Ako Mori

Endothelial damage caused by cytomegalovirus and human herpesvirus-6

Summary:Infection with cytomegalovirus (CMV) or human herpesvirus-6 (HHV-6) may have a role in vascular endothelial damage after bone marrow transplantation (BMT). In total, 41 patients who underwent BMT were classified into four groups (12, 10, 7, and 12 patients who were infected with both CMV and HHV-6, CMV alone, HHV-6, and neither virus, respectively). Levels of thrombomodulin, plasminogen activator inhibitor-1, and cyclic GMP were 7.5±1.7 FU/ml, 76.4±24.1 ng/ml, and 9.51±1.1 pmol/ml, respectively, in the patients with both viruses, while the respective values were 2.9±0.67 FU/ml, 33.8±8.09 ng/ml, and 2.90±1.4 pmol/ml in patients infected with CMV alone, 4.8±0.96 FU/ml, 47.7±9.21 ng/ml, and 5.48±0.55 pmol/ml in patients with HHV-6 alone, and 1.6±0.39, 17.5±7.88 ng/ml, and 0.45±0.3 in those with neither virus. All three markers were significantly higher in the three groups with at least one virus than in the uninfected patients (P<0.05), and were also higher in patients with HHV-6 alone than in those with CMV alone (P<0.05). These results suggest that infection by CMV or HHV-6 causes vascular endothelial injury, with HHV-6 having a stronger effect than CMV, and combined infection having a stronger effect than either virus alone. Such viral infection may be a cause of thrombotic microangiopathy after BMT.

Expression of the antiapoptosis gene survivin in human leukemia

Loss of the inhibition of apoptosis is important in leukemogenesis and may influence the prognosis. Survivin is an inhibitor of apoptosis that shows selective expression during fetal development and in human malignancies. Survivin expression was examined in human leukemias using the reverse transcriptase—polymerase chain reaction. Survivin gene expression was detected in 17 of 31 patients with acute myelocytic leukemia and 11 of 16 patients with acute lymphocytic leukemia but was not identified in normal bone marrow cells. Survivin expression was lower in patients with M3 acute myelocytic leukemia than in patients with other types of acute leukemia. Survivin was not detected in the chronic phase of chronic myelocytic leukemia but was observed in 5 of 7 patients with chronic myelocytic leukemia in blastic crisis. These findings suggest a relationship between survivin gene expression and hematopoietic cell differentiation. In fact, survivin gene expression was down-regulated during the differentiation of HL-60 cells after treatment with dimethyl sulfoxide or all—trans-retinoic acid. Moreover, the disease-free survival rates of patients with survivin expression were lower than in patients without survivin expression. Accordingly, survivin may have a role in leukemogenesis as well as in other malignancies. Detecting survivin may also provide prognostic information.

Effects of total body irradiation on the vascular endothelium

Takatsuka H, Wakae T, Mori A, Okada M, Okamoto T, Kakishita E. Effects of total body irradiation on the vascular endothelium. Clin Transplant 2002: 16: .

Evaluation of CMV/human herpes virus-6 positivity in bronchoalveolar lavage fluids as early detection of acute GVHD following BMT: evidence of a significant relationship

We evaluated the relationship between CMV and human herpes virus-6 (HHV-6) reactivation and the incidence of grades 2 to 4 acute GVHD post BMT. Bronchoalveolar lavage fluid (BALF) samples extracted from 54 BMT recipients on post-BMT day 35 were analyzed by PCR for detection of CMV DNA, HHV-6 DNA and CMV plus HHV-6 DNA. CMV DNA was detected in 26 patients and 13 (50%) developed grades 2 to 4 acute GVHD. Of the 28 who were CMV negative, only six (21.4%) developed grades 2 to 4 acute GVHD. HHV-6 was detected in 18 patients, and 11 (61.1%) developed grades 2 to 4 acute GVHD. Of the 36 who were HHV-6 negative, only eight (22.2%) developed grades 2 to 4 acute GVHD. CMV and HHV-6 were detected in 13 patients, and eight (61.5%) developed grades 2 to 4 acute GVHD. Of the 23 who were negative for both CMV and HHV-6, only three (13%) developed grades 2 to 4 acute GVHD. In all experiments, the difference between the groups was significant (P < 0.05, P < 0.05 and P < 0.01, respectively). we conclude that herpes virus infection, in particular cmv concurrent with hhv-6 reactivation, is predictive of moderate to severe acute gvhd. Bone Marrow Transplantation (2000) 26, 77–81.

Successful treatment of severe cytomegalovirus retinitis with foscarnet and intraocular injection of ganciclovir in a myelosuppressed unrelated bone marrow transplant patient.

A female patient with ALL received a bone marrow transplant (BMT) from an unrelated donor with a one locus HLA mismatch. The donor was heterozygous at the HLA-A locus, while the patient was homozygous at this locus. The patient had cytomegalovirus (CMV) antigenemia on day 42 following an intensive preparative regimen that included anti-thymocyte globulin and BU+CY+TBI to prevent graft rejection. Ganciclovir was given initially for the treatment of CMV antigenemia, although the patient soon developed severe myelosuppression. The patient’s hematopoietic recovery was poor, and CMV and human herpesvirus-6 (HHV-6) were detectable in the peripheral blood. Severe CMV retinitis was treated with foscarnet and the intraocular injection of ganciclovir. The CMV retinitis improved and the marrow gradually recovered. CMV and HHV-6 were no longer detectable in the peripheral blood. Foscarnet and intraocular injection of ganciclovir appeared to be an effective treatment for CMV retinitis in this myelosuppressed BMT patient.

Acute Promyelocytic Leukemia with Marrow Fibrosis at Initial Presentation: Possible Involvement of Transforming Growth Factor-β1

Although the occurrence of marrow fibrosis in acute myeloid leukemia has been described, there have been no reports of acute promyelocytic leukemia (APL) associated with marrow fibrosis. Here we describe an APL patient with severe marrow fibrosis at initial presentation. He had the typical manifestations of APL, except for marrow fibrosis. Complete remission was achieved by treatment with all-trans retinoic acid plus chemotherapy, and his marrow fibrosis gradually improved concomitantly with the decrease in leukemic cells. To clarify the mechanism of marrow fibrosis in this patient, we investigated the expression of genes for several cytokines promoting fibrosis by the reverse transcriptase polymerase chain reaction methods. An overexpression of transforming growth factor-β1 was noted in his leukemic cells at initial presentation, whereas no increase in expression was observed at the time of relapse when he no longer had marrow fibrosis. These findings suggest that overexpression of transforming growth factor-β1 was involved in the development of marrow fibrosis in this APL patient.

Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome following allogeneic bone marrow transplantation

We monitored the levels of various cytokines and chemokines, as well as an adhesion molecule and factors related to vascular endothelial damage, in three patients with thrombotic thrombocytopenic purpura and hemolytic uremic syndrome after bone marrow transplantation. Measurements were done at the onset of this condition and during plasma exchange for treatment. At the onset of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, the levels of interleukin-8, thrombomodulin, and plasminogen activator inhibitor-1 were all markedly increased. A close relationship was observed between improvement in symptoms by plasma exchange and a decrease in interleukin-8 level, suggesting that this chemokine may be related to the development of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome after bone marrow transplantation.

Similarity Between Hepatic Graft-versus-host Disease and Primary Biliary Cirrhosis

Abstract Similarities between hepatic graft-versus-host disease (GVHD) and primary biliary cirrhosis (PBC) have been reported recently. To examine this association, we studied 60 patients who underwent allogeneic bone marrow transplantation (BMT) consecutively at a single medical institution. Among the 60 patients, 12 developed hepatic GVHD after BMT and 48 did not. These two groups were compared with respect to various characteristics seen in PBC, such as autoantibodies, human leukocyte antigen (HLA) status, infection and inflammatory cytokines. The two groups showed a significant difference in HLA DR status. There was also a significant difference in the febrile period and in cytokine levels between the patients with hepatic GVHD and 12 other patients who had no complications after transplantation. These findings suggest that hepatic GVHD resembles PBC and that HLA DR features of PBC may also be risk factors for the onset of hepatic GVHD.

Detection of GPI-anchored protein-deficient cells in patients with aplastic anaemia and evidence for clonal expansion during the clinical course

The incidence of patients with aplastic anaemia (AA) who show a deficiency of glycosylphosphatidylinositol (GPI)‐anchored proteins on their peripheral blood (PB) or bone marrow (BM) cells is higher than that previously reported. We analysed the expression of CD55 or CD59 on PB and BM cells and those of colonies and bursts formed in cultures with marrow cells from AA patients. 4/21 (19%) AA cases later developed paroxysmal nocturnal haemoglobinuria (PNH). 7/17 (41.2%) AA cases showed a subpopulation without GPI‐anchored proteins. The defect characteristic for PNH was observed only on the colonies/bursts but not on the PB or BM cells in three cases. We found the affected colonies/bursts in cultures using thawed marrow cells which had been cryopreserved at the diagnosis of aplasia in one patient who developed PNH 3 years later. Two different mutations of the PIG‐A gene were found in the colonies/bursts at the time of AA. The nucleotide sequences were identical between the colonies/bursts at the time of AA and those after the transition to PNH. However, one of the mutations was detected only at the haemopoietic progenitor level but not in PB granulocytes. There may be latent subclones with PNH abnormalities which could expand to the level of clinical detection, or which do not progress and remain indolent for a relatively long time, implying the different extents of clonal expansion among the affected progenitors.

Superior Vena Cava Syndrome after Bone Marrow Transplantation Caused by Aspergillosis: A Case Report

Abstract Aspergillosis is known for the variety of unusual presentations in immuno-suppressed patients. We report a patient in whom aspergillosis caused the superior vena cava (SVC) syndrome. A 37-year-old woman became febrile soon after bone marrow transplantation (BMT). Chest radiography demonstrated a 5-cm mass extending from the right lung apex to the right supraclavicular fossa beside her Hickman catheter. She then developed SVC syndrome, which progressed despite treatment. Despite recovery of the white blood cell count, the patient continued to deteriorate, became comatose, suffered a cardiac arrest and died 31 days after BMT. Autopsy revealed Aspergillus infection at the apex of the right lung associated with innominate artery thrombosis.