Shear wave elastography for solid breast masses evaluation: Quantitative measurement of mean elasticity value and elasticity ratio.

Purpose: Shear wave elastography (SWE), an ultrasonographic technique to measure the elasticity of mass lesions to evaluate breast mass. This study aimed to find out the cutoff values identifying breast malignancy using the mean elasticity (E-mean) and elasticity ratio (E-ratio) of breast masses. Methods: This retrospective study included women underwent SWE and US-guided biopsy of breast masses. During conventional US, the SWE mode was also performed, determining elasticity measurements, E-mean and E-ratio. Histopathological reports were obtained to identify mass status. The optimal and alternative cutoff values for E-mean and E-ratio to determine malignancy were assessed by receiver operating characteristic (ROC) curve analysis and Youden's index score. Results: Among 147 benign and 93 malignant masses, the median of E-means were 26.20 (IQR 15.70-56.60) and 141.60 (IQR 119.80-154.60) kPa and the median E-ratios were 3.11 (IQR 1.83-5.23) and 9.24 (IQR 6.76-12.44), respectively. Using Youden's index, the optimal cutoff values for E-mean and E-ratio were 90.35 and 5.89, with sensitivity of 87.1 % and 82.8 %, specificity of 89.1 % and 83.7 %, positive predictive value (PPV) of 83.5 % and 76.2 %, negative predictive value (NPV) of 91.6 % and 88.5 %, positive likelihood ratio (LR+) of 8.00 and 5.07, and negative likelihood ratio (LR-) of 0.14 and 0.21, respectively. Conclusion: This study revealed that SWE is useful in predicting malignancy. With the optimal cutoff values of E-mean and E-ratio at 90.35 kPa and 5.89, the sensitivity was nearly 90 % with E-mean and slightly over 80 % with E-ratio, respectively. These findings could be used in conjunction with conventional US.

Immunosuppressive properties of mesenchymal stromal cells derived from amnion, placenta, Wharton's jelly and umbilical cord.

BACKGROUND: The role of bone marrow-derived mesenchymal stromal cells (BM-MSC) in preventing the incidence and ameliorating the severity of graft-versus-host disease (GvHD) has recently been reported. However, as the collection of BM-MSC is an invasive procedure, more accessible sources of MSC are desirable. AIM: This study aimed to explore the alternative sources of MSC from amnion, placenta, Wharton's jelly and umbilical cord, which are usually discarded. METHODS: MSC from those tissues were isolated using mechanical dissociation and enzymatic digestion. Their capacity for proliferation and differentiation, and ability to suppress alloreactive T-lymphocytes were studied and compared with those of BM-MSC. RESULTS: MSC derived from amnion, placenta, Wharton's jelly and umbilical cord were similar to BM-MSC regarding the cell morphology, the immunophenotype as well as the differentiation ability. These MSC also elicited a similar degree of immunosuppression, as evidenced by the inhibition of alloreactive T-lymphocytes in the mixed lymphocyte reaction, compared with that of BM-MSC. MSC from umbilical cord and Wharton's jelly had a higher proliferative capacity, whereas those from amnion and placenta had a lower proliferative capacity compared with BM-MSC. CONCLUSION: The results obtained from this study suggest that MSC from amnion, placenta, Wharton's jelly and umbilical cord can therefore be potentially used for substituting BM-MSC in several therapeutic applications, including the treatment of GvHD.

Hematopoietic stem cell transplantation in Thailand.

Hematopoietic SCT was first performed in Thailand in 1986. At present, there are FOUR active centers: Siriraj, Ramathibodi, Chulalongkorn and Pramongkutklao Hospitals. The annual number of transplants varies from 120 to 150 cases. Although the number of eligible patients is high, only a proportion of the patients can undergo hematopoietic SCT due to the high cost of the procedure. The overall results are comparable to those reported in the Western countries. The incidence of acute GVHD is low, whereas chronic GVHD is high, especially in those who receive PBSC.

SLUG is required for SOX9 stabilization and functions to promote cancer stem cells and metastasis in human lung carcinoma.

Cancer stem cells (CSCs) are a promising target for cancer therapy, particularly for metastatic lung cancers, but how CSCs are regulated is largely unknown. We identify two proteins, SLUG (encoded by SNAI2 gene) and SOX9, which are associated with advanced stage lung cancers and are implicated in the regulation of CSCs. Inhibition of either SLUG or SOX9 sufficiently inhibits CSCs in human lung cancer cells and attenuates experimental lung metastasis in a xenograft mouse model. Correlation between SLUG and SOX9 levels was observed remarkably, we therefore sought to explore their mechanistic relationship and regulation. SLUG, beyond its known function as an epithelial-mesenchymal transition transcription factor, was found to regulate SOX9 by controlling its stability via a post-translational modification process. SLUG interacts directly with SOX9 and prevents it from ubiquitin-mediated proteasomal degradation. SLUG expression and binding are necessary for SOX9 promotion of lung CSCs and metastasis in a mouse model. Together, our findings provide a novel mechanistic insight into the regulation of CSCs via SLUG-SOX9 regulatory axis, which represents a potential novel target for CSC therapy that may overcome cancer chemoresistance and relapse.

Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial.

In the phase 3 Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENESTnd) study, nilotinib resulted in earlier and higher response rates and a lower risk of progression to accelerated phase/blast crisis (AP/BC) than imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). Here, patients' long-term outcomes in ENESTnd are evaluated after a minimum follow-up of 5 years. By 5 years, more than half of all patients in each nilotinib arm (300 mg twice daily, 54%; 400 mg twice daily, 52%) achieved a molecular response 4.5 (MR(4.5); BCR-ABL⩽0.0032% on the International Scale) compared with 31% of patients in the imatinib arm. A benefit of nilotinib was observed across all Sokal risk groups. Overall, safety results remained consistent with those from previous reports. Numerically more cardiovascular events (CVEs) occurred in patients receiving nilotinib vs imatinib, and elevations in blood cholesterol and glucose levels were also more frequent with nilotinib. In contrast to the high mortality rate associated with CML progression, few deaths in any arm were associated with CVEs, infections or pulmonary diseases. These long-term results support the positive benefit-risk profile of frontline nilotinib 300 mg twice daily in patients with CML-CP.

Hematopoietic stem cell transplantation for homozygous ß-thalassemia and ß-thalassemia/hemoglobin E patients from haploidentical donors.

Thalassemia-free survival after allogeneic stem cell transplantation (SCT) is about 80-90% with either matched-related or -unrelated donors. We explored the use of a mismatched-related ('haplo- ') donor. All patients received two courses of pretransplant immunosuppressive therapy (PTIS) with fludarabine (Flu) and dexamethasone (Dxm). After two courses of PTIS, a conditioning regimen of rabbit antithymocyte globulin, Flu and IV busulfan (Bu) was given followed by T-cell-replete peripheral blood progenitor cells. GvHD prophylaxis consisted of cyclophosphamide (Cy) on days SCT +3 and +4 (post-Cy), and on day SCT +5 tacrolimus or sirolimus was started together with a short course of mycophenolate mofetil. Thirty-one patients underwent haplo-SCT. Their median age was 10 years (range, 2-20 years). Twenty-nine patients engrafted with 100% donor chimerism. Two patients suffered primary graft failure. Median time to neutrophil engraftment was 14 days (range, 11-18 days). Five patients developed mild to moderate, reversible veno-occlusive disease, while nine patients developed acute GvHD grade II. Only five patients developed limited-chronic GvHD. Projected overall and event-free survival rates at 2 years are 95% and 94%, respectively. The median follow up time is 12 months (range, 7-33 months).

Spinal cord compression in thalassemia. Report of 12 cases and recommendations for treatment.

Twelve patients with beta-thalassemia/hemoglobin E disease had spinal cord compression. Ten were made and two female, aged 17 to 40 years. The causes of spinal cord compression presumably were extramedullary hematopoietic masses. This was proved by surgery in two cases. In six cases, myelography demonstrated extradural blockade. In the others, the recurrent nature of the paraparesis and the prompt response to deep x-ray therapy were compatible with cord compression by extramedullary hematopoietic masses. Although spontaneous recovery and disappearance of the neurological signs after blood transfusions were observed, these were slow and uncertain. Deep x-ray therapy led to prompt response with more lasting benefit in all cases and is thus recommended as standard treatment for this complication.

Growth of mixed erythroid-granulocytic colonies in culture derived from bone marrow of patients with paroxysmal nocturnal hemoglobinuria without addition of exogenous stimulator.

Hematopoietic progenitor cell cultures were studied in 16 patients with paroxysmal nocturnal hemoglobinuria (PNH). Both erythroid and granulocyte-macrophage progenitors in the blood and bone marrow decreased despite hypercellular marrow. In eight out of 16 patients, mixed erythroid-granulocytic colonies were observed in the bone marrow cultures without erythropoietin and colony-stimulating factor. Removal of monocytes and T-lymphocytes before culture failed to abrogate spontaneous mixed-colony formation. Conditioned media prepared from blood and bone marrow of PNH patients could not promote the growth of mixed colonies in normal individuals. The autonomous, spontaneous mixed-colony formation in patients with PNH is an abnormality of PNH stem cells not described previously.

Use of household pesticides and the risk of aplastic anaemia in Thailand. The Aplastic Anemia Study Group.

BACKGROUND: Aplastic anaemia is a severe blood dyscrasia that is more common in Thailand than in Western countries. Its a etiology remains poorly understood. METHODS: A case-control study was conducted in Bangkok and two rural regions of Thailand. The effect of household pesticides was evaluated among 253 incident cases of aplastic anaemia and 1174 hospital controls. RESULTS: A total of 54% of the cases and 61% of the controls were exposed 1-6 months previously. For most individual household pesticides and for groups classified according to chemical type (organophosphates, pyrethrins, and organochlorines), the relative risk (RR) estimates approximated 1.0; upper 95% confidence limits were below 2.0 for many comparisons. A significant association was observed for exposure to combination products containing dichlorvos and propoxur, with an overall RR estimate of 1.7 (95% confidence interval [CI]: 1.1-2.6); the estimate for regular use was 1.6 (95% CI: 0.9-2.9). CONCLUSIONS: The absence of a higher risk for the regular use of dichlorvos/propoxur reduces the credibility of the apparent association, which could well have been an artefact of multiple comparisons. We conclude that most household pesticides used in Thailand do not appear to increase the risk of aplastic anaemia.

Bone marrow transplantation in Thailand.

In Thailand aplastic anemia and thalassemias as well as leukemias and lymphomas are prevalent. Bone marrow transplantation has been used to cure these patients. The results are more favorable in non-malignant diseases than in hematological malignancies. The incidence of GVHD and CMV infection is low. There are still some unresolved problems, especially lack of personnel, limited facilities and high cost.

Bone marrow transplantation for thalassemia in Thailand.

We report our experience of bone marrow transplantation for thalassemia in Thailand. From July 1988 to September 1992, 10 thalassemic patients underwent allogeneic bone marrow transplantation. Two of them were homozygous beta-thalassemia and 8 were beta-thalassemia/Hb E disease. Seven were male and 3 female. The age ranged from 1.8-14 years. The conditioning regimen comprised busulfan 14 mg/kg and cyclophosphamide 200 mg/kg. For GVHD prophylaxis, either cyclosporine alone or in combination with short methotrexate was given. Five patients were alive and well 104-1534 days after transplantation. Three patients with severe manifestations at the time of transplant had partial engraftment, and lost their graft within 3 months. They survived with thalassemia 1041-1357 days after transplantation. One patient who received one antigen mismatched marrow from her brother had no engraftment and was alive with thalassemia 1429 days posttransplant. One patient died early on day 9 from CNS complication. No GVHD was observed in this series. These results indicate that bone marrow transplantation can cure thalassemia but there is still high autologous recovery rate in those with severe manifestations.

Successful bone marrow transplantation in a child with red blood cell pyruvate kinase deficiency.

We report the first successful use of BMT for the treatment of RBC pyruvate kinase (PK) deficiency in a boy who developed neonatal jaundice and severe transfusion-dependent hemolytic anemia a few months after birth. He received a BMT at the age of 5 from an HLA-identical sister who has normal PK activity after conditioning with busulfan and cyclophosphamide. The post-transplant course was uneventful. At present, 3 years after transplant, he is 8 years old and has a normal hemoglobin level and normal RBC PK activity without evidence of hemolysis. DNA analysis has confirmed full engraftment.

Correlation between hematopoietic progenitors and erythroblasts in cord blood.

Erythroid and granulocyte-monocyte progenitors in cord blood were studied, using the methyl cellulose assay. The mean number of progenitors was 12-16 times higher than that of normal adult blood. The number of both erythroid and granulocyte-monocyte progenitors correlated positively with the number of erythroblasts present in cord blood. The possible origin of hematopoietic progenitors in cord blood was discussed.

Glucose intolerance, hyperinsulinemia and insulin resistance in aplastic anemia.

Oral glucose tolerance tests were conducted in 29 patients with aplastic anemia and 20 nondiabetic controls. Seventeen were men and 12 were women, ranging in age from 15 to 67 years. Based on the results of oral glucose tolerance test, the patients were divided into three groups: 14 previously treated cases with normal glucose tolerance; eight previously treated cases with abnormal glucose tolerance, of whom six had diabetes and two had impaired glucose tolerance; and seven newly diagnosed cases with normal glucose tolerance. Hyperinsulinemia and insulin resistance were observed in all patients. Multivariate analyses show that sex, age, body mass index, previous androgen and corticosteroid therapy, previous blood transfusion, initial hemoglobin and white blood cell and serum ferritin concentrations were not significantly related to hyperinsulinemia as expressed by the integrated insulin area under the curve of glucose tolerance test. Patients in the second group who had abnormal glucose tolerance had a delay in insulin secretion in response to glucose, indicating a deterioration of insulin reserve in the beta cells. Patients in this group were significantly older at the time of diagnosis than those in the first group. No other determinants of the development of abnormal glucose tolerance were demonstrated.

High prevalence of hepatitis C viremia among aplastic anemia patients and controls from Thailand.

Aplastic anemia is a rare, life-threatening disease of unknown etiology, with unusually high prevalence in Thailand. It is sometimes associated with non-A, non-B hepatitis (NANBH). The hepatitis C virus (HCV), one of the causes of NANBH, is similar to flaviviridiae, a family of viruses many of whose members cause acute bone marrow suppression. To test the hypothesis that HCV viremia is associated with aplastic anemia among patients in Thailand, we compared 53 untransfused hospitalized aplastic anemia patients and 39 untransfused controls hospitalized for other conditions. We used the polymerase chain reaction to identify HCV viremia in three (5.7%) untransfused patients and two (5.1%) untransfused controls (P = 1.0, by Fisher's two-tailed exact test). Although our data do not exclude the possibility that a small subset of aplastic anemia cases are precipitated by HCV, we conclude that HCV viremia is not generally associated with aplastic anemia in Thailand. Our results also imply that the prevalence of HCV viremia may be unexpectedly high among untransfused persons in Thailand, a hypothesis that should be tested in other populations.

Agranulocytosis in Bangkok, Thailand: a predominantly drug-induced disease with an unusually low incidence. Aplastic Anemia Study Group.

Agranulocytosis, a syndrome characterized by a marked reduction in circulating granulocytes, is strongly associated with medical drug use in Europe and the United States. Unregulated use of common pharmaceutical agents in developing countries has been suspected of causing large numbers of cases of agranulocytosis and deaths, especially among children. To elucidate the incidence and etiology of agranulocytosis in Thailand, a population-based case-control study of symptomatic agranulocytosis that resulted in hospital admission was conducted in Bangkok from 1990 to 1994. An attempt was also made to study the disease in Khonkaen (in northeastern Thailand) and Songkla (in southern Thailand), but there were insufficient cases in the latter regions, and the analysis was confined to subjects from Bangkok. In that region, the overall incidence of agranulocytosis was 0.8 per million per year; there were no deaths. As expected, the incidence was higher in females (0.9 per million), and it increased with age (4.3 per million beyond age 60). Among 25 cases and 529 controls the relative risk estimate for a combined category of all suspect drugs was 9.2 (95% confidence interval = 3.9-21), and the proportion of cases that could be attributed to drug use was 68%. For individual drugs and drug classes the data were sparse; within these limitations, the strongest association appeared to be with antithyroid drugs. One case and three controls were exposed to dipyrone, a drug known to cause agranulocytosis; with such scanty data the risk could not be evaluated. Exposure to pesticides or solvents was not associated with an increased risk. This is the first formal epidemiologic study of agranulocytosis in a developing country. As in the West, most cases are attributable to medical drug use. However, the incidence of agranulocytosis in Bangkok, and apparently, in Thailand as a whole, is unusually low, and the disease does not pose a public health risk.

Epidemiology of aplastic anemia in Thailand. Thai Aplastic Anemia Study Group.

A population-based case-control study of aplastic anemia has been conducted in Thailand since 1989. This is the largest single epidemiologic study of aplastic anemia ever performed. The objectives have been to document the incidence of the disease and to study the etiologic factors in a case-control analysis. The overall incidence of aplastic anemia was 3.9 per million per year in Bangkok, two times higher than in the West; 3.0 per million in Songkla; and 5.0 per million in Khonkaen. A difference appears in the age incidence pattern between Bangkok and the two rural areas, with double incidence peaks at ages 15 to 24 and over 60 in Bangkok, yet a more steady increase in incidence with increasing age in the rural areas. With regard to possible etiologic factors, there is a strong inverse association between incidence of the disease and socioeconomic status as determined by total household income and years of education. There are also significant positive associations with occupational exposure to solvents and agricultural pesticides. Only a few drugs, including thiazide diuretics, sulfonamide, and mebendazole are associated with the disease. There continues to be no evidence of association with chloramphenicol. The etiologic fraction for all associated drugs is lower than 5%. Household pesticide use is not associated with the disease. Exposure to hepatitis A virus is a risk indicator for aplastic anemia and may be a surrogate marker for another enteric infectious agent.

Clinical paroxysmal nocturnal hemoglobinuria is the result of expansion of glycosyl-phosphatidyl-inositol-anchored protein-deficient clone in the condition of deficient hematopoiesis.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired, clonal hematopoietic stem cell disorder in which PIG-A, gene essential for the biosynthesis of the glycosyl-phosphatidyl-inositol (GPI) anchor, is somatically mutated. Absence of GPI-linked proteins from the surface of blood cells is characteristic of the PIG-A mutant (PNH) clone and is also accountable fo certain manifestations, such as intravascular hemolysis. It is unclear how the PNH clone expands and comes to dominate hematopoiesis. In this study, CD34+ cells--committed progenitors (colony-forming cells) representing immature hematopoietic stem cells--and reticulocytes representing the differentiated erythroid cells were quantitated in peripheral blood of patients with PNH. Compared with normal controls (n = 29), CD34+ cell levels were significantly lower in PNH patients who did not have preexisting aplastic anemia (AA) (n = 12) (2.47+/-1.23 versus 4.68+/-1.05 x 106/L, mean +/- standard error; P = .022). PNH patients with precedent aplastic anemia (AA+/PNH) showed markedly low CD34+ cell levels compared with normal control subjects (0.6+/-0.29 versus 4.68+/-1.05 x 10(6)/L; P = .0001). In addition, colony-forming cells from PNH patients were significantly decreased compared with those from normal volunteers (erythroid burst-forming units, 2.8+/-1.2 versu 25.6+/-6.2/5 x 10(5) mononuclear cells; P = .0006; and granulocyte/macrophage colony-forming units, 1.2+/-0.5 versus 13.3+/-3.0/ 5 x 10(5) mononuclear cells; P = .0006). These findings occur in both aplastic and hemolytic types of PNH, suggesting hematopoietic failure in PNH. On the contrary, the numbers of reticulocytes and the reticulocyte production index of PNH patients were significantly higher than those of normal persons and comparable to those from patients with autoimmune hemolytic anemia, indicating accelerating erythropoiesis in PNH. The degree of reticulocytosis correlated well with the proportion of CD59- (PNH) reticulocytes. All of the findings suggest that in the condition of deficient hematopoiesis, the PNH clone arising from the mutated hematopoietic stem cell expands and maintains a substantial proportion of the patient's hematopoiesis.

TT virus infection in Thailand: prevalence in blood donors and patients with aplastic anemia.

Aplastic anemia has been reported to occur after viral hepatitis of unknown etiology. Recently, TT virus (TTV), a novel DNA virus, was identified in a Japanese patient with posttransfusion non-A-E hepatitis. The prevalence of TTV infection was investigated among blood donors and patients with aplastic anemia in Thailand. Of 99 blood samples from blood donors, 37 tested positive for TTV DNA via semi-nested polymerase chain reaction (PCR) using TTV-specific primers. Seventeen percent of samples from blood donors younger than 20 were positive for TTV DNA, whereas 48% from donors older than 20 were positive. The high prevalence of TTV infection in Thailand is comparable to that reported in China (28%), Mongolia (43%), and Egypt (29%). Forty-two percent of newly diagnosed aplastic anemia patients tested also had TTV DNA in blood. The detection rate of TTV DNA in aplastic anemia patients does not differ significantly from rates in normal blood donors. Our present data thus argue against the role of this novel hepatitis-associated virus in the pathogenesis of aplastic anemia in Thailand. However, larger epidemiological studies may be needed to further evaluate their association.