Shinjiro Todo

Hemophagocytic lymphohistiocytosis in infancy and childhood

OBJECTIVE The current status of hemophagocytic lymphohistiocytosis (HLH) in infants and children has been studied. STUDY DESIGN Eighty-two cases of pediatric HLH, for which there was no confirmed familial inheritance, were comparatively studied between 36 patients less than 2 years of age and 46 patients more than 2 years of age. RESULTS In all cases, persistent fever, cytopenia, liver dysfunction, and hepatosplenomegaly were the most frequently noted symptoms. Hyperferritinemia (> 1000 micrograms/L) and elevated blood levels of lactate dehydrogenase (> 1000 IU/L) were observed in 90% and 89.7%, respectively. These figures were considerably higher than for either hypertriglyceridemia (> 2 mmol/L) (50%) or hypofibrinogenemia (< 1.5 gm/L) (57.4%), indicating that increased serum ferritin and lactate dehydrogenase concentrations might be good diagnostic parameters for HLH. These parameters are nonspecific but are of follow-up and prognostic value in these HLH cases. No differences were found in clinical signs and symptoms or other laboratory findings for the two age groups. Immunochemotherapy was administered in the similar regimens to patients in both groups. Of the 82 patients, 13 (15.9%) succumbed to a fatal course within 2 months after diagnosis, and Kaplan-Meir analysis for all cases predicted the overall disease-free patient survival at 4 years from the onset of disease to be 57.2% (95% confidence interval (CI), 45.1% to 69.3%). There was a slightly, but not statistically significant, poorer prognosis for the younger patients: 44.2% (95% CI, 26.0% to 62.4%) survival for the infant group versus 67.2% (95% CI, 51.8% to 82.6%) survival for the older group (p = 0.0569). CONCLUSIONS Refinement of the treatment is mandatory to improve the outcome of HLH in both infants and older pediatric patients.

High serum ferritin level as a marker of malignant histiocytosis and virus-associated hemophagocytic syndrome

Serum ferritin level was measured serially in three malignant histiocytosis (MH) and five virus‐associated hemophagocytic syndrome (VAHS) patients. Serum ferritin levels were greater than 1000 ng/ml at the early phase of disease. When disseminated intravascular coagulation (DIC) developed in patients, serum ferritin levels elevated further to greater than 12,000 ng/ml. MH patients were treated by combination chemotherapy, and VAHS patients were given prednisone. Each MH and VAHS patient died within 1 week from the onset of DIC, without decrease of serum ferritin level. One MH patient with continued high serum ferritin levels for 3 months after DIC also died. The remaining patients with decreased serum ferritin values less than 1000 ng/ml at 3 months after DIC are now alive with normal serum ferritin levels. These results suggest that serum ferritin level in histiocytic proliferative disorders is a useful indicator of disease activity in both neoplastic and reactive conditions rather than only a marker of malignant process.

Haemophagocytic lymphohistiocytosis, interferon-gamma-naemia and Epstein-Barr virus involvement

Summary. To clarify the correlation between Epstein‐Barr virus (EBV) involvement and hypercytokinaemia in haemophagocytic lymphohistiocytosis (HLH), we analysed serum interferon‐gamma levels and EBV‐DNA in biological specimens obtained from 25 HLH cases (23 children and two adults). We found that HLH patients showed a wide range of serum IFN‐gamma levels from 0.2 to 1300 U/ml, with a median 126U/ml for EBV‐DNA‐positive (n = 9) and 4.5 U/ml for EBV‐DNA‐negative (n = 16) groups. The latter group could be classified further into a group with hyper‐IFN‐gamma‐naemia (> 4.5 U/ml) (n = 8) and a group without hyper‐IFN‐gamma‐naemia (n = 8). The survival of the hyper‐IFN‐gamma‐naemic cases was significantly poorer than non‐hyper‐IFN‐gamma‐naemic cases. We conclude that EBV is probably involved in one third of the HLH cases, all of whom show hyper‐IFN‐gamma‐naemia, and in the half of the HLH cases with hyper‐IFN‐gamma‐naemia who have a rapidly fatal outcome.

Myelodysplasia and acute myeloid leukaemia in cases of aplastic anaemia and congenital neutropenia following G-CSF administration.

Summary. Myelodysplasia and acute myeloid leukaemia (MDS/AML) developed in three cases of severe aplastic anaemia (SAA) and one case of congenital neutropenia (CN, Kostmanns disease) who received recombinant human granulocyte colony‐stimulating factor (G‐CSF) are reported. In these four MDS/AML cases, age at diagnosis of SAA/CN was 0–13 years, the cumulative dose of G‐CSF was 98 μg/kg to 10 mg/kg over 1–57 months, and the interval from initiation of G‐CSF to MDS/AML was 25, 23, 31 and 57 months, respectively. These results suggest a link between SAA/CN and MDS/AML in relation to G‐CSF administration; however, large studies are necessary to determine if such a risk is significant in patients with SAA/CN who are treated with G‐CSF.

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%.

Cancer arising in a choledochal cyst in a 12-year-old girl

An adenocarcinoma was found in a choledochal cyst in a 12-year-old girl. This is the youngest patient so far reported with an adenocarcinoma in a choledochal cyst. The cyst consisted of dilatations of the intrahepatic bile ducts and the extrahepatic bile duct. Most of the cyst wall was resected. However, resection of the distal part of the cyst wall in the infrapancreatic region was impossible because of invasion of the portal vein and the inferior vena cava. This patient is now being treated with chemotherapy. We believe that early diagnosis is mandatory, and that total excision of a choledochal cyst is advisably to prevent the development of carcinoma.

Hyperferritinemia in Malignant Histiocytosis, Virus-Associated Hemophagocytic Syndrome and Familial Erythrophagocytic Lymphohistiocytosis.: A Survey of Pediatric Cases

ABSTRACT. Data on 28 patients with malignant histiocytosis (MH), fourteen patients with virus‐associated hemophagocytic syndrome (VAHS) and two patients with familial erythrophagocytic lymphohistiocytosis (FEL) were collected from 21 hospitals in Japan to study the serum ferritin levels and clinical features. At diagnosis, the serum ferritin values were a median of 3000 ng/ml (range, 59–270000 ng/ml) in MH and 10500 ng/ml (range, 44–68600 ng/ml) in VAHS/FEL. Clinical signs and symptoms were not substantially different between MH and VAHS/FEL. Thus, serum ferritin markedly increased in the majority of MH/VAHS/FEL patients and should be a useful marker of disease activity in either neoplastic or reactive histiocytic proliferative disorders.

Impaired natural killer activity and expression of interleukin‐2 receptor antigen in familial erythrophagocytic lymphohistiocytosis

A 1‐month‐old boy with familial erythrophagocytic lymphohistiocytosis (FEL) had a barely detectable natural killer (NK) activity of 0% to 7% (median, 0.5%) with an effector/target ratio of 20:1. The number of Leu7+ and Leu11+ cells was within normal range. In terms of interleukin‐2 (IL‐2) receptor antigens, IL‐2R/p55 (Tac) was marginally expressed whereas IL‐2R/p75‐related antigen recognized by YTA‐1 monoclonal antibody (MAb), i.e., YTA‐1 antigen, was moderately expressed on the patients mononuclear cells. Since the NK activity was restored in vitro by IL‐2 stimulation, insufficient in vivo IL‐2 production or altered cooperation of IL‐2R/p75 and IL‐2R/p55 (Tac) in the IL‐2 mediated immune response was suspected to be present. The induction of IL‐2R/p55 (Tac) in vitro was found to be impaired after stimulation with IL‐2, or YTA‐1 MAb. When the patient attained remission, the IL‐2R/p55 (Tac) induction had normalized, but low NK activity persisted. The results indicate that the IL‐2/IL‐2R system may play an important role in the etiology and pathogenesis of FEL.

Unsuccessful CTL transfusion in a case of post-BMT Epstein-Barr virus-associated lymphoproliferative disorder (EBV-LPD).

A patient with AML (FAB M4Eo) developed EBV-LPD 1.5 months after allogeneic BMT from his one locus-mismatched mother, the diagnosis being confirmed on day +82. Attempts to eradicate the monoclonally proliferating LPD using chemotherapy (VP16/dexa- methasone) followed by two doses of EBV-specific CTL and one dose of unstimulated donor leukocytes were not successful. We assume delay of infusions (day +100, +107) and insufficient CTL cell doses (total 9.2 × 106) may have been responsible for the poor outcome in this case.

Antitumor effect of γ-linolenic acid on cultured human neuroblastoma cells

Abstract γ-linolenic acid (GLA) was found to suppress the cell growth of 4 human neuroblastoma cell lines. GOTO was the most sensitive, followed by SK-N-DZ and NKP, while NCG was much less sensitive to GLA. In terms of GLA cytotoxicity, neither cyclo-oxygenase inhibitors nor a lipoxygenase inhibitor showed any effect. On the other hand, 4 antioxidants (Coenzyme Q, (D) α-tocopherol, (DL) α-tocopherol, butylated hydroxytoluene) reduced the growth inhibitory effect of GLA, but not in proportion to the decrease of GLA-stimulated lipid peroxidation. Accordingly, prostaglandins and leukotrienes probably do not play a role, and lipid peroxide may only be partly involved in the GLA effect.