DNA hypermethylation of cell cycle (p15 and p16) and apoptotic (p14, p53, DAPK and TMS1) genes in peripheral blood of leukemia patients.

Aberrant DNA methylation of tumor suppressor genes has been reported in all major types of leukemia with potential involvement in the inactivation of regulatory cell cycle and apoptosis genes. However, most of the previous reports did not show the extent of concurrent methylation of multiple genes in the four leukemia types. Here, we analyzed six key genes (p14, p15, p16, p53, DAPK and TMS1) for DNA methylation using methylation specific PCR to analyze peripheral blood of 78 leukemia patients (24 CML, 25 CLL, 12 AML, and 17 ALL) and 24 healthy volunteers. In CML, methylation was detected for p15 (11%), p16 (9%), p53 (23%) and DAPK (23%), in CLL, p14 (25%), p15 (19%), p16 (12%), p53 (17%) and DAPK (36%), in AML, p14 (8%), p15 (45%), p53 (9%) and DAPK (17%) and in ALL, p15 (14%), p16 (8%), and p53 (8%). This study highlighted an essential role of DAPK methylation in chronic leukemia in contrast to p15 methylation in the acute cases, whereas TMS1 hypermethylation was absent in all cases. Furthermore, hypermethylation of multiple genes per patient was observed, with obvious selectiveness in the 9p21 chromosomal region genes (p14, p15 and p16). Interestingly, methylation of p15 increased the risk of methylation in p53, and vice versa, by five folds (p=0.03) indicating possible synergistic epigenetic disruption of different phases of the cell cycle or between the cell cycle and apoptosis. The investigation of multiple relationships between methylated genes might shed light on tumor specific inactivation of the cell cycle and apoptotic pathways.

ABL kinase domain mutations in patients with chronic myeloid leukemia in Jordan.

Mutations of the BCR-ABL tyrosine kinase domain constitute a major cause of resistance to tyrosine kinase inhibitors in patients with chronic myelogenous leukemia (CML). In this study, we analyzed peripheral blood samples from 185 Jordanian CML patients for ABL mutations, who were on imatinib for a minimum of 6 months regardless of their disease status and over a period of 5 years. Mutations were detected by nested RT-polymerase chain reaction, followed by direct sequencing of the ABL kinase domain. Twelve different point mutations were detected 25 times in 21 patients. The resultant mutations were as follows: four patients have T315I, three of each of the following: L248V, F317L, and G250E, two of each of the following: H396R, M244V, and T277A, and one of each of the following: F311I, M318T, Q252H, F359A, F359I, and Y326H. After patient follow-up, the mutation had disappeared in 12 patients; 3 patients died; 3 patients were not retested; and 3 patients had persistent mutation. The finding of our study is in line with what has been described in the literature. Detecting ABL mutations in chronic phase may lead to positive outcome by modifying treatment.

Relationship of serum imatinib trough level and response in CML patients: long term follow-up.

One hundred and three patients with Philadelphia chromosome or BCR-ABL positive chronic myeloid leukemia (CML) in chronic phase who were on oral imatinib were included in this study. The study aimed to assess the relationship between imatinib trough serum levels and clinical outcome (as determined by molecular response) in Jordanian CML patients who have been on imatinib therapy for at least 12 months. The mean trough imatinib serum level in the group with complete molecular response (CMR) was 2891±856 ng/ml, the group with major molecular response (MMR) was 2337±434 ng/ml, the group with complete cytogenetic response (CCyR) was 1817±563 ng/ml, and the group without CCyR was 1723±673 ng/ml. A receiver operating characteristic (ROC) curve was constructed after dividing patient sample into two groups, those with MMR or better and those without MMR, in order to estimate a threshold for imatinib level that correlates with a favorable response (the former group), and analysis yielded a value of 2158 ng/ml.

Osteonecrosis of jaws related to intravenous bisphosphonates: the experience of a Jordanian teaching hospital.

INTRODUCTION: We describe our experience with oncology patients on a frequent dosing schedule of intravenous (i.v.) bisphosphonates at the Jordan University Hospital (JUH). PATIENTS AND METHODS: Patients treated by i.v. bisphosphonates in the medical oncology unit at the JUH were examined for bisphosphonate-related osteonecrosis of the jaws (BRONJ). Diagnosis was made according to the guidelines of the American Association of Oral and Maxillofacial Surgeons (AAOMS) original position paper. RESULTS: Of the 41 patients, four developed BRONJ, two in maxilla, one in mandible and one bimaxillary. Patients with BRONJ were older; mean age was 69.3 +/- 3.1 years compared to 62.8 +/- 12.5 years (P = 0.022). Dental co-morbidities were more commonly present in patients with the disease (P = 0.038). Patients who developed BRONJ were on treatment for a longer duration of time; the mean duration of treatment was 23.5 +/- 8.4 months compared to 11.9 +/- 13.4 months (P = 0.10). CONCLUSIONS: The results of this case series demonstrated that age and poor oral health status are significant risk factors of BRONJ for oncology patients on long-term frequent dosing schedule of i.v. bisphosphonates.

Brucellosis presenting as myelofibrosis: first case report.

We describe the case of a 29-year-old woman who presented with pancytopenia and myelofibrosis. Brucella melitensis was identified in her blood. The patient recovered completely with doxycycline and rifampin. A repeat bone marrow biopsy showed hypercellularity without myelofibrosis. Bone marrow findings in cases of pancytopenia due to brucellosis reveal normocellularity, hypercellularity, hemophagocytosis, or granuloma. To our knowledge this is the first report of brucellosis causing myelofibrosis. Brucellosis should be considered as a possible cause of myelofibrosis in endemic areas.

Primary myelodysplastic syndrome in Jordan: a single-centre experience.

OBJECTIVE: Study of the disease patterns and clinical evaluation of myelodysplastic syndrome (MDS). SUBJECTS AND METHODS: A retrospective analysis was carried out on 85 patients, with MDS who were followed up over a period of 23 years at Jordan University Hospital, Amman, Jordan. Cases were analyzed according to the French, American and British Classification. RESULTS: Of the 85 patients, 42 (49.4%) were females and 43 (50%) males; mean age was 59 +/- 19 years (range 18-88). Most subtypes found in patients were refractory anemia (RA) in 27 (31.8%) and RA with excess blasts (RAEB) in 28 (32.9%). Adverse prognostic indicators were RAEB subtype and requirement for blood transfusion. CONCLUSION: Our findings showed that MDSs appeared at a younger age and tended to be of the aggressive subtype. Chronic myelomonocytic leukemia subtype seemed to appear dominantly in men.

Comparison of platelet aggregation using light transmission and multiple electrode aggregometry in Glanzmann thrombasthenia.

We examined platelet aggregation in platelet-rich plasma (PRP) and in whole blood in nine patients with Thrombasthenia Glanzmann (TG). In PRP, aggregation was measured by monitoring the changes in light absorbance that occurred in response to adenosine 5-diphosphate (ADP), collagen and ristocetin. To measure platelet aggregation in whole blood, we used multiple electrode Impedance aggregometry using the same aggregating agents. In PRP, the patient's platelets showed defective aggregation in response to ADP, collagen, epinephrine and partially to ristocetin in all patients. In whole blood, platelet aggregation in response to the same aggregating agents showed similar response and appeared to be very similar to that which occurred in PRP. Whole blood impedance aggregometry seems to give similar results to PRP light transmission aggregometry in patients with TG. Multiple electrode aggregometry (MEA) is faster and more convenient to use in these patients.

Risk stratification for venous thromboembolism in hospitalized patients in a developing country: a prospective study.

Venous Thrombo-Embolism (VTE) is a serious complication in hospitalized patients but can be preventable. This prospective study addresses risk factors assessment and the use of heparin in this population. About 2,496 non pediatric patients were admitted to Jordan University Hospital between June 12, 2007 and July 19, 2007. A random sample of 624 patients consisting of every fourth admission was chosen. The stratification of risk factors was assessed using Caprini model and the ACCP score. The mean age of the patients (229 males and 395 females) was 45.34 +/- 18.3 years. More than 80% of the admitted patients were considered at high risk for VTE but heparin was used in only 26% of the patients. The majority of our patients constitute a high-risk population. Implementation of strategies including educational sessions and risk stratification guidelines can reduce the incidence, morbidity, and mortality of VTE especially in developing countries.