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Fish allergy is generally thought to be persistent, and approximately 80% of patients with fish allergies do not develop tolerance even 10 years after diagnosis. There have been no reports of rapid tolerance development in patients with severe fish allergies. We report the development of tolerance 16 months after the diagnosis of fish allergies. A 13-month-old boy was diagnosed with rosefish allergy (Sebastes matsubarae) and Japanese jack mackerel allergy (Trachurus japonicus). To find out which species of fish he could consume safely, he under-went several oral food challenge (OFC) tests. It was determined that he could consume tuna, salmon, cod, sardine, chub mackerel (Scomber japonicus), and Japanese amberjack (Seriola quinqueradiata) without eliciting signs of allergy. He continued to eat the fish that did not produce allergic reactions three to four times a week. The titer of serum allergen-specific immunoglobulin E (IgE) to fish had decreased in a subsequent ImmunoCAP®-specific IgE blood test performed 16 months after the diagnosis of the rosefish allergy. Following this test result, he underwent OFCs with rosefish and Japanese jack mackerel, both of which turned out to be negative, and it was determined that he had developed tolerance to fish. In this case, the repeated OFCs were useful in identifying fish species that were safe for consumption. In addition, the decrease in allergen-specific IgE was useful in predicting the development of tol-erance. We hypothesize that proactive consumption of available fish species may lead to this rapid induction of tolerance to fish allergens.

Diamond-Blackfan anemia (DBA) is mainly caused by pathogenic variants in ribosomal proteins and 22 responsible genes have been identified to date. The most common causative gene of DBA is RPS19 [NM...

Monitoring of several sets of neuroblastoma-associated mRNAs (NB-mRNAs) by real-time quantitative PCR (qPCR) can be used to evaluate minimal residual disease in NB patients. Droplet digital PCR (ddPCR) is an adaption of qPCR that potentially provides simpler and more reproducible detection of low levels of mRNAs. However, whether minimal residual disease in NB patients can be monitored by ddPCR using a set of NB-mRNAs is not yet tested. In this study, 208 bone marrow (BM) and 67 peripheral blood samples were retrospectively collected from 20 high-risk NB patients with clinical disease evaluation at two Japanese centers between 2011 and 2018, and level of each NB-mRNA (CRMP1, DBH, DDC, GAP43, ISL1, PHOX2B, and TH mRNAs) was determined by ddPCR. Level of 7NB-mRNAs (defined as the combined signature of each NB-mRNA) was higher in BM than peripheral blood, but correlated significantly with each other. In accordance with disease burden, it varied with disease status (remission, stable, or progression) and collection time point (diagnosis, treatment, post-treatment, or relapse). In 73 post-treatment BM samples, it was significantly higher in 17 relapsed/regrown samples than in 56 nonrelapsed/nonregrown samples. Furthermore, ddPCR had a better prognostic value than qPCR in detecting 7NB-mRNAs in the same 73 post-treatment BM samples. This study suggests that ddPCR detection of 7NB-mRNAs is significantly associated with tumor relapse/regrowth in high-risk NB patients.

The present case underscores the importance of considering the association of severe thrombocytopenia or immune thrombocytopenia with cytomegalovirus (CMV) infection because CMV‐induced thrombocytopenia occasionally requires antiviral therapy.

Highlights • Bone marrow is the most frequent site of metastasis and relapse for neuroblastoma. • Minimal residual disease has been identified in bone marrow and peripheral blood (BM-MRD and PB-MRD) by quantifying several sets of neuroblastoma-associated mRNAs. • BM-MRD has significant prognostic information for high-risk neuroblastoma. • BM-MRD and PB-MRD show a dynamic and disease burden-dependent correlation in high-risk neuroblastoma., s Neuroblastoma (NB) is the most common extracranial solid tumor in children and originates from sympathoadrenal or Schwann cell precursors derived from neural crest. These neural crest derivatives also constitute the hematopoietic and mesenchymal stem cells in bone marrow (BM) that is the most frequent site of NB metastasis and relapse. In NB patients, NB cells have been pathologically detected in BM and peripheral blood (PB), and minimal residual disease (MRD) in BM and PB (BM-MRD and PB-MRD) can be monitored by quantitating several sets of NB-associated mRNAs (NB-mRNAs). Although previous studies have shown varying degrees of correlation between BM-MRD and PB-MRD, the underlying factors and/or mechanisms remains unknown. In the present study, we determined the levels of BM-MRD and PB-MRD by quantitating seven NB-mRNAs in 133 pairs of concurrently collected BM and PB samples from 19 high-risk NB patients with clinical disease evaluation, and examined their correlation in overall and subgroups of sample pairs. The levels of BM-MRD and PB-MRD were moderately (r = 0.418, p

Diamond-Blackfan anemia (DBA) is mainly caused by pathogenic variants in ribosomal proteins and 22 responsible genes have been identified to date. The most common causative gene of DBA is

Vanillylmandelic acid (VMA), homovanillic acid (HVA), neuron-specific enolase (NSE) and lactate dehydrogenase (LDH) are classical tumor markers and are used as standard clinical evaluations for patients with neuroblastoma (NB). Minimal residual disease (MRD) can be monitored by quantifying several sets of NB-associated mRNAs in the bone marrow (BM) and peripheral blood (PB) of patients with NB. Although MRD in BM and PB has been revealed to be a strong prognostic factor that is independent of standard clinical evaluations, its interrelation with tumor markers remains uncharacterized. The present study determined the levels of tumor markers (VMA, HVA, NSE and LDH) and MRD (BM-MRD and PB-MRD) in 133 pairs of concurrently collected BM, PB and urine samples from 19 patients with high-risk NB. The patients were evaluated during the entire course of treatment, which included 10 diagnoses, 32 treatments, 36 post-treatment, 9 relapses and 46 post-relapse sample pairs. The level of BM-MRD and PB-MRD was determined by quantifying 7 NB-mRNAs (collapsin response mediator protein 1, dopamine beta-hydroxylase, dopa decarboxylase, growth-associated protein 43, ISL LIM homeobox 1, pairedlike homeobox 2b and tyrosine hydroxylase) using droplet digital PCR. In overall sample pairs, tumor markers (VMA, HVA, NSE and LDH) demonstrated weak but significant correlations (P

The outcomes of osteosarcoma with poor prognostic factors, such as poor responders, metastatic disease at diagnosis, and relapsed or refractory disease, are poor. We reviewed the clinical records of the patients diagnosed with osteosarcoma at our institute between 2004 and 2018 who received high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) in our institute. Ten patients of osteosarcoma with poor responder, refractory status, and metastatic disease at diagnosis received high-dose chemotherapy followed by ASCT. Four patients underwent high-dose chemotherapy followed by ASCT with the conditioning regimen consisted of thiotepa and melphalan (MEL). Five patients underwent high-dose chemotherapy followed by ASCT with the conditioning regimen consisted of intravenous busulfan (BU) and MEL. One patient underwent tandem high-dose chemotherapy followed by ASCT with BU and MEL followed by carboplatin and etoposide. None of the ten patients died of regimen related toxicities. None of the five patients with poor responders who underwent high-dose chemotherapy followed by ASCT as part of consolidation therapy died of disease after ASCT. High-dose chemotherapy followed by ASCT might be effective for poor responders in osteosarcoma.

Neuroblastoma is a common extracranial solid tumor of neural crest (NC) origin that accounts for up to 15% of all pediatric cancer deaths. The disease arises from a transient population of NC cells that undergo an epithelial-mesenchymal transition (EMT) and generate diverse cell-types and tissues. Patients with neuroblastoma are characterized by their extreme heterogeneity ranging from spontaneous regression to malignant progression. More than half of newly diagnosed patients present highly metastatic tumors and are stratified into a high-risk group with dismal outcome. As many as 20% of high-risk patients have residual disease that is refractory or progressive during induction chemotherapy. Although a majority of high-risk patients achieve remission, larger part of those patients has minimal residual disease (MRD) that causes relapse even after additional consolidation therapy. MRD is composed of drug-resistant tumor cells and dynamically presented as cancer stem cells (CSCs) in residual tumors, circulating tumor cells (CTCs) in peripheral blood (PB), and disseminated tumor cells (DTCs) in bone marrow (BM) and other metastatic sites. EMT appears to be a key mechanism for cancer cells to acquire MRD phenotypes and malignant aggressiveness. Due to the restricted availability of residual tumors, PB and BM have been used to isolate and analyze CTCs and DTCs to evaluate MRD in cancer patients. In addition, recent technical advances make it possible to use circulating tumor DNA (ctDNA) shed from tumor cells into PB for MRD evaluation. Because MRD can be detected by tumor-specific antigens, genetic or epigenetic changes, and mRNAs, numerous assays using different methods and samples have been reported to detect MRD in cancer patients. In contrast to the tumor-specific gene-rearrangement-positive acute lymphoblastic leukemia (ALL) and the oncogenic fusion-gene-positive chronic myelogenous leukemia (CML) and several solid tumors, the clinical significance of MRD remains to be established in neuroblastoma. Given the extreme heterogeneity of neuroblastoma, dynamics of MRD in neuroblastoma patients will hold a key to the clinical validation. In this review, we summarize the biology and detection methods of cancer MRD in general and evaluate the available assays and clinical significance of neuroblastoma MRD to clarify its dynamics in neuroblastoma patients.

Mesenchymal stem cells (MSCs) have considerable therapeutic potential and attract increasing interest in the biomedical field. MSCs are originally isolated and characterized from bone marrow (BM), then acquired from tissues including adipose tissue, synovium, skin, dental pulp, and fetal appendages such as placenta, umbilical cord blood (UCB), and umbilical cord (UC). MSCs are a heterogeneous cell population with the capacity for (1) adherence to plastic in standard culture conditions, (2) surface marker expression of CD73+/CD90+/CD105+/CD45-/CD34-/CD14-/CD19-/HLA-DR- phenotypes, and (3) trilineage differentiation into adipocytes, osteocytes, and chondrocytes, as currently defined by the International Society for Cellular Therapy (ISCT). Although BM is the most widely used source of MSCs, the invasive nature of BM aspiration ethically limits its accessibility. Proliferation and differentiation capacity of MSCs obtained from BM generally decline with the age of the donor. In contrast, fetal MSCs obtained from UC have advantages such as vigorous proliferation and differentiation capacity. There is no ethical concern for UC sampling, as it is typically regarded as medical waste. Human UC starts to develop with continuing growth of the amniotic cavity at 4-8 weeks of gestation and keeps growing until reaching 50-60 cm in length, and it can be isolated during the whole newborn delivery period. To gain insight into the pathophysiology of intractable diseases, we have used UC-derived MSCs (UC-MSCs) from infants delivered at various gestational ages. In this protocol, we describe the isolation and characterization of UC-MSCs from fetuses/infants at 19-40 weeks of gestation.

ETV6–ABL1 fusion is a rare but recurrent oncogenic lesion found in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL), without an established chromosomal abnormality, and is associated with poor outcome. In ETV6–ABL1-positive cases, an in-frame fusion produced by a complex rearrangement results in constitutive chimeric tyrosine kinase activity. Monosomy 7 is also a rare and unfavorable chromosomal abnormality in childhood BCP-ALL. Here, we report a 14-year-old female BCP-ALL patient with ETV6–ABL1 fusion combined with monosomy 7. She was admitted to our hospital because of persistent fever. Bone marrow nuclear cell count on admission was 855,000/µL with 90.0% blastic cells of lymphoid morphology. Blasts were positive for CD10, CD19, CD20, CD34, cyCD79a, cyTdT, HLA-DR, and CD66c, had a karyotype of 45, XX, − 7 [18/20] and a split signal for ABL1 FISH probe (92.7%), and were sensitive to tyrosine kinase inhibitors, imatinib and dasatinib, in vitro. ETV6–ABL1 fusion transcript was identified by whole transcriptome sequencing and confirmed by RT-PCR. She was treated with the high-risk protocol based on ALL-BFM 95, achieved complete remission (CR) after induction chemotherapy, and maintained CR for 4 months. To our knowledge, this is the first report of ETV6–ABL1 fusion combined with monosomy 7 in childhood BCP-ALL.

We herein describe a 2-year-old boy with severe congenital neutropenia (SCN) who was successfully treated with reduced-intensity bone marrow transplantation (HSCT). He had suffered recurrent episodes of bacterial pneumonia from 12 months of age, and was found to have severe neutropenia with white blood cell counts below 100/μl. The patient harbored a heterozygous missense mutation in ELANE exon 4 (p.Gln134Pro, NM_001972.2: c.401AC). This was a novel mutation. Due to intractable pneumonia and severe persistent neutropenia, reduced-intensity HSCT was performed from an HLA-matched sibling donor. The preparative regimen consisted of melphalan, fludarabine, and 4 Gy of total body irradiation. Hematopoietic engraftment was rapidly obtained, i.e., by day +14, and complete donor chimerism was subsequently achieved. The lung complications observed pre-transplantation markedly improved after neutrophil recovery, i.e., by day +60. We concluded that HSCT is a useful treatment for SCN patients, especially for those at high risk of leukemic transformation. Fludarabine-based reduced-intensity HSCT may represent a safe and effective therapeutic option for patients with SCN who need HSCT even if they have intractable infectious complications.

Introduction: ETV6-ABL1 fusion represents a rare subgroup of pediatric acute lymphoblastic leukemia (ALL) with unfavorable outcomes. ETV6-ABL1-positive ALL is recently identified in Philadelphia chromosome (Ph)-like ALL and exhibits a gene expression profile similar to BCR-ABL1-positive ALL. Analogous to BCR-ABL1 fusion, ETV6-ABL1 fusion results in the formation of constitutively active non-receptor tyrosine kinases that can also be targeted by selective ATP-competitive tyrosine kinase inhibitors (TKIs). Since TKIs are currently incorporated into the standard treatment of BCR-ABL1-positive ALL, they will be a promising option also for the treatment ETV6-ABL1-positive ALL. However, TKI resistance becomes a common problem in TKI-treated patients, where it is frequently caused by BCR-ABL1-dependent alterations including mutations, genomic amplification, and enhanced expression of BCR-ABL1-fusion kinase. In addition, BCR-ABL1-independent alterations have also been reported to cause TKI resistance. It includes a variety of activating and/or inactivating alterations in RAS, NF-kB, PI3K-AKT, and JAK-STAT signaling pathways that mediate the oncogenic activity of BCR-ABL1 fusion kinase. In contrast, the molecular mechanisms of TKI resistance have been poorly described in ETV6-ABL1-positive ALL, except for T315I mutation of ETV6-ABL1 fusion gene in a single patient and K89M mutation of GNB1 gene in a cell line model. Patient and Results: A previously healthy 14-year-old girl was admitted to our hospital because of persistent fever. Laboratory data showed white blood cell count of 417,800 /µL and increased LDH level and uric acid level. Bone marrow examination showed nuclear cell count of 855,000 /µL with 90.0% blastic cells of lymphoid morphology. Bone marrow blasts at initial diagnosis were positive for CD10, CD19, CD20, CD34, cyCD79a, cyTdT, HLA-DR, and CD66c; had a karyotype of 45, XX, -7; and were sensitive to TKIs (imatinib and dasatinib) in vitro. A split signal analyzed by ABL1 FISH probe was positive (92.7%), while major and minor BCR-ABL1 fusion transcripts were not detected by RT-qPCR. She was treated with the high-risk protocol based on BFM 95 protocol because of prednisolone poor response. After induction chemotherapy, she achieved complete remission (CR) without ABL1 split signal and IgH gene rearrangement. However, she relapsed 19 months after initial diagnosis, and failed to achieve second CR by alternating administration of dasatinib and antileukemic drugs. Bone marrow blasts at initial diagnosis and after relapse were subjected to whole-transcriptome sequencing. ETV6-ABL1 fusion transcripts were identified in both initial diagnostic and relapsed samples, and their level of expression was not significantly changed. No known alteration in ETV6-ABL1 fusion and GNB1 genes was detected. These results suggested a novel mechanism of TKI resistance in ETV6-ABL1-positive ALL. Conclusion: To our knowledge, this is a first case of ETV6-ABL1-positive ALL who acquired ETV6-ABL1-independent TKI resistance. It will provide a foundation for the treatment of TKI-resistant ETV6-ABL1-positive ALL. Citation Format: Suguru Uemura, Daiichiro Hasegawa, Akemi Shono, Khin Kyae Mon Thwin, Nanako Nino, Satoru Takafuji, Takeshi Mori, Akihiro Tamura, Nobuyuki Yamamoto, Atsuro Saito, Kenji Kishimoto, Toshiaki Ishida, Yoshiyuki Kosaka, Kazumoto Iijima, Noriyuki Nishimura. A pediatric ETV6-ABL1-positive acute lymphoblastic leukemia case with ETV6-ABL1-independent resistance to tyrosine kinase inhibitor [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A11.