Prevalence of the C677T methylenetetra- hydrofolate reductase mutation in Thai patients with deep vein thrombosis.

We investigated the prevalence of a genetic variation in the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene (C677T) using polymerase chain reaction techniques in a sample of 500 general Thai population and among 40 unselected Thai patients with an objectively confirmed history of deep vein thrombosis (DVT). The prevalence of the mutated homozygous and heterozygous C677T MTHFR genotype in the group of 500 healthy Thai population was 1.4 and 25.6%, respectively (allele frequency of 14.2%). Of the 40 patients studied, none were homozygotes and 15% were heterozygotes for the C677T MTHFR gene mutation (allele frequency of 7.5%). There was no significant difference in genotype frequency between patients and control groups (p = 0.09). Odds ratios for the probability of the C677T MTHFR gene mutation in the patient versus control group were 0.49 (95% CI 0. 21-1.12). These data indicated that the C677T MTHF gene mutation was not associated with DVT in the Thai population. The lower frequency of the C677T MTHFR gene mutation in our Thai population compared with reports from other studies suggests a wide heterogeneity in the 677T MTHFR genotype frequencies of the different ethnic populations even among Asians.

Prevalence of the G1691A mutation in the factor V gene (factor V Leiden) and the G20210A prothrombin gene mutation in the Thai population.

We investigated the prevalence of a genetic variation in the factor V gene (G1691A Leiden mutation) and the prothrombin gene (G20210A) using polymerase chain reaction techniques in samples from 500 normal Thai population and among 50 unselected Thai patients with an objectively confirmed history of deep venous thrombosis. The prevalence of factor V Leiden and the prothrombin G20210A gene mutation in a group of 500 healthy controls was 0.2% in both groups (allele frequency of 0.1%). Of the 50 adult patients studied, none was a carrier of factor V Leiden or the prothrombin G20210A gene mutation. Our findings confirm that the prevalence of factor V Leiden and prothrombin G20210A gene mutation is lower among Asians than Caucasians and that the distribution of factor V Leiden is similar to that of the prothrombin G20210A variant. The low prevalence of these two mutations can, at least in part, account for the lower frequency of deep venous thrombosis reported in the Thai population. Screening for factor V Leiden and prothrombin gene mutation is of limited benefit and may not be cost-effective in Thai patients with the first episode of deep venous thrombosis.

Serum C-reactive protein level in postsplenectomized thalassemic patients.

C-reactive protein is an established marker for the detection of acute and chronic inflammatory processes. The most potent stimulator for the hepatic synthesis of this protein is interleukin 6. Previous studies have shown that inflammatory cells and inflammatory cytokines, such as interleukin 6, interferon gamma, etc were elevated in postsplenectomized thalassemic patients. The aim of this study was to determine serum C-reactive protein concentration in postsplenectomized beta thalassemic patients (beta thal/HbE postsplenec), and to compare them with those in nonsplenectomized beta thalassemic patients (beta thal/HbE), postsplenectomized non thalassemic patients (postsplenec), reactive thrombocytosis (RT), chronic myeloproliferative disorders (MPD) and normal adult volunteers. Serum C-reactive protein concentration as determined by an automatic Behring Nephelometer was carried out in 28 beta thal/HbE postsplenec, 22 beta thal/HbE, 12 postsplenec, 23 RT, 21 MPD, and 26 healthy adult volunteers. The values of CRP in beta thal/HbE postsplenec were significantly higher when compared with beta thal/HbE, and normal volunteers (4.1 +/- 0.7 vs 1.6 +/- 0.4 mg/L P = 0.006, and 4.1 +/- 0.7 vs 0.45 +/- 0.09 mg/L, P < 0.001). CRP levels in beta thal/HbE postsplenec were also higher than the postsplenec group (4.1 +/- 0.7 vs 0.19 +/- 0.7 mg/L P = 0.095). On the contrary, they were significantly lower than those in RT (4.1 +/- 0.7 vs 55.4 +/- 14.8 mg/L, P = 0.002). However, when compared to those with MPD, the values were not statistically different (4.1 +/- 0.7 vs 17.1 +/- 12.3 mg/L, P = 0.871). Interestingly, there was a trend towards increasing C-reactive protein levels in beta thal/HbE postsplenec patients with higher platelet count, although no correlation was observed. Besides the inflammatory process, platelet and/or factor(s) that control(s) thrombopoiesis seem(s) to play a role in the high serum C-reactive protein levels in the studied population.

Etiology and incidence of thrombotic and hemorrhagic disorders in Thai patients with extreme thrombocytosis.

A retrospective study of 126 patients with extreme thrombocytosis (defined as a platelet count > or = 1,000 x 10(9)/L) was performed during a five-year period (June 1994-June 1999). The aim of this study was to determine the etiology and to evaluate the clinical consequences of extreme thrombocytosis. Seventy patients (55.5%) had reactive thrombocytosis (RT) with an age range of 43 +/- 2.2 years, 56 (44.5%) had chronic myeloproliferative disorders (MPD) with an age range of 53 +/- 2.4 years. Underlying causes of RT were malignancy (25/70 or 35.7%), infection (16/70 or 22.9%), postsplenectomized beta-thalassemia/Hb E (11/70 or 15.7%), inflammation (12/70 or 17.1%), iron deficiency anemia (6/70 or 8.6%). Duration post splenectomy in our beta-thalassemia/Hb E patients ranged from 4 months to 21 years, with a median of 10 years. Subtypes of our MPD cases were chronic myeloid leukemia (30/56 or 53.6%), essential thrombocytosis (18/56 or 32.1%), polycythemia vera (4/56 or 7.1%), agnogenic myeloid metaplasia (3/56 or 5.4%) and unclassified MPD (1/56 or 1.8%). Bleeding and thrombotic tendency were respectively noted in 7 (12.5%) and 2 (3.6%) of MPD patients. Two patients of the MPD group (3.6%) experienced both bleeding and thrombotic episodes. One patient (1.4%) of the RT group developed vasculitis-associated thrombosis. However, none of the patients in the RT group had bleeding complications. Extreme thrombocytosis was not a rare condition in a university hospital population, and bleeding and/or thrombotic complication was more common in the MPD group.

Levels of serum interleukin-6 and tumor necrosis factor in postsplenectomized thalassemic patients.

Levels of serum interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) were studied in 34 nonsplenectomized thalassemic patients (Thal/nonsplenec), 43 postsplenectomized thalassemic patients (Thal/postsplenec), 13 splenectomized non-thalassemic patients (nonThal/ postsplenec) and 18 normal control by enzyme linked immunosorbent assay method. Serum IL-6 concentration in Thal/postsplenec was significantly increased when compared with Thal/ nonsplenec and normal volunteers (3.55 +/- 2.47 pg/ml vs 2.38 +/- 2.31 pg/ml, p = 0.036 and 3.55 +/- 2.47 pg/ml vs 2.66 +/- 0.45 pg/ml, p = 0.028, respectively). This study also demonstrated that TNF-alpha value in Thal/postsplenec was drastically increased above normal control level (15.8 +/- 4.86 pg/ml vs 9.16 +/- 2.18 pg/ml, p = 0.001) and the level was statistically significantly higher than that in Thal/ nonsplenec (15.5 +/- 4.86 pg/ml vs 9.96 +/- 5.19 pg/ml, p = 0.001). There was a trend toward increasing of cytokine levels in Thal/postsplenec with higher platelet count although no correlation was observed. This study addresses the possible role of IL-6 and TNF-alpha in the pathogenesis of reactive thrombocytosis in Thal/postsplenec.

Cytochemical and immunological phenotying of acute nonlymphoblastic leukemia in Thai patients.

Using morphology and cytochemical reaction, we could subclassify-according to FAB classification, 51 of our 56 cases of acute nonlymphoblastic leukemia (ANLL) as M1-M5. Five cases were undifferentiated. Using the immunophenotypic method, we could subclassify 51 of these patients as M1-M4. In addition, 3 cases of undifferentiated leukemia by the prior method were each classified as M1, M3, and myelo-megakaryoblastic leukemia. Correlation of ANLL subtype classification according to each method was not good. However, combination of both methods, using immunophenotypic analysis as a supplement would better subclassify the disease. One of the remaining 2 cases of undifferentiated leukemia was also shown to be myelo-megakaryoblastic leukemia by a positive platelet peroxidase reaction by ultrastructural cytochemistry. Thus, combination of these 3 methods could diagnose and subclassify 55 of the 56 cases (98%) of our ANLL patients.

Multivariate analysis of prognostic factors in Philadelphia chromosome positive chronic myeloid leukemia: an update of the first series in Thailand.

The prognostic importance of pretreatment clinical and laboratory features was investigated in a group of 243 patients with Philadelphia chromosome positive chronic phase chronic myeloid leukemia from 1977-1995. Chemotherapy consisted of busulfan before 1993 or hydroxyurea after 1993. The overall median survival from diagnosis was 28 months. The mean age of the patients was 38 years, about 10 years below that of Western populations. Univariate analysis identified 4 poor prognostic features: thrombocytopenia, more than 5% peripheral blasts, more than 5% erythroid precursors and less than 7 g/dl of hemoglobin. The median survival times of patients with these 4 risk factors were 5, 11, 11 and 12 months respectively. Multivariate analysis only identified 2 significant prognostic features: thrombocytopenia and more than 5% peripheral blasts. Splenomegaly of more than 10 cm, basophilia and leukocytosis were associated with a shorter median survival but was not statistically significant. A risk scoring system was developed and used to classify patients into low, intermediate and high risk groups at 30.9%, 30.2% and 38.8% respectively. The median survival time according to the low, intermediate and high risk group was observed at 60, 27 and 14 months respectively. Prognostic factors for Thai patients with chronic myeloid leukemia have both similarities and differences with previously observed factors but the median patient survival time is shorter.

Immunoproliferative small intestinal disease (IPSID) in Thailand.

Immunoproliferative small intestinal disease (IPSID) is prevalent in the Mediterranean region and in many Third World countries but is rare in Southeast Asia. Between 1980-1990, 4 cases of IPSID were admitted to Ramathibodi Hospital, Bangkok. Three were males and the mean age was 32 +/- 20.2 years. All patients presented with chronic diarrhea of 7 months to 6 years duration, and weight loss of 15 to 31 kg. All were malnourished, three cachectic, and one patient showed growth retardation. Intestinal parasites were found in all cases: two had multiple infections and three had uncommon protozoal infections (coccidium, cryptosporidium). Barium radiographs revealed intestinal mucosal fold thickening with malabsorption pattern in all cases. Alpha chain IgA was detected in one patient. The remainder underwent exploratory laparotomy and the histological finding was of plasma lymphocytic infiltration of the small intestinal mucosa. All patients responded to oral tetracycline with complete remission occurring in one case. During the follow-up period, 3 cases had progressive retractable clinical courses but all died 2 to 5 years after the diagnosis. The causes of death in these patients were secondary bacterial infection (1 case), intestinal tuberculosis (1 case), fungal infection (1 case) and immunoblastic sarcoma in another case. The results of this study confirm the occurrence of IPSID in Thailand. IPSID responds to oral antibiotic therapy and complete remission may be achieved during the early reversible benign phase, thus an awareness of its occurrence is of clinical importance.

Experience with factor VIII: C inhibitors and acquired von Willebrand's disease in an adult at Ramathibodi Hospital.

Eleven cases of acquired inhibitors against factor VIII: C and von Willebrand's factor (vWF) seen at the Department of Medicine, Ramathibodi Hospital from 1979 to 1991 were reviewed. Factor VIII: C inhibitor was found in 6 of 36 patients (17%) with hemophilia A (median age 18 years). Three patients each were weak (titer < 10 Bethesda units/ml), and strong antibody producers. Two cases of weak antibody producers had spontaneous disappearance of inhibitor, while all 3 strong antibody producers required specific treatment (corticosteroids, immunosuppressive drugs, and plasmapheresis). The inhibitor level temporarily declined in 2 patients, and disappeared in one. Spontaneous acquired inhibitor to factor VIII: C was seen in 3 patients. One each respectively had pemphigus vulgaris and bullous pemphigoid, autoimmune disease, and NIDDM. They were characterized by older age (median age 54 years), frequent skin and soft-tissue hematoma, but less hemarthroses. Inhibitor titer ranged from 15-280 Bethesda units/ml. Disappearance of the inhibitor after treatment with corticosteroids and immunosuppressive drugs were observed in all patients. Acquired von Willebrand's disease developed in 2 previously healthy patients. One patient was in the postpartum period, while the other had simultaneous acute viral hepatitis A infection. Both presented with the recent onset of spontaneous severe gingival bleeding, and demonstrated a prolonged bleeding time, reduced vWF:Ag (F VIIIR:Ag), and ristocetin cofactor (F VIIIR:vWF). Treatment with cryoprecipitate and corticosteroid resulted in remission of bleeding symptoms. Despite the rarity of these disorders, the recognition and proper management are of importance.

Treatment of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma is a common cancer among Thai males. When first seen, the disease is almost always locoregional. Evaluation of the tumor volume at the nasopharynx by computerized axial tomogram must be done prior to therapy. Treatment is done by radiation therapy to the nasopharynx and cervical lymph nodes, and is effective. Chemotherapy has high activity in this disease. However, more studies are needed to define its role. Side effects of treatment are radiation related, and confined to the area of previous radiation. They can be minimized if the patients strictly adhere to the physician's advice. Causes of treatment failure and death can be due to both locoregional failure and distant metastasis, notably to bone, liver and lungs.

Anti-HIV seroconversion in hemophilia A patient after transfusion of anti-HIV negative blood components.

A Thai male hemophiliac A patient has been anti-HIV seroconverted in the hospital after a 2-year admission for a large infected retroperitoneal hematoma. The source of HIV is thought to be one or more of more than 20,000 units of blood components used during the admission. All were screened as anti-HIV negative. Although he received heat treated factor VIII concentrate before this admission, it was not thought to be the cause. Autologous blood transfusion and HIV antigen screening are suggested as a safer way of blood transfusion.

Clinical features of acute lymphoblastic leukemia subclasses in 28 Thai children--a preliminary study.

Twenty-eight Thai children with newly diagnosed acute lymphoblastic leukemia were evaluated for pretreatment characteristic, including immunophenotype of lymphoblast, outcome of treatment, and the correlation among them. By APAAP technique using a panel of eight monoclonal antibodies (HLA-DR, CD 19, CALLA (CD 10), IgM, CD 7, CD 3, CD 4, and CD 8), five subclasses were identified: 67.9, 17.9, 7.1, 3.6, and 3.6 per cent were respectively shown to be common-, null-, mature thymocyte T-, pre B-, and B-ALLs. Clinical features in each subclass conformed to previous reports. All of the 27 evaluable patients attained initial complete remission, but subsequent relapses were noted in 7 patients (25.9%). Three of the 19 cases in the common ALL group relapsed at 6-12 months, whereas, 4 of the 8 cases in the non-common ALL group relapsed at 2-15 months. Probability of relapse at 12 months in the common and non-common ALL groups were 19 and 49 per cent respectively. Disease-free survival from time of remission was shorter in the non-common ALL group. Multivariate analysis of the 6 factors predicting disease-free survival showed that the only strong factor was the immunophenotype of lymphoblast.

Immunophenotype and cytochemical reactions of acute lymphoblastic leukemia in Thai children.

The immunophenotypes of acute lymphoblastic leukemia (ALL) in 28 Thai children were studied by the APAAP technique using a panel of eight specific monoclonal antibodies: HLA-DR, CD 19, CALLA (CD 10), IgM, CD 7, CD 3, CD 4, and CD 8. Sixty-eight, 18, 3.5, 3.5, and 7 per cent were respectively shown to be common, null, pre-B, B, and mature thymocyte T subtypes. Cytochemical reactions (beta-glucuronidase, alpha naphthyl acetate esterase, and acid phosphatase) in this study could identify null, common, and T ALLs with confidence, and could be used in the process of ALL subtyping to reduce cost.

Nasopharyngeal carcinoma: results of treatment by radiotherapy vs chemotherapy plus radiotherapy.

To determine the efficacy of neoadjuvant chemotherapy over radiotherapy alone in locally advanced nasopharyngeal carcinoma, a prospective non-randomized study was performed from 1 January 1982 to 31 December 1985 at Ramathibodi Hospital, Thailand. There were 69 new cases who completed treatment and were followed up at least once. Thirty-three cases were treated by radical radiotherapy (RT) alone and 36 cases by chemotherapy (CT) + RT. CT were by the combination of cis-diamminedichloroplatinum II and 5 fluorouracil. Of 32 cases, 2 courses of CT were given before RT and 1 after. The other 4 received 3 courses prior to RT. For both groups, RT technique and dosage were similar. Follow-up time of both groups ranged from 6-104 months (mean 50.3, median 50) and 8-100 months (mean 52.2, median 54.5), and total failures were 18/33 and 13/36, respectively, with no statistical difference (p greater than 0.05). Estimated actual survival and disease free survival from Kaplan-Meier curves at 3 years were about 75 per cent vs 75 per cent and 65 per cent vs 65 per cent, respectively, with no statistical differences (Log-Rank test). Therefore, we concluded that induction chemotherapy had some benefit but no statistical significance over RT alone. However, the role of maintenance chemotherapy is now being studied.

Nasopharyngeal carcinoma: value of bone and liver scintigraphy in the pre-treatment and follow-up period.

Nasopharyngeal carcinoma (NPC) is a disease with a high potential of distant metastasis, especially to bone and liver. To evaluate the routine use of bone and liver scintigraphy in the evaluation of metastatic disease during the pre-treatment and follow-up period, 112 new cases of NPC were enrolled. The pre-treatment scintigraphs were performed at the time of staging evaluation, while the follow-up ones were performed once a year and whenever clinically indicated. At the pre-treatment period, 3/112 cases showed a true positive result, all at bony sites. At the 3 years follow-up, 10/83 and 8/83 cases respectively showed a true positive result in the bone and liver. All of the positive cases had definite symptoms and signs of metastases, which correlated well with the scintigraphic findings. All without clinical evidence showed a negative finding. Therefore, we conclude that, without clinical indication, routine bone and liver scintigraphy are of limited value.

Multivariate analysis of prognostic factors in chronic myelogenous leukemia.

The prognostic importance of patient pretreatment clinical and laboratory features were investigated in a group of 50 patients with Philadelphia chromosome-positive benign phase chronic myelogenous leukemia. The overall median survival time was 30 months. The patient characteristic associated with shortened survival was the male sex. Anemia, thrombocytosis or thrombocytopenia tened to have adverse effect on survival. A multivariate regression analysis demonstrated only sex difference to be of prognostic importance. Evaluation of the effect of therapy showed that intensive chemotherapy was not superior to single agent chemotherapy.

Changes in T-staging of nasopharyngeal carcinoma by CT-scan.

To evaluate the value of computerized axial tomogram (CT-scan) of the nasopharynx in the management of patients with nasopharyngeal carcinoma (NPC), comparisons between clinical T-staging by means of indirect or direct nasopharyngeal examination, and CT-scan were performed in 101 cases. CT-scan has upstaged clinical T-staging in 83.9 per cent of Tx-T3 cases, or 80 per cent in Tx, 98 per cent in T1, 65.4 per cent in T2, and 50 per cent in T3 cases. CT-scan was also able to show the destruction of the base of the skull in 85.7 per cent of T4 cases. With regard to tumor extensions into the surrounding regions, the CT-scan proved to out-perform clinical T-staging by 82.2, 57.4, and 25.7 per cent respectively in superior, anterior, and lateral and inferior extensions. We, therefore, recommend that a CT-scan be done in every new case of NPC, because it provides more accurate T-staging, and more details of tumor extension, which is essential in the management of NPC, especially in the proper planning of radical radiotherapy.

Pharmacokinetics of amikacin in hematologic malignancies.

The pharmacokinetics of amikacin in 10 patients with hematologic malignancies and 1 patient with aplastic anemia were investigated. At an administered dose of 7 mg/kg of body weight, a volume of distribution of 0.4 liters/kg, an elimination half-life of 3.0 h, and a total body clearance of 2.1 ml/min per kg, amikacin achieved a peak level in blood of 21 micrograms/ml. Results of the study revealed that there was a marked increase in volume of distribution of amikacin in these patients compared with normal.

Lethal midline granuloma and lymphoproliferative disorders.

Seventeen patients, who presented with unhealing ulcers or destructive lesions of the upper aero-digestive tract at Ramathibodi hospital from 1977 to 1985 were reported. Lesions caused by infection, Wegener's granulomatosis or non-hematopoietic malignancy were excluded. A spectrum of histopathologic findings were evident in our patients, ranging from acute and chronic inflammatory changes with or without necrosis, polymorphic reticulosis or lymphamatoid granulomatosis, and malignant lymphoma of the non-Hodgkin's type (NHL). Although some initial histopathologic findings were non-specific, evidence of lymphoproliferative disorders finally emerged. These malignant lymphoid cells had a predilection for the GI tract and skin. Lymphoma staging should thus be done. Bleeding from the lesion, treatment-induced leucopenia, and sepsis were common in these patients. Early aggressive treatment including adequate antibiotic coverage for superimposed infection, improved nutritional status, and early radiation to the primary lesion are suggested for those diseases.