Prevalence of survivors of childhood cancer based on a population-based cancer registry in Osaka, Japan.

Although the survival rate of patients with childhood cancer has greatly improved, long-term survivors face specific problems such as the late effects of cancer treatment. In this study, we estimated the number of people who had experienced childhood cancer to predict their needs for medical care and social resources. Using data from the population-based Osaka Cancer Registry, we identified children aged 0-14 years who were diagnosed with cancer between 1975 and 2019. We estimated the prevalence on December 31, 2019, and the 5- and 10-year prevalence (i.e., the number of survivors living up to 5 or 10 years after the diagnosis of cancer) over time. The prevalence proportion was age-standardized using a direct standardization method. The prevalence estimates for Osaka were applied to the national population to determine the national prevalence in Japan. Among 8186 patients diagnosed with childhood cancer in Osaka, 5252 (987 per million) survived until December 31, 2019. The 5-year prevalence per million increased from 194 in 1979 to 417 in 2019 (+116%), while the 10-year prevalence increased from 391 in 1984 to 715 in 2019 (+83%). Based on the long-term registry data, an estimated 73,182 childhood cancer survivors were living in Japan by the end of 2019. The increasing 5-year and 10-year prevalence proportions indicate the continued need for cancer survivorship support for children, adolescents, and young adults. These estimates of the prevalence of childhood cancer survivors, including long-term survivors, may be useful for policymakers and clinicians to plan and evaluate survivorship care.

Current methods of preventing infectious disease and managing febrile neutropenia in childhood cancer patients: a nationwide survey in Japan.

BACKGROUND: Preventing infection and managing febrile neutropenia (FN) is mandatory for children with cancer undergoing chemotherapy. However, the current situation in Japan is unknown. METHODS: We conducted a nationwide web-based questionnaire survey in 153 institutions treating childhood cancer in Japan. We asked about the type prophylaxis used to prevent infectious disease and manage FN. If patients with childhood cancer were managed by both pediatricians and surgeons at the same institution, we asked both to reply. RESULTS: We received replies from 117 departments at 111 centers: of these, 108 were from pediatricians. Laminar air flow for neutropenic patients, and frequent hand sanitization with ethanol, were widespread. Twenty-eight percent and forty percent of departments performed active surveillance by taking cultures from patients and the environment, respectively, before initiation of chemotherapy. Forty-four percent of departments administered prophylactic intravenous antibiotics according to patient status. Many departments measured serum (1,3)-ß-D glucan, procalcitonin, and aspergillus galactomannan at the onset of FN. Twenty-eight percent of departments used carbapenem as empirical therapy for FN. Some departments used prophylactic granulocyte-colony stimulating factor for acute leukemia. Seventy-two percent of departments used prophylactic immunoglobulin for hypogammaglobinemia caused by chemotherapy. Palivizumab was administered widely for respiratory syncytial virus prophylaxis in immunocompromised infants. CONCLUSION: As a whole, intensive care for infectious prophylaxis or FN is applied in Japan; however, the methods vary among centers, and some are excessive or inadequate. Therefore, it is desirable to conduct clinical trials and establish adequate care protocols for infection in children with cancer in Japan.

[Delayed diagnosis of hydroa vacciniforme-like lymphoproliferative disorder in a patient with skin rashes].

Chronic active Epstein-Barr virus (CAEBV) infection is characterized by persistent EBV infection and can lead to fatal conditions such as hemophagocytic syndrome and malignant lymphoma through the clonal expansion of EBV-infected T or natural killer (NK) cells. Hydroa vacciniforme lymphoproliferative disorder (HV) and hypersensitivity to mosquito bites (HMB) have been identified as skin diseases in EBV-associated T- or NK-cell lymphoproliferative diseases. We present the case of a 33-year-old man. The patient had frequent episodes of a facial rash for three years before he visited our hospital, he visited several dermatologists but did not receive a diagnosis of HV. He was referred to the hematology department of our hospital for assessment of atypical lymphocytes in peripheral blood. Based on routine blood and bone marrow test we were unable to diagnose HV. However, when the patient's liver function deteriorated six months later, we considered the possibility of HV after reevaluating the skin rash. After performing EBV-related tests, we were able to definitively diagnose CAEBV with HV. It is crucial to be able to connect clinical observations to EBV-related tests when diagnosing CAEBV. Hematologists must be knowledgeable of the EBV-associated skin conditions of HV and HMB.

Preemptive hematopoietic cell transplantation for asymptomatic patients with X-linked lymphoproliferative syndrome type 1.

Few reports have examined whether prophylactic allogeneic hematopoietic cell transplantation (HCT) for X-linked lymphoproliferative syndrome type 1 (XLP1) improves the prognosis. We compared the prognosis of symptomatic probands and affected siblings in the same family. Twenty-two cases (10 probands and 12 affected siblings) in Japan, the United Kingdom, and the United States were analyzed. The overall survival (OS) rate at 5 years after diagnosis was 70.0% in probands and 91.7% in affected siblings (p = 0.0789). The prognosis of patients who developed symptoms of XLP1 before HCT and those who did not was also compared. The 5-year probability of OS from the time of diagnosis in asymptomatic patients (100%) was significantly better than that in symptomatic patients (66.7%). These results suggested that early HCT as soon as the diagnosis is made improves the prognosis in asymptomatic XLP1 patients.

Registry data analysis of hematopoietic stem cell transplantation on systemic chronic active Epstein-Barr virus infection patients in Japan.

The effects of allogeneic hematopoietic stem cell transplantation (allo-HSCT) on systemic chronic active Epstein-Barr virus infection (sCAEBV) are yet to be analyzed in a large number of patients. Using the Japanese registry database, Transplant Registry Unification Management Program, we investigated the outcomes of 102 sCAEBV patients who underwent allo-HSCT. The median age at HSCT was 21 years, and the three-year overall survival (3-year OS) rate was 72.5%. Of the 90 patients whose viral load after allo-HSCT was evaluated, 56 (62.2%) achieved a virological complete response, defined by the complete resolution of disease activity with a significant decrease in EBV-DNA in peripheral blood. The multivariate Cox proportional hazard model indicated that advanced age, in adolescents and young adults (AYA) (age, 15-39) and adults (age, ≥40 years) was a risk factor of poor OS. The hazard ratios (HRs) of the AYA and adult groups were 10.87 (95% confidence interval [CI]: 1.98-59.56, p = .006) and 15.93 (95% CI: 2.45-103.8, p = .004), respectively. Disease activity (HR 5.74), elevated soluble IL-2 receptor (sIL-2R) (≥ median, 691 U/mL) at HSCT (HR 6.93), and conditioning without radiotherapy (HR 3.53) were also independently associated with poor survival. Notably, 79% of radiotherapy doses were less than 6 Gy. Regardless of the presence of hemophagocytic lymphohistiocytosis, the group with a high sIL-2R level (≥2000 U/mL) showed a poorer prognosis. Although allo-HSCT is the only curative therapy for sCAEBV, treatment strategies need to be improved for high-risk patients, especially those with high levels of sIL-2R.

Beta-human chorionic gonadotropin-producing neuroblastoma: an unrecognized cause of gonadotropin-independent precocious puberty.

The pathogenesis of gonadotropin-independent precocious puberty (PP) includes both congenital and acquired forms, the latter of which may be associated with neoplasms, such as sex-steroid hormone-producing tumors. Beta-human chorionic gonadotropin (ß-hCG)-producing tumors also cause gonadotropin-independent PP by stimulating the production of testosterone in Leydig cells. Germ cell tumors and hepatoblastoma both produce ß-hCG; however, there is limited evidence to show that gonadotropin-independent PP is caused by other ß-hCG-producing tumors. We herein report the first case of ß-hCG-producing neuroblastoma associated with the development of gonadotropin-independent PP. A 2-year-old boy presented with an increased penile length, enlargement of the testes, pigmentation of the external genitalia, and growth acceleration. Imaging, blood, and urinary examinations revealed the presence of neuroblastoma in the right adrenal region. Decreased levels of luteinizing hormone and follicle-stimulating hormone with an increased testosterone level were indicative of gonadotropin-independent PP. Since serum ß-hCG was elevated, ß-hCG-producing neuroblastoma was suspected. Histological findings of the resected tumor were compatible with neuroblastoma. An immunohistochemical analysis using serial sections revealed staining for ß-hCG in synaptophysin-positive cells. Furthermore, immunofluorescence showed the co-staining of ß-hCG with neuron-specific enolase. These results suggested that ß-hCG was produced by tumor cells. Surgical removal of the tumor promptly normalized serum ß-hCG and testosterone levels. In conclusion, we propose the addition of neuroblastoma to the list of differential diagnoses of gonadotropin-independent PP with ß-hCG positivity in serum that includes germ cell tumors and hepatoblastoma.

Two cases of pregnancy after achieving complete remission of chronic active Epstein-Barr virus infection.

Chronic active Epstein-Barr virus (CAEBV) infection characterized by persistent infectious mononucleosis-like symptoms can lead to cardiovascular diseases. We encountered two pregnant women with CAEBV histories complicated with cardiovascular diseases. A 36-year-old woman with a history of myocardial infarction due to CAEBV and coronary artery bypass grafting became pregnant. Her left ventricular ejection fraction (LVEF) decreased, and cesarean section was performed at 36 weeks of gestation. Her LVEF recovered after delivery. A 32-year-old woman with a history of CAEBV and chronic hypertension was diagnosed with mild pulmonary arterial hypertension (PAH) after conception. She strongly desired to continue the pregnancy. She became complicated with severe superimposed preeclampsia at 31 weeks of gestation, and cesarean section was performed. Her PAH did not deteriorate during pregnancy or the postpartum period. Women treated for CAEBV, even with complete remission, require a preconception evaluation focused on the cardiovascular system and careful management of their pregnancy.

Treatment Outcomes of Langerhans Cell Histiocytosis: A Retrospective Study.

Background and Objectives: Langerhans cell histiocytosis (LCH) is a rare disease characterized by the infiltration of one or more organs by Langerhans cell-like dendritic cells. LCH often involves the bone, and its clinical evidence is limited. The purpose of this study is to report on the treatment of LCH at our institution and to add to the evidence for LCH. Materials and Methods: We reviewed six cases of LCH treated in our hospital between November 2005 and February 2016. Patient age at the first visit, sex, site of origin, symptoms, image tools used for diagnosis, biopsy site, complications, treatment, and final clinical outcome were evaluated. The median follow-up period was 41 months. Results: The median patient age at the first visit was 13.5 years. Three male and three female individuals were enrolled. Multiple lesions were observed in five cases, and a solitary lesion was observed in one case. Pain was the chief complaint in five cases. Radiography was the most commonly used imaging tool. Bone scintigraphy or magnetic resonance imaging and positron emission tomography-computed tomography were also used to diagnose systematic LCH. Biopsy of the femur was performed in two cases, and biopsy of the tibia, lumbar vertebrae, rib, and radius was performed in one case each. Regarding comorbidities, one case of hepatitis B and one case of autism were observed. Chemotherapy was initiated in two patients. The other four patients were observed naturally. Continuous disease-free survival was observed in five patients. One patient remained alive but not without disease during the final follow-up examination. Conclusion: LCH should be diagnosed as early as possible to treat it appropriately.

Impact of melphalan dose during reduced-intensity conditioning on engraftment of cord blood transplantation for chronic Epstein-Barr virus-associated T or NK cell lymphoproliferative diseases.

The rejection rate in cord blood transplants for chronic Epstein-Bar virus-associated T or natural killer cell lymphoproliferative diseases using our standard reduced-intensity conditioning "LPAM140 regimen," which includes fludarabine, melphalan (LPAM), etoposide, and antithymocyte globulin, has been high. To ensure better engraftment, we increased the LPAM dose to 210 mg/m2 ("LPAM210 regimen"). Patient data (n = 22; LPAM140, n = 7; LPAM210, n = 15) were analyzed retrospectively. The engraftment rate after the LPAM210 regimen (100.0%) was significantly higher than that after the LPAM140 regimen (57.1%; P = .002). Fludarabine combined with melphalan (210 mg/m2 ) had a favorable impact on engraftment.

Disordered hemostasis associated with severely depressed fibrinolysis demonstrated using a simultaneous thrombin and plasmin generation assay during L-asparaginase induction therapy in pediatric acute lymphoblastic leukemia.

BACKGROUND: L-asparaginase (L-Asp)-associated thromboembolisms are serious complications in pediatrics patients with acute lymphoblastic leukemia (ALL), especially at ≥10.0 years old, but the pathogenesis remains to be clarified. PROCEDURE: We conducted a multicenter, prospective study of 72 patients with ALL aged 1.0 to 15.2 years treated with either a Berlin-Frankfurt-Münster (BFM) 95-ALL oriented regimen or Japan Association of Childhood Leukemia Study ALL-02 protocol. We divided patients into each treatment protocol and investigated the dynamic changes in coagulation and fibrinolysis using simultaneous thrombin and plasmin generation assay. Patients' plasma samples were collected at the prephase (T0), intermittent phase (T1), and postphase of L-Asp therapy (T2), and postinduction phase (T3). Measurements of endogenous thrombin potential (T-EP) and plasmin peak height (P-Peak) were compared to normal plasma. RESULTS: None of the cases developed thromboembolisms. Median ratios of T-EP and P-Peak for the controls in the JACLS group were 1.06 and 0.87 (T0), 1.04 and 0.71 (T1), 1.02 and 0.69 (T2), and 1.20 and 0.92 (T3), respectively, while those in the BFM group were 1.06 and 1.00 (T0), 1.04 and 0.64 (T1), 1.16 and 0.58 (T2), and 1.16 and 0.85 (T3), respectively. In particular, P-Peak ratios were depressed at T1 and T2 compared to T0 in the BFM group (P < .01). Moreover, P-Peak ratios in patients ≥10.0 years old were lower at T1 in the BFM group (P = .02). CONCLUSIONS: The results demonstrated that hemostatic dynamics appeared to shift to a hypercoagulable state with marked hypofibrinolysis associated with L-Asp therapy, especially in patients ≥10.0 years old following the BFM regimen.