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Background. Identification and management of risk factors for stroke following isolated coronary artery bypass grafting (CABG) could potentially lower the risk of such serious morbidity. Methods. We retrieved data for 30-day stroke incidence and perioperative variables for patients undergoing isolated CABG and used multivariate logistic regression to assess the adjusted effect of preoperative hematocrit concentration on stroke incidence. Results. In 2,313 patients (mean age 65.9 years, 73.6% men), 43 (1.9%, 95% CI: 1.4-2.5) developed stroke within 30 days following CABG (74.4% within 6 days). After adjustment for a priori defined potential confounders, each 1% drop in preoperative hematocrit concentration was associated with 1.07 (95% CI: 1.01-1.13) increased odds for stroke (men, OR: 1.08, 95% CI: 1.01-1.16; women, OR: 1.02, 95% CI: 0.91-1.16). The predicted probability of stroke for descending preoperative hematocrit concentration exceeded 2% for values <37% (<37% for men (adjusted OR: 2.39, 95% CI: 1.08-5.26) and <38% for women (adjusted OR: 2.52, 95% CI: 0.53-11.98), with a steeper probability increase noted in men). The association between lower preoperative hematocrit concentration and stroke was evident irrespective of intraoperative transfusion use. Conclusion. Screening and management of patients with low preoperative hematocrit concentration may alter postoperative stroke risk in patients undergoing isolated CABG.

Efforts to optimize the management of patients with β-thalassemia major (TM) continue to expand. Evidence from biomedical research evaluating safe and careful processing measures of blood products, the efficacy and safety of oral iron chelators, and noninvasive techniques for the assessment of iron overload are translated into better patient outcomes. The construction of TM management guidelines facilitated the incorporation of such evidence into practice. However, as several aspects of the management of TM remain controversial or governed by resource availability, a concern regarding potential variations in recommendations made by the different guidelines becomes rational, especially for physicians treating TM patients outside countries where the guidelines were constructed. In this work, we overview currently available guidelines for the management of TM and explore apparent similarities and differences between them. The evaluated guidelines included the Thalassaemia International Federation, US, Canadian, UK, Italian and Australian guidelines. We noted a general consensus for most aspects of management, although some guidelines provided more comprehensive and contemporary recommendations than others. We did not identify differences warranting concern, although minor differences in iron overload assessment strategy and more notable variations in the recommendations for iron chelation therapy were observed., (Copyright © 2013 S. Karger AG, Basel.)

Left ventricular noncompaction (LVNC) is a rare cardiomyopathy with potentially serious outcomes. It results in multiple and excessive trabeculations, deep intertrabecular recesses, and a thickened ventricular myocardium with two distinct layers, compacted and noncompacted. The condition is most commonly congenital; however, acquired forms have also been described. A recent report of LVNC detected in a β-thalassemia twin suggested an association with cardiac siderosis. In a cross-sectional study of 135 transfusion-dependent patients with β-thalassemia (130 major and 5 intermedia, mean age 29.6 ± 7.7 years, 49.6% males) presenting for cardiac iron assessment by magnetic resonance imaging (MRI), we evaluated the prevalence and risk factors for LVNC. None of the patients had neuromuscular or congenital heart disease. Eighteen patients (13.3%; 95% confidence interval [CI] = 8.6-20.1) fulfilled the preassigned strict criteria for LVNC on cardiac MRI. There were no statistically significant differences between patients with and without LVNC with respect to demographics; hemoglobin levels; splenectomy status; systemic, hepatic, and cardiac iron overload indices; hepatic disease and infection studies; or iron chelator type. Patients with LVNC were more likely to have heart failure (adjusted odds ratio = 1.77; 95% CI = 0.29-10.89); although with high uncertainty. Patients with β-thalassemia have a higher prevalence of LVNC than normal individuals. As this finding could not be explained by conventional risk factors in this patient population, further investigation of the underlying mechanisms of LVNC is warranted. This remains crucial for an entity with adverse cardiac outcomes, especially in patients with β-thalassemia where cardiac disease remains a primary cause of mortality., (Copyright © 2012 Wiley Periodicals, Inc.)

Objective: The aim of this work was to determine the role of MRI in interpreting abnormal signals within bones and soft tissues adjacent to tumor bulk of osteosarcoma and Ewing's sarcoma in a pediatric population by correlating MR findings with histopathology., Materials and Methods: Thirty patients met the inclusion criteria, which included (1) osteosarcoma or Ewing's sarcoma, (2) MR studies no more than 2 months prior to surgery, (3) presence of abnormal MR signal surrounding the tumor bulk, (4) pathological material from resected tumor. The patients received standard neoadjuvant chemotherapy. Using grid maps on gross pathology specimens, the abnormal MR areas around the tumor were matched with the corresponding grid sections. Histopathology slides of these sections were then analyzed to determine the nature of the regions of interest. The MR/pathological correlation was evaluated using Mann-Whitney U test and Fisher's exact test., Results: Twenty-seven patients had osteosarcoma and three patients had Ewing's sarcoma. Of the studied areas, 17.4% were positive for tumor (viable or necrotic). There was no statistically significant correlation between areas positive for tumor and age, gender, signal extent and intensity on MRI, or tissue type. There was, however, a statistically significant correlation between presence of tumor and the appearance of abnormal soft tissue signals. A feathery appearance correlated with tumor-negative areas whereas a bulky appearance correlated with tumor-positive regions., Conclusions: MR imaging is helpful in identifying the nature of abnormal signal areas surrounding bone sarcomas that are more likely to be tumor-free, particularly when the signal in the soft tissues surrounding the tumor is feathery and edema-like in appearance.

Despite remarkable advances in understanding cerebrovascular disease attributed to sickle cell anemia, data from other hemoglobinopathies have only recently started to emerge. Several brain magnetic resonance imaging studies confirm a high prevalence of silent ischemic lesions in patients with β-thalassemia intermedia, especially in splenectomized adults who are transfusion-independent and those with elevated platelet counts. Large-vessel disease is also common in this patient population but without apparent association with silent white matter infarcts, leaving smaller arteriolar involvement as a potential explanation. The hypothesized pathophysiology is multifactorial with hypercoagulability and toxicity from free iron species playing major roles. The long-term sequelae of such covert findings is unknown, although experience from patients with sickle cell anemia confirms their association with subsequent overt stroke and neurocognitive deficits. The roles of transfusion and antiplatelet therapy to prevent the occurrence and progression of silent ischemic lesions in patients with β-thalassemia intermedia should be the focus of future trials., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Despite evidence of considerable iron overload in transfusion-independent patients with β-thalassemia intermedia, data on hepatic outcomes remain scarce. We analyzed data from a cohort of 42 β-thalassemia intermedia adults followed for four years (median age 38years), and evaluated the association between longitudinal changes in serum ferritin levels and transient elastography values, a measure of hepatic stiffness predictive of fibrosis. We observed a significant increase in both serum ferritin levels (+81.2 [μg/l]/year) and transient elastography values in non-chelated patients (n=28) (+0.3kPa/year), with two patients worsening their fibrosis stage. Chelated patients (n=14) had a significant decrease in both measures (-42.0 [μg/l]/year and -0.9kPa/year, respectively), with two patients improving their fibrosis stage. There was a strong correlation between the rate of change in serum ferritin level and the rate of change in transient elastography value (R(2): 0.836, p<0.001) noted in both non-chelated and chelated patients. An association between iron overload status and hepatic disease merits further evaluation in this subset of transfusion-independent patients., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Life expectancy of thalassemia patients has markedly improved over the last few decades, but patients still suffer from many complications of their congenital chronic disease, and several new complications are now being acknowledged, including thrombosis. The high prevalence of thromboembolic events, especially in thalassemia intermedia, has led to the identification of a hypercoagulable state in these patients. This review summarizes current knowledge of the clinical and pathophysiological characteristics of hypercoagulability in thalassemia patients. Strategies to prevent thrombotic events are also discussed.

Objective: To determine the effect of fasting during the month of Ramadan on the rate of preterm delivery (PTD)., Design: A prospective cohort study of women with singleton pregnancies who elected to fast and matched controls., Setting: Four medical centres in Beirut, Lebanon., Population: Women presenting for prenatal care (20-34 weeks of gestation) during the month of Ramadan, September 2008., Methods: Data were collected prospectively. The frequency of PTD was evaluated in relation to the duration of fasting and the stage of gestation at the time of fasting., Main Outcome Measures: The primary endpoint was the percentage of pregnant women who had PTD, defined as delivery before 37 completed weeks of gestation., Results: A total of 468 women were approached, of whom 402 were included in the study. There were no differences in smoking history and employment. There was no difference in the proportion of women who had PTD at <37 weeks (10.4% versus 10.4%) or PTD at <32 weeks (1.5% versus 0.5%) in the Ramadan-fasted group and the controls, respectively. The PTD rate was also similar in those who fasted before or during the third trimester. The mean birthweight was lower (3094 ± 467 g versus 3202 ± 473 g, P = 0.024) and the rate of ketosis and ketonuria was higher in the Ramadan-fasted women. On multivariate stepwise logistic regression analysis, fasting was not associated with an increased risk of PTD (odds ratio 0.72; 95% confidence interval 0.34-1.54; P = 0.397). The only factor that had a significant effect on the PTD rate was body mass index (odds ratio 0.43; 95% confidence interval 0.20-0.93; P = 0.033)., Conclusions: Fasting during the month of Ramadan does not seem to increase the baseline risk of preterm delivery in pregnant women regardless of the gestational age during which this practice is observed., (© 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2012 RCOG.)

Although advances in the care of patients with β-thalassemia translate into better patient survival, this success has allowed previously unrecognized complications to emerge, including several renal abnormalities. Clinical studies continue to show that mild tubular dysfunction and abnormalities in GFR are common in patients with β-thalassemia. Chronic anemia and iron overload are believed to lie behind these abnormalities. Nonprogressive increases in levels of serum creatinine have also been observed after exposure to some iron chelators. Longitudinal studies are needed to understand the true burden of renal dysfunction in patients with β-thalassemia.

Background: Thrombotic thrombocytopenic purpura (TTP) is a rare life-threatening disease. Of surviving patients, 45% develops an exacerbation or a late recurrence. Severe ADAMTS-13 deficiency, both during the acute episode and remission, is a well-established predictor of recurrence. The predictive value of anti-ADAMTS-13 antibodies, their inhibitory activity and Ig class subtype for disease recurrence is still to be established., Objectives: To analyze ADAMTS-13-related biomarkers (ADAMTS-13 and anti-ADAMTS-13 immunoglobulins, classes and subclasses) and their potential relationship with prognosis., Patients/methods: In 115 patients with TTP, we assessed the association between levels of these biomarkers and the severity of acute episodes; we analysed also the hazard ratio (HR) and 95% confidence interval (CI) of recurrence in association with biomarkers levels retrieved at the previous acute episode or during remission, using Cox regression models., Results: During the acute phase, higher IgA, IgG1 and IgG3 titers showed the strongest association with acute episode severity. In the survival analyzes, the only biomarker significantly associated with a high hazard of recurrence after an acute episode was the presence of IgG. Conversly, low ADAMTS-13 activity or antigen levels (<10%), the presence of ADAMTS-13 inhibitor or IgG during remission were all significantly associated with a higher hazard of recurrence., Conclusions: Both the Ig class and subclass are of predictive value for acute episode severity in patients with TTP. Although markers that could predict the risk of recurrence in the acute phase are limited, a thorough assessment of ADAMTS-13-related parameters during remission is warranted., (© 2012 International Society on Thrombosis and Haemostasis.)

The quantification of residual plasmatic ADAMTS13 activity in congenital thrombotic thrombocytopenic purpura (TTP) patients is constrained by limitations in sensitivity and reproducibility of commonly used assays at low levels of ADAMTS13 activity, blunting efforts to establish genotype-phenotype correlations. In the present study, the residual plasmatic activity of ADAMTS13 was measured centrally by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (limit of detection = 0.5%) in 29 congenital TTP patients. The results were used to study correlations among ADAMTS13 genotype, residual plasmatic activity, and clinical phenotype severity. An ADAMTS13 activity above 0.5% was measured in 26 (90%) patients and lower levels of activity were associated with earlier age at first TTP episode requiring plasma infusion, more frequent recurrences, and prescription of fresh-frozen plasma prophylaxis. Receiver operating characteristic curve analysis showed that activity levels of less than 2.74% and 1.61% were discriminative of age at first TTP episode requiring plasma infusion < 18 years, annual rate of TTP episodes > 1, and use of prophylaxis. Mutations affecting the highly conserved N-terminal domains of the protein were associated with lower residual ADAMTS13 activity and a more severe phenotype in an allelic-dose dependent manner. The results of the present study show that residual ADAMTS13 activity is associated with the severity of clinical phenotype in congenital TTP and provide insights into genotype-phenotype correlations.

The association between iron overload indices and pathology of the heart and liver in transfusion-dependent patients with β thalassemia major (TM) has been extensively studied. Nonetheless, data on endocrine disease remains limited. This was a cross-sectional study of 382 TM patients treated with regular transfusions and desferrioxamine at the Thalassemia Center in Dubai, UAE. Retrieved data included demographics, splenectomy status, steady-state serum ferritin levels, and the presence of endocrinopathies (diabetes mellitus, hypothyroidism, hypoparathyroidism, and hypogonadism). Multivariate logistic regression analyses were used to determine which variables were independently associated with the occurrence of each endocrinopathy. The mean age of patients was 15.4 ± 7.6 years, with an equal sex distribution. The mean serum ferritin level was 2597.2 ± 1976.8 μg/l. The frequencies of specific endocrinopathies were diabetes mellitus (10.5%), hypothyroidism (6.3%), hypoparathyroidism (10.5%), and hypogonadism (25.9%). On multivariate logistic regression analysis, patients with a serum ferritin level >2,500 μg/l, but not >1,000-2,500 μg/l, were 3.53 times (95% CI 1.09-11.40) more likely to have diabetes mellitus, 3.25 times (95% CI 1.07-10.90) more likely to have hypothyroidism, 3.27 times (95% CI 1.27-8.39) more likely to have hypoparathyroidism, and 2.75 times (95% CI 1.38-5.49) more likely to have hypogonadism compared to patients with a serum ferritin level ≤1,000 μg/l. However, splenectomized patients with serum ferritin levels ≤2,500 μg/l had comparably high rates of all endocrinopathies as patients with serum ferritin levels >2,500 μg/l. Endocrinopathy is common in TM patients treated with desferrioxamine therapy, especially in patients with serum ferritin levels >2,500 μg/l or those splenectomized.

Our understanding of the molecular and pathophysiological mechanisms underlying the disease process in patients with β-thalassemia intermedia has substantially increased over the past decade. Earlier studies observed that patients with β-thalassemia intermedia experience a clinical-complications profile that is different from that in patients with β-thalassemia major. In this article, a variety of clinical morbidities are explored, and their associations with the underlying disease pathophysiology and risk factors are examined. These involve several organs and organ systems including the vasculature, heart, liver, endocrine glands, bone, and the extramedullary hematopoietic system. The effects of some therapeutic interventions on the development of clinical complications are also discussed.

In this issue of Blood, Neufeld and colleagues present promising results on the safety and efficacy of a novel iron chelator for the treatment of transfusional iron overload.

Iron overload due to increased intestinal iron absorption represents an important clinical problem in patients with non-transfusion-dependent thalassemia (NTDT), particularly as they advance in age. Current models for iron metabolism in patients with beta (β)-thalassemia intermedia (TI) suggest that suppression of serum hepcidin results in increased iron absorption and release of iron from the reticuloendothelial system, leading to depletion of macrophage iron, relatively low levels of serum ferritin, and liver iron loading. The clinical consequences of iron overload in patients with NTDT are multifactorial and include endocrinopathy, bone disease, thromboembolism, pulmonary hypertension, cerebrovascular and neuronal damage, liver fibrosis or cirrhosis, and increased risk of hepatocellular carcinoma. Although serum ferritin levels correlate with liver iron concentration (LIC), they underestimate iron load in these patients compared with transfusion-dependent patients with equivalent LIC. Therefore, direct measurement of LIC is recommended with chelation therapy as indicated., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Beta (β)-thalassemia is characterized by a hypercoagulable state and an increased risk of thrombosis, which can result in significant morbidity and mortality. The molecular and cellular mechanisms contributing to hypercoagulability are diverse and include chronic platelet activation, alteration of red blood cell membranes, abnormal expression of adhesion molecules on vascular endothelial cells, and dysregulation of hemostasis. Regular transfusions decrease the risk of thrombosis, whereas splenectomy significantly increases the risk. Splenectomized adults with non-transfusion-dependent thalassemia are also at high risk for ischemic brain damage. Strategies to lower the risk of thrombosis should be considered, including transfusion therapy to raise hemoglobin levels and avoidance or delay of splenectomy., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Beta-thalassemia intermedia (TI) is associated with a variety of serious clinical complications that require proactive and comprehensive management. These include skeletal deformities and osteopenia, compensatory extramedullary hematopoiesis and tumor formation, progressive splenomegaly, a hypercoagulable state resulting in thromboembolic events and pulmonary hypertension, and increased gastrointestinal iron absorption that often results in nontransfusional iron overload and liver damage. Although TI is generally considered a non-transfusion-dependent thalassemia, transfusion therapy may be an important part of the comprehensive management of this disease. This review describes the current state of the art for medical management of TI, with particular focus on the roles of splenectomy, transfusion, and iron chelation therapy., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: The European Network of Rare Bleeding Disorders (EN-RBD) was established to bridge the gap between knowledge and practise in the care of patients with RBDs., Objectives: To explore the relationship between coagulation factor activity level and bleeding severity in patients with RBDs., Patients/methods: Cross-sectional study using data from 489 patients registered in the EN-RBD. Coagulation factor activity levels were retrieved. Clinical bleeding episodes were classified into four categories according to severity., Results: The mean age of patients at data collection was 31 years (range, 7 months to 95 years), with an equal sex distribution. On linear regression analysis, there was a strong association between coagulation factor activity level and clinical bleeding severity for fibrinogen, factor (F) X, FXIII, and combined FV and FVIII deficiencies. A weaker association was present for FV and FVII deficiencies. There was no association between coagulation factor activity level and clinical bleeding severity for FXI. The coagulation factor activity levels that were necessary for patients to remain asymptomatic were: fibrinogen, > 100 mg dL(-1); FV, 12 U dL(-1); combined FV + VIII, 43 U dL(-1); FVII, 25 U dL(-1); FX, 56 U dL(-1) ; FXI, 26 U dL(-1); FXIII, 31 U dL(-1). Moreover, coagulation factor activity levels that corresponded with Grade III bleeding were: undetectable levels for fibrinogen, FV and FXIII, < 15 U dL(-1) for combined FV + VIII; < 8 U dL(-1) for FVI; < 10 U dL(-1) for FX; and < 25 U dL(-1) for FXI., Conclusions: There is a heterogeneous association between coagulation factor activity level and clinical bleeding severity in different RBDs. A strong association is only observed in fibrinogen, FX and FXIII deficiencies., (© 2012 International Society on Thrombosis and Haemostasis.)

Study Design: Literature review., Objective: To present a comprehensive overview of spinal involvement in patients with β-thalassemia, aiming to orient the spinal surgeon to these potentially disabling complications., Summary of Background Data: β-thalassemia, an inherited disorder of hemoglobin synthesis, is the most common monogenetic disease worldwide. Patients with thalassemia major (TM) suffer a severe anemia that requires regular blood transfusions for survival and iron chelation therapy to control transfusional iron overload. Thalassemia intermedia is a phenotype of thalassemia with a milder course and anemia, wherein most patients remain transfusion independent. Spinal involvement related to disease course and treatment is common in patients with thalassemia syndromes, yet it has not been constructively reviewed in the literature., Methods: Potentially relevant studies were identified from an electronic search of MEDLINE (1966 to the second week of May 2010)., Results: In patients with TM, genetic and acquired risk factors lead to osteoporosis, pathologic fractures of the spine, and back pain. Osteoporosis in TM patients is progressive; thus, early diagnosis and treatment are recommended. Bisphosphonates are relatively safe and effective in this patient population. Characteristic intervertebral disc degeneration is also seen in patients with TM who have evidence of severe iron overload or those who receive the subcutaneous iron chelator deferoxamine. Spinal asymmetry and overt scoliosis are common in patients with TM. The prognosis seems favorable, with many patients showing spontaneous resolution without the need for intervention. In patients with thalassemia intermedia, ineffective erythropoiesis drives extramedullary hematopoietic tissue formation, which is mostly evident on magnetic resonance imaging. Paraspinal involvement is of greatest concern because of the associated spinal cord compression. Several treatment options have been described, including transfusion therapy, laminectomy, radiotherapy, and the use of fetal hemoglobin-inducing agents that decrease the hematopoietic drive., Conclusion: Current knowledge supports that spinal involvement in patients with β-thalassemia is common and diverse yet still requires further prospective evaluation.

Covert brain infarction is an emerging concern in patients with β-thalassemia intermedia (TI). We have recently observed a high prevalence (60%) of silent brain infarction on brain magnetic resonance imaging (MRI) in 30 splenectomized adults with TI. In this work, we further evaluate cerebral involvement in the same 30 patients using fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) scanning. The median age was 32 years (range, 18-54 years) with a male to female ratio of 13:17. Nineteen patients (63.3%) had evidence of decreased neuronal function on PET-CT. Involvement was mostly left sided, multiple, and most commonly in the temporal and parietal lobes. Elevated liver iron concentration, beyond 15 mg Fe/g dry weight, characterized patients with decreased neuronal function. The concordance rate between brain MRI and PET-CT for the detection of brain abnormality was only 36.7% (Kappa 0.056, P = 0.757), highlighting that both modalities reveal different types of brain pathology. Decreased neuronal function is a common finding in patients with TI and is associated with iron overload. Moreover, the addition of PET-CT to MRI identifies a greater proportion of TI patients with silent neuroimaging abnormalities.

To evaluate the association between fetal hemoglobin (HbF) levels and morbidity in β-thalassemia intermedia (TI), we analyzed data from 63 untransfused patients who had also never received HbF induction therapy. Patient records were reviewed for any history of 10 predefined morbidities. Laboratory measurements for markers of ineffective erythropoiesis were also obtained. The mean age of patients was 32.1 years, 47.6% were males, and the median HbF level was 37.2%. HbF levels correlated positively with total hemoglobin, yet negatively with growth differentiation factor-15 and non-transferrin-bound iron levels. Median HbF levels were significantly lower in patients with the majority of evaluated morbidities than in those without. There was a strong negative adjusted linear correlation between the HbF level and the total number of morbidities (R(2) = 0.825, P < .001). The HbF threshold of 63.7% had 95.5% sensitivity and 100% specificity for ensuring absence of morbidity. There exists a strong association between HbF levels and morbidity in the subset of untransfused patients with TI.

Objective: Gemcitabine and platinum-based compounds represent the new standard combination therapy for bladder cancer. In this study, we evaluate the efficacy and safety of gemcitabine and carboplatin followed sequentially by paclitaxel in 27 patients with advanced transitional cell carcinoma., Methods: This phase II multicentre study was based on the doublet gemcitabine 800 mg/m2 and carboplatin area under the concentration-time curve 2 on days 1 and 8 every 21 days for 4 cycles, followed sequentially by paclitaxel 60 mg/m(2)/w for 12 consecutive weeks. The disease was assessed after each sequence., Results: Primary tumor was localized in the bladder and renal pelvis in 25 and 2 patients, respectively. Twenty patients completed all 4 cycles of the gemcitabine and carboplatin sequence. Mean number of cycles was 3.5 (range 1 to 4). Toxicities were mainly hematologic, including Grade 3 neutropenia and anemia in 3 patients. OBJECTIVE response was noted in 11 pts (40.7%), including 1 complete response (CR) and 10 partial responses (PR). Three patients had stable disease and 11 progressed. Among the 20 patients, 14 received the second sequence. Mean number of paclitaxel injections was 7 (range 2 to 12). Toxicities were limited to diarrhea and neurotoxicity in 1 patient each. OBJECTIVE response was documented in 6 patients (30%) (3 CR and 3 PR), including the improvement of PR into CR in 2 patients. Median duration of response was 6 months. After a median follow-up of 7 months, 21 patients died and 6 remained alive, including 2 who maintained CR and 1 PR.Sixteen patients had locally advanced disease and 11 had metastatic disease, better prognostic was noticed with patients with locally advanced disease., Conclusion: the sequential approach of treatment for advanced urothelial cancer using gemcitabine and carboplatine followed by paclitaxel seems to be a safer alternative to the combined triplet, but due to the limited number of patients this study failed to improve outcome. Further investigations with larger population are required.

Objective: To evaluate and compare the prevalence and risk factors for anxiety and depression in adults with beta-thalassemia major (TM) and intermedia (TI)., Method: A cross-sectional study of TI and TM patients at a Chronic Care Center in Lebanon. A total of 80 patients agreed to participate (32 TI (median age 24 years) and 48 TM (median age 23 years)). The Beck Depression Inventory (BDI) and State-Trait Anxiety Inventory (STAI) questionnaires were used to assess the depression and anxiety levels of patients, respectively. Data on patient demographics, clinical complications, and socioeconomic status were also collected., Results: Patients with TM had a significantly longer median duration with a known thalassemia diagnosis than patients with TI (p < 0.001). A considerable proportion of patients had depression (35.0%), State (S)-anxiety (22.5%) or Trait (T)-anxiety (36.2%). Patients with TI had a higher median S-anxiety score compared with TM (p = 0.035), although the median T-anxiety and depression scores were similar. On linear regression analysis, the significant association between the thalassemia diagnosis (TM versus TI) and S-anxiety score (beta: 5.740; 95% CI: 0.201 to 11.278; p = 0.042) was no longer observed upon adjustment for the co-variate duration with a known thalassemia diagnosis (beta: 3.162; 95% CI: -2.949 to 9.274; p = 0.306)., Conclusions: A considerable proportion of adult patients with TM and TI show evidence of depression and anxiety. Patients with TI are more liable to state anxiety than TM patients of a similar age, which is attributed to a shorter duration of living with a thalassemia diagnosis.

Background/aims: Renal manifestations have been described in β-thalassemia major and were attributed to transfusional iron overload and chelation therapy. Patients with the milder phenotype, β-thalassemia intermedia (TI), remain largely transfusion and iron chelation independent while enduring a chronic hemolytic anemia and primary iron overload. Data on renal function in patients with TI is lacking., Methods: In this cross-sectional study of 50 TI patients, we evaluated the association of estimated glomerular filtration rate (eGFR) and urinary protein to creatinine (UPr/UCr) ratio with relevant patient, disease and laboratory indices., Results: The median age of patients was 28 years (44% males). The eGFR was >90 ml/min/1.73 m(2) in all patients, with a median value of 142.3 ml/min/1.73 m(2). The median UPr/UCr ratio was 213.2 mg/g. There was a negative correlation between age and eGFR, while the UPr/UCr ratio correlated positively with markers of anemia, hemolysis and iron overload. A total of 24 (48%) patients had evidence of glomerular hyperfiltration, while 7 (14%) had proteinuria (UPr/UCr ratio >500 mg/g). Patients with proteinuria were characterized by elevated liver iron concentration (>7 mg Fe/g dry weight), non-transferrin-bound iron levels and nucleated red blood cell counts., Conclusions: A considerable proportion of TI patients show evidence of abnormally elevated eGFR, with a declining trend towards advancing age. The occurrence of proteinuria is associated with anemia, hemolysis and iron toxicity., (Copyright © 2012 S. Karger AG, Basel.)

Transfusion-independent patients with β thalassemia intermedia (TI) experience a variety of clinical complications attributed to the underlying ineffective erythropoiesis and subsequent anemia, hemolysis, and iron overload. Growth differentiation factor-15 (GDF-15) was recently investigated as a marker of ineffective erythropoiesis in several anemias. In this work, we evaluated GDF-15 levels in 55 patients with TI. The mean GDF-15 level was 25,197.8±16,208.9pg/ml which is lower than values reported for patients with thalassemia major, yet considerably higher than those reported in patients with other congenital and acquired anemias. GDF-15 levels were significantly higher in splenectomized compared to non-splenectomized patients and correlated with anemia, markers of iron overload, and a pre-defined clinical severity score. Further studies are needed to determine the practical utility of GDF-15 measurement and its potential to reflect the severity of the clinical course in TI patients., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objectives: Several studies addressed the association between antibiotic use and breast cancer risk. The objective of this study was to assess the association between antibiotic use and risk of cervical, ovarian, and uterine cancer., Study Design: We carried out a population-based case-control study using data from Saskatchewan Health administrative databases (Canada) between the years 1981 and 2000. Cases were matched to 4 controls, using incidence density sampling. The effect of dosage and timing of antibiotic use, over a minimum of 15 years before diagnosis, on cervical, ovarian, or uterine cancer risk was assessed. Number of prescriptions and number of pills were used as exposure definitions. The effect of different classes of antibiotics on cancer risk was also studied., Results: A total of 1225 cancer cases [192 cervical, 445 ovarian, and 588 uterine] and 4900 matched controls were included in this study. Antibiotic exposure (number of prescriptions) during the period of 1-15 years in the past was significantly associated with a reduced risk of cervical cancer; Relative Risk (RR)=0.40, 0.31, 0.26, and 0.29 for the four exposure quartiles, respectively. No association was found for ovarian or uterine cancer. When number of pills was considered, similar results were found. There was no effect of the timing or class of antibiotic exposure on cervical cancer risk., Conclusions: Antibiotic exposure up to 15 years in the past was associated with a decreased risk of cervical cancer. The lack of temporal trends and the absence of class specific effects suggest a non-causal relationship., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background:  Hypercoagulability and venous thromboembolism are common in patients with β-thalassemia intermedia (TI), especially in the splenectomized adult. Although arterial involvement is not commonly reported, we have recently observed a high prevalence (60%) of silent brain infarction on brain MRI in 30 splenectomized adults with TI. The pathophysiology of these white matter lesions remains unknown., Methods: In this prospective work, we evaluated magnetic resonance angiography (MRA) scans of the same cohort of 30 patients. Data collected were the presence or absence of vascular lesions, their locations, and severity. Correlations between MRA abnormality and patients/disease characteristics were evaluated. Comparisons between MRA and previous MRI findings were made., Results: Of 29 evaluable patients, 8 (27.6%) had evidence of arterial stenosis on MRA. The majority of lesions had mild narrowing and mostly involved the internal carotid artery. Five patients (17.2%) had evidence of aneurysms. Low total hemoglobin and high non-transferrin-bound iron levels independently characterized patients with evidence of stenosis on MRA. Among the 18 patients with silent brain infarction on MRI, three had evidence of stenosis on MRA with only one patient having lesions that could explain the silent infarcts., Conclusions: Cerebral vasculopathy is common in splenectomized adults with TI. However, large-vessel disease does not explain the occurrence of silent brain infarction. The combined use of MRA and MRI better identifies splenectomized TI adults with neuroimaging abnormalities., (© 2011 John Wiley & Sons A/S.)

Background: Pulmonary hypertension (PHT) is a common yet poorly understood complication of β thalassemia intermedia (TI)., Methods: We herein evaluated risk factors for PHT in TI, through comparing 64 TI patients with evidence of PHT by symptomatology and echocardiography (Group I) to age- and sex-matched TI patients without PHT (Group II). Retrieved data included demographics, laboratory parameters, clinical characteristics, and received treatments that may influence PHT development; and reflected the period prior to PHT occurrence in Group I., Results: The mean age of Group I patients at development of PHT was 37.3±10.6years; with 44% being males. Among studied parameters, Group I patients were more likely to be splenectomized (4.9-times), transfusion-naive (3.5-times); hydroxyurea-naive (2.6-times), or iron chelation-naive (2.3-times); and have nucleated red blood cell count ≥300×10(6)/l (2.59-times) or a previous history of thromboembolic events (3.69-times)., Conclusion: TI patients who eventually develop PHT may be identified early on by being splenectomized, having high nucleated red blood cell counts and a previous history of thromboembolism. Prospective clinical trials that evaluate the efficacy, safety, and cost effectiveness of transfusion, iron chelation, and hydroxyurea therapy in preventing PHT in TI are invited., (Copyright © 2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Background: Patients with β thalassemia intermedia can have substantial iron overload, irrespectively of their transfusion status, secondary to increased intestinal iron absorption. This study evaluates whether iron overload in patients with β thalassemia intermedia is associated with morbidity., Design and Methods: This was a cross-sectional study of 168 patients with β thalassemia intermedia treated at two centers in Lebanon and Italy. Data on demographics, splenectomy status, transfusion status, and presence of co-morbidities were retrieved. Laboratory values of serum ferritin, fetal and total hemoglobin levels, as well as platelet and nucleated red blood cell counts were also obtained. Iron burden was determined directly by measuring liver iron concentration using magnetic resonance imaging. Patients were subdivided according to transfusion and splenectomy status into groups with phenotypes of different severity., Results: The mean age of the patients was 35.2 ± 12.6 years and 42.9% of them were male. The mean liver iron concentration was 8.4 ± 6.7 mg Fe/g dry weight. On multivariate logistic regression analysis, after adjusting for age, gender, splenectomy status, transfusion status, and laboratory indices, an increase in 1 mg Fe/g dry weight liver iron concentration was independently and significantly associated with higher odds of thrombosis, pulmonary hypertension, hypothyroidism, osteoporosis, and hypogonadism. A liver iron concentration of at least 7 and at least 6 mg Fe/g dry weight were the best thresholds for discriminating the presence and absence of vascular and endocrine/bone morbidities, respectively (area under the receiver-operating characteristic curve: 0.72, P<0.001). Elevated liver iron concentration was associated with an increased rate of morbidity in patients with phenotypes of all severity, with a steeper increase in the rate of vascular morbidity being attributed to aging, and an earlier appearance of endocrine and bone disease., Conclusions: Elevated liver iron concentration in patients with β thalassemia intermedia is a marker of increased vascular, endocrine, and bone disease.

Background: Preoperative anaemia is associated with adverse outcomes after cardiac surgery but outcomes after non-cardiac surgery are not well established. We aimed to assess the effect of preoperative anaemia on 30-day postoperative morbidity and mortality in patients undergoing major non-cardiac surgery., Methods: We analysed data for patients undergoing major non-cardiac surgery in 2008 from The American College of Surgeons' National Surgical Quality Improvement Program database (a prospective validated outcomes registry from 211 hospitals worldwide in 2008). We obtained anonymised data for 30-day mortality and morbidity (cardiac, respiratory, CNS, urinary tract, wound, sepsis, and venous thromboembolism outcomes), demographics, and preoperative and perioperative risk factors. We used multivariate logistic regression to assess the adjusted and modified (nine predefined risk factor subgroups) effect of anaemia, which was defined as mild (haematocrit concentration >29-<39% in men and >29-<36% in women) or moderate-to-severe (≤29% in men and women) on postoperative outcomes., Findings: We obtained data for 227,425 patients, of whom 69,229 (30·44%) had preoperative anaemia. After adjustment, postoperative mortality at 30 days was higher in patients with anaemia than in those without anaemia (odds ratio [OR] 1·42, 95% CI 1·31-1·54); this difference was consistent in mild anaemia (1·41, 1·30-1·53) and moderate-to-severe anaemia (1·44, 1·29-1·60). Composite postoperative morbidity at 30 days was also higher in patients with anaemia than in those without anaemia (adjusted OR 1·35, 1·30-1·40), again consistent in patients with mild anaemia (1·31, 1·26-1·36) and moderate-to-severe anaemia (1·56, 1·47-1·66). When compared with patients without anaemia or a defined risk factor, patients with anaemia and most risk factors had a higher adjusted OR for 30-day mortality and morbidity than did patients with either anaemia or the risk factor alone., Interpretation: Preoperative anaemia, even to a mild degree, is independently associated with an increased risk of 30-day morbidity and mortality in patients undergoing major non-cardiac surgery., Funding: Vifor Pharma., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Tumor growth and metastasis are dependent on angiogenesis. Inhibiting angiogenesis has therapeutic potentials for treating cancer. Researchers have identified many of the pathways involved in angiogenesis and proposed selective targeted strategies. A high probability of benefit is desirable to justify the choice of anti-angiogenic therapy from an ever-expanding list of expensive new anticancer agents. However, biomarkers of response to anti-angiogenic agents are inconclusive for predicting benefit from these drugs. This paper reviews the most important biomarker of angiogenesis, namely VEGF, in relation to its expression in cancer and the treatment of these cancers through targeting VEGF and its pathways., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Chronic transfusional iron overload leads to significant morbidity and mortality in patients with β-thalassemia major. The once-daily oral iron chelator, deferasirox, opened new horizons for the management of transfusional siderosis. A large body of evidence is now available regarding its efficacy and safety. Nevertheless, some patients remain unresponsive or intolerant to the adverse events of the drug. Chang et al. evaluated the benefit of twice-daily dosing in this setting. The authors concluded that twice-daily deferasirox improves responsiveness and tolerability. Even though the study included only a small number of patients, it offers promising insights that should be interpreted with caution.

In the STOP II trial, discontinuation of prophylactic transfusions in high risk children with sickle cell disease (SCD) resulted in a high rate of reversion to abnormal blood-flow velocities on transcranial Doppler (TCD) ultrasonography and strokes. We analyzed data from STOP II to determine the effect of discontinuing transfusions on the development or progression of silent brain infarcts on magnetic resonance imaging (MRI). At study entry, 21 of 79 (27%) patients had evidence of silent infarcts. There were no statistically significant differences in baseline characteristics between patients with normal brain MRI or silent infarcts at study entry. At study end, 3 of 37 (8.1%) patients in the continued-transfusion group developed new brain MRI lesions compared with 11 of 40 (27.5%) in the transfusion-halted group (P = .03). The total number of lesions remained essentially unchanged decreasing from 25 to 24 in the continued-transfusion group while increasing from 27 to 45 in transfusion-halted patients. Thus, discontinuation of transfusions in children with SCD and abnormal TCD who revert to low-risk increases the risk of silent brain infarction. Together with data from STOP, these findings demonstrate that transfusions prevent the development of silent infarcts in patients with SCD and abnormal TCD but normal MRA.

Background: In patients with β thalassaemia intermedia (TI), the milder anaemia and transfusion independence imply better health-related quality of life (HR-QoL). However, the unbalanced pathophysiology of the disease allows for several serious clinical complications to manifest, which may have a negative impact on HR-QoL., Methods: This was a cross-sectional study on adult patients with transfusion- and iron chelation-independent TI and β thalassaemia major (TM) attending the Chronic Care Center, Hazmieh, Lebanon. A total of 80 patients agreed to participate in the study [32 TI (median age 24 yr) and 48 TM (median age 23 yr)]. The RAND SF-36 survey was used to assess HR-QoL. Data on patient demographics, clinical complications and socioeconomic status were collected., Results: Patients with TI and TM were comparable with age and gender, but patients with TM had a significantly longer median duration with a known thalassaemia diagnosis. Patients with TI had a higher proportion of multiple complications. Socioeconomic parameters were comparable, except for patients with TI being more commonly married. The mean Total, Physical Health and Mental Health Scores were significantly lower in patients with TI compared to TM, indicating poorer HR-QoL. There was a statistically significant positive correlation between the duration with a known thalassaemia diagnosis and a higher Mental Health Score (r(s) = 0.73, P = 0.020). The mean Physical Health Score was significantly lower in patients with multiple clinical complications compared to patients with single or no complications (P = 0.012). Associations remained independently significant at multivariate analysis., Conclusion: Patients with transfusion-independent TI have lower HR-QoL compared to TM patients. At a comparable age, the shorter duration since diagnosis and the multiplicity of complications may explain these findings., (© 2011 John Wiley & Sons A/S.)

Background: Unlike patients with β-thalassaemia major, where lifelong transfusion and iron chelation therapy are necessary for survival, patients with β-thalassaemia intermedia (TI) generally have a milder course and anaemia. The underlying pathophysiology of the disease still allows several complications to manifest. Surgical management during the course of the disease is common but relevant data from the literature have never been reviewed constructively. This aim of this review was to highlight this clinical entity to the surgeon, and ensure optimal and timely intervention., Methods: The review was based on potentially relevant studies identified from an electronic search of MEDLINE and PubMed databases. There were no language or publication year restrictions. References in published articles were also reviewed., Results: Surgical intervention is often essential to ensure optimal control of the associated morbidity in TI. Several general considerations are necessary before surgical intervention with regard to anaemia, cardiovascular disease, thromboembolic events and the effects of iron overload. Splenectomy, cholecystectomy, leg ulcers, fractures and extramedullary pseudotumours are the most commonly encountered surgical problems related to TI., Conclusion: Awareness of TI and its associated morbidity is important so that appropriate preoperative care can occur., (Copyright © 2011 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

The value of nontransferrin-bound iron (NTBI) as an index of iron overload in patients with thalassemia has been evaluated; however, data in patients with sickle cell disease (SCD) is limited. NTBI levels were evaluated in a cross-sectional study of 43 transfused patients with SCD. Patient charts were reviewed for demographics, status of the spleen, and total number of lifetime transfusions. All patients were chelation naïve and none of the patients had evidence of hepatitis B or C infection. Blood samples were taken for assessment of NTBI and serum ferritin (SF); liver iron concentration (LIC) was determined by R2 magnetic resonance imaging. NTBI levels were generally low with a median of -0.01 μm (range -2.56 to 6.37 μm). Among study variables, NTBI levels were only significantly correlated to age and total number of lifetime transfusions, whereas LIC and SF only significantly correlated with total number of lifetime transfusions. On multivariate analysis, only total number of lifetime transfusions remained independently correlated with NTBI (P = 0.001), SF (P < 0.001), and LIC (P < 0.001). On multivariate stepwise linear regression analysis, SF was a better predictor of LIC than NTBI. In transfused patients with SCD, NTBI levels are low yet correlate significantly with transfusion burden. However, they offer poor predictability of LIC when compared with SF., (© 2010 Blackwell Publishing Ltd.)

Our understanding of the molecular and pathophysiological mechanisms underlying the disease process in patients with β thalassaemia intermedia (TI) has substantially increased over the past decade. The hallmark of disease process in patients with TI includes ineffective erythropoiesis, chronic haemolytic anaemia, and iron overload. There are a number of options currently available for managing patients with TI including splenectomy, transfusion therapy, iron chelation therapy, modulation of fetal haemoglobin production, and several other agents targeting specific clinical complications. Limited studies assessed the efficacy and safety of these modalities; hence, there are currently no clear guidelines for managing patients with TI. Until solid evidence-based guidelines are available, individualised treatment should be entertained., (© 2011 Blackwell Publishing Ltd.)

Increased survival in patients with β thalassemia major (TM) allowed for several complications of the disease and its treatment to manifest, one of which is bone disease. Osteoporosis in this patient population results from a variety of genetic and acquired factors. Early diagnosis and prevention are essential and several measures have been evaluated for management including bisphosphonates. Fracture prevalence in TM patients seems to be clustered in mid adulthood, and is related to vitamin D deficiency and low bone mineral density. Fracture healing in patients with TM does not seem to be different from that in normal individuals. Bone and joint pain are a common manifestation of the underlying pathophysiology or may be related to iron chelator intake. Intervertebral disc changes are seen in patients who are heavily iron overloaded or those who are chelated with deferoxamine. Spinal deformity is common in TM, yet the prognosis is benign with spontaneous resolution frequently observed. Further research is warranted to evaluate the mechanisms, clinical implications, and optimal management of bone disease in this patient population., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Over the last four decades, monumental advances have been made in the understanding, assessment, and management of transfusion-dependent patients, which have translated into significant improvements in patient morbidity and mortality. Important lessons have been learned from extensive clinical experience of iron management in the thalassemias, but greater knowledge of key differences in the sickle-cell disease (SCD) population may impact on our approach to patient assessment and management. The unique pathophysiology of SCD is reflected in a distinct pattern of iron loading with minimal organ-specific injury. An appreciation and understanding of these differences should allow us to develop tailored management approaches that optimize patient outcomes., (Copyright © 2010 Wiley-Liss, Inc.)

Introduction: Despite increasing evidence on the roles of aspirin and clopidogrel in decreasing morbidity and mortality from cardiovascular disease, resistance to therapy remains an emerging clinical entity. The aim of this review was to revisit current knowledge of the mechanisms, laboratory evaluation, clinical impact and management of resistance to aspirin and clopidogrel therapy., Methods: Potentially relevant studies were identified from an electronic search of MEDLINE and PubMed databases. There were no language or publication year restrictions. References in published articles were also reviewed., Results: Several definitions for resistance have been set, and various laboratory testing modalities are available. The pathophysiological mechanisms remain poorly understood; yet, several extrinsic, intrinsic and genetic factors are described. The clinical implications of this phenomenon are alarming and warrant concern. Management is currently limited to dosing alteration and introduction of other antiplatelet agents., Conclusion: Data from ongoing and future studies are awaited to better understand this entity and to highlight the most appropriate treatment strategies., (© 2010 Blackwell Publishing Ltd.)