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Two cases of cytomegalovirus (CMV) retinitis following bone marrow transplantation (BMT) from unrelated donors are reported. 1 patient had been treated for severe aplastic anemia (SAA) and the other for hypoplastic myelodysplastic syndrome (MDS). Because first line therapy with antithymocyte globulin (ATG) and cyclosporin A (CsA) had failed, BMT was performed following a conditioning regimen of ATG, cyclophosphamide, and total lymphoid irradiation. Treatment for CMV retinitis was successfully carried out with gancyclovir (systemic and intraocular injection), foscarnet, and photocoagulation (Case 1) and gancyclovir and foscarnet (Case 2). Both patients also developed Epstein-Barr virus-associated lymphoproliferative disease (EBV-LPD). We compared these 2 cases with 14 SAA patients who did not develop CMV retinitis after BMT using marrow from either HLA-identical siblings (n = 9) or from unrelated donors (n = 5). Unlike the retinitis patients, the latter 5 patients received ATG only once. The retinitis patients had significantly lower CD4+ T-cell levels in their peripheral blood than the 14 patients who did not develop CMV retinitis. We believe that repeated treatment with ATG and transplantation from unrelated donors may lead to immune dysfunction that could increase the likelihood of CMV retinitis, as well as LPD. For such BMT patients, regular ophthalmic examinations and careful testing for CMV antigenemia are recommended.

1993年7月から1997年11月の間に，当科において骨髄移植を行った21例の腎合併症の実態について検討した。腎機能障害をきたした症例は7例で，5例は急性期の腎機能障害を，1例は急性期の腎機能障害が改善した後8カ月目に溶血性尿毒症症候群 (HUS) を，残りの1例は移植後10カ月目にBMT Nephropathy (BMT NP) を発症した。腎傷害性薬物 (アミノグリコシド，FK506，MTX長期投与) を使用した症例，移植片対宿主病 (GVHD) の強い症例，敗血症を合併した症例では腎機能障害の合併頻度が有意に高かったが，複数の要因が絡んでいるものが多く，原因の特定は困難であった。BMT NPを発症した症例は1例のみであったが，観察期間が短く，今後さらに長期にわたる腎機能評価が必要と考えられた。

小児特発性ネフローゼ症候群の長期予後は良好とされるが，成人期まで再発を繰り返す症例が一部に認められる。我々は小児期に発症し17歳以降まで経過観察できた25例について検討した。16歳以降に再発を認めたキャリーオーバー群は15例で，非キャリーオーバー群に比べて発症年齢が低く，初発時の血清アルブミンが低かった。また全経過中の再発回数や再発頻度が高く，頻回再発例が多かった。特に13歳～15歳の再発頻度は非キャリーオーバー群に比べて有意に高く，中学生時代に再発を繰り返す症例はキャリーオーバーに注意すべきであると考えられた。またステロイド剤の成長に及ぼす影響について検討したが，キャリーオーバー群の男児では最終身長が163.8cmと平均を下回った。 小児特発性ネフローゼ症候群では，長期予後を見据え大量のステロイド剤投与を避ける方針で治療すべきであると考えられた。

SECONDARY OR ACQUIRED HYPOGAMMAGLOBULINEMIA has been described in association with malnutrition, cytostatic drug therapy, burns, protein-depleting conditions, and infections (1,2). More recently, rituximab administration has also been demonstrated to cause hypogammaglobulinemia and B cell depletion (3,4). Acquired immunodeficiency syndrome (AIDS) and measles are the most potent immunosuppressing viruses. Particularly, in the post-transplant condition, life-threatening adenovirus infections are associated with marked abnormalities in blood lymphocyte and cytokine profiles, and may also cause hypogammaglobulinemia (5). Varicella was noted under immunodeficiency to cause hypogammaglobulinemia and lymphopenia (6,7). We report here severe and prolonged B cell depletion and hypogammaglobulinemia in a 12year-old female bone marrow transplant recipient with acute promyelocytic leukemia who developed a transplantrelated life-threatening adenoviral infection followed by varicella zoster infection. This child was diagnosed with acute promyelocytic leukemia t(15;17)(q22;q21) in 1994. She attained complete remission (CR) after a year of treatment with alltrans retinoic acid and other anti-leukemic agents. However, in February, 1997, the disease recurred. A second CR was attained following reinduction chemotherapy and at age 7, the patient received an allogeneic bone marrow transplant from an HLA-matched donor sibling in September, 1997. The conditioning regimen employed was BU/CY/melphalan. A combination of cyclosporine A, short-term methotrexate, and prednisolone was used in the prophylaxis for graft-versushost disease (GVHD). The patient suffered a severe post-transplant life-threatening adenoviral infection a month later, with the viral genome detected in her sera (8). Administration of vidarabine as well as ribavirin was not effective and the patient developed severe pancytopenia and renal and cardiac dysfunction. Over the next 3 years, the patient required hospitalization for cardiac, renal, and bone marrow failure. Fortunately, the patient showed no chronic GVHD and gradually recovered from renal and bone marrow dysfunction but continued to suffer from cardiac failure. As shown in Fig. 1, patient serum IgG levels were in the range of 550–700 mg/dl (age-matched control values, 680–1800 mg/dl) prior to transplantation, but rose above 1000 mg/dl during the immediate post-transplant period due to anti-cytomegalovirus (CMV) high-titer intravenous immunoglobulin infusions (IVIG). IgA and IgM levels were within the 30–60 mg/dl range during this period. Thereafter, the patient sustained a serum IgG level above 500 mg/dl until mid 2000, when her serum IgG dropped below 500 mg/dl. We began replacement IVIG therapy, but during early 2001, the patient developed two successive viral infections, herpes zoster and the mumps. During these episodes, the patient received nine doses of IVIG to control viral infections and her serum IgG levels remained above 1000 mg/dl until full recovery. However, her serum IgG levels declined sharply to 78 mg/dl thereafter. Since then, IVIG replacement therapy has been administered monthly, but her serum IgG levels still remain low. The patient’s peripheral blood lymphocyte counts were initially normal, with T cell counts .1500/ml (normal

Severe sensorineural hearing loss (bilateral >80 dB) was diagnosed in a case of familial hemophagocytic lymphohistiocytosis (FHL). The female patient developed HLH at 3 months of age and underwent allogeneic cord blood transplantation at 11 months of age following 7 months of immuno-chemotherapy. The type 2 FHL patient had a homozygous perforin gene mutation of 1090–1091delCT, and was noted to have hearing loss at 3.5 years of age. Retrospective evaluation did not clarify the exact causes of hearing loss. Reports on Kawasaki disease, suggesting a correlation between severe inflammatory status in infancy and the development of sensorineural hearing loss, may shed some light on this rare complication in this case of FHL. Considering the markedly improved prognosis of FHL due to recent advances made in the molecular diagnosis and in the management including allogeneic hematopoietic stem cell transplantation, auditor by screening might be warranted for surviving FHL patients. Pediatr Blood Cancer 2007;49:856–858. © 2005 Wiley-Liss, Inc.

Secondary lymphoid malignancy, particularly acute lymphoblastic leukemia (ALL), is rare. We report one case of ALL and another case of mediastinal lymphoblastic lymphoma developed after treatment for neuroblastoma. The secondary ALL characterized by short latency period and an 11q23 translocation apparently was induced by etoposide treatment. The pathogenesis of the secondary lymphoma is less certain and may be related to previous treatment with cyclophosphamide and radiotherapy, host susceptibility, or chance occurrence. One child died of progressive lymphoma and the other remains in remission 1 year following allogeneic bone marrow transplantation. Additional studies are needed to determine the risk, pathogenesis, and optimal treatment for secondary lymphoid malignancy.

The occurrence of adenopathy in patients with myelodysplastic syndrome-associated extramedullary myeloid cell tumors has rarely been reported. We describe a 7-year-old girl with juvenile myelomonocytic leukemia who showed the novel chromosomal abnormality t(9;12)(p22;q24.1) and who developed severe adenopathy of the cervical lymph nodes, tonsils, and adenoids that was manifested as granulocytic sarcoma. Following chemotherapy, the patient underwent a conditioning regimen of busulfan, cyclophosphamide, and total body irradiation followed by successful allogeneic bone marrow transplantation from her single HLA locus-mismatched mother at 6 months after her diagnosis. The patient continues to be well and in remission 3 years after stem cell transplantation.

The therapeutic results of allogeneic bone marrow transplantation (BMT), following a conditioning regimen of total body irradiation and busulphan and melphalan administration, were evaluated in 20 pediatric patients with high-risk leukemia or lymphoma. Twelve patients received BMT from HLA-matched related (MR) donors while eight received transplants from mismatched related or unrelated (MisR/UR) donors. The post-BMT five-year survival rates were much better for patients in the MR donor group (p = 0.0008). The outcomes of patients in the MisR/UR donor group were significantly worse. This was not due to disease recurrence, but to a high incidence of fatal post-transplant infections (p = 0.004). Nine out of twelve patients who received transplants from MR donors have remained in complete remission for a median of 57 (range 27-78) months. These results suggest that this conditioning regimen has a significant anti-neoplastic benefit useful for the preparation of pediatric patients receiving transplants from MR donors; however, refinement is essential before it can be used in patients receiving transplants from MisR/UR donors.

PURPOSE Although immune dysfunction is suspected in patients with hemophagocytic lymphohistiocytosis (HLH), the difference between immune dysfunction in patients with familial erythrophagocytic lymphohistiocytosis (FEL) and familial inheritance-unproved lymphohistiocytosis (FIU) remains unknown. The aim of this study was to determine useful markers to distinguish patients with FEL from those with FIU. PATIENTS AND METHODS Clinical features and laboratory findings, especially natural killer (NK) cell activity and the relative frequencies of peripheral blood mononuclear cell (PBMC) subsets, and serum levels of interferon-gamma and soluble interleukin-2 receptor were compared in 9 patients with FEL and 14 age-matched patients with FIU. Twenty-seven healthy infants served as controls. The treatment and outcome were also compared for patients with FEL and FIU. RESULTS Comparison between patients with FEL and FIU revealed significantly lower NK activity in those with FEL (p = 0.03) but failed to show any significant differences in PBMC subsets, except that the percentage of CD3+ T cells was higher in patients with FEL (p = 0.02). CD4- and CD8-dominant phenotypes were characteristic findings in both groups of patients, although increased CD19+ B cells were restricted to patients with FIU. NK activity was deficient (< 5%) in four of the seven patients with FEL tested but in only one of eight patients with FIU. By comparison to values for age-matched controls, the percentages of CD3+, CD3+DR+ and CD45RO+ PBMCs in patients with FEL were significantly high (p < 0.05) and those of CD19+ and CD45RA+ subsets were lower than normal. Among patients with FIU, PBMC subsets included significantly reduced CD3+, CD4+, CD45RA+, and CD4+CD45RA+. In this small series, the outcome of patients with FEL and FIU treated with chemotherapy was not significantly different at the time of evaluation. CONCLUSIONS These results indicate considerable immune heterogeneity among patients with HLH younger than 2 years. Although NK activity was useful but not diagnostic, determination of PBMC subsets and patterns of cytokine expression was not helpful in distinguishing patients with FEL from those with FIU, suggesting that the immune responses characteristic of these diseases may reflect different triggering factors, including viruses. The impact of this immune heterogeneity on patients' outcome remains to be determined.

Sir—Adenovirus infection in compromised hosts can become a fatal infection. This disorder, especially adenovirus-triggered severe haemorrhagic cystitis and systemic disease, is one of the most troublesome complications in transplant recipients, and has high morbidity. Serotypes 11, 34, and 35 are most common. We have established a real-time PCR system following the previously described procedure for adenovirus serotype 35. The PCR uses primers upstream 5 -CAGGTAGACTGCCT CGATGATG-3 , downstream 5 -GC CCACCCTGCTTTATCTTCTC-3 , and with a probe of 5 -(FAM)TGCA CTCTGACCACGTCGAAAACTTC (TAMRA)-3 cutoff 50 copies/mL in sera and 50 copies/ g creatinine in urine). We monitored serum and urine adenovirus genome quantitatively, although retrospectively, in one transplant recipient with severe adenovirus systemic disease. The viral genome load well reflected the disease activity. A girl aged 10 years with acute myeloblastic leukaemia (FAB, M3) underwent bone-marrow transplantation from a matched sibling donor after haematological relapse, with busulfan, cyclophosphamide, and melphalan conditioning, and with prophylaxis for graft-versus-host disease of cyclosporin A, methotrexate, and prednisolone. The transplant was successful, but the patient developed haemorrhagic cystitis starting at day 25, followed by severe systemic infection with high fever. We isolated adenovirus serotype 35 from her urine on day 26. Our PCR system showed that samples before transplantation were negative. Serum adenovirus genome became detectable on day 15 with around 75 10 copies/mL. As shown in the figure, serum adenovirus genome increased up to 2·5 10 copies/mL on day 60. Mild decrease of adenovirus genome might have reflected the treatment effect of intravenous vidarabin and ribavirin. Because of bone marrow failure, probably due to systemic adenovirus infection and adverse effect of antiviral treatment, a second bone-marrow transplant from the same donor was done on day 110. Even after the second transplantation, serum adenovirus genome remained high at 5 10 copies/mL, clinically associated with persistent fever and microhaematuria. With intensive care, the patient survived with late sequelae of renal and cardiac dysfunction. The adenovirus genome in urine was similarly changed as those in sera (figure). The detection of serum genome by PCR could be the first step towards predicting the outlook in transplant recipients with adenovirus infection. We suggest that real-time PCR is also useful for assessment of treatment response, as shown in post-transplant Epstein-Barr virus infection.