving chemotherapy with pegfilgrastim between 2015 and 2018. The effects of the timing of pegfilgrastim administration were evaluated. In chemotherapies administered every 2 and 3 weeks, prolongation of chemotherapy cycles was analyzed. Fifty-nine patients received chemotherapy with prophylactic pegfilgrastim for a total 247 cycles. No significant incidence of dose delays was observed with pegfilgrastim administration during the first 1 to 3 days after chemotherapy. When 77 cycles in 2-week regimens were compared with 166 cycles in 3-week regimens, mean cycle durations were 15.19±2.06 and 21.97±2.88 days, respectively (P<0.001). A total of 77 chemotherapy cycles administered every 14 days were subdivided. The incidence of dose delays in pediatric patients receiving chemotherapy for 5 consecutive days was similar to that for 1 day and 2 consecutive days. Pegfilgrastim prophylaxis could be of use for Japanese pediatric patients with solid tumors receiving chemotherapy, including administration every 2 weeks. Its use aids in maintaining the chemotherapy schedule.
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http://dx.doi.org/10.1097/MPH.0000000000002238DOI Listing
March 2022

Cytokeratin-positive Malignant Tumor in the Abdomen With EWSR1/FUS-CREB Fusion: A Clinicopathologic Study of 8 Cases.

Am J Surg Pathol 2022 01;46(1):134-146

Departments of Diagnostic Pathology.

ATF1, CREB1, and CREM, which encode the CREB family of transcription factors, are fused with EWSR1 or FUS in human neoplasms, such as angiomatoid fibrous histiocytoma. EWSR1/FUS-CREB fusions have recently been reported in a group of malignant epithelioid tumors with a predilection to the peritoneal cavity and frequent cytokeratin expression. Here, we studied 8 cytokeratin-positive abdominal malignancies with these fusions for further characterization. The tumors affected males (15 to 76 y old) and presented as intra-abdominal masses with concurrent or subsequent peritoneal dissemination, ascites, and/or metastases to the liver or lymph nodes. Four patients died of the disease within 18 to 140 months. Cases 1 to 5 showed multinodular growth of monomorphic epithelioid cells with focal serous cysts. Lymphoplasmacytic infiltration was prominent and was associated with systemic inflammatory symptoms. Two patients suffered from membranous nephropathy with nephrosis. The tumors displayed partly overlapping phenotypes with malignant mesothelioma, including diffuse strong expression of AE1/AE3 and WT1 and membranous positivity of sialylated HEG1, although calretinin was negative. Case 6 showed similar histology to cases 1 to 5, but expressed smooth muscle actin diffusely, lacked WT1 and HEG1, and harbored prominent pseudoangiomatous spaces. Cases 7 and 8 displayed dense growth of small oval to short spindle cells, with occasional molding and minor swirling, superficially resembling small cell carcinoma. Lymphoplasmacytic infiltration was not observed. The tumors were positive for AE1/AE3 and CD34 (focal), whereas calretinin, WT1, and HEG1 were negative. The detected fusions were FUS-CREM (n=4), EWSR1-ATF1 (n=2), EWSR1-CREB1 (n=1), and EWSR1-CREM (n=1). We confirmed the prior observation that these tumors do not fit perfectly with known entities and provided additional novel clinicopathologic information. The tumors require wider recognition because of more aggressive behavior than angiomatoid fibrous histiocytoma despite similar genetics, and potential misdiagnosis as unrelated diseases, such as neuroendocrine neoplasms.
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http://dx.doi.org/10.1097/PAS.0000000000001742DOI Listing
January 2022

Phase 1 trial of olaratumab monotherapy and in combination with chemotherapy in pediatric patients with relapsed/refractory solid and central nervous system tumors.

Cancer Med 2021 02 20;10(3):843-856. Epub 2021 Jan 20.

Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA, USA.

Olaratumab is a monoclonal antibody that specifically binds to platelet-derived growth factor receptor alpha (PDGFRα) and blocks receptor activation. We conducted a phase 1 trial to evaluate the safety of olaratumab and determine a recommended dose in combination with three different chemotherapy regimens in children. Patients <18 years with relapsed/refractory solid or central nervous system tumors were enrolled to two dose levels of olaratumab. Patients received olaratumab monotherapy at 15 mg/kg (Part A) or 20 mg/kg (Part B) on Days 1 and 8 of the first 21-day cycle, followed by olaratumab combined with standard fixed doses of chemotherapy with doxorubicin, vincristine/irinotecan, or high-dose ifosfamide by investigator choice for subsequent 21-day cycles. In Part C, patients received olaratumab 20 mg/kg plus assigned chemotherapy for all cycles. Parts A-C enrolled 68 patients across three chemotherapy treatment arms; olaratumab in combination with doxorubicin (N = 16), vincristine/irinotecan (N = 26), or ifosfamide (N = 26). Three dose-limiting toxicities (DLTs) occurred during olaratumab monotherapy (at 15 mg/kg, grade [G] 4 alanine aminotransferase [ALT]; at 20 mg/kg, G3 lung infection and G3 gamma-glutamyl transferase). One DLT occurred during vincristine/irinotecan with olaratumab 20 mg/kg therapy (G3 ALT). Treatment-emergent adverse events ≥G3 in >25% of patients included neutropenia, anemia, leukopenia, lymphopenia, and thrombocytopenia. Pharmacokinetic profiles of olaratumab with chemotherapy were within the projected range based on adult data. There was one complete response (rhabdomyosarcoma [Part B vincristine/irinotecan arm]) and three partial responses (two rhabdomyosarcoma [Part A doxorubicin arm and Part C doxorubicin arm]; one pineoblastoma [Part B vincristine/irinotecan arm]). Olaratumab was tolerable and safely administered in combination with chemotherapy regimens commonly used in children and adolescents.
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http://dx.doi.org/10.1002/cam4.3658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897905PMC
February 2021

Vaginal Transmission of Cancer from Mothers with Cervical Cancer to Infants.

N Engl J Med 2021 01;384(1):42-50

From the Departments of Pediatric Oncology (A.A., T. Kumamoto, M.N., C.O.), Laboratory Medicine (T. Kubo, K. Sunami, H.K.), Diagnostic Pathology (N.M., H.Y.), Breast and Medical Oncology (K. Yonemori, E.N.), Pediatric Surgical Oncology (T.H., N.K.), and Experimental Therapeutics (N. Yamamoto), National Cancer Center Hospital, the Departments of Clinical Genomics (H.I., T. Kubo) and Immune Medicine (K.A.), and the Divisions of Genome Biology (K. Shiraishi, T. Kohno), Cancer Genomics (Y.A., T.S.), and Cancer Immunology (Y.T., H.N.), National Cancer Center Research Institute, the Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center (H.I., T. Kubo, T. Kohno), the Children's Cancer Center, National Center for Child Health and Development (T.H.), the Departments of Obstetrics and Gynecology (T. Kuroda, K. Yamada, N. Yanaihara, K. Takahashi, A.O.) and Pathology (T. Kiyokawa), Jikei University School of Medicine, the Departments of Pediatrics (S.H., D.H., A.M.) and Integrated Women's Health (K.O.), St. Luke's International Hospital, and the Department of Pediatrics, Toho University School of Medicine (M.M.), Tokyo, and the Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo (S.H., A.M.) - both in Japan.

Two cases of pediatric lung cancer (in 23-month-old and 6-year-old boys) resulting from mother-to-infant transmission of uterine cervical tumors were incidentally detected during routine next-generation sequencing of paired samples of tumor and normal tissue. Spontaneous regression of some lesions in the first child and slow growth of the tumor mass in the second child suggested the existence of alloimmune responses against the transmitted tumors. Immune checkpoint inhibitor therapy with nivolumab led to a strong regression of all remaining tumors in the first child. (Funded by the Japan Agency for Medical Research and Development and others; TOP-GEAR UMIN Clinical Trials Registry number, UMIN000011141.).
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http://dx.doi.org/10.1056/NEJMoa2030391DOI Listing
January 2021

FLEND (nelarabine, fludarabine, and etoposide) for relapsed T-cell acute lymphoblastic leukemia in children: a report from Japan Children's Cancer Group.

Int J Hematol 2020 Nov 6;112(5):720-724. Epub 2020 Aug 6.

Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie, Japan.

Nelarabine is a key drug for T-cell acute lymphoblastic leukemia (T-ALL). Fludarabine and etoposide might have synergistic effect with nelarabine by inhibiting ribonucleotide reductase and by preparing cell cycle for G1/S phase, respectively. We had started phase 1/2 multicenter clinical trial of combination chemotherapy consisted of nelarabine, fludarabine, and etoposide (FLEND therapy) for children with relapsed/refractory T-ALL which has been conducted since October 2011. Although we could not complete this trial because of recruitment difficulties, we treated five children with first-relapsed T-ALL which were enrolled in the phase 1 dose escalation study of fludarabine and etoposide with nelarabine. No dose-limiting toxicity occurred, and frequent grade 3-4 toxicity was hematological toxicity and febrile neutropenia, as expected. There was no neurotoxicity. All 2 patients who received the target dose of FLEND, in which nelarabine (650 mg/m), fludarabine (30 mg/m), and etoposide (100 mg/m) were administered for 5 consecutive days, were induced to complete remission. We concluded that FLEND might be safe and one of the promising combination chemotherapies to relapsed/refractory T-ALL.
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http://dx.doi.org/10.1007/s12185-020-02962-2DOI Listing
November 2020

[Successful treatment of very severe late-onset sinusoidal obstruction syndrome with recombinant human soluble thrombomodulin, steroids, and control of intra-abdominal pressure].

Rinsho Ketsueki 2020 ;61(7):734-739

Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital.

We report a case of a 16-year-old woman who achieved her third complete remission of acute lymphoblastic leukemia after undergoing allogeneic stem cell transplantation for the second time from an unrelated donor. On post-transplantation day 30, she showed weight gain, hepatomegaly, right hypochondriac pain, and ascites. On day 35, ultrasonography (US) revealed portal vein regurgitation. She was subsequently diagnosed with late-onset sinusoidal obstruction syndrome (SOS) and was transferred to the intensive care unit (ICU) on day 36 for multiple organ dysfunction syndrome (MODS) and disseminated intravascular coagulation, requiring mechanical ventilation. Her SOS was graded as very severe upon ICU admission. Recombinant human soluble thrombomodulin (380 U/kg/day) and methylprednisolone (2 mg/kg/day) therapies were initiated. Additionally, her intra-abdominal pressure had increased to 19 mmHg, which was thought to be the cause of MODS. Ascites drainage (1,000 ml/day), according to the treatment for abdominal compartment syndrome, improved her SOS and MODS. She was weaned from mechanical ventilation on the 10th day after ICU transfer, and US showed resolution of the portal vein regurgitation. She was transferred to the general ward on the 14th day. She had not experienced disease recurrence at her last visit (527 days after the second transplantation).
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http://dx.doi.org/10.11406/rinketsu.61.734DOI Listing
September 2020

A phase 1b study of blinatumomab in Japanese children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia.

Int J Hematol 2020 Aug 20;112(2):223-233. Epub 2020 Jun 20.

Department of Pediatric Oncology, National Cancer Center Hospital, Chūō, Tokyo, Japan.

Novel therapies are needed for children with relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (ALL). Blinatumomab is a bispecific T-cell engager immunotherapy that simultaneously binds to CD3-positive cytotoxic T cells and CD19-positive B cells and redirects the patient's T cells to lyse malignant and normal B cells. We conducted an open-label phase 1b study to determine the safety, pharmacokinetics, efficacy, and recommended dose of blinatumomab in Japanese children with R/R B-cell precursor ALL. Patients received induction blinatumomab for 4 weeks (5 μg/m/day week 1; 15 μg/m/day weeks 2-4), followed by a 2-week treatment-free interval (6-week cycle). In subsequent cycles, patients received blinatumomab 15 μg/m/day. The primary end point was the incidence of dose-limiting toxicities. Nine patients received blinatumomab. Since no dose-limiting toxicities were reported, the maximum tolerated dose was 5 μg/m/day for week 1, followed by 15 μg/m/day weeks 2-4 (5-15 μg/m/day, the global recommended dose of blinatumomab). All patients had ≥ 1 grade ≥ 3 adverse events; 89% had grade ≥ 3 treatment-related adverse events. M1 remission rate within the first two cycles of treatment was 56%; one patient had a minimal residual disease response. Consistent with global studies, blinatumomab appeared to be safe with preliminary evidence of efficacy in Japanese children with R/R B-cell precursor ALL.
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http://dx.doi.org/10.1007/s12185-020-02907-9DOI Listing
August 2020

Association of CD204 macrophages with poor outcomes of malignant lymphomas not in remission treated by allogeneic HCT.

Eur J Haematol 2019 Dec 8;103(6):578-587. Epub 2019 Oct 8.

Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan.

Objective: CD204 tumor-associated macrophages are associated with adverse outcomes of various malignancies. We performed a study to elucidate the role of CD204 macrophages in allogeneic hematopoietic cell transplantation (allogeneic HCT).

Methods: In a total of 81 patients who received allogeneic HCT for non-remission malignant lymphoma, immunohistochemical staining of CD204 using specimens preserved before allogeneic HCT was performed. According to the average number of CD204 macrophages in a high-power field, patients were categorized into three groups: low (<25th percentile), intermediate (≥25th percentile and <50th percentile), and high (≥50th percentile).

Results: The B-cell lymphoma proportion was higher in the low group, while T-cell lymphoma and adult T-cell leukemia proportions were higher in the high group. The 3-year overall survival (OS) was poorest in the high group; low vs intermediate vs high = 83.3% vs 43.7% vs 20.2% (P < .01). The 3-year cumulative incidences of relapse were significantly higher in the high group than the intermediate and low groups: 67.0% vs 38.1% vs 18.2% (P < .01). In multivariate analyses, the numbers of CD204 macrophages were independent risk factors of poorer OS and cumulative incidences of relapse.

Conclusions: CD204 macrophages might be associated with poorer prognosis in allogeneic HCT for malignant lymphomas.
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http://dx.doi.org/10.1111/ejh.13324DOI Listing
December 2019

Bortezomib-containing therapy in Japanese children with relapsed acute lymphoblastic leukemia.

Int J Hematol 2019 Nov 10;110(5):627-634. Epub 2019 Aug 10.

Department of Pediatric Oncology, National Cancer Center Hospital, Tokyo, Japan.

Outcomes of children treated for relapsed acute lymphoblastic leukemia (ALL) remain poor. Bortezomib (BZM), a proteasome inhibitor, has shown promising activity against lymphoid malignancies. We conducted a phase I study to evaluate the safety and tolerability of multidrug chemotherapy including BZM in Japanese children with relapsed ALL. Three of five children with relapsed ALL enrolled in the study between November 2014 and April 2016 were evaluated. BZM (1.3 mg/m) was administered on days 8, 11, 15, and 18 of multidrug induction chemotherapy. Pharmacokinetic studies were performed. Age at study entry was 5, 7, and 7 years old, respectively. Two patients had hyperdiploid B-precursor ALL, and one had T cell ALL. Although all patients experienced grade 3-4 hematologic toxicity and grade 3 elevation of aminotransferases, no dose-limiting toxicities were observed. The maximum tolerated dose was defined as 1.3 mg/m. Peripheral neuropathy and respiratory complications were not observed. Complete remission was achieved in all three patients. The mean maximum plasma concentration and area under the concentration-time curve was 74.0 ng/mL and 73.9 ng h/mL, respectively. Thus, adding BZM to 5-drug induction chemotherapy appears safe and well-tolerated in Japanese children with relapsed ALL.
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http://dx.doi.org/10.1007/s12185-019-02714-xDOI Listing
November 2019

Expanding the Phenotypic Spectrum of Mesenchymal Tumors Harboring the EWSR1-CREM Fusion.

Am J Surg Pathol 2019 12;43(12):1622-1630

Departments of Diagnostic Pathology.

ATF1, CREB1, and CREM constitute the CREB family of transcription factors. The genes encoding these factors are involved in gene fusion events in human tumors. EWSR1-ATF1 and EWSR1-CREB1 are the 2 most characterized fusions, whereas EWSR1-CREM has been less studied. To better understand the phenotypic spectrum of mesenchymal tumors associated with the EWSR1-CREM fusion, we investigated archival cases using fluorescence in situ hybridization and/or RNA sequencing. Among 33 clear cell sarcomas of soft tissue tested, we found 1 specimen, a hand tumor bearing the rearrangements of EWSR1 and CREM, with classic histology and immunophenotype. None of 6 clear cell sarcoma-like tumors of the gastrointestinal tract tested harbored the EWSR1-CREM fusion. Among 11 angiomatoid fibrous histiocytomas, we found that 3 tumors of myxoid variant harbored the rearrangements of EWSR1 and CREM. All 3 tumors occurred in middle-aged men and involved the distal extremities (N=2) and the lung (N=1). Prominent lymphoid cuff, fibrous pseudocapsule, and amianthoid fiber were present in 3, 2, and 2 tumors, respectively, whereas none showed pseudoangiomatoid spaces. All 3 tumors were immunohistochemically positive for epithelial membrane antigen and desmin. These cases suggested a closer relationship between angiomatoid fibrous histiocytoma and a recently proposed novel group of myxoid tumors with CREB family fusions. Our cohort also included 2 unclassifiable sarcomas positive for EWSR1-CREM. One of these was an aggressive pediatric tumor of the abdominal cavity characterized by proliferation of swirling spindle cells immunopositive for cytokeratin and CD34. The other tumor derived from the chest wall of an adult and exhibited a MUC4-positive sclerosing epithelioid fibrosarcoma-like histology. Our study demonstrates that a wider phenotypic spectrum is associated with the EWSR1-CREM fusion than previously reported.
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http://dx.doi.org/10.1097/PAS.0000000000001331DOI Listing
December 2019

Bone marrow examination in patients with Ewing sarcoma/peripheral primitive neuroectodermal tumor without metastasis based on F-fluorodeoxyglucose positron emission tomography/computed tomography.

Med Oncol 2019 May 18;36(7):58. Epub 2019 May 18.

Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, 104-0045, Japan.

Ewing sarcoma/peripheral primitive neuroectodermal tumor (ES/PNET) is an aggressive bone tumor. Bone marrow aspiration and biopsy (BMAB) has been recognized as the gold standard for assessing bone marrow status. While the latest guideline suggests the need to omit bone marrow aspiration in patients with no findings on F-fluorodeoxyglucose positron emission tomography (F-FDG PET) based on one retrospective report, there is no study using F-FDG PET/computed tomography (CT). We retrospectively reviewed 26 consecutive, previously untreated, ES/PNET patients. We compare the results of bone marrow aspiration and biopsy (BMAB) and those of F-FDG PET/CT in ES/PNET patients. All of the 21 patients without metastases on F-FDG PET/CT had negative BMAB. The sensitivity of bone marrow involvement in bone metastases positive patients on F-FDG PET/CT was 75% (3/4), and the specificity was 100% (22/22). In addition to the metastatic findings on F-FDG PET/CT, tumor diameter, lactate dehydrogenase level at diagnosis, and the presence or absence of bone metastasis were factors related to bone marrow involvement. It may be a reasonable option to omit BMAB in ES/PNET patients with no distant metastasis based on F-FDG PET/CT findings.
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http://dx.doi.org/10.1007/s12032-019-1279-8DOI Listing
May 2019

Feasibility and utility of a panel testing for 114 cancer-associated genes in a clinical setting: A hospital-based study.

Cancer Sci 2019 Apr 2;110(4):1480-1490. Epub 2019 Apr 2.

Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan.

Next-generation sequencing (NGS) of tumor tissue (ie, clinical sequencing) can guide clinical management by providing information about actionable gene aberrations that have diagnostic and therapeutic significance. Here, we undertook a hospital-based prospective study (TOP-GEAR project, 2nd stage) to investigate the feasibility and utility of NGS-based analysis of 114 cancer-associated genes (the NCC Oncopanel test). We examined 230 cases (comprising more than 30 tumor types) of advanced solid tumors, all of which were matched with nontumor samples. Gene profiling data were obtained for 187 cases (81.3%), 111 (59.4%) of which harbored actionable gene aberrations according to the Clinical Practice Guidelines for Next Generation Sequencing in Cancer Diagnosis and Treatment (Edition 1.0) issued by 3 major Japanese cancer-related societies. Twenty-five (13.3%) cases have since received molecular-targeted therapy according to their gene aberrations. These results indicate the utility of tumor-profiling multiplex gene panel testing in a clinical setting in Japan. This study is registered with UMIN Clinical Trials Registry (UMIN 000011141).
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http://dx.doi.org/10.1111/cas.13969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447843PMC
April 2019

Phase I clinical study of oral olaparib in pediatric patients with refractory solid tumors: study protocol.

BMC Pediatr 2019 01 26;19(1):31. Epub 2019 Jan 26.

Medical Innovation Promotion Center, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.

Background: There is no established standard chemotherapy for recurrent pediatric solid tumors such as neuroblastoma and sarcoma. Since some of these tumor cells show dysfunctions in homologous recombination repair, the goal is to conduct a phase I study of olaparib, a poly(ADP-ribose) polymerase inhibitor. In this clinical trial, the aims are to evaluate the safety, tolerability, and efficacy of olaparib in pediatric patients with refractory solid tumors and to recommend a dose for phase II trials.

Methods: In this open-label, multicenter study, olaparib tablets (62.5, 125, and 187.5 mg/m b.i.d.) will be administered orally in a standard 3 + 3 dose escalation design. Patients aged 3 to 18 years with recurrent pediatric solid tumors are eligible. Pharmacokinetic and pharmacodynamic analyses will also be performed.

Discussion: This study aims to extend the indications for olaparib by assessing its safety and efficacy in pediatric refractory solid tumor patients.

Trial Registration: UMIN-CTR ( UMIN000025521 ); Registered on January 4, 2017.
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http://dx.doi.org/10.1186/s12887-019-1409-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347807PMC
January 2019

Evaluation of aprepitant and fosaprepitant in pediatric patients.

Pediatr Int 2019 Mar 5;61(3):235-239. Epub 2019 Mar 5.

Department of Pharmacy, National Cancer Center Hospital, Tokyo, Japan.

Background: Single-dose i.v. fosaprepitant has been approved as an alternative to 3 day oral aprepitant, a neurokinin-1 receptor antagonist, and improves prevention of chemotherapy-induced nausea and vomiting (CINV). Because fosaprepitant has shown similar efficacy to aprepitant in adult patients only, this study compared the efficacy and safety of aprepitant and fosaprepitant in pediatric patients.

Methods: Children younger than 18 years who received aprepitant or fosaprepitant to manage CINV between January 2015 and March 2018 at the National Cancer Center Hospital (Tokyo) were recruited to this study. The primary endpoint was complete response (CR; no vomiting/rescue medication) between 0 and 120 h after the start of chemotherapy. Secondary endpoints were safety based on the frequency of severe adverse events, and evaluation of patient characteristics as risk factors (effect of age and sex).

Results: A total of 125 chemotherapy cycles were evaluated. In the aprepitant group, CR was observed in 36 of 80 treatment cycles (45.0%), whereas in the fosaprepitant group, it was observed in 19 of 45 cycles (42.2%; P = 0.852). No treatment-related severe adverse events were observed in either group. The number of non-CR was greater than that of CR in patients aged 6-14 years. The difference in CR rate between male and female patients was not statistically significant (47.1% vs 40.0%, respectively; P = 0.471).

Conclusions: Aprepitant and fosaprepitant were safely used and may be equally useful for pediatric patients receiving highly emetogenic chemotherapy. CR rate may be associated with patient age.
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http://dx.doi.org/10.1111/ped.13780DOI Listing
March 2019

Pediatric oncologic emergencies: Clinical and imaging review for pediatricians.

Pediatr Int 2019 Feb 7;61(2):122-139. Epub 2019 Feb 7.

Department of Pediatrics, St Luke's International Hospital, Tokyo, Japan.

Children with cancer are at increased risk of life-threatening emergencies, either from the cancer itself or related to the cancer treatment. These conditions need to be assessed and treated as early as possible to minimize morbidity and mortality. Cardiothoracic emergencies encompass a variety of pathologies, including pericardial effusion and cardiac tamponade, massive hemoptysis, superior vena cava syndrome, pulmonary embolism, and pneumonia. Abdominal emergencies include bowel obstruction, intussusception, perforation, tumor rupture, intestinal graft-versus-host disease, acute pancreatitis, neutropenic colitis, and obstructive uropathy. Radiology plays a vital role in the diagnosis of these emergencies. We here review the clinical features and imaging in pediatric patients with oncologic emergencies, including a review of recently published studies. Key radiological images are presented to highlight the radiological approach to diagnosis. Pediatricians, pediatric surgeons, and pediatric radiologists need to work together to arrive at the correct diagnosis and to ensure prompt and appropriate treatment strategies.
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http://dx.doi.org/10.1111/ped.13755DOI Listing
February 2019

A case of recurrent histiocytic sarcoma with MAP2K1 pathogenic variant treated with the MEK inhibitor trametinib.

Int J Hematol 2019 Feb 25;109(2):228-232. Epub 2018 Oct 25.

Department of Pediatric Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ki, Tokyo, 104-0045, Japan.

Histiocytic sarcoma in advanced clinical stages is typically an aggressive neoplasm, with poor response to conventional chemotherapy. An 18-year-old male with refractory histiocytic sarcoma that had transformed from Rosai-Dorfman disease was admitted to our hospital. A pathogenic variant of MAP2K1 was detected by next-generation sequencing of tumor specimens. Affected regions showed excellent responses to the MEK inhibitor trametinib. It has been reported that RAS/MEK/ERK pathway is activated in many cases of histiocytic sarcoma. MEK inhibition may represent a useful treatment option in histiocytic sarcoma.
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http://dx.doi.org/10.1007/s12185-018-2553-9DOI Listing
February 2019

Cyclophosphamide-induced hemorrhagic cystitis in young patients with solid tumors: A single institution study.

Asia Pac J Clin Oncol 2018 Oct 10;14(5):e460-e464. Epub 2018 Jul 10.

Department of Pharmacy, National Cancer Center Hospital, Tokyo, Japan.

Aim: Although hemorrhagic cystitis (HC) is a significant complication in young patients who undergo chemotherapy with cyclophosphamide (CPA), risk factors and supportive care to prevent HC are unclear. This study attempted to identify optimal supportive care to prevent CPA-induced HC.

Methods: Patients (< 30-year-old) with malignant solid tumors who had been treated with CPA-containing chemotherapy in inpatient treatment were eligible. Vigorous hydration to increase urine output and intravenous 2-mercaptethane sulfonate (mesna) were used for prophylaxis of CPA-induced HC. We retrospectively analyzed 81 patients who had been treated with CPA-containing chemotherapy over (collectively) 486 cycles, and examined relationships between HC and various factors, especially CPA dosage, use of mesna, and fluid infusion volume/rate.

Results: HC occurred in four patients (4.9%) and five cycles (1%). When stratifying by doses and methods of administration of CPA, HC occurred in 3/323 low- and intermediate-dose (< 1500 mg/m /day) cycles and mesna was used in all three cycles with HC. Patients who were given mesna had a lower flow rate than those given hydration alone in the low- and intermediate-dose CPA (126 ± 25 vs 106 ± 16 mL/m /h; P < 0.01). All patients who received high-dose CPA (≥1500 mg/m /day) were also given mesna and vigorous hydration (115 ± 16 mL/m /h).

Conclusions: Our supportive care measures may be effective in preventing CPA-induced HC. Patients who receive CPA doses < 1500 mg/m /day should get ≥125 mL/m /h of infused fluid, regardless of mesna usage; those who receive of CPA ≥1500 mg/m /day should also receive mesna and vigorous hydration.
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http://dx.doi.org/10.1111/ajco.13048DOI Listing
October 2018

Japanese physicians' attitudes toward end-of-life discussion with pediatric patients with cancer.

Support Care Cancer 2018 Nov 17;26(11):3861-3871. Epub 2018 May 17.

Center for Cancer Control and Information Services, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo, Japan.

Purpose: We explored pediatricians' practices and attitudes concerning end-of-life discussions (EOLds) with pediatric patients with cancer, and identified the determinants of pediatricians' positive attitude toward having EOLds with pediatric patients.

Methods: A multicenter questionnaire survey was conducted with 127 pediatricians specializing in the treatment of pediatric cancer.

Results: Forty-two percent of participants reported that EOLds should be held with the young group of children (6-9 years old), 68% with the middle group (10-15 years old), and 93% with the old group (16-18 years old). Meanwhile, 6, 20, and 35% of participants answered that they "always" or "usually" discussed the incurability of the disease with the young, middle, and old groups, respectively; for the patient's imminent death, the rates were 2, 11, and 24%. Pediatricians' attitude that they "should have" EOLds with the young group was predicted by more clinical experience (odds ratio [OR] 1.077; p = 0.007), more confidence in addressing children's anxiety after EOLd (OR 1.756; p = 0.050), weaker belief in the demand for EOLd (OR 0.456; p = 0.015), weaker belief in the necessity of the EOLd for children to enjoy their time until death (OR, 0.506; p = 0.021), and weaker belief in the importance of maintaining a good relationship with the parents (OR 0.381; p = 0.025).

Conclusions: While pediatricians nearly reached consensus on EOLds for the old group, EOLds with the young group remain a controversial subject. While pediatricians who supported EOLds believed in their effectiveness or necessity, those who were against EOLds tended to consider the benefits of not engaging in them.
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http://dx.doi.org/10.1007/s00520-018-4254-6DOI Listing
November 2018

Treatment outcome of children with acute lymphoblastic leukemia: the Tokyo Children's Cancer Study Group (TCCSG) Study L04-16.

Int J Hematol 2018 Jul 27;108(1):98-108. Epub 2018 Mar 27.

Department of Pediatrics, Toho University, 6-11-1 Omori-Nishi, Ota-ku, Tokyo, 143-8541, Japan.

The survival rate of children with acute lymphoblastic leukemia (ALL) has increased to approximately 90% after substantial progress in risk-oriented treatment strategies. Between 2005 and 2013, the Tokyo Children's Cancer Study Group (TCCSG) conducted a risk-oriented, non-randomized study, L04-16. The principal aim of this study was to assemble background characteristics and treatment outcomes, and gather genetic information on leukemic cells under central diagnosis. This report outlines the background characteristics and treatment outcomes of 1033 children with ALL treated according to a TCCSG platform. The 5-year event-free and overall survival (OS) rates for all children were 78.1 ± 1.3 and 89.6 ± 1.0%, respectively. The OS rate was significantly higher in children with B-cell precursor (BCP)-ALL (91.9 ± 1.0%, n = 916) than in those with T-ALL (71.9 ± 4.3%, n = 117, p < 0.001). In univariate analysis for BCP-ALL, children aged 1-6 years (5y-OS: 94.2 ± 1.0%), with an initial white blood cell count of < 20,000/μL (94.0 ± 1.0%), high hyperdiploidy (95.4 ± 1.6%), ETV6-RUNX1 (97.4 ± 1.2%) or TCF3-PBX1 (96.9 ± 2.1%), and "Day8NoBlasts" (96.4 ± 1.1%) had the best outcomes. Genetic investigation revealed two novel fusion genes within this cohort: ETV6-ZNF385A and ZNF362-TCF4. Our study highlighted the clinical aspects of genomic features of ALL in Japanese children. We provide fundamental information for the further molecular investigation of this disease.
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http://dx.doi.org/10.1007/s12185-018-2440-4DOI Listing
July 2018

Pseudo-Chédiak-Higashi granules and Auer rods in mixed phenotype acute leukaemia, T/myeloid, not otherwise specified.

Br J Haematol 2018 01 29;180(2):175. Epub 2017 Sep 29.

Division of Pathology and Clinical Laboratories, National Cancer Centre Hospital, Tokyo, Japan.

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http://dx.doi.org/10.1111/bjh.14924DOI Listing
January 2018
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