Despite the challenges of studying the epidemiology of a rare disease, the last couple decades have uncovered tremendous knowledge about the probable causes of childhood leukemia, which currently suggests an important role for exposures that influence a child’s immune development and maturation in early life. Advances in our knowledge of fetal immune development and how it is affected by maternal exposures and in utero conditions provide reason to renew our interests in the pregnancy period for pursing immunological hypotheses in childhood leukemia etiology. This review provides a summary of the epidemiological evidence on immune-related exposures in childhood leukemia risk and places them in the context of known mechanisms for fetal immune development and postnatal immune modulation.

Background: We conducted a survey of Japanese childhood cancer survivors (CCSs) to determine their readiness for long-term care as adults and their familiarity of the tools for long-term follow-up. Methods: The participants were selected from the membership directory of Heart Link mutual-aid health insurance and the Millefeuille Childhood Cancer Frontiers. We conducted a cross-sectional survey (a self-rated questionnaire) via postal mail. Results: We analyzed 242 completed questionnaires from 132 males and 110 females with a median age of 26 years (from 12 to 47 years). More than half of the CCSs answered “fair or enough understanding” of the explanation of their cancer and their cancer stage/risk, 31% of the CCSs gave the same answer for their risk of late effects, and 45 and 49% answered the same for warning points in daily life and situations in which they need to contact their physicians, respectively. On the other hand, half of the CCSs could not list the names of the anticancer drugs administered to them and 80% did not know the total dose of each drug. Forty-three percent of the CCSs answered “fair or enough understanding” of treatment summary, 18% for the FU diary, and 13% for Japanese long-term FU guidelines. Younger age at onset/childhood solid cancers (some of which were blastoma) and subjective good health state at survey were negatively associated with their familiarity, and high educational achievement (university/graduate school) was positively associated with their familiarity. Conclusions: Familiarity of the tools for long-term follow-up was unexpectedly low in Japan. Special consideration was needed for CCSs with younger age at onset and low educational achievement.

Few reports refer to recent developments in the transition of pediatric malignant solid tumor survivors from pediatric to adult care. We investigated the long-term outcomes and challenges involved in this transition. The cases of 42 patients (21 male and 21 female subjects; age: ≥15 years) who visited our unit in 2004 were retrospectively reviewed. The courses of their treatment and care from 2004–2014 were reviewed. The diseases included neuroblastoma (11), Wilms tumor (10), germ cell tumor (6), hepatoblastoma (5), pancreatic tumor (5), and others (5). The follow-up levels and the number of patients for each level as per the Japanese guidelines were as follows: Level 1, 7; Level 2, 2; Level 3, 21; Level 4, 1; and Level 5, 11. Seventeen subjects were lost to follow-up, 11 transitioned to adult care, 9 continued under pediatric care, and 5 completed the treatment. Thirteen of those lost to follow-up were classified under Levels 3, 4, and 5, requiring continuous care. Among those who had transitioned, 9 were classified under Level 5 and had complications including renal failure, cardiac failure, hypertension, and viral hepatitis, requiring special treatment in adult departments. Most subjects under pediatric care were classified under Level 3 with no late effects and required no special treatment in the adult departments. The transition of patients classified under Level 3, who have no complications, is not smooth, and the loss of medical records is possible. An early education program and an effective transition system should be developed, especially for intermediate- to high-risk survivors.

Sclerodermatous GVHD is a late effect of hematopoietic stem cell transplantation, which results in the impairment of the quality of a survivor’s life, and is difficult to manage. Most cases are often steroid-refractory and steroid-dependent sclerodermatous GVHD, and secondary treatment sometimes has limited efficacy. We performed a retrospective study on four sclerodermatous GVHD patients presenting severe joint contracture treated with narrow-band ultraviolet B (NB-UVB) from July 2012 to May 2015. All the patients had sclerodermatous grade 2 or higher according to the National Institutes of Health (NIH) grading, and showed less than 70% in the performance scale (PS). Three patients received steroid therapy, namely, two patients with steroid-refractory and one patient with steroid-dependent sclerodermatous GVHD. The remaining patient had a high possibility of acute myeloid leukemia relapse, favoring less immunosuppressant administration. We evaluated the responses of the patients with a photographic range of motion according to the NIH therapeutic response criteria. The observation period after irradiation was 718 days (range: 368–1039 days). A mean cumulative dose of 75 J/cm² (range: 51–221 J/cm²) was applied in a mean number of 69 irradiations (range 53–159). All the patients showed improvement in the range of motion. The PS score was improved from a mean of 40% (pretreatment) to 75% (post-treatment). In western countries, extracorporeal photopheresis (ECP) is the mainstream secondary treatment for sclerodermatous GVHD, and its clinical trial is in progress in Japan. ECP is a promising treatment; however, there are a few problems, such as its high cost and facility accessibility in local areas. Therefore, NB-UVB can be an encouraging alternative to ECP for sclerodermatous GVHD.

Here, we report the case of a 12-year-old male patient with congenital hemophilia A with inhibitors who experienced two life-threatening bleeding episodes. The boy experienced hemarthrosis of the peripheral joints after a fall. Home infusion of recombinant activated factor VII was undertaken to achieve hemostasis. Four days after the trauma, hematochezia occurred, and we diagnosed him as having bleeding of the ileum. The following year, he experienced hemorrhage of the thenar muscle caused by resistance training, and home infusion was undertaken again. Right flank pain, hematuria, and left lower abdominal pain occurred 10, 14, and 15 days after the injury, respectively. We diagnosed him as having iliopsoas and renal hemorrhage. Our case suggests that home infusion for moderate hemorrhage can prevent or delay the onset of concomitant life-threatening bleeding. It is essential that patients are informed on a continuous basis about the symptoms and initial management of hemorrhage.

Castleman’s disease of the hyaline-vascular type is sometimes associated with paraneoplastic pemphigus (PNP) and causes bronchiolitis obliterans. We encountered a case in which bronchiolitis obliterans accompanied Castleman’s disease without PNP symptoms. A 15-year-old girl was referred to our hospital because of dyspnea and abdominal tumor. Open biopsy revealed that the tumor was associated with Castleman’s disease of the hyaline-vascular type. Even after the complete resection of the tumor, dyspnea did not improve. We considered that her dyspnea was derived from bronchiolitis obliterans; therefore, we administered steroids and high-dose immunoglobulin. Because of the possible progression to respiratory failure, she was added to the waiting list for lung transplantation. Despite the lack of clinical skin and mucosa features associated with Castleman’s disease, PNP-specific autoantibodies against plakin family proteins were detected in the serum of this patient, and thus, she was considered as having occult PNP.

Introduction: Although the anti-thymocyte globulin (ATG) formulation has been changed from horse to rabbit ATG [thymoglobulin (TG)], an optimal TG dose has not been established. We report here a case of refractory cytopenia of childhood (RCC) successfully treated with low-dose TG (LDTG). Case: A 2-year-old girl presented with high fever and petechia three weeks before hospitalization and showed pancytopenia (WBC count, 2,100/μL; Hb level, 4.6 g/dL; Plt count, 3,000/μL). After we diagnosed her as having RCC on the basis of bone marrow examination results, she received immunosuppressive therapy (IST) using LDTG (2.5 mg/kg/day for five consecutive days). She recovered from transfusion dependence after a month and showed complete remission six months after the initiation of IST. Conclusion: IST using LDTG was effective for the treatment of pancytopenia; however, the long-term risk of relapse, clonal evolution and infection is still unclear. Further accumulation of cases is required to establish the optimal dose of TG.

Bisphosphonates (BPs) have been increasingly used in pediatric patients recently; however, they have not been established as safe and effective drugs for children undergoing chemotherapy. We report the cases of 3 patients with acute lymphoblastic leukemia (ALL), who were administered BPs during maintenance chemotherapy. They were diagnosed as having ALL at 3 (relapsed at 9), 11, and 16 years of age, and with osteopenia at 11 (during second remission), 13, and 19 years of age, respectively. They had taken a BP (alendronate at 35 mg or risedronate at 17.5 mg) orally once a week for 30 to 72 months without any adverse effect. For two patients, their Z-scores improved from –2.4 to 0.2 and –3.7 to –1.4. All the patients completed chemotherapy and maintained a complete remission for 3 to over 5 years. BPs could be given safely during chemotherapy for ALL without affecting its outcome.

We report four cases of thyroid carcinoma occurring in patients who had been treated for malignancy in childhood. The initial malignant neoplasms were anaplastic sarcoma of the kidney, atypical teratoid/rhabdoid tumor, pleuropulmonary blastoma, and yolk sac tumor. All the patients had undergone surgery and received adjuvant chemotherapy. Two patients had received radiation therapy that included the neck in one patient. The interval between treatment and diagnosis of thyroid carcinoma ranged from 4.3 to 8.8 years (median 7.5 years). Histopathological diagnoses included one papillary carcinoma and three follicular carcinomas. Long-term follow-up with thyroid palpation and ultrasound is recommended for childhood cancer survivors.

An 11-year-old boy was transferred to our hospital because of headache and nausea. Cephalic MRI revealed a tumor in the left frontal lobe. Tumorectomy with subtotal removal was performed. A histopathological diagnosis of central nervous system primitive neuroectodermal tumor (CNS-PNET) was carried out. Chemo-radiotherapy followed by high-dose chemotherapy with stem cell rescue was conducted. However, the tumor increased in size. As severe paralysis was a concern, surgery was not indicated. Therefore, outpatient chemotherapy with vinorelbine and cyclophosphamide was started. There were no serious adverse events except for grade 3 peripheral neuropathy and grade 4 neutropenia, which required dose reduction of VNR. Subsequently, he has been well without CNS-PNET progression. The efficacy of VNR for solid tumors in children has been internationally reported. No standard treatment for refractory or relapsed CNS-PNET has been established. Further studies are needed to improve the outcome of refractory or relapsed CNS-PNET.

Rhabdomyosarcoma is a malignancy of mesenchymal cells, and it may develop in any part of the body. We report the case of a 2-year-old girl presenting with a groin mass that required differential diagnosis from an irreducible inguinal hernia. She underwent surgery because irreducible inguinal hernia was not ruled out. Intraoperatively, a solid mass was found, suggesting a malignancy. Partial tumor resection was carried out and alveolar rhabdomyosarcoma was diagnosed histopathologically. Postoperatively, we employed the protocol recommended by the Japan Rhabdomyosarcoma Study Group, which included total tumor resection. The clinical course was uneventful and no recurrence was observed during the 2-year follow up. In cases where a mass mimics an irreducible inguinal hernia and malignancy cannot be excluded, obtaining a histopathological diagnosis by biopsy or partial resection should be taken into consideration.