Passenger lymphocyte syndrome after ABO-incompatible allogeneic hematopoietic stem cell transplantation; dynamics of ABO allo-antibody and blood type conversion.

Passenger lymphocyte syndrome (PLS) is a specific subtype of graft versus host disease (GVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) characterized by an immune-mediated hemolysis caused by donor-derived B cells. However, precise nature of PLS has not been well characterized due to its rarity. We herein report two cases of PLS following ABO-incompatible HSCT whose clinical course and dynamics of anti-ABO allo-antibody and blood type conversion were closely examined. Both cases demonstrated acute hemolysis upon engraftment, and the presence of high titer allo-antibody against recipients' red blood cells (RBCs) helped us to reach the diagnosis of PLS. Hemolysis in both cases showed spontaneous improvement with prednisolone and supportive therapy including transfusion and fluid support. In one case with blood type O, the patient recursively developed PLS in the second and the third HSCT from ABO-mismatch donors, leading to a hypothesis that original blood type O may serve as a background for acute elevation of serum anti-ABO antibody and therefore a risk for developing PLS in multiple ABO-incompatible HSCTs. When hemolysis is noted following ABO-incompatible HSCTs, PLS should be considered and measurement of anti-ABO antibodies is warranted.

Septicemia from Lactobacillus rhamnosus GG, from a Probiotic Enriched Yogurt, in a Patient with Autologous Stem Cell Transplantation.

Probiotic-rich foods are consumed without much restriction. We report here, a case of septic shock caused by yogurt derived Lactobacillus species in a 54-year-old male patient with acute promyelocytic leukemia, in second complete remission, and who was an autologous stem cell transplantation recipient. He received high dose chemotherapy and autologous peripheral blood stem cell transplantation. He ingested commercially available probiotic-enriched yogurt because of severe diarrhea. One week later, he developed septic shock, and the pathogen was determined by strain-specific PCR analysis as Lactobacillus rhamnosus GG (ATCC 53103), which was found to be identical with the strain in the yogurt he consumed. Thus, because even low virulent Lactobacilli in the probiotic products can be pathogenic in the compromised hosts, ingestion of such products should be considered with caution in neutropenic patients with severe diarrhea, such as stem cell transplantation recipients.

Hyperleukocytosis Complicated by Intracerebral Hemorrhage and Spurious Hypoxemia: A Case Report and Literature Review.

We present the management of a 15-year-old girl with acute myeloid leukemia who presented with massive hyperleukocytosis and neurological deficit due to intracerebral hemorrhage. Surgical intervention was considered but ultimately not undertaken because of the presence of massive hyperleukocytosis, thrombocytopenia, hypokalemia, and considerable discrepancy between the oxygen saturation values determined mechanically and by peripheral oximetry. Aggressive treatment of the hyperleukocytosis was immediately started, which improved the patient's overall condition and rendered surgical intervention unnecessary. This report shows that immediate treatment of massive hyperleukocytosis and critical interpretation of laboratory results in patients with hyperleukocytosis are warranted.

[Successful induction therapy for acute myeloid leukemia complicated with brain hemorrhage and hyperleukocytosis].

Adequate management of hyperleukocytosis in patients with acute myeloid leukemia (AML) is essential for the prevention of life-threatening complications related to leukostasis and tumor lysis syndrome, but the optimal therapeutic strategy remains unclear. We report a 15-year-old girl with newly diagnosed AML who had extreme hyperleukocytosis (leukocyte count at diagnosis, 733,000/µl) leading to a brain hemorrhage. She was initially treated with hydroxyurea, but presented with brain hemorrhage due to leukostasis and underwent leukapheresis emergently with intensive care and mechanical ventilation. Full-dose standard induction chemotherapy was initiated after achieving gradual cytoreduction (leukocyte count, 465,000/µl) within five days after the initiation of therapy with hydroxyurea and leukapheresis. These treatments were successful and she experienced no complications. The patient ultimately recovered fully and was discharged with complete remission of AML. Although the effects of hydroxyurea and leukapheresis in the setting of hyperleukocytosis are still controversial, these initial treatments may contribute to successful bridging therapy followed by subsequent induction chemotherapy, especially in AML cases with extreme hyperleukocytosis or life-threatening leukostasis.

Ultrastructural characterization of surface-induced platelet activation on artificial materials by transmission electron microscopy.

Platelet adhesion is one of the most pivotal events of blood clotting for artificial surfaces. However, the mechanisms of surface-induced platelet activation have not been fully been elucidated or visualized so far. In this study, we attempted to observe the internal structures and adhesion interfaces of human platelets attached to artificial surfaces by transmission electron microscopy (TEM) during the platelet activation process. We prepared observation samples by a conventional embedding method using EPON 812 resin. The sectioning was sliced perpendicular to the a-platelet/material interface. Observation by TEM indicates that internal granules coalesce in the center of the platelet accompanied by pseudopodial growth in the early stage of platelet activation. Pseudopodia from a platelet attach to the material interface not along a plane but at a point. In addition, along with the process of platelet activation, the gap between the platelet membrane and the material surface at the interface disappeared and a-platelet/material adhesion became much tighter. In the fully activated platelet stage, the platelet becomes thinner and tightly adheres to the substrate. As a result of comparative observation of an adherent platelet on polycarbonate (PC) and on amorphous carbon (a-C:H), it was found that internal granules release was inhibited more remarkably on a-C:H coating rather than on PC. Despite numerous technical difficulties in preparing sectional samples, such a study might prove the essential mechanism of biomaterial-related thrombosis, and it might become possible to modify the surfaces of materials to minimize material-related thrombosis.

[Allogeneic hematopoietic stem cell transplantation from HLA one-locus-mismatched related donors].

Fourteen patients who received allogeneic hematopoietic stem cell transplantation (HSCT) from a serologically HLA one mismatched related donor (MMRD) between November 1987 and July 2003, were compared with HSCT from matched sibling donor (MSD) (n=142) or matched unrelated donor (MUD) (n=78). Cumulative incidence of acute graft-versus-host disease (GVHD) in patients with MMRD was significantly higher than in those with MSD, but was not different from that in those with MUD. There was no difference in the incidence of extensive type chronic GVHD in HSCT according to donor type. Overall survival (OS) at 5-years in patients with MMRD, MSD and MUD was 42.8%, 55.6% and 44.3%, respectively. The presence of acute GVHD and disease status at HSCT were identified as risk factors for overall survival by multivariate analysis. Acute GVHD was a risk factor for prognosis in patients with MSD and MUD, but not in those with MMRD. It was confirmed that the therapeutic results could be obtained in HSCT from MMRD as well as MUD.

Notch activation induces the generation of functional NK cells from human cord blood CD34-positive cells devoid of IL-15.

The development of NK cells from hematopoietic stem cells is thought to be dependent on IL-15. In this study, we demonstrate that stimulation of human cord blood CD34(+) cells by a Notch ligand, Delta4, along with IL-7, stem cell factor, and Fms-like tyrosine kinase 3 ligand, but no IL-15, in a stroma-free culture induced the generation of cells with characteristics of functional NK cells, including CD56 and CD161 Ag expression, IFN-gamma secretion, and cytotoxic activity against K562 and Jurkat cells. Addition of gamma-secretase inhibitor and anti-human Notch1 Ab to the culture medium almost completely blocked NK cell emergence. Addition of anti-human IL-15-neutralizing Ab did not affect NK cell development in these culture conditions. The presence of IL-15, however, augmented cytotoxicity and was required for a more mature NK cell phenotype. CD56(+) cells generated by culture with IL-15, but without Notch stimulation, were negative for CD7 and cytoplasmic CD3, whereas CD56(+) cells generated by culture with both Delta4 and IL-15 were CD7(+) and cytoplasmic CD3(+) from the beginning and therefore more similar to in vivo human NK cell progenitors. Together, these results suggest that Notch signaling is important for the physiologic development of NK cells at differentiation stages beyond those previously postulated.

Late onset of autoimmune hemolytic anemia and pure red cell aplasia after allogeneic hematopoietic stem cell transplantation using in vivo alemtuzumab.

Hemolytic anemia and pure red cell aplasia (PRCA) after allogeneic hematopoietic stem cell transplantation (HSCT) have been reported to be mainly related to ABO-incompatibility between donor and recipient. Autoimmune hemolytic anemia (AIHA) without ABO-incompatibility has been also reported after allogeneic HSCT, especially with T-cell depletion. However, optimal management of AIHA or PRCA remains unclear. A 54-year-old male with myelodysplastic syndrome (MDS) underwent haploidentical human leukocyte antigen-mismatched HSCT using in vivo alemtuzumab and developed AIHA and PRCA simultaneously 15 months after transplantation, following the administration of cidofovir and probenecid for persistent cytomegalovirus (CMV) antigenemia and retinitis. AIHA was successfully treated with rituximab, and subsequently PRCA with cyclosporine without relapse of MDS or recurrence of CMV infection. The clinical course suggested that AIHA was mainly caused by humoral immune response, while PRCA was mainly caused by cell-mediated immune response in this patient, although these immune responses might be related to each other.

Fluorine doping into diamond-like carbon coatings inhibits protein adsorption and platelet activation.

The first major event when a medical device comes in contact with blood is the adsorption of plasma proteins. Protein adsorption on the material surface leads to the activation of the blood coagulation cascade and the inflammatory process, which impair the lifetime of the material. Various efforts have been made to minimize protein adsorption and platelet adhesion. Recently, diamond-like carbon (DLC) has received much attention because of their antithrombogenicity. We recently reported that coating silicon substrates with fluorine-doped diamond-like carbon (F-DLC) drastically suppresses platelet adhesion and activation. Here, we evaluated the protein adsorption on the material surfaces and clarified the relationship between protein adsorption and platelet behaviors, using polycarbonate and DLC- or F-DLC-coated polycarbonate. The adsorption of albumin and fibrinogen were assessed using a colorimetric protein assay, and platelet adhesion and activation were examined using a differential interference contrast microscope. A higher ratio of albumin to fibrinogen adsorption was observed on F-DLC than on DLC and polycarbonate films, indicating that the F-DLC film should prevent thrombus formation. Platelet adhesion and activation on the F-DLC films were more strongly suppressed as the amount of fluorine doping was increased. These results show that the F-DLC coating may be useful for blood-contacting devices.

Fluorinated diamond-like carbon as antithrombogenic coating for blood-contacting devices.

Diamond-like carbon (DLC) is being considered for widespread clinical use as a surface coating for cardiovascular devices. We synthesized fluorinated DLC (F-DLC) coatings in order to create a more hydrophobic surface with improved antithrombogenicity and flexibility when compared with conventional DLC coatings by combining the inertness of DLC films with the advantage of fluorination. The purpose of this study was to evaluate the in vitro hemocompatibility and in vivo biocompatibility of the F-DLC coating for medical devices. The in vitro whole blood model confirmed that platelet loss was lower in the F-DLC group than in the noncoated group (SUS316L), which suggests the adhesion of a smaller number of platelets to F-DLC-coated materials. Furthermore, the biomarkers of mechanically induced platelet activation (beta-thromboglobulin) and activated coagulation (thrombin-antithrombin-three complex) were markedly reduced in the F-DLC-coated group. In vivo rat implant model studies revealed no excessive local and systemic inflammatory responses in the F-DLC group. The thickness of the fibrous tissue capsule surrounding the F-DLC-coated disk was almost equal to that of the noncoated SUS316L disk, which has the favorable biocompatibility for metallic implant materials. F-DLC coating thus appears to be a promising candidate for use as a coating material in blood-contacting devices.

Isolated recurrence of granulocytic sarcoma manifesting as extra- and intracranial masses--case report.

A 30-year-old female presented with a rare case of isolated recurrence of granulocytic sarcoma manifesting as extra- and intracranial masses 16 months after successful treatment of acute myeloblastic leukemia (M-2). She presented with a swelling located on her forehead that had appeared just after hitting her forehead, and never diminished in size. The mass was elastic hard and not freely mobile. Computed tomography and magnetic resonance imaging demonstrated enhanced masses in the right frontal extra- and intracranial region with no bone destruction. There was no evidence of relapse in the bone marrow. Needle aspiration biopsy of the subscalpal mass was performed. Fluorescence in situ hybridization revealed AML1/MTG8 fusion gene associated with t(8; 21). Two courses of systemic chemotherapy with high-dose cytarabine and total neural axis irradiation resulted in complete remission.

[Allogeneic peripheral blood stem cell transplantation for a hepatitis B virus carrier with Epstein-Barr virus associated with hemophagocytic syndrome].

We report herein a 21-year-old hepatitis B virus (HBV) female carrier who developed persistent fever, lymphadenopathy and pancytopenia in September of 2000. Hemophagocytes were found in the bone marrow smears. Epstein-Barr virus (EBV) serology showed positive for VCA-IgG, IgM and EB-ER and negative for EBNA. The EBV genome was detected in the peripheral blood. The patient was diagnosed as having EBV-associated hemophagocytic syndrome (EBV-AHS) and received chemotherapy. Although she was treated with lamivudine three months after the initiation of chemotherapy, she developed severe hepatitis. She recovered from the hepatitis through a combination of plasma exchange, immunosuppressive and antiviral therapies. Because of the refractoriness of her EBV-AHS to chemotherapy, she received allogeneic peripheral blood stem cell transplantation (PBSCT) from her HLA-identical brother. Hepatitis B did not recur after the PBSCT under administration of lamivudine. The EBV genome in the peripheral blood disappeared soon after the PBSCT but it was revealed again after the initiation of prednisolone for the treatment of acute GVHD. A donor lymphocyte infusion (DLI) was given on day 169 and the EBV genome copy number in the peripheral blood gradually decreased and disappeared. Although the origin of the EBV-infected cells could not be determined as being from the host or donor, DLI was a useful treatment for the recurrence of EBV infection after allogeneic stem cell transplantation for EBV-AHS.

Conversion disorder with convulsion and motor deficit mimicking the adverse effects of high-dose Ara-C treatment in a posttransplant acute myeloid leukemia patient: a case report and review of the literature.

In this communication, we report an acute leukemia patient who developed conversion disorder mimicking the adverse effects of high-dose cytosine arabinoside (Ara-C) treatment after the patient received high-dose Ara-C treatment. A 21-year-old woman, with acute recurrent leukemia after bone marrow transplantation, received high-dose Ara-C treatment and 10 days later was referred for psychiatric consultation because of an abrupt onset of convulsion. On neurologic examination, she showed convulsion of all the limbs without loss of consciousness. All limbs looked paretic; however, tendon reflexes in all limbs were normal and pathological reflex was not recognized. When her hand was dropped onto her own face, it fell next to her face but not on her face. Laboratory data were unremarkable. She had no history of psychiatric illness or drug or alcohol abuse. The patient explained that she knew about the recurrence of her own leukemia and the news of the death of a close friend due to leukemia at the same time, which was a shocking event for her, focusing her attention on her own fears of dying from the same disease. Conversion disorder in cancer patients is not common; however, appropriate diagnosis is very important to avoid inappropriate examinations and treatments. In leukemia patients receiving chemotherapy, various kinds of signs and symptoms may develop due to the adverse effects of chemotherapy and/or infection. Therefore, conversion disorder might be overlooked and inappropriate treatment and examinations might be performed. Clinicians should consider conversion disorder in the differential diagnosis when patients develop unexplained neurological symptoms.