Reduced-intensity allogenic transplantation for children and adolescents with Philadelphia chromosome-positive acute lymphoblastic leukemia.

Survival rates of patients with Philadelphia chromosome-positive ALL (Ph+ALL) have improved considerably with the introduction of tyrosine kinase inhibitors (TKI); however, hematopoietic stem cell transplantation (HSCT) continues to play an important role. Reduced-intensity conditioning (RIC) regimens have been widely applied particularly for older patients, but their validity for children and adolescents with Ph+ALL has not been investigated. In this study, data from patients receiving HSCT for de novo Ph+ALL in first or second remission at ages younger than 25 years and with a history of pre-HSCT TKI therapy were retrospectively collected through the nationwide registry in Japan. In 265 patients who received myeloablative conditioning (MAC) and 33 patients receiving RIC, 5-year leukemia-free survival (LFS) rates were 67.3% and 79.8%, respectively (p = 0.142). Multivariate analysis of LFS, focusing on patients with good performance status, identified RIC as a significant prognostic factor for LFS (hazard ratio 0.32, p = 0.032), as well as older age, higher leukocyte count at diagnosis, and disease with additional chromosomal abnormalities. These trends were similar when we focused on patients who received prophylactic post-HSCT TKI treatment, as 5-year LFS was 81.0% for MAC and 84.4% for RIC (p = 0.748). In summary, HSCT with RIC regimen showed at least comparable LFS to HSCT with MAC regimen, and RIC was an independent favorable prognostic factor on multivariate analysis adjusting potential prognostic factors. While patient numbers were limited, our data suggest that RIC may be safely applied in this group, particularly combined with prophylactic post-HSCT TKI maintenance therapy.

Haematopoietic cell transplantation for children with acute megakaryoblastic leukaemia without Down syndrome.

Patients with acute megakaryoblastic leukaemia of Down syndrome (DS-AMKL) have an excellent survival rate; however, patients with non-DS-AMKL experience poor outcomes. Therefore, this study retrospectively analysed 203 children with non-DS-AMKL who underwent their first haematopoietic cell transplantation (HCT) from 1986 to 2015 using a nationwide Japanese HCT registry data to assess HCT outcomes for non-DS-AMKL. The 5-year overall survival (OS) and event-free survival (EFS) rates were 43% and 38% respectively. The 5-year OS rate was significantly higher for patients who underwent HCT in the first complete remission (CR1, 72%) than for those in the second CR (CR2, 23%) and non-CR (16%) (p < 0.001), and for those from a human leukocyte antigen (HLA)-matched (52%) than for those from an HLA-mismatched donor (27%) (p < 0.001). Multivariate analysis for OS revealed that HCT in CR2 and non-CR was a significant risk factor (hazard ratio, 5.86; 95% confidence interval, 3.56-9.53; p < 0.001). The 3-year EFS in patients who received HCT in CR1 using reduced-intensity conditioning (RIC, 35%) was significantly lower than in those using myeloablative conditioning (busulfan-based, 71%; total body irradiation-based, 58%) (p < 0.001). Risk stratification in patients with non-DS-AMKL should be established to determine HCT indication in CR1.

Hematopoietic Cell Transplantation for Inborn Errors of Immunity Other than Severe Combined Immunodeficiency in Japan: Retrospective Analysis for 1985-2016.

PURPOSE: Hematopoietic cell transplantation (HCT) is a curative therapy for most patients with inborn errors of immunity (IEI). We conducted a nationwide study on HCT for patients with IEI other than severe combined immunodeficiency (non-SCID) in Japan. METHODS: Data from the Japanese national database (Transplant Registry Unified Management Program, TRUMP) for 566 patients with non-SCID IEI, who underwent their first HCT between 1985 and 2016, were retrospectively analyzed. RESULTS: The 10-year overall survival (OS) and event-free survival (EFS) were 74% and 64%, respectively. The 10-year OS for HCT from unrelated bone marrow (URBM), accounting for 39% of HCTs, was comparable to that for HCT from matched sibling donor (MSD), 79% and 81%, respectively. HCT from unrelated cord blood (URCB), accounting for 28% of HCTs, was also common, with a 10-year OS of 69% but less robust engraftment. The intensity of conditioning was not associated with OS or neutrophil recovery; however, myeloablative conditioning was more frequently associated with infection-related death. Patients who received myeloablative irradiation showed poor OS. Multivariate analyses revealed that HCT in 1985-1995 (hazard ratio [HR], 2.0; P = 0.03), URCB (HR, 2.0; P = 0.01), and related donor other than MSD (ORD) (HR, 2.9; P < 0.001) were associated with poor OS, and URCB (HR, 3.6; P < 0.001) and ORD (HR, 2.7; P = 0.02) showed a higher incidence of retransplantation. CONCLUSIONS: We present the 1985-2016 status of HCT for non-SCID IEI in Japan with sufficient statistical power, highlighting the potential of URBM as an alternative donor and the feasibility of reduced intensity conditioning.

Prognostic factors of children and adolescents with T-cell acute lymphoblastic leukemia after allogeneic transplantation.

Acute lymphoblastic leukemia (ALL) is the most common cancer during childhood, and some high-risk patients with ALL require hematopoietic stem cell transplantation (HSCT). Mainly due to small patient numbers, studies focusing specifically on children and adolescents with T-cell ALL (T-ALL) are limited. Using a nationwide registry, we retrospectively analyzed data from patients under 20 years old who underwent their first HSCT for T-ALL between 2000 and 2018. As a result, total 484 patients were included, and their median follow-up period was 6.9 years after HSCT for survivors. While patients receiving HSCT at first complete remission (CR) showed relatively good 5-year leukemia free survival (5yLFS, 73.5%), once relapse occurred, their prognosis was much worse (44.4%) even if they attained second remission again (p < 0.001). Among patients receiving HSCT at CR1, grade II-IV acute graft versus host disease was associated with worse overall and LFS than grade 0-I (5yLFS 69.5% vs. 82.1%, p = 0.026) mainly due to high non-relapse mortality. Among those patients, patients receiving related bone marrow transplantation, unrelated bone marrow transplantation, or unrelated cord blood transplantation showed similar survival (5yLFS, 73.2%, 76.3%, and 77.0%, respectively). For patients undergoing cord blood transplantation at CR1, total-body irradiation-based myeloablative conditioning was associated with better 5yLFS than other conditioning regimens (85.4% vs. 62.2%, p = 0.044), as it reduced the risk of relapse. These results indicate that relapsed patients have much less chance of cure, and that identifying patients who require HSCT for cure and offering them HSCT with optimal settings during CR1 are crucial for children and adolescents with T-ALL.

Effects of cognitive impairment and assisted peritoneal dialysis on exit-site infection in older patients.

BACKGROUND: Elderly peritoneal dialysis (PD) patients required assistance for a variety of PD-related tasks. The usefulness of assisted PD in reducing the peritonitis risk has been reported; however, there is little evidence on the effectiveness of assisted PD in preventing exit-site infections in older patients. METHODS: This was a single-center, prospective cohort study. Thirty-three patients (mean age: 74.8 ± 5.9 years) on PD were evaluated for cognitive impairment (CI) using the Japanese version of the Montreal Cognitive Assessment. They were also evaluated to determine whether they performed the exit-site care procedure alone or with assistance. Patients were categorized into four groups based on the presence or absence of CI and the presence or absence of exit-site care assistance. They were followed up until the occurrence of peritonitis and exit-site infection at the end of the follow-up. RESULTS: Altogether, 8, 8, and 17 patients were assigned to the "without CI and without assistance", "without CI and with assistance", and "with CI and with assistance groups", respectively; no patients were assigned to the "with CI and without assistance group". Six and 16 patients experienced peritonitis and exit-site infection during follow-up, respectively. Kaplan-Meier analysis and log-rank tests revealed that the "without CI and without assistance group" was significantly associated with exit-site infection (log-rank < 0.05). CONCLUSION: Patients who did not receive assistance for exit-site care were at a higher risk of exit-site infections, even in the absence of CI. Caregiver assistance is important for preventing exit-site infections in older patients on PD.

Malignant brain tumor in an infant showing histopathological features of yolk sac tumor but genetic and epigenetic features of AT/RT.

SMARCA4 pathogenic variants are rarely detected in pediatric brain tumors other than atypical teratoid rhabdoid tumors (AT/RTs) without INI1 deficiency or in some cases of medulloblastoma. Here, we report an atypical intracranial immature teratoma that recurred as a yolk sac tumor with metastatic spinal and lung lesions. Sequencing of the tumor revealed two SMARCA4 variants, including a splice-site variant and a non-synonymous variant of uncertain significance. Additionally, the methylation signature of the tumor was close to that of AT/RTs. Our case might be a yet-unrecognized subtype of pediatric tumors in which inactivation of SMARCA4 contributes to the pathogenesis.

Rhabdoid tumor predisposition syndrome with renal tumor 10 years after brain tumor.

We report a case of rhabdoid tumor predisposition syndrome with a renal tumor developing 10 years after a brain tumor, which demonstrated an unexpectedly favorable outcome. A 2-year-old boy underwent gross total resection of a brain tumor located in the fourth ventricle, and received adjuvant chemotherapy and radiotherapy. At the age of 11 years, a renal tumor was found and nephrectomy was performed. He is currently alive without evidence of disease over 2 years without postoperative therapy. Histologically, rhabdoid cells were observed in both brain and renal tumors. Loss of SMARCB1 (also known as INI1) expression was found in the nucleus of both tumor cells. Genetic testing revealed pathogenic variants of SMARCB1 exon 5 in the renal tumor and SMARCB1 exon 9 in the brain tumor. In addition, heterozygous deletion of 22q11.21-q11.23 containing the SMARCB1 locus was shared by both tumors and this deletion was identified in normal peripheral blood. Considering the histopathological and genetic findings, our case was considered to be rhabdoid tumor predisposition syndrome with atypical teratoid/rhabdoid tumor and late-onset rhabdoid tumor of the kidney.

[Gemcitabine and Docetaxel for the Treatment of Relapsed and Refractory Malignant Rhabdoid Tumor of Kidney and Atypical Teratoid Rhabdoid Tumor].

Gemcitabine and Docetaxel(GEM/DTX)are well known chemotherapeutic drugs for the treatment of soft tissue sarcomas. However, the efficacy of these drugs in the treatment of malignant rhabdoid tumors(MRTs)has not been well described. We used GEM/DTX as salvage chemotherapy for relapsed and refractory MRTs, including 2 patients with malignant rhabdoid tumor of the kidney(MRTK)and 2 with atypical teratoid rhabdoid tumor(ATRT). At the best, partial response was observed in 3 patients(2 MRTK and 1 ATRT). The remaining patient with ATRT had stable disease. Localized edema in the field of recent radiation therapy was discovered in 2 patients. In addition, one had pleural effusion without any evidence of tumor progression. GEM/DTX can be used as a potential chemotherapeutic drug for relapsed or refractory MRTs, although attention should be paid to its unique adverse events.

Strategy to minimize radiation burden in infants and high-risk medulloblastoma using intrathecal methotrexate and high-dose chemotherapy: A prospective registry study in Japan.

BACKGROUND: Most childhood medulloblastoma (MB) cases are curable using multimodal treatment, including craniospinal irradiation (CSI). However, late effects are a serious problem for survivors. This prospective registry study evaluated Japanese patients to determine whether a reduced radiation dose was feasible. PATIENTS AND METHODS: Patients with MB were classified as an infant group (<3 years old) and a high-risk (HR) group (≥3 years old with metastasis). The HR group received intrathecal methotrexate (IT-MTX) and high-dose chemotherapy (HDC) using thiotepa and melphalan, as well as concomitant radiotherapy with a recommended CSI dose of 18 Gy and a total local dose of 50 Gy. Radiotherapy was only considered for infants if residual tumors were present after the HDC. RESULTS: Between 1997 and 2006, we identified 28 HR patients (M1: 9, M2/3: 19) and 17 infant patients (M0: 11, M1: 3, M2/3: 3). During the median follow-up of 9.4 years for the entire HR group, the 5-year progression-free survival (PFS) rate was 82.1 ± 7.2% and the 5-year overall survival (OS) rate was 85.7 ± 6.6%. Subanalyses of the patients who received the recommended treatment revealed that the 5-year PFS and OS rates were both 90.5 ± 6.4%. In the infant group, the 5-year PFS rate was 52.9 ± 12.1% and the 5-year OS rate was 51.8 ± 12.4%. There were no serious adverse events associated with the IT-MTX and HDC treatments. CONCLUSION: Intensified chemotherapy using HDC and IT-MTX might allow for a reduced prophylactic radiation dose in patients with MB with metastases. Further studies are needed to validate these findings.

Phase II study of reduced-dose craniospinal irradiation and combination chemotherapy for children with newly diagnosed medulloblastoma: A report from the Japanese Pediatric Brain Tumor Consortium.

BACKGROUND: Standard doses of craniospinal irradiation (CSI) are 23.4 Gy for patients with average-risk and 36 Gy for those with high-risk medulloblastoma (MB). We investigated whether intensified chemotherapy including intrathecal chemotherapy with simultaneous irradiation is able to reduce CSI dose to 18 Gy. METHODS: Newly diagnosed average-risk patients aged 3-11 years and high-risk patients aged 3-18 years were eligible. Patients with Stage M1-4 disease were classified as high-risk MB and the others, including M0 patients with >1.5 cm2 postoperative residual tumor, were classified as average-risk MB. Patients received chemotherapy consisting of cyclophosphamide, etoposide, cisplatin, and vincristine. Radiotherapy was started concomitantly with the second course of chemotherapy. Radiation doses were 50 Gy to the primary site and 18 Gy to the craniospinal axis. Average-risk patients received five courses of chemotherapy. High-risk patients received high-dose chemotherapy consisting of thiotepa and melphalan following four courses of chemotherapy. All patients received intrathecal methotrexate. RESULTS: From 2006 to 2014, 48 patients (35 average and 13 high risk) who met the eligibility/exclusion criteria were enrolled. The 3-year progression-free survival (PFS) and 3-year overall survival (OS) were 90.5% (standard error 5.2%) and 93.9% (4.2%), respectively, for average-risk patients, and 100% and 100%, respectively, for high-risk patients. There was no leukoencephalopathy or treatment-related deaths. Two patients experienced secondary cancer. CONCLUSIONS: These results suggest that CSI 18 Gy is adequate at least in a proportion of patients with MB treated with intensified chemotherapy including intrathecal methotrexate and simultaneous irradiation, though the results in high-risk patients were only exploratory.

Nationwide study of pediatric B-cell precursor acute lymphoblastic leukemia with chromosome 8q24/MYC rearrangement in Japan.

BACKGROUND: Rearrangements of chromosome 8q24/MYC (8q24/MYC-r), resulting from t(8;14)(q24;q32), t(2;8)(p11;q24), or t(8;22)(q24;q11), are mainly associated with Burkitt lymphoma/leukemia (BL) and rarely observed in patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The characteristics of BCP-ALL with 8q24/MYC-r are poorly understood. PROCEDURE: A retrospective nationwide study of data from patients with pediatric BCP-ALL with 8q24/MYC-r in Japan was conducted to clarify the clinical and biological characteristics associated with 8q24/MYC-r BCP-ALL. RESULTS: Ten patients with BCP-ALL with 8q24/MYC-r, including three with double-hit leukemia (DHL) (two with t(8;14)(q24;q32) and t(14;18)(q32;q21) and one with t(8;14) and t(3;22)(q27;q11)), were identified. Patients with BCP-ALL with 8q24/MYC-r had higher median age and uric acid and lactate dehydrogenase levels, than those without 8q24/MYC-r. All patients were initially treated with ALL-type chemotherapy; however, four, including one with DHL, were switched to BL-type chemotherapy, based on cytogenetic findings. One patient relapsed after standard-risk ALL-type chemotherapy, and two patients with DHL did not attain complete remission with chemotherapy; all three died within 11 months. The other seven patients treated with BL-type or high-risk ALL-type chemotherapy are alive without disease. CONCLUSIONS: The clinical and laboratory features of BL with IG-MYC rearrangement, displaying a BCP immunophenotype (Wagener et al. and Herbrueggen et al. termed it as pre-BLL), are similar to those of BCP-ALL with 8q24/MYC-r. Low-risk ALL-type chemotherapy may not be appropriate for them, and further studies are required to establish an adequate therapeutic strategy. Further studies of DHL to identify new treatment strategies are also needed.

Outcomes of Local Radiation and Intensified Combined Intrathecal Methotrexate and High-dose Chemotherapy for Intracranial Germ Cell Tumors.

Many attempts to reduce radiation fields for intracranial germ cell tumors (iGCTs) remain unsuccessful. To assess the possibility of reduction, we analyzed registry data of 57 patients who mostly underwent local irradiation for iGCTs between 1997 and 2006. The recommended treatment for pure germinomas (PGNs) included 3 courses of cisplatin and etoposide followed by 24 Gy local irradiation. Intensified chemotherapy using a combination of cyclophosphamide and intrathecal methotrexate was recommended for human chorionic gonadotropin-producing germinomas (hCG-GNs) and nongerminomatous germ cell tumors (NGGCTs); both received 50.4 Gy local irradiation. High-dose chemotherapy was only administered for residual NGGCTs after chemoradiotherapy. Craniospinal irradiation was recommended only in metastatic cases. During the median follow-up of 114.8 months, 8 of 9 relapses from 24 PGNs occurred outside irradiation fields, with a 5-year progression-free survival (5-year PFS) of 75%±8.8%. Conversely, no recurrences occurred from 11 hCG-GNs, with a 5-year PFS of 100%. Eleven of 22 patients with NGGCTs received high-dose chemotherapy; the 5-year PFS was 81.3%±8.4%; 2 of 3 relapses occurred in the spinal cord. Thus, local irradiation for PGNs was insufficient without treatment intensification. The introduction of intensified chemotherapy improved outcomes of both patients with hCG-GNs and NGGCTs. However, the contributions of either modality remained unclear.

Design of novel primer sets for easy detection of Ruegeria species from seawater.

Some coral-associated bacteria show protective roles for corals against pathogens. However, the distribution of coral-protecting bacteria in seawater is not well known. In addition, compared with the methods for investigating coral pathogens, few methods have been developed to detect coral-protecting bacteria. Here we prepared a simple method for detecting Ruegeria spp., some strains of which inhibit growth of the coral pathogen Vibrio coralliilyticus. We successfully obtained two Ruegeria-targeting primer sets through in silico and in vitro screening. The primer sets r38F-r30R and r445F-r446R, in addition to the newly designed universal primer set U357'F-U515'R, were evaluated in vitro using environmental DNA extracted from seawater collected in Osaka. These methods and primers should contribute to revealing the distribution of Ruegeria spp. in marine environments.

[Successful unrelated cord blood transplantation for extensive meningeal juvenile xanthogranuloma developing after treatment of Langerhans cell histiocytosis in a child].

A 2-year and 4-month-old boy developed Langerhans cell histiocytosis (LCH) at the left parietal region of the skull. After treatment with chemotherapy, the patient achieved remission but experienced three relapses. After 3 years, he complained of headache, blurred vision, and lethargy. Brain magnetic resonance imaging revealed multiple dura-based meningeal masses. Biopsy was performed, and the patient was then diagnosed with juvenile xanthogranuloma (JXG). The analysis of both LCH/JXG tissues revealed BRAF V600E mutation. The JXG masses were not responsive to prednisolone, which was injected locally, radiotherapy (24 Gy), and chemotherapy (2-chlorodeoxy-adenosine). In addition, since the patient developed macrophage activation syndrome associated with systemic JXG progression, he received unrelated cord blood transplantation (u-CBT) at the age of 10 years and 11 months. Engraftment was performed at day 42, and significant GVHD was not observed. Four months after CBT, the patient was treated with infliximab (Remicade®) and dexamethasone palmitate (Limethasone®). The size of the intracranial JXG masses gradually decreased after u-CBT and disappeared after 4 years. Currently, the patient is doing well at the age of 25 years and is receiving androgen replacement therapy.

Double-conditioning regimen consisting of high-dose thiotepa and melphalan with autologous stem cell rescue for high-risk pediatric solid tumors: A second report.

BACKGROUND: Pediatric patients with high-risk, relapsed, or refractory solid tumors have a poor prognosis. We have previously reported a dose-finding experience of high-dose chemotherapy consisting of thiotepa and melphalan ("double-conditioning regimen"). Using doses derived from that study, we have treated patients since 2005. We now report a retrospective review of patients treated by this fixed dose. PROCEDURE: We reviewed 50 patients (median 4 years; range 0-15 years) with high-risk or relapsed/refractory solid tumors treated by this dose-fixed, double-conditioning regimen from April 2005 to May 2014. Doses were thiotepa 800 mg/m2 and melphalan 280 mg/m2 for children ≥2 years of age, and 32 mg/kg and 6 mg/kg, respectively, for children <2 years of age. Further, doses were reduced according to creatinine clearance with poor renal function. RESULTS: Nonhematological toxicity was mainly gastrointestinal-grade 3 mucositis (n = 41) and grade 3-4 diarrhea (n = 10). Neurological, renal, and endothelial cell toxicity and sinusoidal obstruction syndrome were not observed. There were two toxic deaths (interstitial viral pneumonia). This regimen demonstrated antitumor activity against several types of tumors. Although the frequency of gastrointestinal toxicity was high, other severe toxicity was not observed. CONCLUSIONS: Our double-conditioning regimen was very well tolerated and demonstrated antitumor activity. We are moving forward with multi-institutional trials now.

Successful treatment of metastatic cerebral recurrence of pleuropulmonary blastoma.

Pleuropulmonary blastoma (PPB) is a rare pediatric tumor. The central nervous system (CNS) is the most common site of extrathoracic metastasis. The prognosis of PPB patients with CNS metastases is dismal: most patients die within one year after recurrence. Here, we describe two patients diagnosed with PPB who developed intracranial recurrences shortly after the end of their initial treatment and were successfully treated by gross total resection, radiotherapy, and chemotherapy. Both patients are in complete remission four and three years after recurrence. Although an optimal regimen remains to be determined, these cases demonstrate that PPB with CNS metastases is potentially curable.

Histological and genetic analysis of anaplastic pleomorphic xanthoastrocytoma suspected of malignant progression over a 12-year clinical course.

We report a case of anaplastic PXA for which histological study and molecular analysis were performed at the time of the first resection and two recurrences. A 15-year-old girl had a temporal lobe tumor that had been followed as a cystic lesion from three years of age without histopathological examination. The first and second surgical specimens exhibited typical histological features of PXA such as nuclear and cytoplasmic pleomorphism. In addition, microvascular proliferation was observed in the second surgical specimen. On the other hand, nuclear pleomorphism was unclear in the third surgical specimen and it was mainly composed of spindle cells. Palisading necrosis was observed. Mitotic figures and the Ki-67 proliferation index gradually increased. BRAF V600E and TERT promoter mutation were detected in the first, second, and third surgical specimens. In addition, PTEN mutation and CDNK2A deletion were detected in the third surgical specimen. Considering the histopathological and genetic changes over time, we concluded that our case of anaplastic PXA underwent malignant progression.

A Cryptic NUP214-ABL1 Fusion in B-cell Precursor Acute Lymphoblastic Leukemia.

Fluorescent in situ hybridization (FISH) analysis is the standard methods for screening ABL1 fusions, which is recurrently translocated in pediatric acute lymphoblastic leukemia (ALL), and potentially targetable by kinase inhibitors. Here we demonstrated a case of B-cell precursor ALL with NUP214-ABL1 fusion, which break-apart FISH assay for ABL1 failed to detect. The cryptic fusion was generated by small duplication from ABL1 to NUP214, which was detected by copy number analysis using genomic microarray and confirmed by PCR. In the context of precision medicine, we should establish how to screen targetable abnormalities for minimizing risk of false-negative.

Overexpression of TIFY genes promotes plant growth in rice through jasmonate signaling.

Because environmental stress can reduce crop growth and yield, the identification of genes that enhance agronomic traits is increasingly important. Previous screening of full-length cDNA overexpressing (FOX) rice lines revealed that OsTIFY11b, one of 20 TIFY proteins in rice, affects plant size, grain weight, and grain size. Therefore, we analyzed the effect of OsTIFY11b and nine other TIFY genes on the growth and yield of corresponding TIFY-FOX lines. Regardless of temperature, grain weight and culm length were enhanced in lines overexpressing TIFY11 subfamily genes, except OsTIFY11e. The TIFY-FOX plants exhibited increased floret number and reduced days to flowering, as well as reduced spikelet fertility, and OsTIFY10b, in particular, enhanced grain yield by minimizing decreases in fertility. We suggest that the enhanced growth of TIFY-transgenic rice is related to regulation of the jasmonate signaling pathway, as in Arabidopsis. Moreover, we discuss the potential application of TIFY overexpression for improving crop yield.