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The risk of carcinogenesis increases after 20 years old in patients with Fanconi anemia (FA). We herein report three rare cases of FA combined with esophageal cancer in women; all patients were diagnosed with FA in early childhood. Patients 1 and 2 were diagnosed with advanced and superficial esophageal cancer, respectively, at 21 and 30 years old, respectively. Patient 3 was diagnosed with superficial esophageal cancer, underwent curative surgery at 26 years old, and survived for over 5 years without recurrence. Therefore, establishing a protocol for the early detection of esophageal cancer in FA patients over 20 years old is important.

Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for juvenile myelomonocytic leukemia (JMML), but few large studies of HSCT for JMML exist. Using data from the Japan Society for Hematopoietic Cell Transplantation registry, we analyzed the outcomes of 129 children with JMML who underwent HSCT between 2000 and 2011. The 5-year overall survival (OS) rate and cumulative incidence of relapse were 64% and 34%, respectively. A regimen of busulfan/fludarabine/melphalan was the most commonly used (59 patients) and provided the best outcomes; the 5-year OS rate reached 73%, and the cumulative incidences of relapse and transplantation-related mortality were 26% and 9%, respectively. In contrast, the use of the irradiation-based myeloablative regimen was the most significant risk factor for OS (hazard ratio [HR], 2.92; P = .004) in the multivariate model. In addition, chronic graft-versus-host disease (GVHD) was strongly associated with lower relapse (HR, 0.37; P = .029) and favorable survival (HR, 0.22; P = .006). The current study has shown that a significant proportion of children with JMML can be cured with HSCT, especially those receiving the busulfan/fludarabine/melphalan regimen. Based on the lower relapse and better survival observed in patients with chronic GVHD, additional treatment strategies that focus on enhancing graft-versus-leukemia effects may further improve survival.

Fanconi anemia is a rare recessive disease characterized by multiple congenital abnormalities, progressive bone marrow failure, and a predisposition to malignancies. It results from mutations in one of the 22 known FANC genes. The number of Japanese Fanconi anemia patients with a defined genetic diagnosis was relatively limited. In this study, we reveal the genetic subtyping and the characteristics of mutated FANC genes in Japan and clarify the genotype-phenotype correlations. We studied 117 Japanese patients and successfully subtyped 97% of the cases. FANCA and FANCG pathogenic variants accounted for the disease in 58% and 25% of Fanconi anemia patients, respectively. We identified one FANCA and two FANCG hot spot mutations, which are found at low percentages (0.04-0.1%) in the whole-genome reference panel of 3,554 Japanese individuals (Tohoku Medical Megabank). FANCB was the third most common complementation group and only one FANCC case was identified in our series. Based on the data from the Tohoku Medical Megabank, we estimate that approximately 2.6% of Japanese are carriers of disease-causing FANC gene variants, excluding missense mutations. This is the largest series of subtyped Japanese Fanconi anemia patients to date and the results will be useful for future clinical management.

Fludarabine/cyclophosphamide-based conditioning regimens are standard in bone marrow transplantation (BMT) for acquired bone marrow failure in children, however, graft failure may occur. Using the data from a nationwide transplantation registry, we compared the outcomes of children aged

Mixed-phenotype acute leukemia (MPAL) is a rare type of leukemia expressing both myeloid and lymphoid markers. There is limited information, especially on pediatric cases. Therefore, the optimal therapeutic approach to pediatric MPAL has not been defined. Here, we report two pediatric cases of MPAL. According to the 2008 World Health Organization (WHO) classification and European Group for the Immunological Characterization of Leukemias (EGIL) criteria, patient 1 was diagnosed with overt MPAL positive for the myeloid marker myeloperoxidase (MPO), and B-lymphoid markers. Patient 2 was diagnosed with T-cell acute lymphoblastic leukemia (T-ALL) using EGIL criteria. According to the 2008 WHO classification, however, patient 2 was diagnosed with overt MPAL positive for CD3, T-lymphoid markers and MPO. We chose an ALL-type therapy consisting of both lymphoid- and myeloid-directed agents; these patients have maintained complete remission following treatment. Further information on pediatric MPAL is needed to establish an appropriate therapeutic strategy including stem cell transplantation for this rare condition.

We report a case of HIV-negative Burkitt lymphoma (BL) that relapsed 9 years after complete remission. We performed a polymerase chain reaction analysis of three regions of the VDJ junction of the immunoglobulin heavy chain (IGH) gene and compared the clonality of the first and second BL lesions, which were found to be clonally distinct. The patient received the R-Hyper CVAD/R-MA regimen; however, leukoencephalopathy subsequently developed due to the effect of cytarabine, and the regimen was changed to R-IVAM. The patient achieved complete remission and received high-dose chemotherapy following autologous stem cell transplantation. He maintained the complete remission for 72 months after transplantation. Given this outcome, we suggest that clonally distinct relapse of HIV-negative BL may exhibit a good prognosis.

We retrospectively studied 108 marrow harvests from 105 pediatric sibling donors. The median age of donors was 8 years (range: 1-15) and the median body weight was 27 kg (range: 10-100). The volumes of aspirated marrow were 5.0-23.8 mL/kg donor body weight, and harvested bone marrow volume exceeded 15 mL/kg in 42% of the donors. A total of 100 autologous blood donations were performed, and eight donors had red cells salvaged from their harvests reinfused. The median Hb levels before and after harvests were 12.3 g/dL (range: 10.0-14.7) and 11.0 g/dL (range: 8.9-13.8), respectively. None of the donors received allogeneic blood transfusions or hematopoietic growth factors such as EPO and G-CSF before or after collection. Transplanted dose was 1.4-10.8 × 10(8) cells/kg recipient body weight without differences due to donor age. Higher concentrations of nucleated and CD34(+) cells were obtained from younger donors. All donors tolerated the procedures well, with no serious complications. Thus, children may safely donate marrow for allogeneic transplantation, and the yields of nucleated cells for engraftment are substantial.

Fatty liver and male gonadal dysfunction are potential late effects of therapy in adult survivors treated with stem cell transplantation (SCT) in childhood. Obesity and metabolic syndrome also are associated with low serum testosterone levels in the general population. However, the relationship between the degree of fatty liver and changes in serum testosterone levels in adult survivors has not been fully studied. We reviewed the clinical records of 34 male patients who received allogeneic SCT in childhood or adolescence. The median age at SCT was 10.0 years, and the median follow-up after SCT was 15.9 years. All but one patient showed no tendency toward overweight/obesity during the follow-up period. Fatty liver was diagnosed by ultrasound in 15 patients at 4 to 20 years after SCT. Patients who received cranial radiation therapy before SCT were more likely to develop fatty liver and insulin resistance. Moreover, fatty liver was statistically associated with decreased serum testosterone levels, whereas nonfatty liver was not (median, 527 ng/dL [range, 168-944 ng/dL] versus 302 ng/dL [165-698 ng/dL]; P < .0001). Changes in testosterone levels after SCT are affected not only by primary gonadal dysfunction but also by subsequent development or exacerbation of fatty liver.

SCT from HLA-identical sibling donors is generally associated with an excellent survival in FA patients if performed prior to the development of MDS or leukemia. However, the optimal conditioning regimen has not been defined. We report here our experience with 15 Japanese FA patients who underwent HLA-matched sibling donor SCT. The aim of this study is to compare radiation-based conditioning to Flu-based conditioning for FA patients in a Japanese population where the T-cell somatic mosaicism is higher than in the Caucasian population. Eight patients (a-group) received a radiation-based conditioning (500-600 cGy of thoracoabdominal/TBI) with CY dose modification (20-120 mg/kg), and ATG; two patients exhibited rejection. Seven patients (b-group) received CY (40 mg/kg), 150-180 mg/m(2) of Flu, and ATG. Durable engraftment was demonstrated in all patients. In FA patients, Flu-based conditioning may allow stable engraftment in matched sibling donor transplantation without radiation, even in patients with T-cell somatic mosaicism.

Fanconi anemia is a rare autosomal recessive disease characterized by multiple congenital anomalies, pancytopenia, and cancer susceptibility, especially to leukemia and squamous cell carcinoma of the head and neck or esophagus. F-FDG PET/CT is a useful tool to assess tumor staging and follow-up of esophageal cancer. We report a rare case of cervical esophageal cancer and lymph node metastases detected on F-FDG PET/CT in a patient with Fanconi anemia after bone marrow transplantation.

Background Several studies have suggested that Langerhans cell histiocytosis (LCH) is responsive to treatment with bisphosphonates (BPs). However the efficacy and safety of BPs therapy for childhood LCH is unknown. Procedure Data on children with LCH who had received BPs therapy were collected retrospectively from hospitals participating in the Japanese Pediatric Leukemia/Lymphoma Study Group. Results Twenty-one children with histologically proven LCH were identified. Of these, the case histories of 16 children who had been treated with pamidronate (PAM) for disease reactivation were analyzed in detail. The median post-PAM therapy follow-up period was 2.8 years (range: 0.9–9.3 years). The median age at commencement of PAM therapy was 9.4 years (range: 2.3–15.0 years). All children had one or more bone lesions but none had risk organ (RO) involvement. In the majority of the children, six courses of PAM were administered at a dose of 1.0 mg/kg/course at 4-week intervals. In 12 of the 16 children, all active lesions including lesions of the skin (n = 3) and soft tissues (n = 3) resolved. Of these children, eight children had no active disease for a median of 3.3 years post-PAM therapy (range: 1.8–9.3 years). Progression-free survival (PFS) was 56.3 ± 12.4% at 3 years. PFS was significantly higher in children with a first reactivation compared with children experiencing a second or subsequent reactivation. Conclusions PAM may be an effective treatment for reactivated LCH with bone lesions. A prospective trial of the efficacy of PAM in recurrent pediatric LCH is warranted. Pediatr Blood Cancer. 2010;56:110–115. © 2010 Wiley-Liss, Inc.

Overweight/obesity among adult survivors of childhood SCT has been considered to be predictive of eventual development of metabolic abnormalities. Fatty liver is increasingly recognized as a major cause of liver-related morbidity and mortality in the general population. However, the real incidence of fatty liver in adult survivors of SCT has not been fully elucidated. We determined whether adult survivors are at risk for overweight/obesity, metabolic abnormalities and fatty liver and whether these risks are associated with cranial radiotherapy (CRT) before SCT. Among the 51 patients (30 males), only two male patients were overweight/obese at the last evaluation. On the other hand, 9 male (30%) and 15 female (71%) patients were underweight. Fatty liver was diagnosed in 11 male (37%) and 10 female (48%) patients during the follow-up period, although patients who had fatty liver did not tend to be overweight/obese. Significantly more patients who received CRT before SCT developed fatty liver with insulin resistance than those who did not (P

The number of long-term surviving stem cell transplant (SCT) recipients has increased steadily, and attention has now extended to the late complications of this procedure. The objective of this study was to investigate relationship among growth and endocrine functions in long-term adult survivors of childhood SCT. The inclusion criteria of this study were survival at least 5 yr after SCT and achievement of adult height. Fifty-four patients (39 males) fulfilled these criteria and were included in this study. Growth was mainly evaluated by height standard deviation score (SDS) and individual longitudinal growth curves. Among the 54 patients, those that received SCT before 10 yr of age showed significantly greater reductions in changes in height SDS (mean –1.75, range –4.80 to –0.10) compared with those that received SCT at or after 10 yr of age (mean –0.50, range –1.74 to 1.20; P

We report an 81-year-old man who had leukemic presentation of ALK-positive anaplastic large cell lymphoma (ALCL) as an initial manifestation. He had been well after chemotherapy and irradiation for the advanced lung adenocarcinoma, but suddenly suffered from severe lactic acidosis and hypotension. The peripheral blood smear and bone marrow aspiration revealed the infiltration of atypical large cells with horseshoe-shaped or lobulated nuclei. The detection of CD30 expression and the t (2;5) (p23;q35) translocation in these cells was confirmatory of a diagnosis of common variant ALK-positive ALCL in a leukemic phase. He deteriorated rapidly and died before administration of the chemotherapy. An adequate, prompt diagnosis is necessary for this rare disease status in oncologic emergency to improve the disease management.

We evaluated the efficacy of treatment using reduced cumulative doses of anthracyclines in children with acute promyelocytic leukaemia (APL) in the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-P05 study. All patients received two and three subsequent courses of induction and consolidation chemotherapy respectively, consisting of all-trans retinoic acid (ATRA), cytarabine and anthracyclines, followed by maintenance therapy with ATRA. Notably, a single administration of anthracyclines was introduced in the second induction and all consolidation therapies to minimize total doses of anthracycline. The 3-year event-free (EFS) and overall survival rates for 43 eligible children were 83·6% [95% confidence interval (CI): 68·6-91·8%] and 90·7% (95% CI: 77·1-96·4%), respectively. Although two patients died of intracranial haemorrhage or infection during induction phases, no cardiac adverse events or treatment-related deaths were observed during subsequent phases. Patients not displaying M1 marrow after the first induction therapy, or those under 5 years of age at diagnosis, showed inferior outcomes (3-year EFS rate; 33·3% (95% CI: 19·3-67·6%) and 54·6% (95% CI: 22·9-78·0%), respectively). In conclusion, a single administration of anthracycline during each consolidation phase was sufficient for treating childhood APL. In younger children, however, conventional ATRA and chemotherapy may be insufficient so that alternative therapies should be considered.

An increasing number of long-term surviving bone marrow transplant (BMT) recipients have recovered from their primary disease but are at risk of developing failure of endocrine organs. We investigated 147 patients who underwent allogeneic BMT. Thyroid function was evaluated by serial measurement of basal TSH and free T4 levels as well as by TRH provocative test. Thyroid ultrasound examination was performed for evaluation of thyroid tumor after BMT. Five patients were found to have overt thyroid dysfunction (hypothyroidism in four patients and hyperthyroidism in one patient). Twenty-three patients in the under 9-yr-old group at BMT and 16 patients in the over 10-yr-old group at BMT had subclinical compensated hypothyroidism. Younger age at BMT was the strongest factor for developing thyroid dysfunction, compared with older age (P0.001). Only in patients with subclinical compensated hypothyroidism did median basal and peak TSH increase to the upper half of the normal range by 8 yr after BMT and then returned slightly to the middle of the normal range spontaneously. These results suggest that thyroid dysfunction in long-term BMT survivors depends on age at BMT, with a greater risk among younger patients, indicating the need for life-long surveillance.

To establish the most appropriate prophylactic therapy and risk factors for predicting hemorrhagic cystitis (HC) after stem cell transplantation (SCT), we retrospectively analyzed the clinical records of 450 transplant patients treated from 1982 to 2002. In all, 81 patients developed early- and/or late-onset HC (early=29, late=48, both=4). For the incidence of early-onset HC, administration of cyclophosphamide (CY) (p=0.0079, odds ratio (OD)=5.109, 95% confidence interval (CI)=1.533-17.030), busulfan (BU) (p=0.0015, OD=3.336, 95% CI=1.584-7.027), BU+CY (p=0.0001, OD=4.369, 95% CI=2.055-9.292), antithymocyte globulin (p=0.0009, OD=3.368, 95% CI=1.642-6.911), nonradiation (p=0.0163, OD=2.564, 95% CI=0.181-0.841), 2-mercaptoethane sodium sulfonate (Mesna) (p=0.0001, OD=7.519, 95% CI=2.847-19.858), and bladder irrigation (p=0.0001, OD=4.950, 95% CI=2.328-10.523) were risk factors. By Fisher's exact test, the combination of BU and Mesna was a more significant risk factor (P

Lymphoid malignancies are rare in patients with Fanconi anemia (FA), particularly after bone marrow transplantation. A boy, who was diagnosed with FA at the age of 5; underwent successful bone marrow transplantation at the age of 11. One year later, he presented with fever and dry cough, and was found to have an anterior mediastinal tumor. Biopsy of the tumor revealed precursor-T cell lymphoblastic lymphoma. Human leukocyte antigen analysis confirmed that the tumor cells were derived from the patient's own cells. He received mild chemotherapy for lymphoma, but his condition deteriorated rapidly and he died from excessive chemotherapy-related toxicity. The literature contains no reports of successful chemotherapy for lymphoid tumors in patients with FA, and therefore, alternatives to chemotherapy should be considered in the treatment of such patients.

We report the outcomes of 30 patients with juvenile myelomonocytic leukemia (JMML) who received unmanipulated hematopoietic stem cell transplantation (HSCT) with oral or intravenous busulfan, fludarabine, and melphalan between 2001 and 2011. Mutations in PTPN11 were detected in 15 patients. Six patients received human leukocyte antigen (HLA)-matched HSCT from related donors, and 24 patients received HSCT from alternative donors, including 13 HLA-mismatched donors. Primary engraftment failed in five patients, all of whom had received allografts from HLA-mismatched donors. HLA-mismatched HSCT resulted in poorer event-free survival than HLA-matched HSCT (28.8 vs. 70.6 %). Three patients died of transplantation-related causes, and eight patients experienced hematological relapse (including five patients who died due to disease progression). Eight patients received a second HSCT, and four of these patients have survived. The 5-year estimated overall survival for all patients was 72.4: 88.9 % for the patients without a mutation in PTPN11 (n = 10) and 58.3 % for the patients with a mutation in PTPN11 (n = 15) (P = 0.092). The conditioning regimen reported in the present study achieved hematological and clinical remission in >50 % of patients with JMML who received HSCT from alternative donors, and may also be effective for JMML patients with PTPN11 mutation.

The clinical characteristics and prognostic relevance of acute myeloid leukaemia (AML) with myelodysplastic features remains to be clarified in children. We prospectively examined 443 newly diagnosed patients in a multicentre clinical trial for paediatric de novo AML, and found 'AML with myelodysplasia-related changes' (AML-MRC) according to the 2008 World Health Organization classification in 93 (21·0%), in whom 59 were diagnosed from myelodysplasia-related cytogenetics alone, 28 from multilineage dysplasia alone and six from a combination of both. Compared with 111 patients with 'AML, not otherwise specified' (AML-NOS), patients with 'AML-MRC' presented at a younger age, with a lower white blood cell count, higher incidence of 20-30% bone marrow blasts, unfavourable cytogenetics and a lower frequency of Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD), NPM1 and CEBPA mutations. Complete remission rate and 3-year probability of event-free survival were significantly worse in 'AML-MRC' patients (67·7 vs. 85·6%, P < 0·01, 37·1% vs. 53·8%, P = 0·02, respectively), but 3-year overall survival and relapse-free survival were comparable with 'AML-NOS' patients. By multivariate analysis, FLT3-ITD was solely associated with worse overall survival. These results support the distinctive features of the category 'AML-MRC' even in children.

Growth hormone (GH) deficiency has been regarded as a principal determinant for growth failure following bone marrow transplantation (BMT). We herein analyzed final height and GH secretion in the patients who received BMT during childhood. The study on final height in 30 patients (23 males; 19 with malignant disease) who underwent BMT before or at the onset of puberty showed the following findings: (1) Final height SD score (SDS) significantly decreased compared to pretreatment height SDS. (2) Patients who underwent BMT before the age of 10 years showed significantly greater reduction in height SDS compared to those who received after the age of 10 years. (3) The type of disease or a difference in preconditioning regimen did not influence the outcome of growth. (4) No patient showed GH deficiency. The study on GH secretion included 71 patients who had been followed for more than 5 years and who underwent insulin tolerance test more than twice following BMT. Thirteen patients experienced poor GH response at least once. Two of these patients had poor GH response repeatedly. In conclusion, children who undergo BMT at younger age have a higher risk of growth failure, and GH deficiency is not a major contributing factor for growth impairment following BMT.

Therapy-related myelodysplastic syndrome of recipient origin in a juvenile myelomonocytic leukemia patient 17 years after allogeneic BMT

The ability of mixed epidermal cell-lymphocyte reactions to detect allogeneic reactivities in an in vivo model was investigated by developing an in vivo model of acute graft-versus-host disease (GVHD), using SCID mice with a C.B-17 background in which human skin structures were generated by transplantation of cultured human epidermal cells (HEC) with dermal fibroblasts (HDFC). Suspensions containing cultured HEC and HDFC from a single donor were mixed with autologous peripheral blood mononuclear cells (PBMNC) or with PBMNC from unrelated individuals, and were injected into the flanks of C.B-17-SCID mice. Ten and 21 days after injection, subcutaneous nodules generated in the mice were examined histologically and immunohistochemically. Cystic structures developing after injection of HEC and HDFC without human PBMNC showed normal epidermislike tissue. Human skin generated in SCID mice injected with HEC and HDFC with auto-PBMNC showed no graft-versus-host reaction (GVHR) histologically, whereas those mice injected with PBMNC from siblings that shared an HLA haplotype showed mild GVHR. Human skin in SCID mice injected with HEC and HDFC with histoincompatible unrelated PBMNC showed moderate to severe GVHR. The severity of GVHR paralleled the dose of unrelated PBMNC, and GVHR was prevented by peroral treatment with cyclosporine A. Immunohistochemically, inflammatory cells infiltrating human cutaneous tissue formed in the SCID mice were stained by an anti-human CD45RO antibody that reacts with human T cells but not with murine lymphocytes, and most T cells were stained by an anti-human CD8 antibody recognizing HLA class I antigens. These findings are similar to those in clinical skin graft-versus host disease (GVHD) observed in patients undergoing allogeneic bone marrow transplantation. This experimental system should be useful as an in vivo model of human skin GVHD.

The flow cytometric analysis of surface immunoglobulin light chains (sIgL) is used as a simple method for evaluating monoclonal B-cell proliferation. However, the sIgL expression, κ or λ, is occasionally undetectable in cases with B-cell non-Hodgkin lymphomas (B-NHL). The purpose of this study was to investigate the clinical and pathological characteristics of these B-NHL cases.We retrospectively analyzed 50 cases with previously untreated sIgL-negative B-NHL. All of these cases had been diagnosed at Tokai University Hospital between January 2001 and February 2011. Their medical charts were reviewed.These cases had several clinical features: diffuse large B-cell lymphoma (DLBCL) (72%), a high serum lactate dehydrogenase level (66%), clinical stage III and IV (68%), and complex karyotypes (58%). Seven out of eight evaluated patients (87%) did not express cytoplasmic IgL, and the DNA rearrangement pattern of IgL showed diversity in 10 analyzed patients. The 5-year event-free survival of all the sIgL-negative B-NHL cases was significantly better with rituximab-containing chemotherapies in comparison to the regimens without it (57.9% vs. 17.9%, p=0.0207), although there was no statistical significance when the DLBCL cases were analyzed (56.6% vs. 22.2%, p=0.1530).These findings suggest that sIgL-negative B-NHL cases predominantly developed DLBCL in advanced disease, but were heterogeneous at the molecular level.

Living-donor lobar lung transplantation was performed in a 10-year-old boy with bronchiolitis obliterans after bone marrow transplantation for recurrent acute myeloid leukemia. He developed posterior reversible encephalopathy syndrome (PRES) due to calcineurin inhibitor (CNI) postoperatively, which was recovered with suspension of CNI. PRES should be considered one of the important morbidity after lung transplantation.

Hemorrhagic cystitis (HC) is a major cause of morbidity after allogeneic bone marrow transplantation (BMT). Many therapies have been investigated to prevent or treat HC, but effective treatment for HC is still limited. While the efficacy of hyperbaric oxygen therapy has been established for HC due to chemotherapy and/or radiation therapy, its role in HC occurring after allogeneic BMT has yet to be defined. We report two cases of life-threatening late-onset HC after allogeneic BMT in children, which resolved after treatment with hyperbaric oxygen.

The Tokyo Children’s Cancer Study Group (TCCSG) and the Kyushu Yamaguchi Children’s Cancer Study Group (KYCCSG) performed a collaborative analysis of data on children with Down syndrome and acute lymphoblastic leukemia (DS-ALL). Among the 1,139 patients who were enrolled in the TCCSG L99-15, L99-1502, or the KYCCSG ALL 96 study, 13 patients with newly diagnosed ALL had DS. In the DS patients, a significantly higher proportion of patients developed ALL at age 5 years or older compared with the non-DS ALL patients (P < 0.001). The 5-year relapse-free or overall survival of DS-ALL patients was 50.0 or 61.5%, respectively. Relapse accounted for all causes of death. In the TCCSG L99-15 cohort, the overall survival of DS-ALL patients was 42.9%, which was significantly worse compared with 87.9% in the non-DS population (P < 0.001). The survival of patients who received reduced-dose chemotherapy was significantly worse than those who received full-dose chemotherapy (P < 0.001). However, a higher dose of methotrexate was not associated with a better outcome. Results of our preliminary study suggest that the survival of DS-ALL patients could be improved by treatment without dose reduction if possible, although the appropriate dose of methotrexate for DS-ALL needs to be determined.

Allogeneic bone marrow transplantation was performed in 94 patients with hematologic malignancies or other various diseases during the period between March 1982 and November 1990 at Tokai University Hospital. Projected disease-free survival rates of HLA genotypically identical marrow recipients were 88.9% for chronic myeloid leukemia transplanted in the first chronic phase (N = 9), 90.9% for acute leukemia in the first complete remission (N = 15), 54.5% for acute leukemia in later remissions (N = 14), 62.5% for solid tumors (N = 8) and 0% for patients transplanted in relapse (N = 7). The rate for HI A-mismatched marrow recipients with leukemia was 27.8% (N = 16). For patients with non-neoplastic diseases it was 100% regardless of HLA-compatibility (N = 26). The quality of life in long-term surviving pediatric marrow recipients has been acceptable. Common abnormalities among survivors are long-lasting hypogonadism due to radiation and subclinical impairment of lung function in the first year post-BMT. About two-thirds of children experienced a transient decrease in growth velocity in the immediate posttransplant period.

In order to study the role of CD34+ cells in hematological recovery following bone marrow transplantation (BMT), bone marrow cells stained with HPCA-1 (CD34) and MY-9 (CD33) monoclonal antibodies were analyzed by using a fluorescence-activated cell sorter on or about days 14 and 28, as well as at later times, following BMT in 6 recipients. Single cell cultures of CD34+ cells were also performed to evaluate their in vitro hematopoietic function. CD34+ cells were detectable in bone marrow cells on day 14. More than 80% of CD34+ cells co-expressed the CD33 antigen, and macrophage (Mac) colony-forming cells predominated among total colony-forming cells of CD34+ cells. In normal bone marrow cells, CD34+, CD33+ cells amounted to about 40% of CD34+ cells, and the incidences of erythroid bursts, granulocyte/macrophage (GM) colonies, and Mac colonies were similar to each other. After more than 10 weeks, CD34+, CD33- cells gradually recovered, as erythroid burst colony-forming cells increased following GM colony-forming cells. This phenomenon was well-correlated with the time course of peripheral blood cell recovery. CD34+, CD33+ cells as committed progenitors and CD34+, CD33- cells as multipotent stem cells have distinctive biological behaviors in BMT.

Growth of the patients with hematological malignancies, aplastic anemia, Fanconi's anemia, and Wiscott-Aldrich syndrome who had been treated with bone marrow transplantation (BMT) was studied. Fourteen out of 21 patients showed suppression of linear growth after BMT. Recovery of the growth velocity after 1-2 years tended to occur if BMT was performed at younger age. Six of eight patients with chronic graft-versus-host-disease (CGVHD) had impaired growth after BMT, whereas eight of 13 (61%) without CGVHD did. Provocative tests for growth hormone (GH) performed 5-72 months after BMT revealed three boys who showed poor response to more than two different stimuli. Two of these three boys had prolonged suppression of growth. Neither the age at BMT, difference in disease, nor presence of posttransplant growth retardation gave significant difference in the response of GH to provocative tests. It was concluded that approximately two-thirds of marrow-grafted children experienced transient decrease in growth velocity after BMT.

A pilot study was undertaken using a myeloablative conditioning with fludarabine, busulfan, and melphalan to improve the outcome of HSCT in 10 children, aged six months to six yr, with JMML. All patients were conditioned with oral busulfan (560 mg/m(2)), fludarabine (120 mg/m(2)), and melphalan (180-210 mg/m(2)) prior to HSCT, and received stem cells from bone marrow in seven cases, and from cord blood in three cases. Engraftment was documented in eight patients, whereas graft failure occurred in two, one of whom had received HLA-mismatched cord blood and other had received bone marrow from HLA-mismatched mother. Three patients, including two in who graft failure had occurred, relapsed. Five patients developed acute GVHD and two developed chronic GVHD. Seven patients are alive and in remission 27-69 months after transplantation. Thus, our study showed that HSCT following conditioning with fludarabine, busulfan, and melphalan was well tolerated and appeared to be effective for JMML.

An increasing number of long-term surviving bone marrow transplantation (BMT) recipients have recovered from their primary disease but are at risk of developing failure of endocrine organs. We investigated 30 recipients who underwent allogeneic BMT during childhood or adolescence. Testicular growth and function were evaluated by serial measurement of testicular volume, basal luteinizing hormone (LH), basal follicle-stimulating hormone (FSH) and testosterone levels and by gonadotropin-releasing hormone (GnRH) provocative test. Puberty started spontaneously in all patients. However, all except four patients had normal testosterone levels with elevated LH, indicating partial Leydig cell dysfunction. Standard deviation scores of testicular volume at last evaluation were statistically lower in those who had received irradiation without gonadal shield compared to those with (-2.04+/-0.45 vs -0.30+/-1.17, respectively, P

A pilot study was undertaken using a fludarabine-based conditioning regimen to improve haematopoietic cell transplantation (HCT) from alternative donors in 27 Fanconi anaemia (FA) patients. Patients were conditioned with 150-180 mg/m2 of fludarabine, 40 mg/kg of cyclophosphamide, 5-10 mg/kg of antithymocyte globulin, and 300-450 cGy of thoracoabdominal/total body irradiation. One patient who received unrelated cord blood transplantation failed to engraft, another patient died of sepsis. The 1-year overall survival was 96.3% (95% CI, 89-100). This conditioning regimen exerted an immunosuppressive effect that enabled durable engraftment in alternative donor HCT without severe toxicity.

Survival after stem cell transplantation (SCT) in children with acquired bone marrow failure (aBMF) has improved over decades. However, we have experienced a certain number of patients who presented with bone marrow aplasia with full donor chimerism after SCT, especially in the last decade. We named the complication “donor-type aplasia”, and now, this is one of the main causes of treatment failure after SCT in children with aBMF. Because fludarabine (FLU)-based conditioning regimen has been often used for Japanese children with aBMF since the 2000s, use of FLU was suspected to associate with donor-type aplasia. On the other hand, when FLU was introduced in the regimen for children with aBMF, the dose of cyclophosphamide (CY) was reduced by half, to reduce the toxicity. Given these, we previously investigated the risk factors for donor-type aplasia, and reported that the dose reduction of CY rather than the use of FLU in itself was relevant to the recent increase of donor-type aplasia (Yoshida N, et al. ASH 2012). To reduce the risk for donor-type aplasia, the conditioning regimen for children with aBMF needs to be reconsidered. The purpose of the present study is to evaluate the outcomes of SCT using FLU/melphalan (MEL)-based conditioning instead of the standard FLU/CY-based regimen in children with aBMF. We retrospectively reviewed the clinical data of 488 patients ( The 5-year overall survival and event free survival of all patients who received the FLU/MEL-based regimen was 88%. Engraftment was achieved in 27 out of 28 patients (96%) and secondary graft failure including donor-type aplasia was not observed. Regarding the MEL dose, the favorable survival in patients who received 120 mg/m2 or more was observed (100% vs. 62%; P=0.006). Notably, all patients who received bone marrow transplantation (BMT) were alive without any complication. We then compared the outcomes in the setting of BMT with the FLU/MEL-based regimen (n=19) to those with the FLU/CY-based regimen (n=219). The event free survival was inferior in patients treated with the FLU/CY-based regimen (85% vs. 100%), although this difference was not statistically significant. With the FLU/CY-based regimen, engraftment was achieved in 214 patients (98%), whereas secondary graft failure including donor-type aplasia was seen in 18 patients. In conclusion, the FLU/MEL-based conditioning regimen provided excellent outcomes especially in the setting of BMT. To validate whether this regimen can reduce the risk of donor-type aplasia, a larger study is necessary. Therefore, a prospective study on SCT with this conditioning for aBMF children with high risk of donor-type aplasia is now planned by the Japan Childhood Aplastic Anemia Study Group. Disclosures No relevant conflicts of interest to declare.

Background: Dyskeratosis congenita (DKC) is an inherited bone marrow failure syndrome typified by reticulated skin pigmentation, nails dystrophy, and mucosal leukoplakia. Hoyeraal-Hreidarsson syndrome (HHS) is considered to be a severe form of DKC. Unconventional forms of DKC, which develop slowly in adulthood without physical anomalies characteristic to DKC, have been reported. Clinical and genetic features of DKC have been investigated in Caucasian, Black, and Hispanic populations, but never in Asian populations. Therefore, the present study aimed to determine the clinical and genetic features of DKC, HHS, and cryptic DKC among Japanese patients. Methods: We analyzed 16 patients diagnosed with DKC, 3 patients with HHS, and 21 patients with cryptic DKC between 2003 and 2014 in Japan. Telomere length was measured by Southern blot and/or flow-fluorescence in situ hybridization methods. Mutation analyses were performed using direct sequencing for DKC1, TERC, TERT, NOP10, NHP2, and TINF2. In some patients, we also analyzed the exon sequence and genome copy number using a next-generation sequencer. Results: Age at diagnosis was significantly older in the following order: HHS, DKC, and cryptic DKC (p Conclusions: The present study is the first to address DKC, HHS, and cryptic DKC in Japanese people, an Asian race. We found marked reductions in platelet counts in DKC patients in blood tests at diagnosis, a high prevalence of TINF2 mutations as the causative genetic mutation, and the existence of DKC patients with large deletions in the TERT gene and cryptic DKC patients with RTEL1 mutations on both alleles. Disclosures No relevant conflicts of interest to declare.

Introduction: Anthracyclines (Atc) are the key drugs in the treatment of acute promyelocytic leukemia (APL) combined with all-trans retinoic acid (ATRA), however, dose-dependent risk of long-term cardiac toxicity is sometimes problematic especially in pediatric patients. To evaluate efficacy of the treatment with reduced cumulative doses of Atc in childhood APL, we conducted a nationwide non-randomized prospective study, AML-P05, in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG). Patients & Methods: Between April 2006 and March 2011, forty-six children with newly diagnosed APL were enrolled in this study. All patients received at least 3-day precedence of ATRA monotherapy (45mg/m2/d for 35 days in total), followed by chemotherapeutic agents consisted of cytarabine (200mg/m2/d for 7 days) and daunorubicin (DNR, 45mg/m2/d for 3 days) as the first induction therapy. The second induction therapy and subsequent 3 courses of consolidation therapy consisted of ATRA, either high- or intermediate-dose of cytarabine, triple intrathecal injection, and single dose of Atc; 10mg/m2 of mitoxantrone (MIT) in the first 2 courses and 45mg/m2 of pirarubicin (THP) in the last 2 courses. Finally, patients received one-year maintenance therapy with ATRA for 15 days every 3 months. Results: Among the 46 patients registered in this study, 3 were excluded because of PML/RARA negativity, and the remaining 43 patients including 2 with molecular variants were evaluated. The median age at diagnosis was 9 years (range, 11 months to 15 years old). The median follow up period was 4.47 years (0.00-7.45 years). FLT3-ITD was positive in 6 out of 40 patients examined. Two patients died during induction therapies; one of coagulopathy in first course and the other of infection in second course. Two patients developed differentiation syndrome but resolved with temporary cessation of ATRA and supportive therapies. Three patients did not achieve complete remission (CR) after 2 courses of induction therapy, and overall CR rate was 85.7% (36/42, 95%CI: 71.5-94.6%). Neither cardiac adverse events nor treatment-related death were observed during consolidation and maintenance therapies. Three patients exhibited relapse during or after maintenance therapy, and another one developed secondary acute myeloid leukemia. Consequently, the 3-year event-free (EFS) and overall survival rate were 83.6% (95%CI: 68.6-91.8%) and 90.7% (95%CI: 77.1-96.4%), respectively. Age less than 4 years old at diagnosis and non-M1 marrow after first induction therapy were associated with lower EFS. High WBC count (>10,000/μL), low platelet count ( Conclusions: According to the JPLSG criteria of Atc equivalents, cumulative Atc dose in this study was converted to 246mg/m2 of doxorubicin (for 1:0.83 for DNR, 1:4 for MIT, and 1:0.6 for THP). The dose was much lower than that in recent US or European protocols, especially in those designed primarily for adult APL patients where more than 600mg/m2 of Atc were used. Comparing with these studies, we have achieved equivalent good results with minimum does of Atc. Therefore, single administration of Atc in each consolidation phases seems sufficient in the treatment of childhood APL. This trial is registered with UMIN Clinical Trials Registry (UMIN-CTR, URL: http://www.umin.ac.jp/ctr/index.htm), number UMIN000000645 Disclosures No relevant conflicts of interest to declare.

We retrospectively analyzed the clinical results of 81 patients with congenital genetic diseases who were treated with bone marrow transplantation (BMT) from unrelated donors identified through the Japan Marrow Donor Program. The patients were aged between 1 and 38 years (median, 4 years). Thirty-five patients underwent transplantation for metabolic disease (MD), ie, mucopolysaccharidosis (n = 25), adrenoleukodystrophy (n = 7), and others (n = 3). The remaining 46 patients had Wiskott-Aldrich syndrome (n = 16), hemophagocytic syndrome including the inherited type (n = 9), severe combined immunodeficiency (n = 6), hyper-IgM syndrome (n = 4), Chédiak-Higashi syndrome (n = 3), Kostmann syndrome (n = 3), and others (n = 5). Fifty-two donor-patient pairs were fully matched at HLA-A, HLA-B, and HLA-DRB1 alleles. The remaining 24 patients received allele-mismatched grafts (20 matched at 5 of 6 loci and 4 matched at 4 of 6 loci). Engraftment occurred in 82.4% of the MD group and 90.7% of the other genetic disease (OGD) group; however, 14 patients (18.2%) experienced either early or late graft failure. The cumulative incidence of grade II to IV acute graft-versus-host disease (GVHD) was 35.5% - 9.8% in the MD group and 47.3% - 9.5% in the OGD group, and the rate of chronic GVHD was 20% in both groups. Forty-nine patients have survived for 3 to 96 months (median, 20 months). The probabilities of 5-year overall survival and event-free survival were 72.6% - 11.5% and 65.3% - 8.6%, respectively, for MD (n = 35) and 72.5% - 7.3% and 63.6% - 7.3% for OGD (n = 46). Although patient status before BMT and the occurrence of grade III to IV acute GVHD significantly affected outcome, unrelated BMT is a curative therapeutic option for children with congenital genetic diseases who have no HLA-matched family donors.

Fetomaternal microchimerism has been demonstrated, and immunologic tolerance to unshared HLA antigens between mother and offspring may be suggested. We used T-cell-repleted bone marrow transplantation (BMT) from their HLA-haploidentical mothers to treat 6 patients with fatal nonmalignant diseases. The number of mismatched HLA loci in the graft -versus-host disease (GVHD) direction was 3 in 4 patients and 2 in 2 patients. The number in the host-versus-graft direction was 3 in 4 patients, 2 in 1 patient, and 1 in 1 patient. Microchimerism of inherited paternal antigens was demonstrated in 5 donors, and microchimerism of noninherited maternal antigens was detected in 3 recipients. GVHD prophylaxis consisted of short-course methotrexate, tacrolimus, and mycophenolate mofetil (3 patients) or short-course methotrexate, tacrolimus, and methylprednisolone (1 patient). Engraftment was achieved in 5 patients who had received preconditioning, and T-cell engraftment was confirmed in 1 patient with severe combined immunodeficiency. Acute GVHD developed in 3 patients: grade 1 in 2 patients and grade 2 in 1 patient. Chronic GVHD was observed in 5 patients: localized type in 3 patients and extended type in 2 patients. Five patients were alive 11 to 30 months after BMT and 1 patient died of chronic GVHD. Unmanipulated haploidentical BMT from a maternal donor may be the treatment of choice of poor-prognosis nonmalignant diseases.

Background: Changes in thyroid function among young patients who received bone marrow transplantation (BMT) were evaluated. Methods: The study included 91 patients (50 males) who underwent BMT from 1985 to 1995 at the age of 0.6−21 years. Sixty patients had neoplastic disease such as leukemia or lymphoma, and the remainder had non-neoplastic diseases. Preconditioning regimen for BMT included 12 Gy of fractionated-total body irradiation (TBI) for patients with neoplastic disease and 3−8 Gy of irradiation for the remaining patients, in addition to chemotherapy. Evaluation of thyroid function was performed by serial assessment of basal serum FT4, FT3, TSH concentrations as well as by TRH test. Results: No patient had overt hypothyroidism or elevated basal TSH concentrations (>10 mU/L). However, 6 (7%) of patients experienced exaggerated peak TSH response to TRH stimulation several years after BMT. In 33 patients whose thyroid status was evaluated before, within 3 months, and 1 year after BMT, serum FT3 concentrations as well as peak TSH response to TRH stimulation significantly decreased immediately after BMT (

The present study compares immune reconstitution after allogeneic cord blood transplantation (CBT) and CD34+ stem cell transplantation (CD34-SCT) with that after bone marrow transplantation (BMT). Eighty-eight children who underwent CBT (20 patients), BMT (58), and CD34-SCT (10) were enrolled, and lymphocytes and T-, B-, and natural killer—lymphocyte subsets were monitored for more than 5 years after transplantation. CBT recipients showed significant increases in (1) total lymphocyte counts (P < .001), (2) CD4+/CD8+ cell ratios (P < .01), (3) CD4+ and CD4+CD45RA+ cells (P < .001), (4) CD8+CD11b+ cells (P < .001), and (5) CD19+ and CD19+CD5+ cells (P < .0001) and marked decreases in the frequencies of CD8+ and CD8+CD11b- cells (P < .0001). CD34-SCT recipients showed lower lymphocyte counts in the first 6 months and an emergence of lymphocyte and CD4+CD45RA+ cells at approximately 9 months and 1 year. Both CBT and CD34-SCT recipients showed increased frequencies of CD56+ cells at 1 month (CD34-SCT versus BMT, P < .001) but decreased frequencies after 6 months (CBT versus BMT, P < .001). Lymphoproliferative responses to exogenous interleukin 2 were constantly lower in CBT and CD34-SCT recipients than in BMT recipients.These results suggest that the delay in immune reconstitution after CBT in the early phase was mainly qualitative and related to the immaturity of cells, whereas the delay in CD34-SCT was mainly quantitative in the first several months. Int J Hematol. 2003;77:399-407.

Successful allo-HSCT with a minimal myeloablative conditioning regimen in an adult patient with Fanconi’s anemia

To the editor: Capillary leak syndrome (CLS) is a severe complication of allogeneic stem cell transplantation (SCT) characterized by weight gain, generalized edema, hypotension, and hypoalbuminemia.[1][1] The main CLS pathogenesis is injury of the capillary endothelium resulting in a loss of

Bone marrow failure is often associated with skeletal defects, as seen in Fanconi anemia [1], Diamond-Blackfan anemia [2], or thrombocytopenia-absent radius syndrome [3]. Congenital amegakaryocytic thrombocytopenia with radio-ulnar synostosis has been reported to be related with HOXA11 mutation [4]. We present a boy with congenital bone marrow failure with radio-ulnar synostosis, but without HOXA11 mutation. A boy, born to non-consanguineous parents, was delivered via Cesarean section at 31 weeks’ gestation for hydrops fetalis resulting from severe anemia. He had severe anemia (hemoglobin 2.7 g/dl), severe neutropenia (white blood cells 3,220/ll with 1.5% neutrophils), and moderate thrombocytopenia (platelets 89,000/ll) at birth. Neutrophils continued to be nearly absent and platelet counts progressively decreased below 20,000/ll by 2 weeks of age. He had no hepatosplenomegaly, lymphadenopathy, or cafe-au-lait spot, but had hydrocele testicle, sensorineural hearing loss, and overlapping fingers without abnormalities of bone. Supination of his bilateral forearms was restricted and X-rays revealed bilateral proximal radio-ulnar synostosis (Fig. 1). Bone marrow aspiration showed aplasia without dysplasia. Chromosomal analysis revealed a 46, XY, inv(9)(p12q13) karyotype, which is considered to be normal variant without physiologic role. He lacked a family history of hematological or skeletal disorders. No excessive chromosomal breakage was detected by mitomycin C stimulation, and no mutation was found for the Shwachman–Bodian–Diamond syndrome (SBDS) gene. He had repeated bacterial and viral infections after birth, requiring antibiotics and prophylactic antifungal agents. He also needed repeated transfusions of red blood cells and platelets until 8 months of age when he underwent a 5/6 human leukocyte antigen (HLA)-matched unrelated bone marrow transplantation (BMT). Pretransplant conditioning was with fludarabine, cyclophosphamide, and thoracicabdominal irradiation (2 Gy). Prophylaxis for graft-versushost disease (GVHD) was short-term methotrexate and tacrolimus. Engraftment was prompt and grade 1 acute cutaneous GVHD was observed. By 20? days following BMT, he became independent of all transfusions. He has had normal hematological studies for 14 months after BMT. Limb formation is regulated by HOX genes during embryonic development. The most 50 members of the HOXA and HOXD clusters (HOXA9–HOXA13 and HOXD9–HOXD13) are particularly important in limb development [5]. HOX genes are also well known to be associated with hematopoiesis and leukemogenesis [6]. The effects of Hoxa10 and Hoxd11 were found to be on forearm development from studies of mutant mice [7, 8]. Radio-ulnar synostosis with congenital thrombocytopenia has been reported to be associated with HOXA11 mutation [4], which prompted us to examine HOX genes. However, we detected no mutations of HOXA11 and HOXD11. Of the three patients with radio-ulnar synostosis and thrombocytopenia reported by Thompson et al. [9], one H. Yoshida Y. Hashii T. Okuda S. Kusuki E. Sato H. Ohta (&) K. Ozono Department of Pediatrics, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Japan e-mail: ohta@ped.med.osaka-u.ac.jp

The most important clinical features of Fanconi anemia (FA) are hematologic disorders and these are responsible for high incidence of morbidity and mortality. During birth, the blood count is usually normal and macrocytosis is often the first detected abnormality. This is typically followed by thrombocytopenia and anemia; then, progresses to pancytopenia. The majority of patients develop progressive bone marrow failure or acute myelogenous leukemia, both of which are diagnosed with peak frequencies at the age of 7 and 10–15 years, respectively [1, 2]. The disease has generally been managed by the administration of blood products, treatment of infections, and prolonged administration of androgens and hematopoietic growth factors. However, the only curative treatment for the bone marrow failure is hematopoietic stem cell transplantation (HSCT). We describe a patient demonstrating pancytopenia from birth, who received HSCT at the age of 13 months. The patient showed a tendency toward intrauterine growth retardation on ultrasonographic examination at 29 weeks of gestation. He was delivered by cesarean section at 36 weeks and 6 days of gestation because of fetal distress. Birth weight was 2070 g, and 1and 5-min Apgar score were 6 and 8, respectively. He was referred to the neonatal intensive care unit in our hospital for respiratory distress and cardiac murmur on the day of birth. On admission, white blood cell count was 2.8 9 10/L, hemoglobin 5.1 g/dL, platelet count 95 9 10/L. Congenital abnormalities suggestive of FA were bilateral radial hypoplasia, bilateral defective thumbs, defect of the left kidney and L-form fused kidney on the right side, and small patent ductus arteriosus. Bone marrow showed a hypo cellular picture, being comprised mainly of lymphocytes. Karyotyping of 20 cells that were in metaphase exclusively showed 46, XY. A diagnosis of FA was established at the age of 3 months based on the increased chromosomal breakage induced by mitomycin C. The rate of chromosomal breakage in him was increased (443/ 100 cells) compared with control cells (18/100 cells). Levels of FANCA and monoubiquitinated and non-ubiquitinated forms of FANCD2 were determined using immunoblotting analyses of whole cell extracts with antiFANCA and anti-FANCD2 antibodies, and he lacked FANCA protein expression and FANCD2 monoubiquitination. For about a year before transplant, he became progressively dependent on red blood cell and platelet concentrate transfusion and the absolute neutrophil count was 0.05–0.65 9 10/L. He was not treated with any growth factors or androgens. He developed severe sepsis twice at the ages of 9 and 12 months, respectively. Bone marrow at the age of 12 months was hypo cellular with dysplastic features suggesting myelodysplastic syndrome (MDS) and the percentage of myeloblasts was \5%. That indicated refractory cytopenias with multilineage dysplasia. Karyotyping of 20 cells exclusively showed 46, XY with abnormality of add(2)(q33). Before transplant, he had been transfused with red blood cells 18 times and platelet K. Oshima (&) A. Kikuchi S. Mochizuki D. Toyama N. Uchisaka R. Hanada Division of Hematology/Oncology, Saitama Children’s Medical Center, 2100 Magome, Iwatsuki-ku, Saitama 339-8551, Japan e-mail: oshima-k@umin.ac.jp

AIM—To examine the long term effect of bone marrow transplantation (BMT) on ovarian function in girls. METHODS—Eighteen girls who underwent BMT before menarche, had been disease free for more than six years, and were over 14 years of age at the time of study were investigated. The preparative regimen consisted of irradiation and chemotherapy. The occurrence of menarche and changes in basal serum follicle stimulating hormone (FSH) concentrations were studied. RESULTS—Twelve patients achieved menarche at a median age of 12.8 years. Age at transplant was significantly younger in patients who achieved menarche than in those who did not (mean (SD), 7.2 (0.5) v 11.1 (1.7) years). Basal FSH began to rise to menopausal concentrations after 10 years of age, and the girls who did not experience menarche had a sustained rise in FSH concentrations. Among those with raised FSH concentrations, five girls experienced menarche while serum FSH values were decreasing and four achieved menarche while FSH remained raised. CONCLUSIONS—The high incidence of menarche suggests a favourable outcome of ovarian function in girls who undergo BMT at a young age.