Myelodysplastic syndromes in Thailand: a retrospective pathologic and clinical analysis of 117 cases.

To gain more insight into the understanding of myelodysplastic syndromes (MDS) as they occur in Thailand, a retrospective clinicopathologic analysis was conducted in patients (age > 15 years) diagnosed as MDS from January 1992 to December 1996 at the five major medical centers in various geographic regions of the country. The central reviewers independently examined the bone marrow and peripheral blood smears of all the patients and classify the disease according to the French-British-American (FAB) classification. There were a total of 117 eligible patients. The median age of the patients was 56 years (range 16-86). The male:female ratio was 1:1. Thirty-two percent of the patients were younger than 40 years. The frequency of the FAB subtypes was RA/RARS, 54.7; RAEB, 23.1; CMML, 9.4; and RAEB-T, 12.8%. Anemia was the most common symptom presenting in 84.6% of the patients. In the 34 patients in whom the cytogenetics in the bone marrow were analysed, 44.1% revealed abnormalities. Of these, monosomy 7 and trisomy 8 were the most common aberration, each being detected in 26.7% of the patients. Transfusions were the main therapeutic modality in 80% of the patients. Kaplan-Meier analysis revealed a 5 year survival rate of 29% for the whole group with a median survival of 24 months. Twenty-five percent of the patients had progressed to acute myelogenous leukemia (AML) with a median time to disease-progression of 23 months. The median survival for RA/RARS, RAEB, CMML and RAEB-T were 58.4, 19.9, 10.7 and 8.7 months, respectively (P < 0.001). The stepwise Cox regression analysis revealed the percentage of blasts in the bone marrow as the only parameter significantly associated with survival and disease progression. On comparison with data from other countries, the age of Thai patients with MDS is considerably lower than the western population but is comparable to other asian countries. The distribution of the FAB subtypes and the survival of the patients are similar. The major prognostic features, however, lie in the percentage of blasts in the bone marrow rather than the degree of the observed cytopenia.

CHOP versus CHOP plus ESHAP and high-dose therapy with autologous peripheral blood progenitor cell transplantation for high-intermediate-risk and high-risk aggressive non-Hodgkin's lymphoma.

The purpose of the study was to compare conventional cyclophosphamide/doxorubicin/vincristine/prednisolone (CHOP) chemotherapy with CHOP (3 courses) plus etoposide/methylprednisolone/high-dose cytarabine/cisplatin (ESHAP), high-dose therapy (HDT), and autologous peripheral blood progenitor cell transplantation (PBPCT) as front-line treatment for poor-prognosis aggressive non-Hodgkin's lymphoma (NHL). Between May 1, 1995, and April 30, 1998, 58 patients, aged 15-55 years, newly diagnosed with poor-prognosis aggressive NHL (category F-H by the Working Formulation) were enrolled. According to the age-adjusted international prognostic index, 65% of the patients were high-risk cases and 35% made up the high-intermediate group. After 3 courses of CHOP, 25 of 48 patients were randomized to continue with CHOP, and 23 were randomized to receive 2-4 cycles of ESHAP followed by HDT and PBPCT. There was no significant difference in the rate of complete remission between the two groups (36%, 95% confidence interval [CI]: 18%-57% in CHOP vs. 43%, 95% CI: 23%-65% in ESHAP/HDT) (P = 0.77). With a median follow-up duration of 39 months, the 4-year failure-free survival (FFS) was superior in the ESHAP/HDT group (38%, 95% CI: 18%-58% vs. 15%, 95% CI: 4%-32%) (P = 0.04). The disease-free survival was marginally different in favor of the ESHAP/HDT arm (90%, 95% CI: 47%-98% vs. 37%, 95% CI: 7%-69%) (P = 0.06). The 4-year overall survival between the two treatment arms was comparable (51%, 95% CI: 28%-70% for ESHAP/HDT vs. 30%, 95% CI: 13%-48% for CHOP) (P = 0.25). Treatment-related mortalities were not significantly different between both groups (17%, 95% CI: 5%-39% for ESHAP/HDT vs. 8%, 95% CI: 1%-26% for CHOP) (P = 0.41). However, only 61% of the patients assigned to the ESHAP/HDT arm underwent HDT and PBPCT. As compared with CHOP, the corporate regimen of CHOP/ESHAP/HDT seems to improve the FFS in patients with newly diagnosed, poor-prognosis aggressive NHL.

Treatment of myelodysplastic syndrome with low-dose human granulocyte colony-stimulating factor: a multicenter study.

The objective of this study was to determine the hematopoietic effects and toxicity of low-dose granulocyte colony-stimulating factor (G-CSF) in myelodysplastic syndrome (MDS) patients with neutropenia. Recombinant human G-CSF (Lenograstim) was administered by daily subcutaneous injection with an initial dosage of 0.5 microg/kg per day for 2 weeks. Patients not responding to the initial dosage received the escalated dosage, 1 to 2 microg/kg per day for 2 weeks. Eligibility criteria were the following: French-American-British disease classification subtype refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), or refractory anemia with excess blasts (RAEB) with an absolute neutrophil count (ANC) of <1.5 x 10(9)/L. Criteria indicating response to treatment were ANC of >1.5 x 10(9)/L and doubling of ANC on at least 2 occasions. Thirty-two MDS patients were recruited from 6 university hospitals. Eighteen patients had RA, 4 had RARS, and 10 had RAEB. Median age was 56.4 years (range, 28-87 years). Twenty-six patients (81.2%) had an increase in ANC from a median of 0.94+/-0.35 x 10(9)/L to 4.24+/-3.78 x 10(9)/L. Three of 6 patients who did not respond to the initial dosage responded to the escalated dosage of 1 microg/kg per day. Eighteen (81.8%) of 22 patients with RA or RARS responded compared with 8 (80%) of 10 patients with RAEB. The response rates in patients with ANCs of <0.5 x 10(9)/L. 0.5 to <1.0 x 10(9)/L, and 1.0 to 1.5 x 10(9)/L were 80%, 70%, and 88.2%, respectively. The side effects were minimal. No significant changes in hemoglobin levels or platelet counts were observed. In conclusion, low-dose G-CSF administered by subcutaneous injection is well tolerated and effective in improving neutropenia in MDS patients.

A prospective randomized study of Chop versus Chop plus alpha-2B interferon in patients with intermediate and high grade non-Hodgkin's lymphoma: the International Oncology Study Group NHL1 Study .

UNLABELLED: The addition of a brief alpha interferon regimen to each CHOP induction cycle, plus one year of alpha interferon thrice weekly maintenance therapy, has no early effect on response rates or survival in patients with Intermediate or High grade cell NHL. BACKGROUND: The CHOP (Cyclophosphamide, Adriamycin. Vincristine, Prednisone) regimen is the most widely used first-line therapy for patients with Intermediate or High Grade (IG/HG) non-Hodgkin's lymphoma (NHL). Alpha 2b interferon (INF) enhances response rates and improves survival in low-grade NHL. The International Oncology Study Group (IOSG) conducted a prospective randomized study comparing CHOP alone or combined with INF in patients with IG/HG-NHL. The primary study aim was to compare the objective response rates in these patient cohorts. PATIENTS AND METHODS: Patients with a confirmed diagnosis of measurable NHL of International Working Formulation (IWF) groups D to H histology were randomized to receive CHOP alone or CHOP with 5Mu INF s.c. for 5 days on days 22 to 26 of each 28 day cycle with INF 5 million units (Mu) given three times per week subcutaneously for 52 weeks in those patients who responded to CHOP plus INF. RESULTS: The overall response rates were equivalent in both groups: CHOP alone (214 patients) 81% (complete 55%, partial 26%); CHOP plus INF (221 patients) 80% (complete 54%, partial 26%). At 36 months, the actuarial survival rate was equivalent in both groups. CONCLUSIONS: There is no apparent early advantage in terms of response or survival conferred by adding the study INF regimen to CHOP therapy for patients with IG/HG-NHL.

Platelet dysfunction in malaria.

Platelet function tests including platelet aggregation, PF3, bleeding time and clot retraction were studied in 48 malarial patients. The suppression of platelet aggregation was demonstrated in both P. vivax and P. falciparum infection. However, this abnormality was more prominent in malarial patients who had systemic complications and bleeding. The recovery of the impaired platelet aggregation was observed at period of 7 and 14 days after parasitemia in malarial patients without and with systemic complications. The correlation between the suppression of platelet aggregation and thrombocytopenia was observed. From this study, bleeding in malaria are operated by two mechanisms: thrombocytopenia and severely depressed platelet aggregation.

Mutations at the activated protein C cleavage sites Arg336 and Arg562 of factor VIII in Thai patients with venous thrombosis.

Venous thrombosis is a multicausal disease, more than one genetic risk factor may cooperate to effect thrombotic risk. Factor V Leiden is found to be an important hereditary risk factor for venous thromboembolism. Analogous to factor V Leiden, a point mutation at amino acid positions Arg336 and Arg562 in factor VIII may predispose patients to thrombosis. Eighty-one Thai patients with venous thrombosis and 100 Thai healthy volunteers have been studied. Neither heterozygous nor homozygous mutations were detected both thrombosis patients or normal volunteers. However, further studies with larger samples of venous thrombosis patients are recommended.

Clinical manifestations and therapy of heat stroke: consumptive coagulopathy successfully treated by exchange transfusion and heparin.

This report of 8 cases (6 severe and 2 mild) heat stroke patients seen during the hot summer of 1987 at Pramongkutklao Hospital, Bangkok, represent the first report of this syndrome in Thailand. Severe cases presented with deep coma, shock, ARDS, DIC and other systemic complications. Two cases of mild heat stroke recovered completely with conventional treatment. Two of the 6 severe cases died with DIC, bleeding and acute renal failure. The other 4 surviving cases received early exchange transfusion and low dose heparin therapy. The clinical features of these 4 cases were as severe as those recorded for fatal heat stroke patients, including shock over 10 hours in 4, coma longer than 120 hours in 3, ARDS and DIC in 1. From these findings, early exchange transfusion plus low dose heparin should be considered as one effective treatment in severe fatal heat stroke patients.

Exchange transfusion therapy in severe complicated malaria.

Nine cases of severe complicated falciparum malaria treated by exchange transfusion were studied. Eight patients survived and one patient died. Multisystemic complications were found in all cases. The CNS complications, acute renal failure, pulmonary insufficiency, jaundice, bleeding, sepsis, and DIC were found in 9, 7, 5, 7, 2, 4 and 1 cases, respectively. The fatal case presented with severe multisystemic complications together with 40% parasitemia. In eight survivors, whose parasitemia ranged from 0.3%, to 90%, had milder degrees of systemic complications. With the use of blood exchange 10-15 units, the parasitemia was decreased to less than 5% within 24 hours in all expect one who had parasitemia 90%. In comparison with the other 10 matched non-exchanged patients, there was no significant difference in survival rate between these two group (89% vs 80%). However, in the patients with ARDS the survival rate in the group who received the exchange transfusion therapy was superior (75% vs 0%). The exchange transfusion therapy is therefore strongly recommended in the treatment of malarial patients who present with parasitemia > 30% and severe systemic complications, particularly those who have severe acute renal failure or have lung complications. The amount of blood used for exchange transfusion should at least 1.2 times the blood volume for rapid removal of parasites and toxic metabolites from the circulation.

Detection of factor V Leiden in Thai patients with venous thrombosis.

The molecular defect underlying activated protein C resistance (APC-R) is caused by a G to A point mutation in the codon for arginine 506 in the factor V gene (factor V Leiden) which is a major risk factor for venous thrombosis, especially in Caucasian populations. This study is an analysis of the Thai population to determine the prevalence of the factor V Leiden mutation. Twenty-seven patients with apparent venous thrombosis were divided into two groups according to APC-R test. Thirteen patients were diagnosed as positive for n-APC-SR, ratio < 0.8 and fourteen patients were diagnosed as negative for n-APC-SR, ratio > 0.8. Two of thirteen APC-R positive patients and one of fourteen APC-R negative patients were found to have the heterozygous allele for the factor V Leiden mutation but the homozygous allele was not detected in these groups of patients. Neither the heterozygous nor homozygous Leiden mutation was detected in 200 healthy volunteer blood donors. In conclusion, our findings indicate that factor V Leiden mutation is related to venous thrombosis in Thai people. Moreover, a further study of other mutations at the activated protein C cleavage sites of factor V and factor VIII is recommended.

A preliminary study of HLA class II alleles in Thai patients with non Hodgkin's lymphoma.

The HLA class II alleles were analyzed by the PCR-SSP technique in the DNA samples obtained from 27 Thai patients with non Hodgkin's lymphoma (NHL). It was found that (1) the incidence of HLA-DRB1*15 and HLA-DRB1*09 was slightly decreased (P > 0.05). On the other hand, the incidence of HLA-DQB1 alleles was the same as control. However, further study is suggested in order to conclude the close relationship between the presence of certain HLA class II alleles and susceptibility to NHL in Thai patients.

Pleomorphic large cell hemato-lymphoma (the so-called "malignant histiocytosis"): clinicopathological and immunophenotypic studies in 35 cases.

Thirty-five patients diagnosed with "malignant histiocytosis" from 1984 to 1989 were studied for clinical, laboratory, histopathological features as well as survival and response to therapy, Immunocytochemistry and immunophenotypic studies were performed in 12 cases using the paraffin immunoperoxidase method. The staining included alpha-1 antichymotrypsin, muramidase, immunoglobulins and monoclonal antibodies specific for T, B lymphocytes and macrophage. From the clinical features, responsiveness to therapy and survival, the patients were divided into 2 groups: the non-responders (25 cases) and responders (10 cases) groups. Very short median survival of 1.25 months was found in the non-responders, whereas, longer median survival of 14.15 months was found in the responder group. Important different clinical and laboratory features were observed among these two groups. Unresponsiveness to treatment; rapidly progressive pancytopenia, increased hemophagocytosis, presentation of immature cells in blood with extensive infiltration of malignant cells in the bone marrow; severe jaundice and deterioration of hepatic function accompanied by early extranodal involvement were almost exclusively observed initially in the non-responder group. Satisfactory response to treatment was observed only in the responder group. Similarity of histopathology, cytology and immunophenotype was observed in these two groups. The immunophenotypic study in 12 cases showed 5 cases of B-cell lymphoma, 3 cases of T-cell (with 1 Ki-1 -positive) lymphoma; 1 case of Ki-1 positive non-T, non-B anaplastic large cell lymphoma; and 3 cases of undetermined cell lineage. From this study, so-called "malignant histiocytosis" appears to be a disorder of heterogeneity. The immunophenotypes of malignant cells indicated that their origin belonged mostly to lymphoid cell lineage. Based on their clinical feature of the early hematogenous spread along with the distinct histopathological and immunophenotypic findings, the term "pleomorphic large cell hematolymphoma" is proposed to be used instead of the old misnomer, "malignant histiocytosis" (MH).

Levels of serum tumor necrosis factor alpha in relation to clinical involvement and treatment among Thai adults with Plasmodium falciparum malaria.

UNLABELLED: Concentrations of tumor necrosis factor alpha (TNF-alpha) in serum were measured in 17 Thai men infected with Plasmodium falciparum malarial infections to determine whether they were affected by severity of infections or exchange transfusions. Twelve patients were considered having complicated malarial infections, eight of whom had cerebral malaria. Five patients had uncomplicated malarial infections. The results showed that malarial infection markedly raised TNF-alpha level above normal values (mean +/- SEM 406 +/- 38 vs 15 +/- 5, p = 0.004). In complicated malaria, cerebral involvement appeared to significantly increase concentration of TNF-alpha when compared to values in uncomplicated malaria (mean +/- SEM 496 +/- 64 vs 339 +/- 12, p = 0.01). Degree of parasitemia, intravenous quinine (day 0 value vs day 7 value) and exchange transfusion did not significantly affect TNF-alpha levels. CONCLUSION: Serum level of TNF-alpha is increased in Plasmodium falciparum malarial infections and may be a useful index to predict severity of malarial infection, cerebral malaria in particular.

A prospective evaluation of normal mean platelet volume in discriminating hyperdestructive thrombocytopenia from hypoproductive thrombocytopenia.

Bone marrow (BM) examination is the gold standard test in discriminating between hyperdestructive thrombocytopenia and hypoproductive thrombocytopenia. However, this procedure is invasive. Mean platelet volume (MPV) is simple and may be used as an alternative diagnostic test in distinguishing these two types of thrombocytopenia. All thrombocytopenic patients (platelet count: <150.0 x 10(9)/l), except those with congestive splenomegaly, thrombotic thrombocytopenic purpura, and disseminated intravascular coagulopathy, were enrolled into the study prospectively. The mean MPV of normal Thais (7.9 fl) was tested as a cutoff value. Any thrombocytopenic patient with MPV of >7.9 fl would be presumptively diagnosed as hyperdestructive thrombocytopenia, whereas one with MPV of 7.9 fl could predict hyperdestructive thrombocytopenia with a sensitivity of 82.3% (95% CI: 70.5-90.8), a specificity of 92.5% (95% CI: 79.6-98.4), a positive predictive value of 94.4% (95% CI: 84.6-98.8), a negative predictive value of 77.1% (95% CI: 62.7-88.0), and a likelihood ratio of 11.0. In conclusion, the mean MPV of normal Thais may be used as a cutoff value in distinguishing these two types of thrombocytopenia.

Comparison between the conventional tube technique and the gel technique in direct antiglobulin tests.

OBJECTIVES: The direct antiglobulin test (DAT) is a diagnostic procedure demonstrating in-vivo antibody or complement coating on red cells. The gel technique (GT) for this test is sensitive and easier to do than the conventional tube technique (CTT). METHODS: We tested 52 newborns with hyperbilirubinemia and 6 children and 17 adults with autoimmune hemolytic anemia (AIHA) using the (DAT) in the form of the conventional tube technique (CTT) and the gel technique (GT) simultaneously. The gradings of the agglutination reactions of both techniques were scored as 12, 10, 8, 5, 3, 0 for 4+, 3+, 2+, 1+ and w+ and negative, respectively. RESULTS: The GT yielded higher scores than the CTT (p < 0.01). The overall sensitivity and specificity of the GT were 93.5 and 88.6%, respectively. The specificity of the DAT-positive results in newborns was determined by IgG only, while in AIHA, it was determined by IgG and/or C3d and, in only one sample, by IgM. CONCLUSION: The GT is equal to or better than the CTT. Since the GT is simple, the exposure of blood bank personnel to the blood sample is low. We highly recommend the GT, especially in areas where HIV infection is prevalent.

Suppression of erythroid progenitor cells during malarial infection in Thai adults caused by serum inhibitor.

The bone marrows of 21 Thai adults infected with Plasmodium falciparum malaria were cultured for CFU-E and BFU-E by using AB serum, autologous serum (parasitaemia) and autologous serum (post-parasitaemia). Six patients had no complication and 15 patients had pulmonary, renal or haematologic complications. In the non-complicated cases, sera during parasitaemia did not suppress the post-parasitaemia CFU-E and BFU-E. Post parasitaemia, there was suppression of CFU-E by parasitaemia sera. In the complicated cases, the autologous sera during parasitaemia suppressed the growth of both CFU-E and BFU-E both during and after parasitaemia (P < 0.05). The post-parasitaemia sera had neither a suppressive nor a stimulating effect. In the complicated cases, the progenitor cells cultured from the bone marrow post-parasitaemia were fewer in number than those cultured from the bone marrow during parasitaemia using the same sera. Two possible mechanisms of suppression are postulated, namely the reduction of erythropoietin or the increased tumour necrosis factor during malarial infection. Further studies to clarify this are being carried out.

HLA class II polymorphism in Thai patients with non-Hodgkin's lymphoma.

The distribution of HLA-DRB1 alleles and DQB1 alleles in 100 Thai patients with non-Hodgkin's lymphoma (NHL) was analysed using the polymerase chain reaction with sequence-specific primer (PCR-SSP) method, and the association between the disease and the presence of certain HLA class II alleles was investigated. The frequencies of HLA-DRB1*1502 and DRB1*09012 were increased while those of DRB1*0404, DRB1*0803 and DRB1*1106 were decreased. On the other hand, the incidence of HLA-DQB1 alleles was similar to that in the normal population. Interestingly, only HLA-DRB1*1502 showed a significant positive association with NHL, especially in patients < or / = 45 years and in male patients. It is concluded that the DRB1*1502 allele may contribute to NHL susceptibility in the Thai population. However, further studies on the functional roles of the HLA class II alleles are necessary to elucidate NHL susceptibility.