Yoshiro Amano

Treatment of intracranial nongerminomatous germ-cell tumor by high-dose chemotherapy and autologous stem-cell rescue.

Nongerminomatous germ-cell tumor (NGGCT) in the central nervous system (CNS) is still highly lethal. The present study evaluated the outcome of high-dose chemotherapy followed by autologous stem-cell rescue (ASCR). The patients included three cases of choriocarcinoma, two cases of embryonal carcinoma and one case of yolk sac carcinoma. High-dose cisplatin (200 mg/m2), etoposide (1250 mg/m2) and ACNU (150 mg/m2) were administrated in combination with ASCR to patients at complete remission as a result of surgical removal, irradiation, and from four to seven courses of induction chemotherapy. All the patients treated with this therapy were alive from one to seven years after the diagnosis, living with good performance status. The patients have not required any additional treatments after ASCR. The myelosuppression period, characterized by fewer than 500/µl peripheral neutrophils, ranged from 8 to 15 days (median, 11.5 days). Within seven days of ASCR, high fever was found in four patients. Although mild liver dysfunction was found in all patients, renal dysfunction was not observed. Hearing disturbance was found in 50% of the patients. This treatment regime will improve long-term survival for patients with NGGCT.

Hypercalcemia associated with all-trans-retinoic acid in the treatment of acute promyelocytic leukemia

Recent reports have described clinical benefits of all-trans-retinoic acid (ATRA) therapy for acute promyelocytic leukemia (APL). This paper describes severe hypercalcemia (serum calcium: 18.7 mg/dl) in association with ATRA treatment in a 14 year old girl with APL. Serum parathyroid hormone (PTH) concentrations were normal (0.21 ng/ml), which precludes the possibility of primary hyperparathyroidism or ectopic PTH secretion as a cause of the hypercalcemia. As for the factors which can accelerate mineral resorption, there were no apparent increases in the levels of PTH-related protein (PTH-rP), prostaglandins and vitamin D metabolites. In our in vitro experiment, ATRA did not stimulate the leukemic cells to produce PTH-rP. We speculate that ATRA, like PTH, may increase osteoclastic activity and induce hypercalcemia.

Stem cell factor enhances the growth of primitive erythroid progenitors to a greater extent than interleukin-3 in patients with aplastic anaemia

Summary We examined the combined effects of stem cell factor (SCF). or interleukin‐3 (IL‐3) with erythropoietin on the development of haemopoietic progenitors in 19 patients with aplastic anaemia (AA) and eight normal controls by using an in vitro clonal assay. SCF significantly enhanced the growth of total erythroid colonies (erythroid bursts, mixed colonies) in 11 patients and all normal controls, whereas IL‐3 did so in only three patients. The number of SCF‐ or IL‐3–dependent erythroid colonies was substantially lower in AA patients than in the controls. Comparison of the capacity of SCF and IL‐3 to increase total erythroid colony growth indicated that half of the AA patients responded more strongly to SCF than the normal controls, while few patients responded in such a manner to IL‐3. These findings suggest that SCF in vivo will have a more dramatic effect than IL‐3 in improving anaemia in patients with AA.

Improvement of neutropenia and neutrophil dysfunction by granulocyte colony-stimulating factor in a patient with glycogen storage disease type Ib

Patients with glycogen storage disease type Ib (GSD Ib) suffer from recurrent bacterial infections due to neutropenia and neutrophil dysfunction. To improve the quality of life in a 9-year-old boy with GSD Ib, we subeutaneously administered recombinant human granulocyte colony-stimulating factor (G-CSF). Daily injections of 100 μg/m2 of G-CSF significantly increased absolute neutrophil counts and augmented neutrophil mobility. The patient was then treated with 70 and 100 μg/m2 of G-CSF daily and twice-weekly. The treatment maintained absolute neutrophil counts at significantly higher levels than those without treatment for 22 months and markedly decreased the frequency of infections and the necessity for hospitalisation. No adverse effects were observed during treatment. These findings indicate that daily and twice-weekly treatment with G-CSF of long duration are safe and effective for patients with GSD Ib. G-CSF may be a useful therapeutic agent in patients with neutrophilic impairment as a consequence of a metabolic disorder.

Successful treatment of fulminant Wilson's disease without liver transplantation

Fulminant Wilsons disease (WD) is life‐threatening. The revised WD prognostic index (RWPI) has been used to predict the severity of the disease, with a score ≥11 indicating fatal outcome without liver transplantation (LTx). We here report the case of a 10‐year‐old female patient with fulminant WD (RWPI, 16) who recovered fully after plasma exchange and continuous hemodiafiltration, followed by treatment with copper chelate agents. To the best of our knowledge, there have been five fulminant WD patients with RWPI ≥ 11 including the present patient, in whom LTx was not done. Based on the therapeutic modalities in these five cases, non‐surgical treatment (blood purification and copper chelate agents) may be able to avoid LTx in fulminant WD even with very high RWPI, although preparation for LTx is necessary.

The clinical characteristics of vitamin D deficiency in childhood: a systematic literature review of Japanese patients.

To describe the characteristics of children with vitamin D deficiency, we reviewed the reports of vitamin D deficiency among Japanese children that were published between 1989 and 2008. We identified 25 patients with vitamin D deficiency in 9 published studies and evaluated their clinical characteristics together with those of 3 patients we recently treated. The patients were distributed in two distinct age groups at diagnosis: < 1 year old and > or = 1 year old. The main symptom of the < 1 year old age group was hypocalcemic convulsions and that of the > or = 1 year old age group was bowed legs. Serum calcium, intact PTH, and 1,25(OH)2D levels were significantly lower in the < 1 year age group than in the > or = 1 year age group. It would be useful to find and make early interventions in cases of children at a high-risk of vitamin D deficiency.

Subcutaneous abscess due to the basidiomycete Phellinus mori in a patient with chronic granulomatous disease

Chronic granulomatous disease (CGD), a primary immunodeficiency caused by impaired phagocyte killing of intracellular pathogens, is characterized by recurrent, life-threatening, bacterial and fungal infections. As a result of improvements in microbiologic culture and identification techniques, a number of unique filamentous fungi have been reported as significant pathogens in patients with CGD. We report a case of subcutaneous basidiomycete Phellinus mori infection in a patient with CGD. To the best of our knowledge, this is the first reported case of human infection by this fungus. The causative fungus was identified on the basis of its morphological characteristics and nucleotide sequence on the internal transcribed spacer region of the ribosomal RNA gene. This is the fifth case report of filamentous basidiomycetes infecting a patient with CGD; all of these cases have been caused by Phellinus species. We highlight the importance of recognizing filamentous basidiomycetes Phellinus species as possible agents of non-Aspergillus fungal infections in patients with CGD.

Renal complications in 6p duplication syndrome: Microarray‐based investigation of the candidate gene(s) for the development of congenital anomalies of the kidney and urinary tract (CAKUT) and focal segmental glomerular sclerosis (FSGS)

6p duplication syndrome is a rare chromosomal disorder that frequently manifests renal complications, including proteinuria, hypoplastic kidney, and hydronephrosis. We report a girl with the syndrome, manifesting left hydronephrosis, proteinuria/hematuria, and focal segmental glomerular sclerosis (FSGS) resulting in chronic end‐stage renal failure, successfully treated with renal transplantation. Microarray comparative genomic hybridization showed the derivative chromosome 6 to have a 6.4‐Mb duplication at 6p25.3–p25.1 with 32 protein‐coding genes and a 220‐Kb deletion at 6p25.3 with two genes of no possible relation to the renal pathology. Review of the literature shows that variation of renal complications in the syndrome is compatible with congenital anomalies of the kidney and urinary tract (CAKUT). FSGS, observed in another patient with 6p duplication syndrome, could be a non‐coincidental complication. FOXC1, located within the 6.4‐Mb duplicated region at 6p25.3–p25.2, could be a candidate gene for CAKUT, but its single gene duplication effect would not be sufficient. FSGS would be a primary defect associated with duplicated gene(s) albeit no candidate could be proposed, or might occur in association with CAKUT.

Myelodysplastic syndrome in a child with 15q24 deletion syndrome

15q24 deletion syndrome is a recently‐described chromosomal disorder, characterized by developmental delay, growth deficiency, distinct facial features, digital abnormalities, loose connective tissue, and genital malformations in males. To date, 19 patients have been reported. We report on a 13‐year‐old boy with this syndrome manifesting childhood myelodysplastic syndrome (MDS). He had characteristic facial features, hypospadias, and mild developmental delay. He showed neutropenia and thrombocytopenia for several years. At age 13 years, bone marrow examination was performed, which showed a sign suggestive of childhood MDS: mild dysplasia in the myeloid, erythroid, and megakaryocytic cell lineages. Array comparative genomic hybridization (array CGH) revealed a de novo 3.4 Mb 15q24.1q24.3 deletion. Although MDS has not been described in patients with the syndrome, a boy was reported to have acute lymphoblastic leukemia (ALL). The development of MDS and hematological malignancy in the syndrome might be caused by the haploinsufficiency of deleted 15q24 segment either alone or in combination with other genetic abnormalities in hematopoietic cells. Further hematological investigation is recommended to be beneficial if physical and hematological examination results are suggestive of hematopoietic disturbance in patients with the syndrome.

Three pentraxins C-reactive protein, serum amyloid p component and pentraxin 3 mediate complement activation using Collectin CL-P1.

BACKGROUND Pentraxins (PTXs) are a superfamily of multifunctional conserved proteins involved in acute-phase responses. Recently, we have shown that collectin placenta 1 (CL-P1) and C-reactive protein (CRP) mediated complement activation and failed to form terminal complement complex (TCC) in normal serum conditions because of complement factor H inhibition. METHODS We used CL-P1 expressing CHO/ldlA7 cells to study the interaction with PTXs. Soluble type CL-P1 was used in an ELISA assay for the binding, C3 and TCC deposition experiments. Furthermore, we used our previously established CL-P1 expressing HEK293 cells for the C3 fragment and TCC deposition assay. RESULTS We demonstrated that CL-P1 also bound serum amyloid p component (SAP) and pentraxin 3 (PTX3) to activate the classical pathway and the alternative pathway using factor B. CRP and PTX3 further amplified complement deposition by properdin. We found that CRP and PTX3 recruit CFH, whereas SAP recruits C4 binding protein on CL-P1 expressing cell surfaces to prevent the formation of TCC in normal serum conditions. In addition, depletion of CFH, C4BP and complement factor I (CFI) failed to prevent TCC formation both in ELISA and cell experiments. Furthermore, soluble complement receptor 1, an inhibitor of all complement pathways prevents PTX induced TCC formation. CONCLUSION Our current study hypothesizes that the interaction of pentraxins with CL-P1 is involved in complement activation. GENERAL SIGNIFICANCE CL-P1 might generally inhibit PTX induced complement activation and host damage to protect self-tissues.