Ewing sarcoma/primitive neuroectodermal tumor of the kidney treated with chemotherapy including ifosfamide.

Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET) of the kidney is extremely rare, and is usually diagnosed after nephrectomy without neoadjuvant chemotherapy. Although ifosfamide and etoposide improve survival to a great extent in ES/PNET, the use of nephrotoxic agent, particularly ifosfamide, is a concern after nephrectomy. We describe the case of a 14-year-old female patient with abdominal mass who was diagnosed with ES/PNET of the right kidney after nephrectomy. Adjuvant chemotherapy including ifosfamide and etoposide were given. The estimated glomerular filtration rate decreased to 75% after the end of therapy. There was no evidence of recurrence 70 months after initial diagnosis.

Acute megakaryoblastic leukemia with acquired trisomy 21 and GATA1 mutations in phenotypically normal children.

UNLABELLED: GATA1 mutations are found almost exclusively in children with myeloid proliferations related to Down syndrome (DS). Here, we report two phenotypically and cytogenetically normal children with acute megakaryoblastic leukemia (AMKL) whose blasts had both acquired trisomy 21 and GATA1 mutation. Patient 1 was diagnosed with transient abnormal myelopoiesis in the neonatal period. Following spontaneous improvement of the disease, leukemic blasts increased 7 months later. He received less intensive chemotherapy, and he is now 6 years old in complete remission. Patient 2 was diagnosed with AMKL at the age of 18 months. Although he received intensive chemotherapy and a cord blood transplantation, he died without gaining remission. In both cases, trisomy 21 and GATA1 mutation were detected only in leukemic blasts, but not in germline samples. Based on a literature review, we identified reports describing 14 non-DS AMKL with GATA1 mutation and acquired trisomy 21. Of those, 12 cases were diagnosed during the neonatal period, whereas the remaining 2 cases were diagnosed at the age of 22 and 31 months, respectively. CONCLUSION: These cases suggest that GATA1 mutation may cooperate with the additional chromosome 21 in developing myeloid proliferations even in non-DS patients.

Factors influencing timing of neonatal discharge in Japan: retrospective study.

BACKGROUND: The aim of this study was to evaluate the birth and discharge dates of neonates and analyze their distribution over days of the week and the old lunar calendar. METHODS: A retrospective study of the neonates discharged in the years 1990, 2000, 2005, and 2010 was conducted in a general hospital in Tokyo, Japan. Data are represented as odds ratios (OR) of the total number of discharges per day divided by the expected number of days per year, for each day of the week as well as each 6 day cycle of the lunar calendar. RESULTS: The timing of discharge has an uneven distribution across the days of the week, with weekday discharge rates significantly lower than weekend discharge rates. This uneven distribution is particularly significant in the preterm subgroup. In contrast, there is a minor uneven distribution of births across the days of the week and that of discharges across the 6 day cycle of the lunar calendar. Logistic regression analysis for 2005 and 2010 identified admission fee paid by insurance and prematurity as significant factors associated with weekend/holiday discharge (OR, 1.84; 95% confidence interval [CI]: 1.23-2.75; OR, 1.71; 95% CI: 1.15-2.55, respectively). The average length of stay of neonates discharged on the weekend was longer than that for those discharged on a weekday, in both term and preterm infants. CONCLUSIONS: Japanese parents prefer the convenience of weekends over old superstitions about using the lunar calendar to determine the discharge date.

Temporal lobe epilepsy with hippocampal sclerosis in acute lymphoblastic leukemia.

Of 71 acute lymphoblastic leukemia survivors at our hospital over the past 10 years, 2 children developed mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). This is the first report to describe the clinical course of MTLE-HS observed longitudinally by EEG and MRI. Patient 1 experienced a seizure during chemotherapy involving intrathecal methotrexate. Postseizure MRI suggested methotrexate encephalopathy or leukemic invasion. Anticonvulsant therapy was initiated; subsequent EEGs and MRIs revealed normal results. Three years after chemotherapy, a diffuse, irregular spike-and-wave pattern was observed on interictal EEG. Five years after chemotherapy, the patient developed MTLE-HS comprising complex partial seizures, typical temporal spikes on EEG, and hippocampal sclerosis (HS). Patient 2 did not experience seizures during chemotherapy. Four years later, the patient started experiencing complex partial seizures, and a diffuse, irregular spike-and-wave pattern was observed on interictal EEG. A clinical picture of MTLE-HS developed 2 years later. In both patients, nonspecific EEG abnormalities (ie, diffuse, irregular spike-and-wave activity) preceded the appearance of HS on MRI by 2 years, suggesting an insidious advance of HS during the latent period. Such atypical EEG findings may indicate MTLE-HS during follow-up of leukemia patients. MTLE-HS develops several years after an initial precipitating incident such as prolonged seizures, central nervous system infection, and brain trauma. In our cases, the initial precipitating incident may have been chemotherapy and/or prolonged seizures. Thus, MTLE-HS associated with leukemia may not be as rare as generally believed. A large cohort study of late neurologic complications is warranted.

Novel Bernard-Soulier syndrome variants caused by compound heterozygous mutations (case I) or a cytoplasmic tail truncation (case II) of GPIbα.

A defective platelet glycoprotein (GP) Ib/IX/V complex [von Willebrand factor (VWF) receptor] results in Bernard-Soulier syndrome (BSS), which is characterized by macrothrombocytopenia and impaired ristocetin- and thrombin-induced platelet aggregation. We found 2 independent BSS-variant families: Case I [compound heterozygous mutations, p.Glu331X and a frame shift by a deletion at c.1444delA of GPIbα (GP1BA) terminating at a premature stop codon (p.Thr452ProfsX58)], and case II [homozygous nonsense mutation at c.1723C>T, p.Gln545X]. Case I platelets expressed no GPIbα, resulting in absence of ristocetin-induced platelet aggregation (RIPA) and 50% reduction in thrombin-induced aggregation with no shape change. The mother's platelets had 50% the expression level of A-type GPIbα (4-repeated VNTR: variable number of tandem repeats, p.[Thr145Met; Ser399_Pro411[4]]); the father's platelets had the same expression level of C-type GPIbα (2-repeated VNTR, p.Ser399_Pro411dup) as the mother's platelets. The mother's RIPA was significantly higher than the father's. Thrombin-induced aggregation was normal in both parents. Case II platelets expressed a GPIbα with an abnormal cytoplasmic tail, p.Gln545X-truncated GPIbα, which complexed with GPIX and GPV on the cell surface; its expression level of the complex was normal. Case II platelets had reversible RIPA, with no ATP release, and weak thrombin-induced aggregation without shape change. These results suggest that a signaling process through the GPIbα cytoplasmic tail required for full platelet activation is defective in BSS variant case II and a length polymorphism of GPIbα is associated with a modified level of RIPA heterozygous BSS case I.

Intellectual development after treatment in children with acute leukemia and brain tumor.

BACKGROUND: The influence of central nervous system (CNS)-directed chemotherapy on intelligence remains controversial. In this study, we investigated the influence of treatment on intellectual development in acute lymphoblastic leukemia (ALL) and brain tumor patients undergoing CNS-directed treatments. METHODS: Among patients treated in the Department of Pediatrics, St Luke's International Hospital between April 2000 and March 2009, the subjects were 38 patients with ALL or brain tumors who underwent regular Wechsler intelligence tests. RESULTS: The subjects consisted of 26 patients with ALL and 12 with brain tumors. Prophylactic cranial irradiation was not performed in patients with ALL, whereas it was done for all those with brain tumor. In patients with ALL, the IQ 1 year later was not changed from the start of treatment. In those with brain tumors, the verbal IQ 1 year later was significantly lower than that at the start of treatment. In patients with ALL, intelligence tests were performed 3 years after the start of treatment and there were no marked changes between the two time-points (n = 11). In those with a brain tumor, intellectual functions further decreased after the completion of treatment to as late as 5 years after the initiation of treatment (n = 7). CONCLUSIONS: There is no intellectual impairment in any patient with ALL at post-treatment follow-up 3 years after the start of treatment, while intelligence is serially reduced in brain tumor patients. An innovative intervention may be needed for this group of patients.

Bullous exudative retinal detachment due to infiltration of leukemic cells in a child with acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is known to cause several ocular involvements, but exudative retinal detachment is a rare complication. We describe a case report of a 4-year-old boy with T cell ALL who developed bilateral exudative retinal detachment caused by leukemic infiltration in the retinas after achieving hematological remission. Intravenous steroid pulse therapy and local irradiation reversed the condition, but it recurred concurrently with disease progression after a second relapse in the bone marrow. It is suggested that ophthalmic examination is crucial for ALL patients, especially for those whose white blood cell count is very high at onset.

[Effectiveness of remission induction with high-dose cytarabine for relapsed or refractory pediatric acute leukemia].

We conducted a multicenter postmarketing study to investigate the efficacy and safety of reinduction therapy with a high-dose cytarabine-containing regimen for pediatric patients with relapsed or refractory acute leukemia. Seven of 13 patients (53.8%) with ALL achieved complete or partial remission, and only 1 of 6 patients (16.7%) with AML achieved partial remission. The frequent non-hematologic adverse events were gastrointestinal toxicities, such as vomiting, diarrhea and abdominal pain, as well as pyrexia and headache. Infection appeared in 9 of 20 (45%) patients. There were two death during reinduction therapy. One died of invasive bronchopulmonary aspergillosis, and the other died of intracranial hemorrhage and renal failure. These results indicated that a high-dose cytarabine regimen is effective as reinduction therapy in pediatric patients with relapsed ALL, and supportive care is essential to prevent or control treatment-related adverse events, such as infection.

The ex vivo production of ammonia predicts L-asparaginase biological activity in children with acute lymphoblastic leukemia.

Patients with acute lymphoblastic leukemia (ALL), who develop antiasparaginase antibodies without clinical allergic reactions ("silent inactivation") during L: -asparaginase (L: -Asp) treatment, have poor outcomes. Ammonia is produced by hydrolysis of asparagine by L: -Asp. We postulated that plasma ammonia level might reflect the biological activity of L: -Asp. Five children with ALL treated according to the Tokyo Children's Cancer Study Group (TCCSG) protocol were enrolled. Plasma ammonia levels were analyzed immediately and 1 h after incubation at room temperature and "ex vivo ammonia production" was defined as increase in ammonia concentration. Ex vivo ammonia production well correlated with L: -Asp activity (r = 0.882, P < 0.01, n = 23). It always exceeded 170 microg/dL (170-345 microg/dL) in induction therapy. We found 3 patients whose ammonia production was negligible during later phases of therapy. Antiasparaginase antibody was detected and L: -Asp activity decreased in these patients. Ex vivo ammonia production is a surrogate marker of L: -Asp biological activity.

Detection of submicroscopic disease in the bone marrow and unaffected testis of a child with T-cell acute lymphoblastic leukemia who experienced "isolated" testicular relapse.

Testicular relapse has an impact on the prognosis of boys with acute lymphoblastic leukemia (ALL). Because isolated testicular relapse often precedes hematological relapse, systemic therapy is required in addition to local therapy. However, a rationale for the use of a combination of systemic chemotherapy and local therapy is unclear. A 12-year-old boy with T-ALL suffered from isolated testicular relapse at 27 months after diagnosis. He was successfully treated with systemic chemotherapy with orchiectomy and prophylactic irradiation to the contralateral testis. We retrospectively estimated the minimal residual disease in the bone marrow (BM) and the testis by detection of clone-specific T-cell receptor rearrangement of leukemic cells. We detected leukemic cells in the affected testis at relapse, as well as in the BM at initial diagnosis. In addition, we confirmed submicroscopic disease in the unaffected testis and the BM at relapse. We conclude that molecular analysis could reveal the submicroscopic disease in the patient with apparently isolated testicular relapse. This finding may provide a rationale for intensified systemic treatment of patients with isolated testicular relapse.

Iodine-131-metaiodobenzylguanidine therapy with reduced-intensity allogeneic stem cell transplantation in recurrent neuroblastoma.

Neuroblastoma is the most common extracranial solid tumor of childhood, and iodine-131-metaiodobenzylguanidine (MIBG) therapy is a new approach for grade IV neuroblastoma. We describe the case history of a 3-year-old girl with recurrent neuroblastoma who received MIBG therapy with reduced-intensity allogeneic stem cell transplantation (RIST) because of an extensive bone marrow involvement. The post-transplant course was uneventful and complete chimerism was obtained. Neither acute nor chronic graft-versus-host disease (GVHD) was observed. The patient remained in remission for 3 months after RIST until the second relapse. MIBG therapy combined with RIST warrants further trials.

Development of diffuse large B cell lymphoma during the maintenance therapy for B-lineage acute lymphoblastic leukemia.

Non-Hodgkin lymphoma (NHL) is a very rare complication of acute lymphoblastic leukemia (ALL). A Japanese boy presented with B-lineage ALL at the age of 2.5. He was treated with chemotherapy for standard-risk ALL. While he was receiving maintenance treatment 2 years and 9 months after the diagnosis of ALL, diffuse large B cell lymphoma (DLBL) was diagnosed from a biopsy of an abdominal mass. DLBL was treated by surgical resection followed by chemotherapy for 6 months. The patient has been free from the recurrence of ALL or DLBL for 16 months after the development of DLBL.

Successful treatment for intractable chylous ascites in a child using a peritoneovenous shunt.

Intractable post-operative chylous ascites had been managed successfully using a peritoneovenous shunt (PVshunt). A 4-year-old girl with neuroblastoma originated from the right adrenal gland was admitted to our hospital. Following the preoperative chemotherapy, tumor resection, and lymph node dissection of the abdominal paraaortic region were carried out. Post-operative radiation therapy 9.6 gray to the tumor bed and to the paraaortic region and a high dose chemotherapy supported by auto bone marrow transplantation were completed. Three months later some enlarged lymph nodes along the duodeno-hepatic ligament were detected and these had gradually increased in size. Lymph node dissection along the hepatic artery and the abdominal aorta was carried out. Pathological examination of the specimen showed reactive lymph node swelling. Chylous ascites developed several days after surgery. Despite the medium-chain triglycerides meal or total parental nutrition, the ascites persisted for more than 80 days. Multiple paracenteses were mandatory. A PV shunt was implanted and the ascites was resolved by the fourth post-operative day. Thirty months later, the vascular end tube of the shunt was ligated. As ascites had not accumulated for 2 weeks, the PV shunt was removed. The patient has been doing well without recurrence of ascites or neuroblastoma for 12 years. As PV shunts were mostly used for long lasting disease, it has not been referred as to how to know when the shunt should be removed. If the shunt is inserted for transient management of ascites, less invasive methods of investigation to know when to remove the shunt need to be developed.