Aamer Aleem

The use of preoperative erythropoiesis-stimulating agents (ESAs) in patients who underwent knee or hip arthroplasty: a meta-analysis of randomized clinical trials.

Erythropoiesis-stimulating agents (ESAs) have been used in orthopedic patients to reduce allogeneic blood transfusion (ABT). The purpose of this systematic review of randomized clinical trials is to evaluate the efficacy of preoperative administration of ESAs on hemoglobin level at discharge and frequency of ABT in patients undergoing hip or knee surgery. Pooled results of 26 trials with 3560 participants showed that the use of preoperative ESAs reduced ABT in patients undergoing hip or knee surgery [RR: 0.48, 95% CI: 0.38 to 0.60, P<0.00001]. Hemoglobin mean difference between ESA and control groups was 7.16 (g/L) [95% CI of 4.73 to 9.59, P=0.00001]. There was no difference in the risk of developing thromboembolism between ESA and control groups [RD: 0, 95 % CI: -1%-2%, P=0.95]. ESAs offer an alternative blood conservation method to avoid ABT in patients undergoing hip or knee surgery.

Renal involvement in lymphoma: prevalence and various patterns of involvement on abdominal CT

AbstractObjectiveThe kidney is a frequent site of involvement in lymphoproliferative disorders. The aim of this study was to demonstrate the prevalence and spectrum of morphologic appearances of renal involvement in patients with lymphoma on helical computed tomographic (CT) scan.MethodsThree phases of post-contrast helical CT of the abdomen in 74 patients with lymphoma were reviewed for possible renal involvement: the cortico-medullary, nephrographic and delayed excretory phases. Tumor characteristics, patterns of distribution and enhancement features were evaluated.ResultsOf the 74 patients with lymphoma, 11 had CT evidence of renal involvement—ten with non-Hodgkin’s lymphoma and one with Hodgkin’s lymphoma—representing 15% of all patients scanned for routine staging of histologically diagnosed lymphoma. Five types of renal involvement were observed: enlarged lobular non-enhancing kidneys (four patients); bilateral multiple renal masses (two patients); focal single non-enhancing mass (two patients); perirenal infiltrations from retroperitoneal extension (two patients); bilateral diffuse areas of non-enhancing hypo-densities (one patient).ConclusionFive distinct patterns of renal involvement with lymphoma were detected with helical CT. The most common appearance was enlarged lobular kidneys. CT with intravenous contrast enhancement is currently the approach of choice for both the evaluation of renal involvement as well as for accurate staging of lymphoma. Awareness of different patterns of renal involvement in lymphoma allows proper differentiation from other similar diseases.

Sickle cell disease subphenotypes in patients from Southwestern Province of Saudi Arabia.

Sickle cell disease (SCD) is common in the Eastern and Southwestern (SW) Provinces of Saudi Arabia. We studied 159 patients with SCD to better characterize its phenotype in the SW Province, where patients usually have a HBB haplotype of African origin. All cases had history and examination, chart review, and laboratory testing. Blood tests were obtained during steady state and included: complete blood count, reticulocytes, hemoglobin electrophoresis, lactate dehydrogenase, and G6PD level. HBB haplotype and presence of &agr;-thalassemia were also determined. Frequency of various SCD complications was as follows: painful episodes of variable severity occurred in majority of patients (98%), osteonecrosis (14%), acute chest syndrome (22%), splenic sequestration (23%), gallstones (34%), stroke (7.5%), priapism (2.6%), serious infections (11.5%), and persistent splenomegaly (11%) beyond 5 years of age. No patient had leg ulcer. History of asthma and high steady state white blood cells count were associated with increased risk of acute chest syndrome. Coinheritance of &agr;-thalassemia was associated with a lower frequency of gallstones. Higher fetal hemoglobin level was associated with persistent splenomegaly but not with other complications. Splenic sequestration was more common among males and was associated with lower steady state hemoglobin. SCD phenotype in the SW Province is variable and comparable with African Americans except for the rarity of priapism and the absence of leg ulcers. Fetal hemoglobin level was not associated with SCD vaso-occlusive complications. New genetic modifiers and environmental factors might modulate the phenotype of SCD in Saudi Arabia.

Fetal hemoglobin in sickle cell anemia: Saudi patients from the Southwestern province have similar HBB haplotypes but higher HbF levels than African Americans†

Patients with sickle cell disease (SCD) from the Southwestern (SW) Province of Saudi Arabia have variable fetal hemoglobin (HbF) levels and have HBB gene cluster haplotypes of African origin. We studied 77 patients, aged 17.7 ±10 (range 4-46) years (69% HbS homozygotes and 31% HbS-β 0 thalassemia), to determine the associations of known HbF quantitative trait loci (QTL) with HbF concentration. HBB gene cluster haplotypes were 74% Benin, 22% Bantu, and 4% others. Genotyping Single nucleotide polymorphism (SNPs) in BCL11A, HBS1L-MYB, and OR51B5/6 showed that BCL11A was the sole QTL associated with HbF level. We compared these findings with two studies of African American with SCD. After adjusting for the BCL11A genotype, Saudi cases from the SW Province had HbF levels almost twice that of African Americans (P < 0.0001). When we examined the genetic population structure of the African Americans and Saudi patients using genome-wide data, we found that African Americans were similar to Yoruban, Mandenka, and Bantu Africans while Saudi patients resembled Arab populations. The commonality of HBB haplotypes coupled with the genetic distance between these populations suggests that genetic modifiers remote from the HBB cluster or unknown environmental influences are likely to account for the higher HbF in these Saudi patients.

Five most common prognostically important fusion oncogenes are detected in the majority of Pakistani pediatric acute lymphoblastic leukemia patients and are strongly associated with disease biology and treatment outcome.

BACKGROUND AND OBJECTIVES Acute lymphoblastic leukemia (ALL) is a complex genetic disease involving many fusion oncogenes (FO) having prognostic significance. The frequency of various FO can vary in different ethnic groups, with important implications for prognosis, drug selection and treatment outcome. METHOD We studied fusion oncogenes in 101 pediatric ALL patients using interphase FISH and RT-PCR, and their associations with clinical features and treatment outcome. RESULTS Five most common fusion genes i.e. BCR-ABL t (22; 9), TCF3-PBX1 (t 1; 19), ETV6-RUNX1 (t 12; 21), MLL-AF4 (t 4; 11) and SIL-TAL1 (del 1p32) were found in 89/101 (88.1%) patients. Frequency of BCR-ABL was 44.5% (45/101). BCR-ABL positive patients had a significantly lower survival (43.7±4.24 weeks) and higher white cell count as compared to others, except patients with MLL-AF4. The highest relapse-free survival was documented with ETV6-RUNX1 (14.2 months) followed closely by those cases in which no gene was detected (13.100). RFS with BCR-ABL, MLL-AF4, TCF3-PBX1 and SIL-TAL1 was less than 10 months (8.0, 3.6, 5.5 and 8.1 months, respectively). CONCLUSIONS This is the first study from Pakistan correlating molecular markers with disease biology and treatment outcome in pediatric ALL. It revealed the highest reported frequency of BCR-ABL FO in pediatric ALL, associated with poor overall survival. Our data indicate an immediate need for incorporation of tyrosine kinase inhibitors in the treatment of BCR-ABL+ pediatric ALL in this population and the development of facilities for stem cell transplantation.

HYPOCALCEMIA DUE TO HYPOPARATHYROIDISM IN β-THALASSEMIA MAJOR PATIENTS

BACKGROUND This is a retrospective analysis of case records of β-thalassemia major patients who developed hypoparathyroidism (HPT). The objective of this study was to assess the prevalence of hypoc...

Prognostically Significant Fusion Oncogenes in Pakistani Patients with Adult Acute Lymphoblastic Leukemia and their Association with Disease Biology and Outcome

BACKGROUND AND OBJECTIVES Chromosomal abnormalities play an important role in genesis of acute lymphoblastic leukemia (ALL) and have prognostic implications. Five major risk stratifying fusion genes in ALL are BCR-ABL, MLL-AF4, ETV6-RUNX11, E2A-PBX1 and SIL-TAL1. This work aimed to detect common chromosomal translocations and associated fusion oncogenes in adult ALL patients and study their relationship with clinical features and treatment outcome. METHODS We studied fusion oncogenes in 104 adult ALL patients using RT-PCR and interphase-FISH at diagnosis and their association with clinical characteristics and treatment outcome. RESULTS Five most common fusion genes i.e. BCR-ABL (t 9; 22), TCF3-PBX1 (t 1; 19), ETV6-RUNX1 (t 12; 21), MLL-AF4 (t 4; 11) and SIL-TAL1 (Del 1p32) were found in 82/104 (79%) patients. TCF3-PBX1 fusion gene was associated with lymphadenopathy, SIL-TAL positive patients had frequent organomegaly and usually presented with a platelets count of less than 50 x10(9)/l. Survival of patients with fusion gene ETV6-RUNX1 was better when compared to patients harboring other genes. MLL-AF4 and BCR-ABL positivity characterized a subset of adult ALL patients with aggressive clinical behaviour and a poor outcome. CONCLUSIONS This is the first study from Pakistan which investigated the frequency of 5 fusion oncogenes in adult ALL patients, and their association with clinical features, treatment response and outcome. Frequencies of some of the oncogenes were different from those reported elsewhere and they appear to be associated with distinct clinical characteristics and treatment outcome. This information will help in the prognostic stratification and risk adapted management of adult ALL patients.

Durability and factors associated with long term response after splenectomy for primary immune thrombocytopenia (ITP) and outcome of relapsed or refractory patients.

Splenectomy is the usual form of therapy for immune thrombocytopena (ITP) after steroid failure. We retrospectively studied the data in adult patients who underwent splenectomy for ITP from July 1996 to June 2008 to evaluate the long term responses, clinical and laboratory factors associated with long term responses and outcome of relapsed or refractory patients. Thirty eight patients, 30 (79%) females, with a median age of 23 years (range 15–69), underwent splenectomy. The procedure was laparoscopic in 28 (73.5%) and open in 10 patients. Splenectomy resulted in a response in 34/38 (89.5%) patients and failed in four (10.5%) patients. After a median follow-up of 58 months (range 7–144), 24 (63%) patients had a maintained response without treatment (platelet count of >50 × 109/l). Most of the relapses occurred during the first year but two patients had late relapses. There were procedure-related complications in seven (18.0%) patients but no cases of overwhelming sepsis. Only four relapsed or refractory patients had a platelet count below 50 × 109/l at the last follow-up indicating response to alternative therapies. Responsiveness to steroids before the procedure (p = 0.025) along with a platelet count of ≥150 × 109/l at 4 weeks (p = <0.0001) and a highest platelet count of ≥400 × 109/l at any time post-splenectomy (p = 0.005), were associated with a long term response in univariate analysis. In conclusion, splenectomy remains an effective treatment for ITP after steroid failure in terms of long term responses, and the majority of relapsed or refractory patients respond to alternative therapies.

Chronic myeloid leukemia presenting with extramedullary disease as massive ascites responding to imatinib mesylate

Patients with chronic myeloid leukemia (CML) can develop extramedullary involvement during the course of the illness. This usually occurs during the accelerated phase or blast crisis. We describe a patient who presented with massive ascites probably due to mesenteric/peritoneal infiltration during chronic phase CML. There was an excellent response to imatinib with a complete cytogenetic response and total disappearance of ascites.

Sensitive Detection of Pre-Existing BCR-ABL Kinase Domain Mutations in CD34+ Cells of Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia Patients Is Associated with Imatinib Resistance: Implications in the Post-Imatinib Era

Background BCR-ABL kinase domain mutations are infrequently detected in newly diagnosed chronic-phase chronic myeloid leukemia (CML) patients. Recent studies indicate the presence of pre-existing BCR-ABL mutations in a higher percentage of CML patients when CD34+ stem/progenitor cells are investigated using sensitive techniques, and these mutations are associated with imatinib resistance and disease progression. However, such studies were limited to smaller number of patients. Methods We investigated BCR-ABL kinase domain mutations in CD34+ cells from 100 chronic-phase CML patients by multiplex allele-specific PCR and sequencing at diagnosis. Mutations were re-investigated upon manifestation of imatinib resistance using allele-specific PCR and direct sequencing of BCR-ABL kinase domain. Results Pre-existing BCR-ABL mutations were detected in 32/100 patients and included F311L, M351T, and T315I. After a median follow-up of 30 months (range 8–48), all patients with pre-existing BCR-ABL mutations exhibited imatinib resistance. Of the 68 patients without pre-existing BCR-ABL mutations, 24 developed imatinib resistance; allele-specific PCR and BCR-ABL kinase domain sequencing detected mutations in 22 of these patients. All 32 patients with pre-existing BCR-ABL mutations had the same mutations after manifestation of imatinib-resistance. In imatinib-resistant patients without pre-existing BCR-ABL mutations, we detected F311L, M351T, Y253F, and T315I mutations. All imatinib-resistant patients except T315I and Y253F mutations responded to imatinib dose escalation. Conclusion Pre-existing BCR-ABL mutations can be detected in a substantial number of chronic-phase CML patients by sensitive allele-specific PCR technique using CD34+ cells. These mutations are associated with imatinib resistance if affecting drug binding directly or indirectly. After the recent approval of nilotinib, dasatinib, bosutinib and ponatinib for treatment of chronic myeloid leukemia along with imatinib, all of which vary in their effectiveness against mutated BCR-ABL forms, detection of pre-existing BCR-ABL mutations can help in selection of appropriate first-line drug therapy. Thus, mutation testing using CD34+ cells may facilitate improved, patient-tailored treatment.