Genomic insights into familial adenomatous polyposis: unraveling a rare case with whole APC gene deletion and intellectual disability.

A young patient diagnosed with advanced colon cancer and liver metastasis was found to have familial adenomatous polyposis (FAP) through comprehensive genomic analysis. Whole-genome array comparative genomic hybridization (aCGH) revealed germline deletions at chromosome 5q22.1-22.2 encompassing the entire APC gene. The patient and her son exhibited mild intellectual disability without developmental delay. This case highlights the need for further exploration of the characteristics associated with whole APC deletions. aCGH is a valuable tool for studying FAP and provides a detailed analysis of large deletions.

Minimal Residual Disease Detected by the 7NB-mRNAs ddPCR Assay Is Associated with Disease Progression in High-Risk Neuroblastoma Patients: A Prospective Multicenter Observational Study in Japan.

High-risk neuroblastoma (HR-NB) patients remain far from obtaining optimal outcomes, with more than 50% relapse/regrowth rate despite current intensive multimodal therapy. This originated from the activation/proliferation of chemoresistant minimal residual disease (MRD). MRD with a significant prognostic was reported by several quantitative PCR (qPCR) or droplet digital PCR (ddPCR) assays quantitating different sets of NB-associated mRNAs (NB-mRNAs). The 7NB-mRNAs ddPCR assay quantitating CRMP1, DBH, DDC, GAP43, ISL1, PHOX2B, and TH mRNAs was reported to outperform other qPCR assays by a retrospective in-house observational study. In the present study, the Japan Children's Cancer Group (JCCG) Neuroblastoma Committee conducted a prospective multicenter observational study aimed at evaluating a prognostic value of MRD in bone marrow (BM-MRD) and peripheral blood (PB-MRD) detected by 7NB-mRNAs ddPCR assay. Between August 2018 and August 2022, 7 HR-NB patients who registered for JCCG clinical trials (JN-H-11 and JN-H-15) were enrolled. A total of 19 BM and 19 PB samples were collected, and 4/15 BM and 4/15 PB samples were classified as progressive disease (PD)/non-PD samples. BM-MRD and PB-MRD estimated area under curve (AUC) of 0.767 and 0.800 with a significant accuracy (AUC > 0.7). The present study validated a prognostic value of BM-MRD obtained by a previous study (AUC 0.723) and revealed the significant accuracy of PB-MRD as well as BM-MRD.

An infantile case of hereditary folate malabsorption with sudden development of pulmonary hemorrhage: a case report.

BACKGROUND: Hereditary folate malabsorption-a rare disorder caused by impairment of the folate transporter-can develop into severe folate deficiency manifesting as megaloblastic anemia and occasionally thrombocytopenia. Reportedly, megaloblastic anemia can manifest with hemorrhagic episodes, possibly due to ineffective platelet production and platelet dysfunction. However, life-threatening hemorrhage events in hereditary folate malabsorption have not been well investigated. CASE PRESENTATION: A 3-month-old Japanese boy was transferred to our hospital due to thrombocytopenia and severe megaloblastic anemia. During a thorough examination of hematopoietic abnormalities, the patient suddenly went into cardiac arrest due to pulmonary hemorrhage. Although intravenous folate supplementation was started soon after the identification of folate deficiency, the patient died of circulatory defect and multiple organ failure. The cause of pulmonary hemorrhage, such as respiratory infection, could not be confirmed. Genetic investigation revealed a mutation in the SLC46A1 gene to be the cause of the hereditary folate malabsorption. CONCLUSION: We report an infantile case of hereditary folate malabsorption that progressed to lethal pulmonary hemorrhage before folate deficiency was identified. Clinicians should consider that megaloblastic anemia could lead to severe bleeding without warning, and that nutrient supplementation should be initiated as soon as possible.

[The Hokkaido Medical Personnel Training Plan Connecting Humans and Medicine].

The Hokkaido medical personnel training plan connecting humans and medicine aims to train"Medical personnel for genome medicine"," Medical personnel for rare cancer and childhood cancer", and"Medical personnel who promote cancer measures according to patient's life stage". We have worked on preparing medical professionals who undergo training courses not only in the graduate school but also in the community medicine centers cooperating with central medical centers in Hokkaido. Furthermore, we have been committed to training medical staff who provide comprehensive healthcare for patients with cancer cross-regionally, cross-sectionally, and tumor-agnostically and researchers who can pursue genome medicine. The evaluation committee concluded that the plan was substantially advanced according to the evaluation guideline, and a committee member commented that the information through Web was assessable during the COVID-19 pandemic; in fact, it should be ensured by everyone. Based on these comments, we continuously work to develop human resources using content and information dissemination know-how accumulated in the Hokkaido medical personnel training plan.

Lymphomatoid Papulosis Development in Acute Lymphoblastic Leukemia.

Lymphomatoid papulosis (LyP) is a chronic, recurrent benign skin disease characterized by histological features of a CD 30-positive cutaneous T-cell lymphoproliferative disorder. It is rare, with an annual, worldwide incidence of 1.2 - 1.9 per million, and accounts for 16-47% of pediatric cutaneous lymphoproliferative disorders. It often occurs on the extremities or the trunk and rarely affects the face or genitals. Its onset may be triggered by irradiation therapy, immunomodulating agents, infection or atopic dermatitis. It has a benign course but is associated with certain hematological malignancies. Mycosis fungoides and primary cutaneous anaplastic large cell lymphoma are the most commonly associated hematological malignancies. The incidence of lymphoma in children with LyP has been reported to be 8.5% at most. Most patients who develop lymphomas do so within 4 years of the LyP onset; therefore, patients with LyP should be carefully followed up. Herein, we report a case in which tumors appeared in the left scrotum and under the left lip during maintenance therapy for precursor B-cell acute lymphoblastic leukemia. We needed to distinguish the tumor from extramedullary recurrence of ALL or de novo other cutaneous lymphoma; however, the histological findings of a tumor biopsy resulted in a diagnosis of LyP.

Reduced-intensity conditioning is effective for hematopoietic stem cell transplantation in young pediatric patients with Diamond-Blackfan anemia.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for the hematologic manifestations of Diamond-Blackfan anemia (DBA). However, data regarding the optimal conditioning regimen for DBA patients are limited. We retrospectively compared the outcomes of DBA patients who underwent HSCT using either myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC) regimens. The patients belonged to a cohort treated at our hospitals between 2000 and 2018. HSCT was performed in 27 of 165 patients (16.4%). The median age at the time of HSCT was 3.6 years. Stem cell sources included bone marrow for 25 patients (HLA-matched sibling donors, n = 5; HLA-mismatched related donors, n = 2; HLA-matched/mismatched unrelated donors, n = 18) or cord blood for 2 patients. MAC or RIC regimens were used in 12 and 15 patients, respectively. Engraftment was successful in all 27 patients who underwent HSCT. Three patients who underwent HSCT using MAC regimens developed sinusoidal obstruction syndrome. The 3-year overall survival (OS) and failure-free survival rates (FFS) post-transplantations were 95.2% and 88.4%, respectively, with no significant differences between MAC and RIC regimens. Our data suggest that HSCTs using RIC regimens are effective and obtain engraftment with excellent OS and FFS for young DBA patients.

B-Cell Precursor-Acute Lymphoblastic Leukemia With EBF1-PDGFRB Fusion Treated With Hematopoietic Stem Cell Transplantation and Imatinib: A Case Report and Literature Review.

A 9-year-old girl was diagnosed with B-cell precursor-acute lymphoblastic leukemia (BCP-ALL). Although she entered remission after induction therapy, she relapsed 15 months after maintenance therapy cessation. Since further investigation revealed EBF1-PDGFRB fusion, her condition was treated as BCR-ABL1-like acute lymphoblastic leukemia. She was started on a tyrosine kinase inhibitor, imatinib, and chemotherapy and underwent umbilical cord blood transplantation following reduced intensity conditioning. She has remained in complete remission for 36 months after cord blood transplantation. This case demonstrates the successful use of a tyrosine kinase inhibitor to treat BCP-ALL with a fusion transcript and highlights the need for a standardized treatment protocol.

Spontaneous pneumothorax caused by an inflammatory myofibroblastic tumor-like lesion in a 14-year-old girl: a case report.

BACKGROUND: Spontaneous pneumothorax occurs more often in younger, slim, and shallow-chested men. Although less common, differential diagnoses for secondary pneumothorax in children are asthma, emphysematous blebs, catamenial pneumothorax, and others. We report a patient who presented with pneumothorax and was found to have an inflammatory myofibroblastic tumor (IMT)-like lesion, and present a review of the related literature. CASE PRESENTATION: A 14-year-old girl visited her physician for chest pain that developed while exercising. Although chest drainage was performed, the symptoms associated with a collapsed lung did not improve, and she was referred to our hospital. Computed tomography revealed the presence of a 19 × 17-mm cyst with a thick wall in the apex of the right lung. She was tested for infectious diseases, namely tuberculosis, but the results were not definitive. Catamenial pneumothorax was also suspected because she was menstruating when she presented to our hospital. As a therapeutic diagnosis, we performed a thoracoscopic partial resection of the right upper lobe of the lung. Three small openings were identified inside the cyst, suggesting connection with the bronchiole. The lesion was pathologically diagnosed as an IMT-like lesion. Considering the progress so far, we considered that the final diagnosis to be an IMT. The patient was discharged on postoperative day 3, and we have followed her for the past 6 months with no local recurrence or metastasis. CONCLUSIONS: IMT is not uncommon in children. Therefore, this lesion should be considered as a possible diagnosis if children and young adults develop spontaneous pneumothorax.

Clinical features of children with polycythemia vera, essential thrombocythemia, and primary myelofibrosis in Japan: A retrospective nationwide survey.

Background: Philadelphia-negative (Ph-negative) myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are exceptionally rare during childhood. Thus, clinical features of pediatric Ph-negative MPNs remain largely unknown. This study was therefore performed to address this. Methods: We performed a retrospective study to collect clinical information of children diagnosed with Ph-negative MPNs from 2000 to 2016 using questionnaires in qualified institutions in Japan. The results obtained from the questionnaire survey were then combined with those from the national registry data. Results: Among 50 children identified, five had PV, 44 had ET, and one had PMF. Median age at diagnosis was 14.0, 9.0, and 0 years, respectively. Male to female ratio was 4:1, 21:23, and 1:0, respectively. Detection rates of the JAK2 V617F variant were 0/5 in PV and 9/39 in ET. Frequencies of complications, such as thrombosis and subsequent leukemia, were lower than complication frequencies in adults. We identified two children who developed subsequent leukemia, which has not been reported previously, and one of them died. Conclusion: This is the first nationally representative survey of pediatric Ph-negative MPNs. Given its rarity, an international collaboration with comprehensive genetic analyses might be needed to fully elucidate the clinical and genetic features.

Differential efficacy of empirical antibiotic therapy for febrile neutropenia in adolescent/young adult (AYA) and child patients.

Survival rates in adolescent/young adult (AYA) patients with malignant diseases have improved with the introduction of pediatric-type chemotherapy; however, the higher frequency of treatment-related complications, including infections, remains a major challenge. We hypothesized that the efficacy of antibiotics may differ between AYA and younger children. We aimed to evaluate differences in the efficacy of antibiotics between them by retrospectively analyzing patients registered in previous first-line antibiotic comparative studies on febrile neutropenia (FN). Patients were classified into two groups: patients younger than 15 years of age (children group) and those aged 15 years or older (AYA group). The efficacy of antibiotic therapy was compared between groups. Success of therapy was defined as resolution of febrile episodes and clinical signs of infection within 120 h of the initiation of antibiotic therapy. A total of 818 febrile episodes in 204 patients were analyzed. Antibiotic therapy success rates were lower in the AYA group than in the children group (53.8 vs. 63.7%, P = 0.028), even when patients were restricted to those with bacteremia (11.8 vs. 41.4%, P = 0.025). However, mortality rates did not differ (0 vs. 0.5%, P = 1.000). The efficacy of first-line antibiotic therapy for FN was poorer in AYA patients than in child patients.

Severe adverse events by tyrosine kinase inhibitors decrease survival rates in patients with newly diagnosed chronic-phase chronic myeloid leukemia.

OBJECTIVE: This multicenter cooperative study aimed to analyze the adverse events (AEs) associated with tyrosine kinase inhibitors (TKIs) used as initial treatment for chronic-phase chronic myeloid leukemia (CML-CP) and their impact on outcome. METHODS: We retrospectively evaluated 450 patients with CML-CP who received TKIs between 2004 and 2014. RESULTS: The 5-year overall survival (OS) and event-free survival (EFS) rates were 95.1% and 89.0%, respectively. Patients with comorbidities (46.4%) and aged ≥60 years (50.4%) at diagnosis had significantly inferior OS to those without comorbidities and aged <60. Patients achieved higher rates of major molecular response (MMR) at 6 and 12 months after initial treatment with dasatinib or nilotinib compared to imatinib, but final MMR rates were almost the same. Sixty-six percent of patients required treatment modifications from first-line TKI therapy; the main reasons were AEs (48.4%) and failure (18%). Grade III-IV AEs in first-line TKI therapy were significantly correlated to inferior OS/EFS compared to grade 0-II AEs. CONCLUSION: Although long-term outcomes were similar in CML-CP patients treated with each TKI regardless of first-line TKI selection, severe AEs in first-line TKI therapy decreased their survival rates. Early change in TKIs is recommended, when faced with severe AEs of specific TKIs.

A case of primary familial congenital polycythemia with a novel EPOR mutation: possible spontaneous remission/alleviation by menstrual bleeding.

A 10-year-old girl with persistent erythrocytosis and ruddy complexion was diagnosed with primary familial congenital polycythemia (PFCP) involving a novel heterozygous mutation of c.1220C>A, p.Ser407X in exon 8 of the erythropoietin receptor gene (EPOR). This mutation causes truncation of EPOR, resulting in loss of the cytoplasmic region, which is necessary for negative regulation of erythropoietin signal transmission. Genetic analysis showed that the mutated EPOR was inherited from her mother. Her mother had polycythemia and had undergone venesection several times when she was young, but her polycythemic state appeared to have resolved. Venesection was not needed to maintain Hct levels within normal range. For the case reported here, venesection was also conducted to maintain the blood Hct level below 50%. We observed that after the patient experienced menarche, the volume and frequency of venesection needed to maintain Hct level < 50% were clearly reduced compared with those before menarche. These findings suggest that, in female patients with this type of EPOR mutation, menstruation might reduce blood volume in a manner similar to venesection. Spontaneous remission of erythrocytosis may thus occur after the start of menstrual bleeding.

The Collagen Gel Droplet-embedded Culture Drug Sensitivity Test in Relapsed Hepatoblastoma.

There are few treatment options for patients with unresectable or refractory hepatoblastoma which has failed to respond to the standard treatment. The rarity of the disease and lack of experimental materials have hampered the development of new treatments. In this study, the collagen gel droplet-embedded culture drug sensitivity test was used to evaluate the effectiveness of the multikinase inhibitors sorafenib and sunitinib, and other drugs, in relapsed hepatoblastoma tumor tissues. Tumor samples from 6 patients with relapsed hepatoblastoma were tested for drug sensitivity by the collagen gel droplet-embedded culture drug sensitivity test; evaluable results were obtained from 5 of them. All samples were judged to be sensitive to sorafenib with a 50% growth inhibitory concentration (IC50) of 0.5 to 3.1 µg/mL. Sunitinib did not achieve IC50 in 2 of 3 samples within the tested concentration range based on clinically observed serum concentrations. In the drug combination assay using a hepatoblastoma cell line, sorafenib showed synergistic effects with SN-38, an active metabolite of irinotecan. Our results provide the basic science background warranting future clinical trials of a combination of sorafenib and irinotecan for relapsed or refractory hepatoblastoma.

Population pharmacokinetics of thrombomodulin alfa in pediatric patients with hematological malignancy and disseminated intravascular coagulation.

BACKGROUND: Thrombomodulin alfa (TM-α) is a new class of anticoagulant drug for patients with disseminated intravascular coagulation (DIC). This study aimed to determine the pharmacokinetics of TM-α and determine the optimal dose in pediatric patients with hematological malignancy and DIC. PROCEDURE: Pediatric patients with hematological malignancy and DIC were administered TM-α at a dose of 0.06 mg/kg (380 U/kg) over 30 min every 24 hr. Blood samples were taken at steady state before the start, immediately after the end, and 24 hr after the start of the sixth administration. Population pharmacokinetic analysis was performed using sparse samples with the nonlinear mixed-effect modeling program NONMEM® , version 7.3. RESULTS: The actual and predicted plasma concentrations of TM-α based on the final population pharmacokinetic model showed a good linear correlation. Clearance and volume of distribution of TM-α were affected by body weight. The clearance of TM-α in pediatric patients with hematological malignancy and DIC was higher than that in adults as previously reported. Six of eight patients did not achieve the target trough concentration at steady state. Furthermore, the pharmacokinetic simulation based on the estimated pharmacokinetic parameters from the final model demonstrated that TM-α administered at a dose of 0.06 mg/kg every 24 hr also failed to achieve the target trough concentration at steady state in the majority of pediatric patients. CONCLUSIONS: Our study shows that further dose adjustment of TM-α is necessary considering the higher clearance per body weight in pediatric patients with hematological malignancy and DIC.

Hematopoietic stem cell transplantation for pediatric mature B-cell acute lymphoblastic leukemia with non-L3 morphology and MLL-AF9 gene fusion: three case reports and review of the literature.

Mature B-cell acute lymphoblastic leukemia (B-ALL) is typically associated with French-American-British (FAB)-L3 morphology and MYC gene rearrangement. However, rare cases of mature B-ALL with non-L3 morphology and MLL-AF9 fusion have been reported, and such cases are characterized by a rapid and aggressive clinical course. We here report three such cases of pediatric mature B-ALL in female patients respectively aged 15 months, 4 years, and 4 months. Bone marrow smears at diagnosis showed FAB-L1 morphology in all patients. Immunophenotypically, they were positive for cluster of differentiation (CD)10, CD19, CD20 (or CD22), Human Leukocyte Antigen-DR, and surface immunoglobulin λ. No evidence of MYC rearrangement was detected in any of the cases by fluorescent in situ hybridization (FISH) analysis. However, MLL rearrangement was detected by FISH, and MLL-AF9 fusion was confirmed by reverse transcriptase-polymerase chain reaction. All patients achieved complete remission after conventional chemotherapy and subsequently underwent hematopoietic stem cell transplantation as high-risk ALL; patient 3 for infantile ALL with MLL rearrangement and the others for ALL with MLL rearrangement and hyperleukocytosis (white blood cell count at diagnosis >50 × 10(9)/L). At the latest follow-up for each case (12-98 months post-transplantation), complete remission was maintained. Moreover, we discuss the clinical, genetic, and immunophenotypic features of this rare disease.

Extramedullary Tumor of Cerebral Falx: An Unusual Presentation of Acute Megakaryocytic Leukemia.

In childhood acute myelogenous leukemia, extramedullary tumor is an occasional clinical symptom. However, extramedullary acute megakaryocytic leukemia is extremely rare. Here, we report an extremely rare case of acute megakaryocytic leukemia in a patient who presented with extramedullary tumor of cerebral falx as a first manifestation before the diagnosis of systemic bone marrow leukemia.

A randomized trial of cefozopran versus cefepime as empirical antibiotic treatment of febrile neutropenia in pediatric cancer patients.

BACKGROUND: Febrile neutropenia (FN) is a common and serious complication of cancer chemotherapy associated with significant morbidity and mortality. Cefozopran (CZOP) is a potential candidate for empirical monotherapy in FN. However, studies on the use of CZOP as empirical treatment for pediatric patients with FN are quite limited. The purpose of this study was to compare the efficacy and safety of CZOP with cefepime (CFPM) empirical monotherapy in pediatric cancer patients with FN. PROCEDURES: A total of 64 patients with 224 episodes of FN were randomly assigned to receive antibiotic therapy with either CZOP (100 mg/kg/day) or CFPM (100 mg/kg/day). Of these episodes, 223 were considered eligible for the study. Success was defined as resolution of febrile episodes and clinical signs of infection within 120 hr following the start of antibiotic therapy. RESULTS: The success rate was not significantly different between the CZOP (64.0%) and CFPM (56.3%) groups (P = 0.275). Duration of fever, duration of antibiotic therapy, and the success rate in patients with blood stream infection did not differ between the two groups. There was no infection-related mortality in the study period. CONCLUSION: Both CZOP and CFPM as monotherapy appear to be effective and safe in pediatric patients. This study suggests that CZOP has satisfactory efficacy and is well tolerated as initial empirical therapy for pediatric cancer patients with FN.