Akinari Toda

Reduced-Intensity Conditioning Followed by Unrelated Umbilical Cord Blood Transplantation for Advanced Hematologic Malignancies: Rapid Engraftment in Bone Marrow

Reduced-intensity (RI) conditioning followed by cord blood transplantation (CBT) is a new treatment modality, but failure to engraft is a major concern. We describe 12 patients with advanced hematologic malignancies who underwent RI conditioning and CBT with a conditioning regimen consisting of 200 mg/m2 fludarabine (Flu), 50 mg/kg cyclophosphamide (CY), and 3 Gy total body irradiation (TBI). Cyclosporin A and/or methotrexate were used for graft-versus-host disease prophylaxis. Cord blood grafts were not mismatched for more than 2 serologically defined HLA alleles but were later found by high-resolution DNA typing to be mismatched for 2 to 4 alleles in most cases. Short tandem repeat analysis of bone marrow cells at day 14 showed complete donor chimerism in 6 of the patients and mixed chimerism in 5, indicating rapid engraftment in the bone marrow, whereas the remaining patient experienced graft rejection. Neutrophil recovery was achieved at a median of day 17 (range, days 11-24) in 10 of the 11 patients with marrow chimerism at day 14. Of these 10 patients, however, transplantation-related mortality within 100 days occurred in 4 patients who showed failed platelet recovery and a lack of durable engraftment. Overall survival and disease-free survival rates were 41.7% and 33.3%, respectively.These results show that CB mismatched at 2 to 4 HLA alleles and transplanted with the Flu/CY/3 Gy TBI regimen is able to engraft in the bone marrow as early as day 14.

Association of Helicobacter pylori with thrombotic thrombocytopenic purpura and hemolytic uremic syndrome after bone marrow transplantation.

Abstract:  Thrombotic microangiopathy (TMA) has attracted attention as a complication of bone marrow transplantation (BMT). The association of Helicobacter pylori (H. pylori) with thrombotic thrombocytopenic purpura and hemolytic uremic syndrome (TTP/HUS) after BMT was studied. Among 74 consecutive patients undergoing transplantation, six developed TTP/HUS (the TTP/HUS group) and 68 did not (controls). These six patients were compared with the other 68 patients to investigate differences of the IL‐12 and 8 levels, H. pylori and various clinical characteristics. The patients who developed TTP/HUS seemed not apparently different from those who did not in background characteristics, except that they had a significantly higher H. pylori‐positive rate (p < 0.05). In the TTP/HUS group, however, the levels of interleukin‐12 and interleukin‐8 increased significantly during the leukocyte recovery after BMT and at the onset of TTP/HUS, respectively, to 45.8 ± 57.6 pg/mL and 274.8 ± 65.9 pg/mL (p < 0.05 for both), when compared with their levels of 5.0 pg/mL in the control group. Thus, H. pylori may play a role in the pathogenesis of TTP/HUS after BMT, with cytokines (interleukin‐8 and interleukin‐12) also being involved.

Changes of clotting factors (7, 9 and 10) and hepatocyte growth factor in patients with thrombotic microangiopathy after bone marrow transplantation.

Abstract:  To investigate risk factors for thrombotic microangiopathy (TMA) after bone marrow transplantation (BMT), the levels of three clotting factors (7, 9 and 10) and hepatocyte growth factor (HGF) were measured. Among 46 consecutive patients who underwent BMT, six developed TMA and 40 did not. The levels of the clotting factors and HGF did not differ significantly between the six patients with TMA and the 40 patients without it. In two patients who developed TMA during the earlyperiod after BMT, however, the levels of the three clotting factors were significantly decreased even before BMT, along with a significant increase of HGF. These findings suggest that patients with severe hepatic dysfunction before BMT, especially those with impaired protein synthesis, had an increased risk of developing TMA soon after BMT. It was also suggested that measurement of clotting factors (7, 9 and 10) and HGF may be useful to predict the occurrence of TMA in the early period after BMT.

Heparin cofactor II as a predictor of thrombotic microangiopathy after bone marrow transplantation

Abstract The pathogenesis of thrombotic microangiopathy (TMA) after allogeneic bone marrow transplantation (BMT) remains unclear since ADAMTS13, which is implicated in primary thrombotic thrombocytopenic purpura (TTP), has been shown to have no role in this condition. We investigated whether the onset of TMA after BMT could be predicted by measuring heparin-cofactor II (HC II), a marker for thrombosis of unknown etiology. In 30 consecutive BMT patients, the serum HC II level was measured before conditioning and one week after recovery from leukopenia. Four of the 30 patients developed TMA, and 26 did not. Before conditioning, the mean serum HC II level was 1.748 ± 0.37 U/mL in the TMA group and 0.889 ± 0.25 U/mL, in the non-TMA group, being higher in the former group (p < 0.01, t-test). After recovery from leukopenia, the two groups showed no significant difference of serum HC II. The HC II level at the onset of TMA was above the upper limit of normal in only one out of four patients. These results suggest that vascular endothelial damage due to chemotherapy before BMT increases the risk of TMA, and that HC II is useful for predicting the occurrence of TMA after BMT.

Prognosis value of atrial natriuretic peptide and brain natriuretic peptide for heart failure in patients undergoing allogeneic bone marrow transplantation

Abstract It is essential to evaluate the organ function of the recipient before bone marrow transplantation (BMT). This study investigated the usefulness of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) levels as indicators of cardiac function. Seventy-five consecutive patients undergoing allogeneic BMT were enrolled. All of them had an ejection fraction of 55% or more on echo cardiography. Six of the 75 patients died of heart failure after transplantation and these 6 patients were compared with the other 69 patients to assess the prognostic value of the two natriuretic peptides. Both peptides remained normal from before conditioning until recovery from leukopenia in all 69 surviving patients. Among the 6 patients who died of heart failure, however, BNP was increased in all 6 patients and ANP was increased in five of them at an average of 43.6 ± 16.7 days before the onset of heart failure. Monitoring of these peptides may not only be useful for assessment of cardiac function but also for predicting the occurrence of heart failure.

Serum elastase and antithrombin-3 levels after umbilical cord blood transplantation or bone marrow transplantation.

Abstract The severity of graft-versus-host disease (GVHD) was compared after cord blood transplantation (CBT) and bone marrow transplantation (BMT). The severity of GVHD was also analyzed in relation to serum elastase and antithrombin-3 (AT-3) levels. There was no significant difference in the average grade of acute GVHD between 49 BMT patients and 20 CBT patients (X2-test). However, there was a lower incidence of patients without acute GVHD (grade 0) or patients with severe acute GVHD (grade 3 or 4) in CBT compared with BMT group. Linear regression analysis found no significant correlation between the serum elastase level and the grade of acute GVHD, between the serum AT-3 level and the grade of acute GVHD, or between the serum levels of elastase and AT-3 before conditioning and after engraftment. The AT-3 level after engraftment was significantly higher in the CBT group than in the BMT group and it did not fail along with the elevation of elastase in the CBT group (p < 0.01 by the Mann–Whitney U-test vs. the BMT group). In conclusion, the lower risk of severe acute GVHD in the CBT group may have been related to the smaller decrease of AT-3 after transplantation.

Serum elastase and antithrombin-3 in patients with acute graft-vs.-host disease after bone marrow transplantation.

Abstract:  The mechanism by which inflammatory cytokines are involved in acute graft‐vs.‐host disease (GVHD) after hematopoietic stem cell transplantation has only been studied recently. We focused on the changes of serum elastase and antithrombin‐3 (AT‐3) from before pre‐treatment until the leukocyte recovery period after transplantation. We examined the correlation between these two parameters and the grade of acute GVHD, as well as the mechanism of onset. We measured the serum elastase and AT‐3 levels before pre‐treatment and during the leukocyte recovery period in 49 consecutive patients receiving bone marrow transplantation. The severity of acute GVHD was divided into five grades (0–4). No significant differences of pre‐transplantation elastase levels were observed among the GVHD grades, but the elastase level during the leukocyte recovery period showed a significant correlation with the grade of GVHD (p < 0.01). A significant inverse correlation was also observed (p < 0.05) between the pre‐transplantation level of AT‐3 and the grade of GVHD, as well as a significant correlation at the time of leukocyte recovery (p < 0.0001). Furthermore, a significant correlation (p < 0.0001) was observed between the elastase and AT‐3 levels during the leukocyte recovery period. These results suggest that elastase levels during the leukocyte recovery period are related to the grade of acute GVHD and the mechanism appears to include vascular endothelial injury mediated via AT‐3.

Serum mucin-like glycoprotein antigen (KL-6) as a specific marker of interstitial pneumonia: a case report

metastatic tumor. Postoperatively, he was admitted to the ICU and was discharged on February 8 with a good clinical course. Hypoxemia (PaO2 50mmHg on room air) appeared immediately after discharge. He was readmitted to the ICU on February 12 after endotracheal intubation. Since chest computed tomographic (CT) examination showed pneumonia in the upper left lung and pyothorax in the right thoracic cavity, combined antibiotic treatment with imipenem/cilastatin and sulbactam/ampicillin was started. Fever, hypotension, and tachycardia occurred on February 15 (0 postoperative day; POD). We suspected that the symptoms were due to sepsis caused by pyothorax or pyopoiesis in the right lung and conducted pyothorax drainage by thoracotomy, followed by continuous hemodiafiltration (CHDF) conbined with endotoxin removal therapy (polymyxin B removal, PMX) for 2 consecutive days. Methicillin-resistant Staphylococcus aureus (MRSA) was detected in the pleural exudate collected at chest drainage, and intrathoracic lavage with physiological saline was started on February 16 (1 POD). Despite the administration of antibiotics (imipenem and vancomycin), no improvement was seen in the inflammatory findings or respiratory distress. The retiform shadow was revealed in the left lung on chest radiography, and neutrophils and lymphocytes increased in the bronchoalveolar lavage (BAL) fluid. Therefore, we suspected IP and prescribed steroid pulse therapy (methylprednisolone 500mg·day21) for 3 days starting on March 4 (17 POD). CPR decreased, MRSA disappeared, and respiratory distress improved. Pseudomonas aeruginosa was detected in the sputum and pleural exudate on March 10 (23 POD), and lung infection symptoms were repeatedly exacerbated. Although chest radiography findings of IP in the left lung tended to improve, hypercapnia persisted. We conducted steroid pulse therapy (methylprednisolone 500mg·day21) again between March 24 (37 POD) and March 26 (39 POD) and began oral administration of