Treatment outcome and prognostic factors in PCNSL.

OBJECTIVES: Standard treatment with a thiotepa-based regimen in countries with a limited resource is less feasible. Aims of the study were to evaluate the treatment outcome, and identify the prognostic factors in patients with primary central nervous system lymphoma (PCNSL). METHODS: We conducted a retrospective study of 43 patients diagnosed with PCNSL, DLBCL subtype, who were treated with either HDMTX-based regimen, whole brain radiotherapy (WBRT), or both between 2010 and 2017. RESULTS: There were 43 patients with a median age of 65 years (range 34-89 years). Protein expression of CD10, Bcl6, MUM1, Bcl2 and MYC were found in 19, 86, 91, 91 and 23%, respectively. Both germinal center B cell (GCB) and double-expressor (MYC+/Bcl2+) lymphomas were found in 21%. Multiple brain lesions and maximum tumor diameter (MTD) ≥5 cm were seen in 27 and 10 patients, respectively. Chemotherapy combined with WBRT, chemotherapy and WBRT were given to 20, 14 and 9 patients, respectively. Overall complete remission (CR) rate was 55.8%. Those receiving a combined-modality therapy had a higher CR rate than those treated with either chemotherapy (75% versus 36%, p = 0.036) or WBRT (75% versus 44%, p = 0.109). Median follow-up time was 17 months, and a 7-year overall survival (OS) was 40%. Features associated with a prolonged OS were an ECOG score ≤ 2 (p = 0.001), multiple brain lesions (p = 0.010), multiple area of brain involvement (p = 0.023), MTD < 5 cm (p = 0.004), GCB subtype (p = 0.003) and positive CD10 staining (p = 0.007). Expression of Bcl2 protein was associated with a significantly worse OS in the non-GCB DLBCL patients. DISCUSSION: The factors affecting treatment outcomes in PCNSL were cell of origin of DLBCL, lesion characteristics, patients' status and treatment regimen.

Hydroxyurea and colonic ulcers: a case report.

BACKGROUND: Hydroxyurea at a relatively low dose is frequently prescribed to induce hemoglobin F production in patients with sickle cell and ß-thalassemia diseases because of its good efficacy and safety profiles. However, a potentially fatal gastrointestinal ulceration was recently found and herein reported. CASE PRESENTATION: A thirty-seven-year-old man with transfusion dependent hemoglobin E/ß-thalassemia disease was treated with hydroxyurea to induce hemoglobin F production since 2007 without incident. From 2008 to April 2010, episodes of hematochezia, mucous diarrhea and epigastric pain intermittently manifested. Four colonoscopies done during the period repeatedly showed ulcerative lesions from the terminal ileum to the ascending colon with a non-specific histo-pathologic finding. Subsequently, ulcerative lesions also developed at the pharynx, histo-pathologic findings of which were not different from those in the colon. These ulcerative lesions resolved within a month after discontinuing hydroxyurea in April 2010 and have not recurred since. CONCLUSION: The findings suggested role of hydroxyurea in the pathogenesis of these ulcers, and that it must be immediately discontinued to prevent further damage to the digestive mucosa.

Intravascular hemolysis, vascular endothelial cell activation and thrombophilia in splenectomized patients with hemoglobin E/ß-thalassemia disease.

The relationship between asplenia and thrombophilia in ß-thalassemia disease patients is not yet completely understood. One hundred and ten adult hemoglobin (Hb) E/ß-thalassemia (E/ß-Thal) disease outpatients, dichotomized according to the presence or absence of the spleen, were prospectively studied for evidence of intravascular hemolysis (IVH) and vascular endothelial cell (EC) activation. Biomarkers of IVH (serum cell-free Hb), EC [soluble E-selectin (sE-selectin) and soluble vascular cell adhesion molecule 1 (sVCAM-1)], platelet and EC [soluble P-selectin (sP-selectin)], inflammation [high-sensitivity C-reactive protein (hs-CRP)], and coagulation [thrombin-antithrombin complexes (TAT)] activation, as well as other selected blood tests were determined. The 61 splenectomized patients had a more severe hemolytic disease and higher levels of cell-free Hb and ferritin (p = 0.003), sE-selectin, sP-selectin, hs-CRP, and TAT (p < 0.05). However, serum levels of sVCAM-1 were not different between the two groups. The findings suggested IVH and EC activation. Together with chronic iron overload and chronic low-grade inflammation activation, the findings extend our understanding of the mechanism of thrombophilia in splenectomized E/ß-Thal disease patients.

Prevalence and risk factors for pulmonary hypertension in patients with hemoglobin E/ß-thalassemia disease.

OBJECTIVES: To find the prevalence and risk factors of pulmonary hypertension (PHT) in adult patients with hemoglobin E/ß-thalassemia disease (E/ß-Thal). METHODS: One hundred and ten clinically stable E/ß-Thal outpatients, sixty-one of whom had undergone splenectomy, were prospectively studied using their clinical profiles, selected blood tests, chest roentgenogram, and transthoracic echocardiogram. Based on the pulmonary artery systolic pressure (PASP) values estimated by the echocardiogram of ≥36 mmHg, they were dichotomized into those with (PHT+) and without (PHT-) PHT. RESULTS: PHT was found in 41 (37.3%) patients without gender preponderance. It was not due to the left heart and was not severe (PASP = 46.3 ± 10.4 mmHg). PASP was higher in splenectomized patients (48.0 ± 11 vs. 40.3 ± 4.7 mmHg (P = 0.004)). PHT was found in 32 of 61 (52.5%) splenectomized patients, mostly (53%) in the second decade, and rarely (6.3%) during the first 5 yr after splenectomy. PHT+ patients had more hemolysis (P = 0.001-0.04 depending on the parameters), more asplenic cases (P < 0.001), and higher serum soluble vascular cell adhesion molecule-1 (sVCAM-1) and high-sensitivity C-reactive protein levels (P = 0.004 and 0.008, respectively). Strong risk factors by univariate analysis were serum sVCAM-1 levels ≥1600 ng/mL, serum cell-free Hb ≥ 3 mg/dL, asplenia, and amount of NRBCs/100 WBCs >40. CONCLUSIONS: Prevalence of PHT in E/ß-Thal patients was 37.3% without gender preponderance. Those with severe hemolysis and asplenia invariably had severer PHT. Strong risk factors were asplenia and associated markedly elevated values of sVCAM-1, cell-free Hb, and NRBCs in blood.

Activation of mononuclear phagocytes and its relationship to asplenia and phosphatidylserine exposing red blood cells in hemoglobin E/ß-thalassemia patients.

Aged or abnormal red blood cells with exposed phosphatidylserine (PSRBCs) are cleared from the circulation by splenic macrophages. In asplenic patients, other mononuclear phagocytic cells in tissues and in circulation may function in this capacity. To better understand these changes and the relationship among splenic status, PS-RBCs, blood monocytes, and serum tumor necrosis factor (TNF-α), a product of mononuclear phagocyte activation, patients with hemoglobin E/ß-thalassemia (E/ß-Thal) were studied. Whole blood of 20 nonsplenectomized, 20 splenectomized E/ß-Thal patients, and 20 healthy subjects was assayed for PS-RBCs; for monocytes, activated monocytes, and monocyte response to lipopolysaccharide stimulation; and serum was assayed for TNF-α. Asplenic E/ß-Thal patients had significantly increased (P < 0.05) amounts of PS-RBCs, monocytes, activated monocytes, and levels of serum TNF-α. The amount of PS-RBCs correlated with levels of serum TNF-α, but the amount of activated monocytes did not correlate with either the amount of PS-RBCs or levels of serum TNF-α. Monocyte response to lipopolysaccharide stimulation in asplenic patients was not as efficient as in the other patients or in normals (77 vs. 404, and 304 folds increment, respectively). The results suggest that splenectomy in E/ß-Thal patients led to an increased amount of PSRBCs and activation in the mononuclear phagocytic system.

Treatment outcome of thalidomide based regimens in newly diagnosed and relapsed/refractory non-transplant multiple myeloma patients: a single center experience from Thailand.

BACKGROUND: Thalidomide based regimen is an effective and well tolerated therapy in multiple myeloma (MM) patients, however, there were a small number of studies written about the results of thalidomide therapy in non-transplant MM patients. We therefore conducted a retrospective study of 42 consecutive patients with newly diagnosed and relapsed/refractory MM treated with thalidomide- based induction regimens followed by thalidomide maintenance therapy. RESULTS: Induction regimens with thalidomide and dexamethasone, and the oral combination of melphalan, prednisolone and thalidomide were administrated in 22 and 16 patients, respectively. The remaining 4 patients received other thalidomide- containing regimens. Twenty-nine patients received thalidomide as a salvage regimen. Twenty-three out of 26 patients achieving complete remission (CR) and very good partial remission (VGPR) received thalidomide maintenance. Of the 41 evaluable patients, median time of treatment was 21 months (3- 45 months), ORR was 92.7% with a 63.4% CR/VGPR. With a median follow up of 23 months, 3-year- PFS and 3-year-OS were 58.6 and 72.6%, respectively. Median time to progression was 42 months. While 3-year-PFS and 3-year-OS in non-transplant patients receiving thalidomide maintenance therapy were 67 and 80%, respectively. CONCLUSIONS: Prolonged thalidomide therapy enhanced survival rate and less frequently developed serious toxicity in non-transplant multiple myeloma patients.

Long-term outcomes of de novo acute myeloid leukemia in Thai patients.

BACKGROUND: Acute myeloid leukemia (AML) is the heterogeneous disease. As per previous reports, there are some differences in clinical features and cytogenetic biomarkers of AML among different ethnic backgrounds. Therefore, we conducted a retrospective study to analyze clinical outcomes and predictive factors of Thai AML patients receiving chemotherapy treatment. MATERIAL AND METHOD: The authors performed a retrospective analysis of 106 adults with newly diagnosed de novo AML at Ramathibodi Hospital between 2003 and 2007. Of 101 patients with non- M3 subtype, the patients received induction and consolidation chemotherapy with anthracyclin plus cytarabine based regimens (3 + 7). All patients achieving complete remission (CR) were treated with intensive chemotherapy using intermediate dose cytarabine plus anthracyclin based protocol. All patients with M3 subtype, the induction chemotherapy consisted of a combination of all-trans retinoic acid (ATRA) and anthracyclin. All patients achieving complete remission (CR) were treated with three courses of mitoxantrone as consolidation chemotherapy, followed by maintenance chemotherapy with methotrexate, etoposide and ATRA. RESULTS: Of the 106 patients, median age was 43.5 years (15-73 years) and 19 (17.9%) were older than 60 years. Fifty-six patients (52.8%) were female. Common subtypes were M4 (28.3%), M1 (26.4%) and M2 (20.8%). Of the 95 patients who were performed with cytogenetic analysis, 55 (58%) had abnormal karyotype. AML with recurrent cytogenetic translocations, complex chromosome, trisomy 8, polyploidy, del 5q and del 7q were found in 16.8, 6.3, 5.3, 5.3, 2.1 and 3.2%, respectively. Most patients (70.5%) had intermediate-risk cytogenesis. Eighty patients (75.5%) were treated with idarubicin and cytarabine induction regimen. Of the 96 evaluable patients, 60 (62.5%) achieved complete remission (CR), 38 (39.6%) with the first course of chemotherapy. Median time to CR was 54 days (25-168 days). The CR rate was 78.6% for the good-risk cytogenetic group, 67.2% for the intermediate- risk cytogenetic group, and 37.5% for the poor-risk cytogenetic group. Median follow-up time was 10.4 months, 5-year-DFS and 5-year-OS were 41 and 22.2%, respectively. Patients with poor-risk cytogenetic factors had significantly lower CR rate (p = 0.021). The CR status significantly predicted OS (p < 0.001). CONCLUSION: The overall complete remission rate of Thai AML patients is in 60%. Only a small proportion of the presented patients have long-term DFS and OS, the significant factor for predicting survival of Thai AML patients is the complete remission status. Poor-risk cytogenetic factors are associated with poor treatment outcomes.

Successful treatment of acquired amegakaryocytic thrombocytopenic purpura refractory to corticosteroids and intravenous immunoglobulin with antithymocyte globulin and cyclosporin.

Four patients with acquired amegakaryocytic thrombocytopenic purpura, who had failed corticosteroids, intravenous immunoglobulin and cyclophosphamide therapy, were treated with antithymocyte globulin, followed by cyclosporin. Three patients achieved complete remission in 28-178 days and the response duration was 16-60 months from the beginning of treatment. One patient achieved a partial response for 2 months followed by myelodysplastic syndrome 5 months later. He died in 9 months due to intracerebral bleeding. Marrow cytogenetics showed 47, XY, +21.

Hemostatic and thrombotic markers in patients with hemoglobin E/beta-thalassemia disease.

Increased frequency of thrombosis has been observed in patients with hemoglobin E/beta-thalassemia (Hb E/beta-thal) disease, particularly those who have previously been splenectomized. We compared various hemostatic and thrombotic markers in blood from 15 Hb E/beta-thal patients who were not splenectomized (NS), 15 who had been splenectomized (S), and 15 normal controls (NC). Levels of plasma thrombin-antithrombin, beta2 thromboglobulin, C-reactive protein, tissue plasminogen activator antigen were significantly higher in the S group than in either the NS or the NC groups, and levels of prothrombin fragment 1.2 were significantly higher in the S than in the NC group. Levels of plasminogen activator inhibitor-1 antigen were significantly higher in the S than in the NS group. Levels of protein C, protein S, antithrombin, and fibrinogen were significantly lower in the S and NS groups than in the NC group. Plasma lipoprotein(a) levels in the S and NS groups were not statistically different from NC. Our findings indicated that there is evidence of chronic low-grade coagulation and platelet activation, chronic low-grade inflammation, endothelial cell injury, impaired fibrinolysis, and decreased naturally occurring anticoagulants in splenectomized Hb E/beta-thal patients. These changes may account for the increased risk of thrombosis in these patients.

Risk factors of venous thromboembolism in thai patients.

Venous thromboembolism (VTE) has been reported to be less common among Thais than Caucasians. Whether this observation reflects genetic or environmental factors, or both, is uncertain. To identify genetic and acquired risk factors of Thai patients with VTE, we enrolled in the study 105 consecutive Thai patients (34 men, 71 women) who had an objectively confirmed history of VTE. A complete clinical summary was obtained from each patient, with emphasis on personal and family history of VTE, as well as circumstantial vascular risk factors (surgery, immobilization, pregnancy, postpartum condition, trauma, oral contraceptive use, and malignancy). Of the 105 patients, 19% were found to have a malignancy. The mean age at the time of the first thrombotic episode was 52.1 years (range, 29-76 years), compared with 42.6 years (range, 17-82 years) for the patients without malignancy. Of the 85 patients without malignancy, 12.3% had protein S deficiency, 8.9% had protein C deficiency, 4.7% had antithrombin deficiency, 10.4% had antiphospholipid antibody, 30.4% had an elevated factor VIII level, 26.8% had an elevated factor XI level, 5.3% had hyperhomocysteinemia, and 16.5% were on oral contraceptives before the thrombotic episode. Factor V Leiden, the G20210A prothrombin gene mutation, and homozygosity for the C677T methylenetetrahydrofolate reductase (MTHFR) gene variant were not found. The VTE in 7.1% of the patients was considered to be secondary to recent surgery, trauma, and/or immobilization. Compared with studies of Caucasian patients, there were significant differences in the risk factors for VTE, with protein S deficiency and protein C deficiency being more common in the Thai patients. In contrast, factor V Leiden, the G20210A prothrombin gene mutation, and the C677T MTHFR gene mutation are not genetic risk factors among Thai patients with VTE. Malignancy and the use of oral contraceptives were the most common acquired risk factors for VTE in the Thai patients.

Hematopoietic features and apoptosis in the bone marrow of severe Plasmodium falciparum-infected patients: preliminary study.

The mechanism of anemia in severe falciparum malaria is still not completely understood. The purpose of this study was to determine whether apoptosis in the erythroid lineage causes anemia in falciparum malaria. Bone marrow aspirated from 8 severe falciparum malaria patients, 3 normal volunteers and 5 retrospective normal bone marrow smears were investigated. By light microscopic study, 5 of 8 hyperparasitemic patients had hypocellular bone marrows and erythroid hypoplasia, whereas the other 3 patients had normal cellularity. The mean myeloid : erythroid ratio of these 5 patients was significantly (p < or = 0.05) higher than normal. Apoptosis of bone marrow nucleated cells (BMNC) could be determined from the exposure of phosphatidylserine (PS) on the cell membrane but not DNA fragmentation (180-250 bp) or ultrastructural morphology. The percentages of apoptotic BMNC and apoptotic erythroid cells in bone marrow from each patient and controls varied from low to high, and were not associated with parasitemia. This study suggests that destruction of erythroid lineage, particularly through apoptosis regulation, cannot solely account for anemia in falciparum malaria.

Correction of hypercoagulability and amelioration of pulmonary arterial hypertension by chronic blood transfusion in an asplenic hemoglobin E/beta-thalassemia patient.

Chronic transfusion of packed red blood cells, in addition to other ongoing treatment with warfarin, acetyl salicylic acid, desferrioxamine, and other supportive measures, was given to a splenectomized hemoglobin E/beta-thalassemia woman with pulmonary arterial hypertension (PHT). Serial measurements of plasma thrombin-antithrombin III complex (TAT) levels and right-sided cardiac catheterization were used to monitor changes after treatment. Reduction of plasma TAT levels from 7.5 to 3.8 microg/L (normal, 3 +/- 2.4 microg/L), pulmonary vascular resistance (PVR) from 553.8 to 238.6 dyne.sec.cm(-5) (normal, 67 +/- 30 dyne.sec.cm(-5)), and mean pulmonary arterial pressure from 51 to 32 mm Hg (normal, 9 to 19 mm Hg) occurred in tandem. Normalization of blood hypercoagulability as reflected in plasma TAT level by chronic blood transfusion was the likely basis for improvement of increased PVR, being secondary to thrombotic pulmonary arteriopathy and subsequently PHT.

Pulmonary arterial hypertension in previously splenectomized patients with beta-thalassemic disorders.

Our aim was to study the cause and describe the clinical features of pulmonary arterial hypertension (PHT) in splenectomized beta-thalassemia (beta-Thal) patients. Ten splenectomized beta-Thal patients with systolic pulmonary artery (PA) pressure >30 mm Hg were evaluated by echocardiography, right-heart catheterization, and pulmonary angiography. Five of these patients later underwent hemodynamic studies. Echocardiography and pulmonary angiography on the 10 patients showed normal values of left ventricular systolic function and no findings of acute or chronic pulmonary embolism. Hemodynamic evaluation showed very high PA pressures associated with markedly increased pulmonary vascular resistance indices (PVRIs). Hematological evaluation of the 10 patients showed marked anemia, markedly increased numbers of nucleated red blood cells (nRBCs), and serum ferritin. Mean platelet count, plasma beta2 thromboglobulin, and thrombin-antithrombin III complex levels were significantly increased. It was concluded that PHT can be found in splenectomized beta-Thal patients. Features associated with PHT were female sex, hemoglobin E/beta-Thal, status many years postsplenectomy, marked anemia, markedly increased nRBC count, thrombocytosis, and very high serum ferritin levels. PHT was not due to pulmonary emboli. Our findings suggested that severe PHT was due to increased PVRI from thrombotic pulmonary arteriopathy, likely from chronic low-grade hypercoagulability and platelet activation after splenectomy.

In vivo platelet activation and hyperaggregation in hemoglobin E/beta-thalassemia: a consequence of splenectomy.

Patients with hemoglobin E/beta-thalassemia (E/beta-Thal) who have undergone splenectomy are prone to thrombosis in the small pulmonary arteries. To study the role of platelets in this situation, we assayed plasma beta2-thromboglobulin (betaTG) and performed whole blood platelet aggregation analysis of 30 E/beta-Thal patients, half of whom had undergone splenectomy. We compared results with those obtained with 15 healthy control subjects. Plasma betaTG levels in splenectomy patients were significantly higher than in control subjects and patients who had not undergone splenectomy, and platelets in splenectomy patients exhibited hyperaggregation in response to adenosine diphosphate, thrombin, and ristocetin. Levels of plasma thrombin-antithrombin III complex were also significantly higher. This finding is likely due to an increased number of erythrocytes with exposed phosphatidylserines, an effect that has been associated with splenectomy. The increased presence of thrombin in the blood may well be the cause of platelet hyperactivity, which was evident only in the asplenic patients Platelet hyperactivity very likely plays a pathogenetic role in the thrombosis of small pulmonary arteries that occurs in E/beta-Thal patients who have undergone splenectomy.

Relationship between hypercoagulable state and erythrocyte phosphatidylserine exposure in splenectomized haemoglobin E/beta-thalassaemic patients.

Small pulmonary arterial thromboses can occur following splenectomy of patients with haemoglobin E/beta-thalassaemia (Hb E/beta-thal). We compared plasma markers of coagulation activation in vivo and red blood cell (RBC) markers of procoagulant activity in 15 Hb E/beta-thal patients who were not splenectomized (NS), 15 who had been splenectomized (S), and 15 normal controls (NC). Levels of plasma thrombin-antithrombin III complex (TAT) were significantly higher in the S group than in either the NS or the NC groups, and levels of prothrombin fragment 1.2 (F 1.2) were significantly higher in the S than in the NC group. Diluted Russell's viper venom clotting times were significantly shorter when RBCs from group S patients were added to the assay compared with RBCs from the NC group. Phosphatidylserine (PS) expression (% of annexin V-positive RBCs) on the outer leaflet of RBC membrane of both 'larger'- and 'smaller'-sized RBCs was significantly higher for the S than the NC group. The RBC PS expression of the S and the NS groups, respectively, accounted for 25 x 3% (P = 0 x 174) and 6.3% (P = 0 x 675) of the variation in plasma TAT levels. Our findings indicated that, when compared with NC, splenectomized patients with Hb E/beta-thal were in a chronic low-grade hypercoagulable state associated with increased numbers of circulating PS exposed RBCs. This condition may have a role in the risk of these patients for pulmonary arterial thromboses.