Successful treatment of toxoplasmic encephalitis diagnosed early by polymerase chain reaction after allogeneic hematopoietic stem cell transplantation: two case reports and review of the literature.

Toxoplasmic encephalitis represents a rare, but often fatal infection after allogeneic hematopoietic stem cell transplantation. Polymerase chain reaction (PCR)-based preemptive therapy is considered promising for this disease, but is not routinely applied, especially in low seroprevalence countries including Japan. We encountered 2 cases of toxoplasmic encephalitis after transplantation that were successfully treated. The diagnosis of toxoplasmic encephalitis in these cases was confirmed by PCR testing when neurological symptoms were observed. Both patients received pyrimethamine and sulfadiazine treatments within 2 weeks of the development of neurological symptoms, and remained free of recurrence for 32 and 12 months. These results emphasized the importance of the PCR test and immediate treatment after diagnosis for the management of toxoplasmic encephalitis.

Prognostic significance of S-phase kinase-associated protein 2 and p27kip1 in patients with diffuse large B-cell lymphoma: effects of rituximab.

BACKGROUND: The F-box protein S-phase kinase-associated protein 2 (Skp2) positively regulates the G1-S transition by promoting degradation of the cyclin-dependent kinase inhibitor p27(kip1) (p27). Recent evidence has indicated an oncogenic role of Skp2 in not only carcinogenesis but also lymphomagenesis. MATERIALS AND METHODS: Clinicopathologic features and immunohistochemical expression of Skp2 and p27 were studied retrospectively in 671 patients treated with cyclophosphamide, vincristine, doxorubicin and prednisolone (CHOP) or cyclophosphamide, vincristine, doxorubicin and prednisolone plus rituximab (R-CHOP). The median follow-up periods were 43.2 months in the CHOP group (n = 425) and 24.0 months in the R-CHOP group (n = 246). RESULTS: High Skp2 or low p27 expression correlated significantly with poor overall survival (OS) and progression-free survival (P < 0.001) in both treatment groups. The prognostic value of Skp2 or p27 expression was independent of the parameters included in the International Prognostic Index by multivariate analysis. Patients with high Skp2 expression in combination with low p27 expression showed the worst survival. CONCLUSIONS: Addition of rituximab to the CHOP regimen did not provide a beneficial outcome to patients with diffuse large B-cell lymphoma with high Skp2 expression and low p27 expression. Skp2 and p27 may be useful prognostic markers in the rituximab era.

Small number of HTLV-1-positive cells frequently remains during complete remission after allogeneic hematopoietic stem cell transplantation that are heterogeneous in origin among cases with adult T-cell leukemia/lymphoma.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can provide long-term remission for patients with adult T-cell leukemia/lymphoma (ATLL) caused by human retrovirus, human T-lymphocyte virus (HTLV-1). To understand how HTLV-1-positive cells including ATLL cells were suppressed by allo-HSCT, we examined HTLV-1 provirus load and residual ATLL cells in peripheral blood of transplant recipients using PCR-based tests. We found that the copy number of HTLV-1 genome, called provirus, became very small in number after allo-HSCT; however, in most cases, provirus did not disappear even among long-term survivors. Tumor-specific PCR tests demonstrated that most of HTLV-1-positive cells that remained long after transplantation were not primary ATLL cells but donor-derived HTLV-1-positive cells. We also found a case having very low amount of residual disease in peripheral blood even long after transplantation. There was only one recipient in whom we failed to show the presence of HTLV-1 genome and antibody against HTLV-1 even with an extensive search, which strongly suggested the elimination of HTLV-1 after allo-HSCT. These results demonstrated that after allo-HSCT the small amount of residual HTLV-1-positive cells were heterogeneous in origin and that long-term disease control for ATLL could be obtained without the complete elimination of HTLV-1.

Allogeneic hematopoietic stem cell transplantation provides sustained long-term survival for patients with adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATLL) is a distinct peripheral T-cell neoplasm that is highly resistant to chemotherapy. Several groups, including ours, have reported encouraging results of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with ATLL. To confirm our previous report and to establish the basis for a phase II clinical study, we analyzed 40 allo-HSCT for acute and lymphoma types of ATLL in seven institutions in Japan between 1997 and 2002. All evaluable cases entered complete remission (CR) after allo-HSCT and the median survival time was 9.6 months for all patients. The estimated 3-year overall and relapse-free survival, and disease relapse were 45.3, 33.8 and 39.3%, respectively. Among 10 cases with ATLL relapse, five cases achieved CR again: three by the reduction or cessation of immunosuppressive agents, which suggested a graft-versus-ATLL (GvATLL) effect. However, univariate or multivariate analysis did not show any benefit of graft-versus-host disease (GVHD) on the prevention of relapse. These results suggested that allo-HSCT was effective for some patients with aggressive ATLL, and that the GvATLL effect could be achieved even without GVHD. A new phase II trial to test the efficacy of allo-HSCT for ATLL is warranted.

Early application of related SCT might improve clinical outcome in adult T-cell leukemia/lymphoma.

Allogeneic hematopoietic SCT (allo-HSCT) is a curative treatment for aggressive adult T-cell leukemia/lymphoma (ATLL). Considering the dismal prognosis associated with conventional chemotherapies, early application of allo-HSCT might be beneficial for patients with ATLL. However, no previous study has addressed the optimal timing of allo-HSCT from related donors. Hence, to evaluate the impact of timing of allo-HSCT for patients with ATLL, we retrospectively analyzed data from patients with ATLL who received an allo-HSCT from a related donor. The median age was 52 years. Patients were grouped according to the interval from diagnosis to allo-HSCT: early transplant group, <100 days, n=72; late transplant group, ⩾100 days, n=428. The corresponding constituents of disease status were not statistically different between the two groups (P=0.11). The probability of OS in the early transplant group was significantly higher than that in the late transplant group (4-year OS, 49.3% vs 31.2%). Multivariate analysis revealed that late allo-HSCT was an unfavorable prognostic factor for OS (hazard ratio, 1.46; 95% confidence interval (CI), 1.01-2.11; P=0.04). Despite the limitations of a retrospective study, it might be acceptable to consider early application of allo-HSCT for ATLL.

Allogeneic bone marrow transplantation improves the outcome of de novo AML with trilineage dysplasia (AML-TLD).

De novo acute myeloid leukemia (AML) with dysplastic features in erythroblasts, granulocytes and megakaryocytes, similar to those in myelodysplastic syndrome (MDS) has been described as AML with trilineage dysplasia (AML-TLD) since 1987. Several reports have suggested that AML-TLD is a subtype of de novo AML in adults and has a poor clinical outcome when treated by conventional chemotherapy. It is not certain whether allogeneic bone marrow transplantation (BMT) brings a favorable outcome for AML-TLD. To evaluate the therapeutic efficacy of allogeneic BMT for AML-TLD, we investigated the clinical data and outcomes of conventional chemotherapy and allogeneic BMT for 118 patients with de novo AML. These patients were registered consecutively for the Japan Adult Leukemia Study Group (JALSG) protocols at our institutes. We treated 28 AML-TLD patients and 90 AML-nonTLD patients with conventional chemotherapeutic protocols. AML-TLD patients did not have a significantly different complete remission (CR) rate (75.0% and 88.4% P = 0.1234), but had a significantly higher relapse rate than AML-nonTLD patients (94.1% and 49.3%, P= 0.0007). The outcome of chemotherapy for AML-TLD was significantly worse than that for AML-nonTLD. The overall survival (OS) and leukemia-free survival (LFS) at 6 years were 9.4% and 0% in AML-TLD group, and 51.9% (P= 0.0017) and 46.3% (P< 0.0001) in AML-nonTLD group, respectively. Meanwhile, among the patients who underwent allogeneic BMT, five of eight AML-TLD patients and eight of 14 AML-nonTLD patients were alive, and three and five patients survived more than 3 years, respectively. These results suggest that allogeneic BMT can improve the outcome for AML-TLD, which is poor when conventional chemotherapy is given alone. Allogeneic BMT before relapse may be the best therapeutic strategy for AML-TLD patients under 50 years of age if a donor is available.

Characteristic patterns of relapse after allogeneic hematopoietic SCT for adult T-cell leukemia-lymphoma: a comparative study of recurrent lesions after transplantation and chemotherapy by the Nagasaki Transplant Group.

Allogeneic hematopoietic SCT (allo-SCT) is a promising therapy that may provide long-term durable remission for adult T-cell leukemia-lymphoma (ATL) patients; however, the incidence of relapse associated with ATL remains high. To determine the clinical features of these patients at relapse, we retrospectively analyzed tumor lesions in 30 or 49 patients who relapsed following allo-SCT or chemotherapy (CHT), respectively, at three institutions in Nagasaki prefecture between 1997 and 2011. A multivariate analysis revealed that the development of abnormal lymphocytes in the peripheral blood of patients at relapse was less frequent after allo-SCT than after CHT (P<0.001). Furthermore, relapse with a new lesion only in the absence of the primary lesion was more frequent in allo-SCT (P=0.014). Lesions were more frequently observed in the central nervous systems of patients who relapsed with new lesions only (P=0.005). Thus, the clinical manifestation of relapsed ATL was slightly complex, especially in post-transplant patients. Our results emphasized the need to develop adoptive modalities for early and accurate diagnoses of relapsed ATL.

Intravascular malignant lymphomatosis: a case of T-cell lymphoma probably associated with human T-cell lymphotropic virus.

Intravascular malignant lymphomatosis (IML) is an unusual condition characterized by proliferation of lymphoma cells exclusively within the blood vessels. Most of the cases reported are of B-cell origin. We report a rare case of T-cell IML probably associated with human T-lymphotropic virus (HTLV-1) infection. The present case suggests that T-cell lymphoma and HTLV-1-associated lymphoma occasionally represent a form of intravascular proliferation.

Poor outcome of autologous stem cell transplantation for adult T cell leukemia/lymphoma: a case report and review of the literature.

A limited number of patients with adult T cell leukemia/lymphoma (ATL) who received autologous stem cell transplantation (ASCT) have been reported. We report here a case of fatal systemic Candida krusei infection in a female patient with ATL undergoing ASCT. All of the eight patients (including seven patients in the literature) with ATL who received ASCT developed relapse of ATL or death due to ASCT complication, irrespective of subtype or remission state of ATL, source or selection of SCT or conditioning regimen. At present, ASCT appears to provide little benefit for ATL in contrast to that for other types of aggressive non-Hodgkin's lymphoma.

Increased plasma M-CSF concentration in patients with adult T cell leukemia: clinical correlation.

Plasma concentration of M-CSF was measured in 35 patients with adult T cell leukemia (ATL), using a radioimmunoassay (RIA). ATL patients showed elevated levels of plasma M-CSF concentration when compared with healthy adult volunteers. Higher M-CSF levels were observed in acute ATL patients than in patients with chronic or smouldering ATL (P < 0.0001). There was a significant positive correlation of M-CSF concentration with serum lactic dehydrogenase (LDL) level, a reliable marker for assessing the grade of malignancy in ATL (P = 0.0003). There was, however, no correlation of M-CSF concentration with total counts of peripheral blood ATL cells, neutrophils or monocytes, or with serum calcium levels. Although there was a significant positive correlation of M-CSF concentration with body temperature (P = 0.003), there was not a significant correlation of M-CSF concentration with C-reactive protein (CRP), a protein indicative of the severity of inflammation (P = 0.063). These results indicate that plasma M-CSF concentration reflects the disease activity of ATL, and can thus serve as a marker in the clinical subclassification of ATL patients.

[Infectious complications in patients with adult T-cell leukemia].

Between January, 1982, and January, 1992, a total of 112 patients with adult T-cell leukemia (ATL) and 109 patients with non-Hodgkin's lymphoma (NHL) were admitted to our hospital. They were studied for their infectious complications. Infectious complications were seen in 90 patients (80.4%) with ATL, and 51 patients (46.8%) with NHL (p < 0.001). Documented infections were seen in 70 patients (62.5%) with ATL, and 30 patients (27.5%) with NHL (p < 0.001). Pneumonia (p < 0.005), skin infections (p < 0.05), Pneumocystis carinii pneumonia (p < 0.05), fungal infections (p < 0.05), cytomegalovirus infections (p < 0.05) and herpes simplex virus infections (p < 0.01) were identified infections at high risk for patients with ATL. Tuberculosis, listeriosis and salmonella infections were seen only in patients with ATL.

[Empiric therapy with aztreonam for febrile neutropenic patients with hematological malignancies].

Combination of aztreonam/amikacin/ticarcillin (AAT) and latamoxef/amikacin/ticarcillin (LAT) were compared in a prospective randomized trial of empiric therapy for febrile neutropenic patients with hematological malignancies. Low dose amphotericin B was also added to each regimen from the beginning. Of 45 evaluable episodes, 23 were treated with AAT and 22 with LAT. The response rates were 61 percent for AAT and 50 percent for LAT, statistically not significant. There was one infection-related death among patients assigned to AAT therapy and also one among those assigned to LAT therapy. Dose escalation of amphotericin B seemed to be effective for those patients who did not improve with initial therapy.

[Infection prophylaxis in patients with hematological malignancies (II)--Successful prophylaxis of tuberculosis with isoniazid].

In a retrospective study to evaluate the efficacy of isoniazid (INH) for the prevention of tuberculosis, we studied 1760 patients with hematological malignancies over a twenty-year period (1970-1989). 759 patients received oral INH, most of all received 400 mg per day. Only one (0.1%) of the patients receiving INH developed tuberculosis, whereas nine (0.9%) of the 1001 patients who did not receive INH developed tuberculosis (p less than 0.05). We found that INH was very effective in the prevention of tuberculosis in patients with hematological malignancies, and was well tolerated.

[Infection prophylaxis in patients with hematological malignancies (I)--Successful prophylaxis of Pneumocystis carinii pneumonitis with sulfamethoxazole-trimethoprim].

In a retrospective study to evaluate the efficacy of sulfamethoxazole-trimethoprim (SMX-TMP) for the prevention of Pneumocystis carinii pneumonitis, we studied 1760 patients wit hematological malignancies over a twenty-year period (1970-1989). 449 patients received oral SMX-TMP, most of all received 400 mg of SMX and 80 mg of TMP twice per day. None of the patients receiving SMX-TMP developed P carinii pneumonitis, whereas twenty-six (2.0%) of the 1311 patients who did not receive SMX-TMP developed P carinii pneumonitis (p less than 0.01). We found that the SMX-TMP was very effective in the prevention of P carinii pneumonitis in patients with hematological malignancies, and was well tolerated.

[Trisomy of chromosome 11 in a case of common ALL antigen-positive acute myeloblastic leukemia (FAB-M1)].

In February 1986, a 68-year-old woman was diagnosed as having acute myeloblastic leukemia (FAB-M1). At the time of diagnosis, 86.0% of the bone marrow cells were myeloblastoid, and 15% of these myeloblastoid cells were positive to myeloperoxidase. Surface marker analysis by flow cytometry disclosed granulocyte-associated antigen (MY7) and also lymphocyte-associated antigen (CALLA) on the leukemic cells. Chromosomal banding studies of bone marrow cells revealed trisomy 11 in 6 of 19 metaphases examined and normal karyotype in the others. Complete remission was attained after intensive combination chemotherapy, and has remained for 38 months. Only 19 patients with trisomy 11-associated acute nonlymphocytic leukemia (ANLL) including the present case have been reported. Morphologic analyses have revealed that the frequency of FAB-M1 is high. However, except for the present case, surface marker findings were apparent in only one M5a patient, in whom monocyte-macrophage-associated antigen was detected. Accordingly, careful surface marker studies will be needed to clarify the frequency of acute mixed lineage leukemia in such patients.

[Comparison of ciprofloxacin with polymyxin B for infection prophylaxis in neutropenic patients with acute non-lymphocytic leukemia].

Twenty-four neutropenic patients receiving intensive chemotherapy for acute non-lymphocytic leukemia were studied in a randomized trial comparing ciprofloxacin with polymyxin B for prevention of infections. Both groups (12 patients each group) received amphotericin B for antifungal prophylaxis. 20 febrile episodes occurred in 22 courses of oral prophylactic ciprofloxacin and 22 occurred in 24 courses of oral prophylactic polymyxin B. Patients receiving ciprofloxacin had a mean time to the first infection-related febrile episode of 7.2 days, compared with 4.3 days for the polymyxin B group (p less than 0.01). Patients receiving ciprofloxacin also had fewer days of fever (average 6.5 days versus 9.8 days for the polymyxin B group, p less than 0.02). Duration of administration of parental antibiotics were also shorter in the ciprofloxacin group (p less than 0.001). Although modifications of the empiric antibiotic regimen were required more frequent in patients receiving polymyxin B, this did not reach statistical significance. These results suggest that ciprofloxacin is a more efficacious oral antimicrobial agent than polymyxin B for the prevention of infections in neutropenic patients with acute non-lymphocytic leukemia.

[Clinical characteristics and poor outcomes in patients with de novo AML with trilineage myelodysplasia].

De novo AML with trilineage myelodysplasia (AML/TMDS) is reported to account for 10-15% of de novo AML and respond poorly to conventional intensive chemotherapy, In our series, 12 (25%) of 48 patients with de novo AML were diagnosed as AML/TMDS. We found that the platelet count was significantly higher (p < 0.05), and the blast percentage of the bone marrow was significantly lower (p < 0.05) in the AML/TMDS group than in the AML/non-TMDS group. Sex ratio, age, WBC and RBC count did not significantly differ between the two groups. The immunological markers and the myeloperoxidase positivity of the blasts of AML/TMDS varied widely. The CR rate was 66.7% in the AML/TMDS group and 83.3% in the AML/non-TMDS group. Dysplastic changes were still detected in the bone marrow smears in 7 of 8 AML/TMDS cases who achieved complete remission. The AML/TMDS group showed significantly shorter CR duration (median; 169 days) and survival (median; 511 days, p < 0.05). However, in two cases which underwent allogeneic bone marrow transplantation (allo-BMT) during early relapse phase the disease-free survival has extended over 4 years and 2 years 8 months, respectively. Thus, we would like to propose that allo-BMT should be performed as early as possible to overcome poor outcome of AML/TMDS.

[Clinical study on the effect of natural alpha-interferon (HLBI) in the treatment of adult T-cell leukemia].

The phase II trial of natural interferon-alpha (HLBI) in treatment of adult T-cell leukemia was carried out as a cooperative study. Of the 24 cases which could be evaluated, 3 cases in crisis type and 5 cases in chronic type with lymphadenopathy and/or skin infiltration achieved PR, giving a response rate of 33.3%. The anti-tumor effect of HLBI for skin lesion could be assessed in 16 cases with skin infiltration, giving a response rate of 50.0% (5 CR and 3 PR) and demonstrating a high efficacy. Of the 31 eligible patients, side effects were recognised in 27 (87.1%). Major subjective and objective symptoms were fever (38.7%), fatigue (25.8%), anorexia (12.9%) and nausea (12.9%), and leukopenia (22.6%), granulocytopenia (38.7%), thrombocytopenia (38.7), elevation of GPT (12.9%) and GOT (12.9%) were observed.

Expression of myeloperoxidase in acute myeloid leukemia blasts mirrors the distinct DNA methylation pattern involving the downregulation of DNA methyltransferase DNMT3B.

Myeloperoxidase (MPO) has been associated with both a myeloid lineage commitment and favorable prognosis in patients with acute myeloid leukemia (AML). DNA methyltransferase inhibitors (decitabine and zeburaline) induced MPO gene promoter demethylation and MPO gene transcription in AML cells with low MPO activity. Therefore, MPO gene transcription was directly and indirectly regulated by DNA methylation. A DNA methylation microarray subsequently revealed a distinct methylation pattern in 33 genes, including DNA methyltransferase 3 beta (DNMT3B), in CD34-positive cells obtained from AML patients with a high percentage of MPO-positive blasts. Based on the inverse relationship between the methylation status of DNMT3B and MPO, we found an inverse relationship between DNMT3B and MPO transcription levels in CD34-positive AML cells (P=0.0283). In addition, a distinct methylation pattern was observed in five genes related to myeloid differentiation or therapeutic sensitivity in CD34-positive cells from AML patients with a high percentage of MPO-positive blasts. Taken together, the results of the present study indicate that MPO may serve as an informative marker for identifying a distinct and crucial DNA methylation profile in CD34-positive AML cells.