Background: The most life-threatening late effects in childhood cancer survivors (CCSs) after the completion of therapy is the development of secondary cancer.

Methods: The study design is a case series. A retrospective cohort study comprising 10,069 CCSs who were diagnosed between 1980 and 2009 was conducted in 15 Japanese hospitals. We selected secondary thyroid cancer patients who were diagnosed pathologically and obtained their detailed clinical courses using additional questionnaires.

Results: Twelve CCSs developed secondary thyroid cancer. The primary cancers were ALL (n=3), Hodgkin’s lymphoma (n=1), neuroblastoma (n=4), bone/soft tissue sarcoma (n=2), brain tumor (n=1) and pleuropulmonary blastoma (n=1). The average age at diagnosis of the primary cancer was 3 years (range, 0.1–15.5 years), and the boy/girl ratio was 4/8. The histological classifications of the primary cancers were papillary type (n=6), follicular type (n=5), and papillary with follicular variant (n=1). The median latency time from the primary cancer diagnosis to the secondary cancer was 13.3 years (range, 4.5–21.9 years). Eleven out of the 12 CCSs received some radiation therapy, and 5 CCSs received some hematopoietic stem cell transplantation. At the time of the last follow-up, all CCSs with secondary thyroid cancer were alive except for one with a disease.

Conclusions: CCSs with secondary thyroid cancer had a risk of rigorous treatment. Ultrasound screening may be recommended for CCSs with radiation therapy near the thyroid gland and/or stem cell transplantation.

The current treatment for patients with high-risk neuroblastoma is high-intensity chemotherapy, which results in myelosuppression and severe infections. According to the European Group, busulphan-melphalan high-dose chemotherapy following a rapid induction regimen known as COJEC is superior and less toxic than other treatments. In this study, we retrospectively assessed the disease status and side effects of the COJEC regimen (cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide) and compared them with those of regimen A (cyclophosphamide, vincristine, pirarubicin, and cisplatin). From February 2007 to December 2015, 18 patients with newly diagnosed high-risk neuroblastoma were treated at our institution. Ten patients underwent regimen A, and 8 patients underwent the rapid COJEC. After induction treatments, the CR or VGPR response was achieved in 7 of 10 patients in regimen A and in 7 of 8 patients in the rapid COJEC. The patients in the rapid COJEC had significantly fewer days with severe leucopenia (P<0.002) and neutropenia (P<0.005) per 100 days. There was no significant difference in the number of days with G-CSF and febrile neutropenia episodes between the two groups. The rapid COJEC induction regimen appears safe against severe leucopenia and neutropenia in pediatric patients in whom high-risk neuroblastoma was newly diagnosed. However, follow-up of long-term effects including hearing loss and renal toxicity is needed.

Extended half-life (EHL) factor IX products could improve the quality of life in patients with hemophilia B. Here, we report the effectiveness of the EHL product recombinant factor IX Fc fusion protein (rFIXFc) in 4 patients with severe hemophilia B as a prophylactic treatment. Patients 1 and 2 are brothers who have played tennis in junior and senior high schools, respectively. They received prophylaxis with recombinant factor IX (rFIX) at 40 U/kg body weight every 2 or 3 days. On the basis of the factor IX activity in plasma during sport activity, the regimen has been replaced with rFIXFc at 40 U/kg every 4 days. More than 10% of factor IX activity was estimated during club activity after school, resulting in no bleeding episodes. Patients 3 and 4 are also brothers who have prophylactically received pdFIX twice a week. The older brother’s dose was 44 U/kg, and that of the younger brother was 33 U/kg. After switching to rFIXFc, the frequency of infusion was reduced to every 6 days. The older brother’s dose was 56 U/kg, and that of the younger brother was 42 U/kg. The trough level of FIX was more than 3% without the increase in the annual bleeding rate (ABR) in both patients. These results suggest that the prophylactic use of rFIXFc is effective in reducing the frequency of venipuncture and in obtaining the appropriate factor IX level for an individual without the increase in ABR.

We retrospectively analyzed the arrangement of sperm cryopreservation in 19 patients aged ≥10 years for whom allogeneic hematopoietic stem cell transplantation (HSCT) was planned to be performed between 2008, when the practice of sperm cryopreservation commenced, and 2015 in our hospital. The median age of the 19 patients was 15 years (range, 10–27); eight patients had hematological malignancies and 11 patients had nonmalignant diseases. Ten of the 19 patients were informed about sperm cryopreservation. Among the 10 patients, sperm cryopreservation was attempted in seven patients and was successful in five patients. Six of the ten patients who received myeloablative conditioning and four of the nine patients who received reduced-intensity conditioning were informed about sperm cryopreservation. Three of the six patients who received chemotherapy were informed just before HSCT. The current study reveals various problems encountered in sperm cryopreservation for pediatric and young adult patients, who are still mentally and physically immature. Therefore, retrospective multicenter analysis will be required to investigate semen examination, fertilization and the preservation system in each institution.

Urinary vanillylmandelic acid (VMA) and homovanillic acid (HVA) detection is useful as an adjunct to the diagnosis of neuroblastoma. Previously, the “VMA spot test” was the only method of detecting urinary VMA. However, the spot test tended to yield false-positive results. Instead of the spot test, high-performance liquid chromatography (HPLC) is widely used nowadays. We have known that neither VMA nor HVA levels are elevated in approximately 10% of neuroblastoma patients. However, even in one-half of cases of such tumors, catecholamines or related metabolites were more or less secreted. Some previous studies demonstrated that the VMA spot test could detect various catecholamines and their metabolites, which are not specific for VMA. We have successfully identified two cases of VMA-negative neuroblastoma in the early phase on the basis of the positive results of the VMA spot test. In patients with tumors detected by image inspection, the VMA spot test would be a powerful tool for identifying neuroblastoma, even if the patients are negative for VMA and HVA.

Lung transplantation is the only curative therapy for refractory bronchiolitis obliterans (BO) after hematopoietic stem cell transplantation. In cases of lung transplantation in growing children, the adaptation of lung allografts to substantial somatic growth changes has been a concern, in addition to complications such as rejection and infections. A 10-year-old boy who suffered from acute myeloid leukemia developed BO after unrelated bone marrow transplantation, and received a living-donor lung transplant from his parents. He had complications of chronic rejection, cytomegalovirus infection, and renal dysfunction, which were all treated successfully. His quality of life improved dramatically, and he now lives an almost normal life. Both height catch-up and adequate growth of bilateral lungs were achieved seven and a half years after lung transplantation. Careful long-term follow-up should be performed by not only thoracic surgeons and pediatric hematologists but also various medical specialists such as pediatric endocrinologists, nephrologists, and neurologists.

We report the case of 5-year-old boy with BCP ALL who had very early bone marrow relapse. He received an allogeneic HSCT from his HLA haploidentical mother in his second remission. Although he had developed acute and chronic GVHD, he was free from all immunosuppressive agents 18 months after the HSCT. Then, he contracted his first IPD 26 months after the HSCT, and he contracted it again (serotype of 15A) 7 months after the first one. Because Howell Jolly bodies were detected in his peripheral blood before the first IPD, technetium 99m-labelled tin colloidal scintiscan was conducted, which revealed a perfusion defect of his spleen. Sequential CT images taken after the HSCT showed that his spleen was gradually shrinking, which resulted in atrophy before the first IPD. Trimethoprim/sulfamethoxazole given after the second IPD resulted in no recurrence of IPD.

Mucormycosis can be life-threatening, especially when the infection is disseminated. Early diagnosis is essential, although a lack of specific biomarkers renders this difficult. We present the case of a patient with acute myeloid leukemia with disseminated cutaneous mucormycosis treated successfully. We initiated liposomal amphotericin B treatment before a definitive diagnosis was made, basing the decision on the presence of multiple risk factors for mucormycosis, such as severe neutropenia and monocytopenia due to bone marrow suppression and exacerbation of the primary disease, malignant hematological disease, bone marrow transplantation, excess iron due to blood transfusion, and precedent initiation of voriconazole. The skin lesions improved without surgical resection. This case illustrates that understanding the risk factors for mucormycosis and prompt administration of appropriate therapy are essential for its treatment in patients with hematological malignancies.

The treatment of bilateral Wilms’ tumors aims at preserving renal function. We report the cases of two patients with bilateral Wilms’ tumors, who successfully underwent nephron-sparing surgery following chemotherapy. Patient 1 was a 1-year-old girl who initially underwent bilateral renal biopsy. Patient 2 was a 2-year-old boy with WAGR syndrome who did not undergo tumor biopsy in accordance with the latest protocol. Each patient underwent chemotherapy before tumor resection, and we evaluated tumor size by imaging studies over time. Computed tomography revealed a reduction in the size of the tumors initially, and no significant changes were observed subsequently. Then, partial nephrectomies were performed. Static renal scintigraphies were performed to evaluate the renal function pre- and postoperatively. The renal function of each patient was well preserved and they are doing well without tumor recurrence. During the treatment of bilateral Wilms’ tumors, it is important to evaluate renal function and tumor size on a regular basis.

A 3-year-old female with nephroblastoma received doxorubicin (DOX)-containing adjuvant chemotherapy in combination with 10.5 Gy of whole abdominal irradiation. Twenty-five weeks after the start of treatment (cumulative dose of DOX: 116 mg/m²), she was tachypneic with low oxygen saturation. Chest X-ray demonstrated bilateral pulmonary congestion and pleural effusion, and marked cardiac dilation. Echocardiography demonstrated a decrease in the left ventricular ejection fraction (36%). Under diagnosis of acute cardiac failure, fluid restriction as well as intravenous treatment with dobutamine, olprinone, human atrial natriuretic peptide, and furosemide relieved symptoms of heart failure. Nine months after chemotherapy, she was alive without any disease and her cardiac function was improved by treatment with oral enalapril, carvedilol, and furosemide. Patients with nephroblastoma may potentially develop severe cardiotoxicity despite a lower cumulative dose of DOX, since they often have other risk factors for cardiotoxicity, such as younger age at diagnosis and irradiation around the heart.

Malignant rhabdoid tumor of the kidney (MRTK) in infants often shows poor prognosis. Here, we report a fatal case of an infant with MRTK that was refractory to multidisciplinary treatment. An eight-month-old male infant initially presented with an abdominal mass and gross hematuria. Computed tomography revealed a mass 75 mm in diameter in the right kidney without metastasis. He was tentatively diagnosed as having stage I right renal tumor and underwent one-stage surgical resection followed by postoperative chemotherapy. However, postoperative histopathological findings confirmed MRTK with renal capsule invasion. Despite receiving focal abdominal irradiation and three courses of chemotherapy comprising vincristine, doxorubicin, and cyclophosphamide, the patient developed peritoneal metastasis and died on day 130. MRTK shows rapid progression with a fatal outcome, mainly in infants. Development of novel therapeutic agents based on the pathology and biology of MRTK is warranted to improve the treatment outcome of MRTK.

The survival of patients with childhood cancer has improved in recent decades and there is growing recognition of the importance of fertility preservation in these patients. Here, we describe the case of a 17-year-old patient with extraosseous Ewing’s sarcoma of the pelvis who underwent testicular sperm extraction (TESE) to preserve fertility before starting chemotherapy. The patient was admitted because of bladder-rectal disturbance and buttock pain and Ewing’s sarcoma was diagnosed. Sperm collection by masturbation was attempted but ejaculation was not possible because of nerve compression by the pelvic tumor. TESE was then performed and an adequate amount of sperm was collected and cryopreserved. Chemotherapy was started on the same day and there were no complications from the TESE. TESE is a safe and minimally invasive option for fertility preservation in postpubertal boys who have childhood cancer and cannot masturbate or ejaculate.

A 14-year-old girl was admitted to our hospital because of left hip joint pain due to a pelvic mass. She was diagnosed as having Ewing’s sarcoma of the left pubic bone with distant metastasis to the right femur and left ischium on the basis of imaging and tumor biopsy findings. The primary lesion was removed after chemotherapy. Since metastasis remained and postoperative pelvic irradiation was required, laparoscopic right ovarian transposition was performed at the same time to preserve endocrine function. The whole tumor was resected macroscopically. Histopathological findings showed microscopic tumor remnants in part. On the 9th postoperative day, chemotherapy was resumed. Pelvic irradiation (total, 50.4 Gy) was initiated on the 16th postoperative day. Nine months after surgery, normal E2 and FSH levels were found. Multiple relapses were observed in the thoracolumbar vertebrae at 14 months postoperatively. Chemotherapy was resumed, but she died 25 months after surgery.

A 14-year-old male with osteosarcoma (OS) in the left tibia achieved complete remission after neoadjuvant and adjuvant chemotherapy and total resection of the primary tumor; however, he experienced pulmonary relapse twice. FDG PET-CT after wide resection of the left lung for the second recurrence showed a tumor embolism in the left popliteal vein, although he did not exhibit any embolism-associated symptoms. He underwent six courses of chemotherapy with gemcitabine and docetaxel, resection of the tumor-embolism-containing vessel with saphenous vein bypass graft, and postoperative oral pazopanib treatment. However, he experienced a third recurrence in the right lung. The patient was alive without disease while on treatment at 1 year and 6 months after the third recurrence. Since the incidence of tumor embolism is relatively higher in OS, FDG PET/CT examination is recommended for a systemic monitoring of this disease.