Salvage allogeneic hematopoietic SCT for primary graft failure in children.

Primary graft failure (pGF) is associated with considerable morbidity and mortality. Salvage hematopoietic SCT (HSCT) can rescue pGF patients; however, the optimal preconditioning regimen and stem cell source are yet to be determined, particularly in children. In this study, we retrospectively analyzed 102 pediatric patients who received salvage allogeneic HSCT for pGF. Salvage HSCT from matched or one-Ag-mismatched related donors (rMM01) provided superior OS compared with that from two- or three-Ags-mismatched related donors (rMM23) or cord blood transplantation (CBT). CBT showed a trend toward a slightly lower engraftment rate and late engraftment achievement compared with rMM23; however, the OS rate was similar between the two groups (47.6±7.7% for rMM23 and 45.7±8.6% for CBT, at 1 year after salvage HSCT). Multivariate analysis showed that preconditioning regimens with fludarabine or irradiation were associated with a higher engraftment rate and those with alkylating agents were associated with better OS. In conclusion, our results showed that rMM01 was the most suitable donor for salvage HSCT for pediatric pGF, and that CBT was an equally important option compared with rMM23 for patients without rMM01.

Second allogeneic hematopoietic SCT for relapsed ALL in children.

A second SCT is generally accepted as the only potentially curative approach for ALL patients that relapse after SCT, but the role of second SCT for pediatric ALL is not fully understood. We performed a retrospective analysis of 171 pediatric patients who received a second allo-SCT for relapsed ALL after allo-SCT. OS at 2 years was 29.4 ± 3.7%, the cumulative incidence of relapse was 44.1 ± 4.0% and non-relapse mortality was 18.8 ± 3.5%. Relapse occurred faster after the second SCT than after the first SCT (117 days vs 164 days, P=0.04). Younger age (9 years or less), late relapse (180 days or more after first SCT), CR at the second SCT, and myeloablative conditioning were found to be related to longer survival. Neither acute GVHD nor the type of donor influenced the outcome of second SCT. Multivariate analysis showed that younger age and late relapse were associated with better outcomes. Our analysis suggests that second SCT for relapsed pediatric ALL is an appropriate treatment option for patients that have achieved CR, which is associated with late relapse after the first SCT.

Long-term outcome of cord blood transplantation from unrelated donors as an initial transplantation procedure for children with AML in Japan.

To assess the outcome of unrelated umbilical cord blood transplantation (UCBT), 141 children with AML who underwent UCBT (39 in first CR (CR1), 33 in CR2, 4 in CR3 and 65 at more advanced stages (not in CR)) were analyzed in a retrospective multicenter study in Japan. Short-term MTX was used for prophylaxis of acute GVHD in 80 cases (57%). The cumulative incidences of neutrophil recovery, platelet recovery and acute GVHD (grades 2-4) were 78.7, 62.4 and 40.1%, respectively, and the 100-day transplantation-related mortality (TRM) was 10.8%. Multivariate analysis showed that an infused CD34(+) cell dose of 1.35 x 10(5) cells per kg or more was associated with favorable neutrophil and platelet recovery, and that short-term MTX was associated with a lower 100-day TRM. The 6-year relapse rate was 38.8% and was associated with disease status. Six-year overall survival was 45.8% (70.4+/-8.3% in CR1, 59.3+/-11.3% in CR2, 75.5+/-21% in CR3 and 20.6+/-6.2% for children with non-CR). We conclude that the results of UCBT are particularly promising for children with a karyotype suggesting a poor prognosis, and for those who receive transplants in CR2 and CR3 after an early relapse.

Survival after cord blood transplantation from unrelated donor as a second hematopoietic stem cell transplantation for recurrent pediatric acute myeloid leukemia.

The Japan Cord Blood Bank Network (JCBBN) reports the treatment of 22 children with acute myeloid leukemia (AML) who received umbilical cord blood transplantation from unrelated donors (CBT) as their second hematopoietic stem cell transplantation (HSCT). Provided by the JCBBN, between February 1997 and September 2006, 22 patients had CBT as a second HSCT. In the initial HSCT, eight received autologous, seven received CBT, and the remaining had allogenic BMT. At the time of CBT as a second HSCT, seven were in the second complete remission (CR2), two in the third CR (CR3), the remaining were not in remission. Reduced intensity conditioning (RIC) conducted for 10 cases and myeloablative conditioning (MAC) for 12 cases. The overall survival rate was 31.3%, 5 years after CBT. Second complete remission at second transplantation was favorable prognosis (58.3 +/- 18.6%, compared with 17.1 +/- 10.8% for the non-CR group. Mortality after CBT as a second HSCT accounted for 15 cases, 8 from treatment-related mortality. In conclusion, CBT combined with RIC as second HSCT may be useful against a recurrence of AML in children after the initial HSCT.

Therapy-related myelodysplastic syndrome in childhood: a retrospective study of 36 patients in Japan.

We report here a retrospective analysis of 36 children with therapy-related myelodysplastic syndrome (t-MDS) diagnosed between 1990 and 1999 in Japan. Their median age was 7.7 years and the median latency period for the development of t-MDS was 38.5 months. The primary tumors were hematologic in 15 of the cases and nonhematologic in 21. Chromosomal abnormalities were detected in 32/34(94%) patients: abnormalities of chromosomes 5and/or 7 in 41% and notably, 11q23 abnormalities in 31%. The prognosis of children with t-MDS was very poor as compared to children with primary MDS (5 year survival: 16% versus 54%, p<0.0001).

Cytologic features of desmoplastic infantile ganglioglioma: a report of two cases.

BACKGROUND: Desmoplastic infantile ganglioglioma (DIG) is a rare intracranial tumor of infancy, characterized by solid and cystic components, voluminous size and supratentorial location. Although its histologic features have been reported, there has been no cytologic description of the tumor. Cytologic findings on imprint and aspirated material from two cases of histologically verified DIG are discussed. CASES: A 12-month-old male with cutis marmorata telangiectatica congenita and a 44-month-old female with episodes of spasm were referred to our center. Radiologic examination revealed a large, cystic, supratentorial mass in both patients. The mass was surgically removed, and histology revealed prominent desmoplasia with a mixture of astroglial and neuronal cells. Cytologic findings on imprint material and the needle aspirates taken from the cystic area of the tumor revealed a few isolated or sheetlike arrangements of small cells positive for glial fibrillary acidic protein and a few large cells with abundant cytoplasm and prominent nucleoli, positive for neuronal marker. CONCLUSION: Although distinction between ganglioglioma and DIG may be difficult by cytology alone, with the characteristic clinical presentation and radiologic findings, the possibility of DIG should be kept in mind when the specimens contain both astroglial and neuronal elements.

Ewing's sarcoma family of tumor arising in the adrenal gland--possible diagnostic pitfall in pediatric pathology: histologic, immunohistochemical, ultrastructural, and molecular study.

We present an adrenal Ewing's sarcoma family of tumor (ESFT) arising in an 11-year-old Japanese boy. Although intensive chemoradiotherapy and radical surgery were performed, the patient died of obstinate disease 1 year and 3 months after the initial presentation. The primary site (adrenal gland) with radiologic findings (with foci of calcification), high titer of serum neuron specific enolase, and sheets of monotonous primitive rounded cells on histology mostly favored neuroblastoma. However, a diagnosis of ESFT was confirmed by immunohistochemical profile, including MIC2-positivity and molecular study disclosing EWS-FLI1 chimera gene verified by direct sequencing. Recognition of adrenal ESFT and use of newly developed diagnostic techniques are required for differential diagnosis of undifferentiated small round cell tumor of the adrenal gland.

Late recurrence of neuroblastoma stage 4S with unusual clinicopathologic findings.

The authors present unusual clinicopathologic findings of a patient with neuroblastoma stage 4S that recurred 11 years after induction of complete remission with chemotherapy. A 12-year-old girl presented with recurrent tumor in the liver. Urinary catecholamine metabolites were within normal range in contrast to the increased values at initial presentation. She underwent left lateral segmentectomy and biopsy of the right lobe. Histologic analysis of the recurrent tumor showed undifferentiated neuroblastoma intermingled with mature ganglioneuromatous lesions. There also were scattered ganglioneuromatous lesions throughout nontumorous area of the liver. Although multimodal intensified treatments including autologous bone marrow transplantation were performed, the patient died of obstinate recurrent tumor at age 14 years. The clinicopathologic findings suggested dedifferentiation from the ganglioneuromatous lesion rather than ordinary recurrence of the primary tumor. The current case and the literature review may indicate that long-term follow-up would be necessary for neuroblastoma stage 4/4S cases. J Pediatr Surg 36:953-955.

Radiation therapy for life- or function-threatening infant hemangioma.

PURPOSE: To assess the effectiveness and long-term results of radiation therapy in infants with life- or function-threatening hemangiomas. MATERIALS AND METHODS: Thirteen patients with life- or function-threatening hemangiomas (eight male, five female; age range, 0-8 months; median age, 2 months) were treated with radiation therapy. Life-threatening hemangiomas were treated with five fractions of radiation per week, and function-threatening hemangiomas were treated with two fractions per week. A median dose of 10 Gy was delivered to each hemangioma. The presence of residual hemangiomas, skin changes, functional problems, and growth delay was evaluated. RESULTS: All patients with Kasabach-Merritt syndrome (KMS) showed regression of the hemangioma and an increase in platelet counts to greater than 100,000 per cubic millimeter (1.0 x 10(11) per liter) within 40 days after radiation therapy. The treatment field was inadequate in two patients who required reirradiation or a change of treatment portal. With the exception of the patients with KMS, all but one patient experienced relief from symptoms in 40 days. Severe long-term radiation-related morbidity was noted in one patient who required reirradiation for a relapsed hemangioma. CONCLUSION: Radiation therapy (in doses of < or = 10 Gy in 2-Gy fractions) is indicated for life-threatening hemangiomas and for some function-threatening hemangiomas.

Congenital dyserythropoietic anemia type 1 with fetal onset of severe anemia.

We report a patient with congenital dyserythropoietic anemia type 1 with characteristic anomalies and two novel clinicopathologic presentations: intrauterine onset of severe anemia resulting in cardiac failure and relatively mild dyserythropoietic features on bone marrow aspiration in contrast to severity of anemia. After repeated transfusions and a trial of erythropoietin administration, the patient died from respiratory infection at age 7 months. Autopsy revealed characteristic dyserythropoietic features of the bone marrow by light microscopy and electron microscopy, which confirmed a diagnosis of congenital dyserythropoietic anemia type 1.

Prophylactic cranial irradiation of acute lymphoblastic leukemia in childhood: outcomes of late effects on pituitary function and growth in long-term survivors.

It is well known that prophylactic cranial irradiation is highly effective in preventing central nervous system (CNS) relapse of acute lymphoblastic leukemia (ALL). Nevertheless, there have been very few reports on the late effects, especially pituitary function and growth, in long-term survivors who were treated with 18 Gy cranial irradiation in childhood. The subjects consisted of 35 children with ALL who were treated with prophylactic 18 Gy cranial irradiation at Kanagawa Children's Medical Center between October 1981 and February 1995. All patients received cranial irradiation after first attaining complete remission with induction chemotherapy, according to the treatment protocols prescribed by the Tokyo Children's Leukemia Study Group (TCLSG) and Tokyo Children's Cancer Study Group (TCCSG). Their ages at the time of cranial irradiation ranged from 2.2-15.0 years (mean 6.8). We evaluated their pituitary functions by measuring their pituitary hormone values 0.7-11.3 years (mean 6.0) after cranial irradiation and their growth by analyzing their height standard deviation score (SDS) at diagnosis of ALL and their final height SDS at the mean follow-up period of 8.2 years after cranial irradiation. Height SDS is defined as the difference between the patient's height and the mean height of their age and sex, divided by the standard deviation of their age and sex. Eight of 35 patients had ALL relapse, involving the bone marrow in seven patients and the CNS in only one. Six of the eight patients with relapse died 1.5-6.6 years after cranial irradiation and the other two patients were salvaged by further intensive therapies. The remaining 27 relapse-free patients have survived for 1.4-15.8 years (mean 10.1) after cranial irradiation. Twenty-six of the 29 survivors are long-term survivors of more than 5 years. Although there was one patient with an abnormal result in each value of growth hormone (GH), adrenocorticotropic hormone (ACTH), and prolactin (PRL), and two patients with abnormal results in thyroid-stimulating hormone (TSH) values, none of the patients had clinical symptoms of pituitary hormone abnormality and none required hormone supplements. The final height SDS decreased significantly compared with the height SDS at diagnosis of ALL in the long-term survivors (P = 0.001) and the height SDS of the patients who had received cranial irradiation at a young age tended to decrease gradually (P = 0.019). However, no patient showed severe growth failure. It is considered that prophylactic 18 Gy cranial irradiation plus chemotherapy for ALL in childhood can effectively prevent CNS relapse and is unlikely to produce clinically significant late effects, although it may cause slight pituitary hormone abnormality.

Epithelioid leiomyosarcoma in a non-immunocompromised infant: additional differential diagnosis of pediatric "round cell tumors".

We report an 18-month-old Japanese girl with purely epithelioid leiomyosarcoma presenting as a huge intraabdominal mass. The patient had been well from birth and had shown no signs of immunodeficiency. She was negative for human immunodeficiency virus. Blood examination revealed elevated serum neuron specific enolase (NSE). Histologically, the tumor was comprised of solid growths of round or polygonal cells with vesicular nuclei and often vacuolated cytoplasm rich in glycogen. The tumor cells were positive for vimentin, NSE, and MIC2, and were negative for desmin and neurofilament. The age, clinical presentation, and histologic findings mostly favored Ewing's sarcoma/primitive neuroectodermal tumor. Silver stain, however, demonstrated well-developed reticulin fibers often outlining individual tumor cells. An expanded panel of immunostains showed that the tumor cells were intensely positive for smooth muscle actin, and ultrastructural study revealed abundant fine cytoplasmic filaments with focal subsarcolemmal densities, various amounts of glycogen, and irregularly arranged, thick basal lamina. The diagnosis of epithelioid leiomyosarcoma was made. Following reduction in tumor size by chemotherapy, the serum NSE level was normalized. From the surgical finding, the primary site was presumed to be the urachus or the urinary bladder dome. Although extremely rare, epithelioid leiomyosarcoma should be added in the list of differential diagnoses of pediatric "round cell tumors."

Natural course of neuroblastoma detected by mass screening: s 5-year prospective study at a single institution.

PURPOSE: To describe various favorable courses of neuroblastoma (NBL) detected by mass screening and to present our observation program as a temporary treatment option, to be used until a final decision is made regarding the mass screening program for 6-month-old infants. PATIENTS AND METHODS: Between October 1993 and November 1999, 26 of 51 patients with NBL detected by mass screening were enrolled in our observation program. The criteria for observation included urinary vanillylmandelic acid (VMA) and homovanillic acid (HVA) levels less than 50 microg/mg creatinine, smaller tumor size (< 5.0 cm), preoperative status, and granted informed consent. Patients were divided into four groups according to changes in urinary VMA and HVA values and tumor size. Patients who no longer fulfilled criteria underwent surgery. RESULTS: The observation period ranged from 4 to 73 months. Urinary VMA and HVA levels decreased in 19 of 26 patients, often by age 16 months. Eighteen patients had regressing tumors, and in 10 of these cases, the tumor was undetectable or barely detectable by imaging techniques. Four patients younger than 12 months had increased tumor marker levels and tumor volume, histologically reflecting neuroblastic proliferation. The remaining three patients, all older than 18 months, had varied tumor marker levels but increased tumor volume, histologically reflecting an increase in Schwann cells. No upgrading of tumor stage or unfavorable biologic factor was noted in any patient. CONCLUSION: None of our patients showed evidence of transition from favorable to unfavorable prognosis, a finding that points to a reduction in the significance of screening as a public health measure. Until results of ongoing screening trials involving older patients have been evaluated, the observation program can be used as a temporary measure to avoid, with little risk, unnecessary surgical intervention.

Clinicopathologic study of mass-screened neuroblastoma with special emphasis on untreated observed cases: a possible histologic clue to tumor regression.

Spontaneous regression and maturation of neuroblastoma (NB) are well documented and occur frequently in infants, including those detected by mass screening. To seek histologic clues for regression/maturation in mass-screened NB, clinicopathologic features of 12 tumors that were resected after 2 to 18 months of untreated observation were reviewed. Unobserved screened and age-matched unscreened patients were also studied. To evaluate the possible important role of apoptosis, apoptotic cells were detected by in situ deoxyribonucleic acid (DNA) nick end labeling and immunohistochemical stain for activated caspase-3. Nests with a varying degree of reduced cellularity ("less cellular" and "hypocellular" nests) were common in patients younger than 18 months of age, and were rare in older patients. Two characteristic cells, which have not been focused previously, were frequent, especially in the hypocellular nests. One showed amorphic eosinophilic cytoplasm with pyknotic nuclei and the other contained plump cytoplasm with well-maintained nuclei. These cells were also observed in 89% of the unobserved screened NBs and 79% of the age-matched unscreened patients with good outcome, whereas they could not be confirmed in any of the age-matched unscreened NBs with poor outcome. The amorphic and plump cells were negative for activated caspase-3 and in situ DNA nick end labeling. From these results, the authors hypothesize that these cells most likely represent a degenerative process, in either a state before the activation of caspase-3 or a caspase-independent form of cell death. The presence of less cellular and hypocellular nests with amorphic/plump cells may serve as one of the important clues in predicting tumor prognosis.

A new sensitive and specific combination of CD81/CD56/CD45 monoclonal antibodies for detecting circulating neuroblastoma cells in peripheral blood using flow cytometry.

PURPOSE: Intensive chemoradiotherapy followed by peripheral blood stem cell transplantation has been introduced to treat children with advanced neuroblastoma (NBL). Detection of NBL cells in peripheral blood (PB) is important to prevent reinfusion of NBL cells. Several immunologic methods have been proposed for detecting NBL cells in hematologic samples. The development of a sensitive and specific combination of monoclonal antibodies (MoAbs) for detecting small numbers of NBL cells in PB using flow cytometry remains an important challenge. METHODS: Twenty-one clinical samples from NBL tissues or smears containing NBL cells were examined for reactivity against CD81, CD56, and CD9 using an immunocytochemical technique. The expressions of CD81, CD56, CD9, and antihuman disialoganglioside GD2 MoAb (GD2) in five NBL cell lines were assayed by flow cytometry. For the evaluation of sensitivity, five NBL cell lines were added to normal PB and the detection level of the combination of CD81/CD56/CD45 MoAbs was compared with that of CD9/CD56/CD45 MoAbs (reported previously). One hundred thirty-three normal PB samples were examined to determine the sensitivity and specificity of this method. RESULTS: All NBL cell lines showed strong positivity with CD81 and CD56 MoAb. However, CD9 MoAb was weakly positive against the five NBL cell lines. GD2 MoAb reacted strongly with four NBL cell lines, although almost the entire cell population of the SK-N-SH NBL line failed to bind the GD2 MoAb. In vitro experiments using NBL cell lines demonstrated that tumor cells added to normal PB cells could be detected by flow cytometry using CD81/CD56/CD45 MoAbs even at a concentration of 0.005%. Through comparative studies, the combination of CD81/CD56/CD45 MoAbs was found to be more sensitive and specific than that of CD9/CD56/CD45 MoAbs for detecting small numbers of NBL cells using the above cell lines. CONCLUSIONS: Triple-color flow cytometric analysis using CD81/CD56/CD45 MoAbs is useful for detecting NBL cells in PB. Further studies testing this approach using samples of PB with NBL contamination are needed to test this approach in patients.

Allogeneic hematopoietic stem cell transplantation for patients with hemophagocytic syndrome (HPS) in Japan.

Seventeen cases (age at onset, 1 month to 18 years; M/F, 9/8) of hemophagocytic syndrome which received allogeneic hematopoietic stem cell transplantation (SCT) in Japan during the period 1988-1998 are reported. The patients consisted of six familial inheritance-proven erythrophagocytic lymphohistiocytosis (FEL), five familial inheritance-unknown and infective agents-unknown HLH (of which two were highly likely to have been FEL with characteristic CNS signs), and six aggressive Epstein-Barr virus (EBV)-related HLH (of which two were natural killer cell-type large granular leukemia/lymphoma-associated hemophagocytic syndrome, EBV-NK-LGLL-HPS). All cases were treated intensively with immuno-chemotherapy, or with chemotherapy before SCT. As sources of SCT, 12 cases received bone marrow cells (sibling six, father one, URD five), two cord blood, two purified CD34-positive cells, and one PBSC. SCTs were successful in all 17 cases, apart from one receiving CD34-positive SCT. Following SCT, four patients relapsed and five died with a median follow-up of 23 months. Among the relapsed cases, the two EBV-NK-LGLL-HPS previously published as successfully transplanted were included. Among the fatal cases, three patients died from relapsed active disease and the remaining two from fatal post-SCT EBV-positive T cell lymphoma and extensive chronic GVHD, respectively. As of the end of September 1998, 10 patients are alive without disease for 3.5 months to 147 months, while two post-SCT patients are still having therapy for residual/recurrent disease. The Kaplan-Meier analysis showed a 2-year event-free survival after SCT as 54.0+/-13.0%.