Chikako Kiyotani

Poor responses to tyrosine kinase inhibitors in a child with precursor B‐cell acute lymphoblastic leukemia with SNX2‐ABL1 chimeric transcript

In addition to BCR, various rare fusion partners for the ABL1 gene have been reported in leukemia. We have identified the fusion gene SNX2‐ABL1 in a pediatric case of acute lymphoblastic leukemia (ALL), which has only once previously been reported in an adult patient. Cytogenetic analysis detected this fusion gene arising from a t(5;9)(q22;q34) translocation. ALL cells carrying a SNX2‐ABL1 fusion exhibited a BCR‐ABL1+ ALL‐like gene expression profile. The patient poorly responded to dasatinib but partially responded to imatinib. Treatment using tyrosine kinase inhibitors requires further investigation to optimize the genotype‐based treatment stratification for patients with SNX2‐ABL1 fusion.

Secondary cancers among children with acute lymphoblastic leukaemia treated by the Tokyo Children's Cancer Study Group protocols: a retrospective cohort study

With improvement in survival, it is important to evaluate the impact of treatment on secondary cancers in acute lymphoblastic leukaemia (ALL) survivors. A retrospective cohort study comprising 2918 children diagnosed with ALL and enrolled on Tokyo Childrens Cancer Study Group (TCCSG) protocols between 1984 and 2005 was conducted to evaluate the incidence of secondary cancers and associated factors including treatment protocol, cranial irradiation and other characteristics of the primary ALL. Thirty‐seven patients developed secondary cancers, including acute myeloid leukaemia (n = 11), myelodysplastic syndrome (n = 5), non‐Hodgkin lymphoma (n = 2), brain tumours (n = 13) and other solid carcinomas (n = 6) within a median follow‐up duration of 9·5 years. The cumulative incidence of any secondary cancers was 1·0% (95% confidence interval (CI), 0·7–1·4%) at 10 years and 2·4% (95% CI, 1·5–3·7%) at 20 years, respectively. Standardized incidence rate ratio of secondary cancers was 9·3 (95% CI, 6·5–12·8). Multivariate analyses showed an increased risk of secondary cancers associated with the recent treatment protocol and cranial irradiation. There was no evidence of a reduction in secondary cancer incidence despite marked decreases in cranial irradiation use in the recent protocols.

Second-look surgery for intracranial germ cell tumors.

BACKGROUND The role of second-look surgery in intracranial germ cell tumors (GCTs) needs to be reviewed. OBJECTIVE To present our experience of second-look surgery in patients with intracranial GCTs who showed less than complete response despite normalizing or decreasing tumor markers after chemotherapy. METHODS Retrospective review of 7 patients who underwent second-look surgery for an intracranial GCT was performed. RESULTS Of 23 consecutive patients with newly diagnosed intracranial GCTs treated between August 2003 and August 2013, 7 patients (30%) underwent second-look surgery. The mean age was 9.4 years. The initial diagnoses were mixed germ cell tumor in 5 and immature teratoma in 2. Second-look surgery was performed after 1 to 3 courses of chemotherapy. Magnetic resonance imaging at the surgery demonstrated increasing residual tumor in 4 and stable residual tumor in 3. Tumor markers were normalized in 5 and nearly normalized in 2. Gross total resection was achieved in all patients. Histopathology at second-look surgery revealed mature teratoma in 5, fibrosis with atypical cells in 1, and fibrosis in 1. All patients subsequently underwent additional chemoradiation therapy according to the initial diagnosis. All patients are alive with no evidence of recurrence, with a mean follow-up of 48 months. CONCLUSION Second-look surgery plays an important role in the treatment of intracranial GCTs. Surgery may be encouraged at a relatively early phase after chemotherapy when the residual tumor increases or does not change size despite normalized or nearly normalized tumor markers in order to achieve complete resection and improve outcome.

Vaginal yolk sac (endodermal sinus) tumors in infancy presenting persistent vaginal bleeding.

Vaginal yolk sac (endodermal sinus) tumors were diagnosed in two girls (ages 12 and 46 months). In both, the only manifestation was persistent vaginal bleeding. Pelvic ultrasonography, computed tomography, and magnetic resonance imaging revealed solitary vaginal masses (diameter, 5 and 2 cm, respectively). Serum α‐fetoprotein was highly elevated in one patient and normal in the other. Biopsy was performed in the first patient, and a tumor excision, in the second. Combination chemotherapy with cisplatin, etoposide, and bleomycin or carboplatin was administered to the first patient, and shortly thereafter, the tumor size decreased by more than half; serum α‐fetoprotein was normalized after four chemotherapy cycles. After chemotherapy, magnetic resonance imaging revealed a small residual lesion, however the second biopsy revealed no viable tumor cells. In the second patient, no visible tumor was observed after chemotherapy by vaginoscopy. Both patients are well at 19 and 14 months after diagnosis, respectively.

Unusual chromaffin cell differentiation of a neuroblastoma after chemotherapy and radiotherapy: report of an autopsy case with immunohistochemical evaluations.

Neuroblastomas are derived from neural crest cells that are capable of multilineage differentiation. Ganglionic neuronal differentiation of childhood neuroblastoma is seen with increasing age, leading to more differentiated tumors called ganglioneuroblastomas or ganglioneuromas. Despite the fact that neuroblastomas most often arise from the adrenal medulla, chromaffin-cell differentiation in neuroblastomas is not widely recognized. Tumor cells with a chromaffin-cell nature have only been detected using histochemical techniques in neuroblastoma cell lines or focal areas of certain in vivo tumors. We describe a neuroblastoma that exhibited an unusual differentiation toward chromaffin cells in a patient that had been treated with surgery, intensive chemotherapy, and radiotherapy. Although a biopsy specimen of the retroperitoneal primary tumor was extensively necrotic, possibly because of a previous chemotherapy regimen, surgically resected metastatic tumors of bilateral ovaries were viable and diagnosed as poorly differentiated neuroblastomas according to the International Neuroblastoma Pathology Classification system. However, metastatic tumors of bilateral lungs examined at the time of autopsy exhibited histologic features similar to those of a pheochromocytoma/paraganglioma, and immunohistochemical examinations demonstrated that these tumors were composed of extra-adrenal chromaffin cells. This case confirms that neuroblastomas in childhood can transform into pheochromocytoma/paraganglioma-like tumors under special conditions.

Pain management during bone marrow aspiration and biopsy in pediatric cancer patients

The pain associated with bone marrow aspiration and biopsy (BMAB) has an enormous impact on pediatric cancer patients and their families, but no specific reference standards for sedation and analgesia have been developed in Japan. To determine the problems associated with pain management during BMAB, a cross‐sectional investigation was conducted.

Neoadjuvant chemotherapy for brain tumors in infants and young children.

OBJECT Because of their large size and high vascularity, complete removal of brain tumors in infants and young children is often difficult. In most cases the degree of resection is associated with prognosis. Neoadjuvant chemotherapy may facilitate resection by reducing the vascularity of the tumor. The authors evaluated the effectiveness of neoadjuvant chemotherapy in the management of these tumors. METHODS The authors performed a retrospective review of infants and young children who underwent tumor removal after neoadjuvant chemotherapy. RESULTS Nine consecutive patients underwent resection after neoadjuvant chemotherapy during the period February 2004 to December 2012. The mean age at diagnosis was 18 months (range 2-50 months). The average largest tumor diameter was 71 mm (range 30-130 mm) at initial surgery. Five patients underwent partial resection, and 4 underwent biopsy as the initial surgery. The histopathological diagnoses were ependymoma in 2 patients, anaplastic ependymoma in 1, primitive neuroectodermal tumor (PNET) in 2, choroid plexus carcinoma in 1, atypical teratoid/rhabdoid tumor (AT/RT) in 1, glioblastoma in 1, and embryonal tumor with abundant neuropil and true rosettes in 1. After 2-4 courses of multiagent chemotherapy (mainly with vincristine, cyclophosphamide, etoposide, and cisplatin), the second-look surgery was performed. In 1 patient with a PNET, intratumoral hemorrhage was observed after 2 courses of chemotherapy. The mean interval between the initial and the second-look surgery was 3 months. The tumor volume was reduced to varying degrees in 5 patients (56%) after chemotherapy. Intraoperatively, the vascularity of the tumor was considerably reduced, and the tumor was more circumscribed in all cases. Gross-total resection was achieved in 8 patients (89%) and neartotal resection in 1 (11%). Histopathological examination demonstrated fibrotic tissue circumscribing the tumor in 6 of 9 cases (67%). The average blood loss was 20% of the estimated blood volume, and 3 patients (33%) required a blood transfusion. There was no surgical mortality. One patient had transient dysphasia postoperatively. The mean follow-up period was 28 months. At the last follow-up, 2 patients (22%) had died (1 died of tumor progression and 1 of sepsis), and 4 patients (44%) had no tumor recurrence. CONCLUSIONS Neoadjuvant chemotherapy for brain tumors in infants and young children was effective in reduction of tumor vascularity and clarification of the tumor-brain interface, which significantly facilitated maximal tumor resection.

Pharmacokinetics of Carboplatin in a One‐Year‐Old Anuric Boy Undergoing Hemodialysis and a Review of the Literature

There have been few reports of carboplatin‐based chemotherapy for anuric infants. As we had a chance to treat a one‐year‐old anuric hepatoblastoma patient with carboplatin, we performed a pharmacokinetic analysis and examined the optimal treatment strategy. A one‐year‐old anuric boy under peritoneal dialysis was diagnosed with hepatoblastoma. Surgical resection was performed, and administration of carboplatin was scheduled postoperatively aiming at 5 mg·min/mL of the area under the curve from the time of dosing to the time of the last observation (AUC0‐t). We set the initial dose at 50 mg, higher than that calculated by the Calvert formula (34 mg); the time from the end of carboplatin infusion to the initiation of hemodialysis at 2 h; and the hemodialysis duration at 24 h. The actual AUC0‐t was 3.05 mg·min/mL because the elimination half‐lives before and during hemodialysis were shorter than expected. The AUC0‐t after the second dose (100 mg) and the third dose (80 mg) were 7.00 and 4.68 mg·min/mL, respectively. The Calvert formula is not suitable for hemodialysis patients because removal of platinum by hemodialysis is not taken into account. It appears that extrarenal clearance in anuric infants is different from that in adults. We obtained an optimal AUC0‐t using a dose of 80 mg (200 mg/m2), setting the time from the end of carboplatin infusion to the initiation of hemodialysis at 2 h, and performing 8‐h hemodialysis. Further accumulation of the pharmacokinetic data of carboplatin is necessary for anuric children.

Preoperative diagnosis of clear cell sarcoma of the kidney by detection of BCOR internal tandem duplication in circulating tumor DNA

Clear cell sarcoma of the kidney (CCSK) is the second most common renal malignancy in children. The prognosis is poorer in CCSK than in Wilms’ tumor, and multimodal treatment including surgery, intensive chemotherapy, and radiation is required to improve the outcome for children with CCSK. Histological evaluation is required for the diagnosis. However, biopsies of tumors to obtain diagnostic specimens are not routinely performed because of the risk of spreading tumor cells during the procedure. Recently, internal tandem duplication (ITD) of BCOR has been recognized as a genetic hallmark of CCSK. We herein established a novel BCOR‐ITD‐specific polymerase chain reaction method with well‐designed primers, and then performed a liquid biopsy for cell‐free DNA (cfDNA) obtained from plasma of three children with nonmetastatic renal tumors (stage II) and from one control. BCOR‐ITD was positively detected in the cfDNA of two cases, both of which were later diagnosed as CCSK based on histological feature of the resected tumor specimen, while it was not detected for a normal control and a patient diagnosed with Wilms’ tumor. Our study is the first one of preoperative circulating tumor DNA assay in pediatric renal tumors. The liquid biopsy method enables less invasive, preoperative diagnosis of CCSK with no risk of tumor spillage, which can avoid iatrogenic upstaging.

A prospective study of allogeneic transplantation from unrelated donors for chronic granulomatous disease with target busulfan-based reduced-intensity conditioning

To the Editor: Chronic granulomatous disease (CGD) is a primary immunodisorder caused by impairment of the phagocyte NADPH-oxidase function. Despite improvements in treatment, cases of CGD have been associated with serious infection, episodes of surgery, and hospitalization [1]. Survival probability of CGD patients has improved over the decades, but infections are still a major cause of morbidity and mortality when treated conservatively [2]. Allogeneic hematopoietic stem cell transplantation (HSCT) is performed as a curative approach for CGD [3]. A recent survey revealed high rates of medical and social handicaps in non-transplanted cases reaching adulthood that suggest an extended indication of HSCT for CGD cases [4]. Myeloablative conditioning regimens have been used historically, and have achieved improved survival compared to cases without HSCT [5]. In this decade, reduced-intensity conditioning (RIC) regimens have been increasingly adopted to avoid transplantation-related morbidity and mortality. However, previous challenges of RIC regimens resulted in high risk of graft failure or mixed chimerism that could be associated with graft loss and other complications [6, 7]. Recently, a multicenter prospective clinical trial conducted by the European Bone Marrow Transplantation (EBMT) Group demonstrated that a targeted busulfan (BU)based conditioning regimen for HSCT from HLA-matched donors (including HLA-9/10 matched donors) achieved a high rate (89%) of event-free survival with excellent donor chimerism and minimal toxicity [8]. However, further evidence is required to establish an optimal conditioning regimen in HSCT for CGD. We conducted a prospective clinical trial, aiming to confirm the efficacy and safety of RIC with targeted BU in HSCT from unrelated donors, including HLA-mismatched donors. In our study, conditioning consisted of targeted BU, fludarabine (FLU), and anti-thymoglobulin (ATG). BU was