Overexpression of survivin levels in circulation and tissue samples of lung cancer patients.

BACKGROUND: Survivin, an apoptosis inhibitor protein, has multiple functions that favor cancer cell survival. We sought to determine survivin levels in blood samples and biopsies from patients with lung cancer compared to normal individuals and healthy lung tissues respectively. PATIENTS AND METHODS: Blood samples were obtained from 32 patients with non-small cell lung cancer (NSCLC) and 49 healthy individuals. Tissue samples were also collected, 15 NSCLC biopsies and 15 histopathologically normal lung tissues. For quantitative evaluation of survivin mRNA expression levels, the hybridization polymerase chain reaction (PCR) method was used. RESULTS: Overexpression of survivin was detected in all malignant samples. In spindle carcinomas survivin expression levels were higher than in adenocarcinomas (p=0.009) and squamous carcinomas (p=0.026). In moderately-differentiated tumors, survivin levels were higher compared to poorly differentiated ones. (p=0.0054). Disease's stage was not associated with survivin expression in blood and biopsies from patients with NSCLC. CONCLUSION: Survivin is overexpressed in blood and tissue of patients with NSCLC and is associated with histological type and tumor grade.

Effect of deferiprone or deferoxamine on right ventricular function in thalassemia major patients with myocardial iron overload.

BACKGROUND: Thalassaemia major (TM) patients need regular blood transfusions that lead to accumulation of iron and death from heart failure. Deferiprone has been reported to be superior to deferoxamine for the removal of cardiac iron and improvement in left ventricular (LV) function but little is known of their relative effects on the right ventricle (RV), which is being increasingly recognised as an important prognostic factor in cardiomyopathy. Therefore data from a prospective randomised controlled trial (RCT) comparing these chelators was retrospectively analysed to assess the RV responses to these drugs. METHODS: In the RCT, 61 TM patients were randomised to receive either deferiprone or deferoxamine monotherapy, and CMR scans for T2* and cardiac function were obtained. Data were re-analysed for RV volumes and function at baseline, and after 6 and 12 months of treatment. RESULTS: From baseline to 12 months, deferiprone reduced RV end systolic volume (ESV) from 37.7 to 34.2 mL (p=0.008), whilst RV ejection fraction (EF) increased from 69.6 to 72.2% (p=0.001). This was associated with a 27% increase in T2* (p<0.001) and 3.1% increase in LVEF (p<0.001). By contrast, deferoxamine showed no change in RVESV (38.1 to 39.1 mL, p=0.38), or RVEF (70.0 to 69.9%, p=0.93) whereas the T2* increased by 13% (p<0.001), but with no change in LVEF (0.32%; p=0.66). Analysis of between drugs treatment effects, showed significant improvements favouring deferiprone with a mean effect on RVESV of -1.82 mL (p=0.014) and 1.16% for RVEF (p=0.009). Using regression analysis the improvement in RVEF at 12 months was shown to be greater in patients with lower baseline EF values (p<0.001), with a significant difference in RVEF of 3.5% favouring deferiprone over deferoxamine (p=0.012). CONCLUSION: In this retrospective analysis of a prospective RCT, deferiprone monotherapy was superior to deferoxamine for improvement in RVEF and end-systolic volume. This improvement in the RV volumes and function may contribute to the improved cardiac outcomes seen with deferiprone.

Prevention of cardiomyopathy in transfusion-dependent homozygous thalassaemia today and the role of cardiac magnetic resonance imaging.

Transfusion and iron chelation therapy revolutionised survival and reduced morbidity in patients with transfusion-dependent beta thalassaemia major. Despite these improvements, cardiac disease remained the most common cause of death in those patients. Recently the ability to determine the degree of cardiac iron overload, through cardiac magnetic resonance imaging (CMR) has allowed more logical approaches to iron removal, particularly from the heart. The availability of two oral chelators, deferiprone and deferasirox has reduced the need for the injectable chelator deferrioxamine and an additional benefit has been that deferiprone has been shown to be more cardioprotective than deferrioxamine. This review on the prevention of cardiac disease makes recommendations on the chelation regime that would be desirable for patients according to their cardiac iron status as determined by CMR determined by CMR. It also discusses approaches to chelation management should CMR not be available.

Effects of combined deferiprone and deferoxamine chelation therapy on iron load indices in beta-thalassemia.

The benefits of combined deferoxamine (DFO) and deferiprone (L1) chelation therapy, focusing on reducing myocardial iron loading, have been widely reported. Herein, we present the efficacy of combined chelation and its effects on iron load indices. Five thalassemia major (TM) patients who were undergoing chelation monotherapy with DFO were enrolled. Inclusion criteria were magnetic resonance imaging (MRI) T2* values, indicating serious heart and/or liver transfusional hemosiderosis. Combined therapy was started with the same dose of DFO and the addition of L1. The MRI T2* studies were repeated 18 months later. An Echo-Doppler study was performed in order to further evaluate the left ventricular (LV) systolic function. Within the 18 months' follow-up period, there was a significant statical decrease in mean serum ferritin levels. All patients increased their MRI T2* liver values, while two patients with very low MRI T2* also increased their myocardial values. The MRI ejection fraction (EF) and Echo-Doppler study measurements confirmed the improvement of systolic function. No adverse effects were reported. Combined L1 and DFO therapy seems to be effective in reducing iron excess in organ iron overloaded thalassemic patients. Magnetic resonance imaging can accurately quantify iron load, while echocardiography remains a reliable monitoring technology.

Congestive heart failure and treatment in thalassemia major.

The homozygous beta-thalassemias are a group of genetically inherited hemoglobin (Hb) disorders characterized by dyserythropoietic anemia. According to the degree of anemia, two main forms, sharing a common basic molecular mechanism, are distinguished: thalassemia major (TM) and thalassemia intermedia (TI). The severity of the clinical phenotype differentiates the two forms. Thalassemia major usually presents as a severe anemia requiring life-long transfusion therapy for survival. The dramatic improvement in life expectancy of beta-thalassemia (thal) patients achieved during the past few decades by virtue of therapeutic advances, has motivated investigators' interest in a better understanding of the clinical consequences of this genetic defect. Heart complications still represent the leading cause of mortality from the disease. The mechanisms of cardiac injury along with its treatment and prevention have attracted the main research efforts in this field. In this review, we present existing knowledge and our personal experience of 30 years of follow-up of over 1,000 thalassemic patients, regarding the basis of the cardiac injury, the clinical findings and the global strategy of the therapeutic intervention in TM patients who develop congestive heart failure (CHF).

The heart in transfusion dependent homozygous thalassaemia today--prediction, prevention and management.

Cardiac disease remains the major cause of death in thalassaemia major. This review deals with the mechanisms involved in heart failure development, the peculiar clinical presentation of congestive heart failure and provides guidelines for diagnosis and management of the acute phase of cardiac failure. It emphasizes the need for intensive medical--cardiac care and aggressive iron chelating management as, with such approaches, today, the patients outcomes can be favourable in the long term. It covers advances in the assessment of cardiac iron overload with the use of magnetic resonance imaging and makes recommendations for preventing the onset of cardiac problems by tailoring iron chelation therapy appropriate to the degree of cardiac iron loading found.

Intervertebral disc calcification in thalassemia intermedia.

OBJECTIVES: Intervertebral disc calcification, an age-related phenomenon of variable clinical significance is described in hemochromatosis. As beta-thalassemia is characterized by excessive tissue iron deposition and secondary hemosiderosis, and skeletal abnormalities are often observed in these patients, this study is conducted to identify the prevalence of Intervertebral Disc Calcification (IDC) in thalassemia intermedia population. METHODS: We investigated all the elder than 30 years beta-thalassemia intermedia patients of our Department thalassemia unit. Patients underwent thoracic and lumbar spinal X-rays for IDC presence. Patients presenting IDC were compared to those not presenting, regarding back pain anamnesis, presence of back pain, extramedullary hemopoiesis, sex, age, Hb levels, ferritin levels, reticulocytes, bilirubin values, thyroid-parathyroid abnormalities. Student's t-test was used to compare variables between patients with and without IDC. A P-value under 0.05 was considered statistically significant. RESULTS: We investigated 30 beta-thalassemia intermedia patients (19 women) with an age range 38-61 yr (42.5 +/- 11.46 yr). Intervertebral disc calcifications were observed in seven patients (23.33%). No sex and laboratory parameters statistically significant differences were observed differences for IDC prevalence, while mean age and back pain history was statistically significantly different between the two groups. CONCLUSIONS: In thalassemia patients, the big variety of spinal deformities may hide the presence of IDC and thus, this entity may be overlooked or underestimated. The clinical significance of IDC development as well as the possible prevention by early transfusion chelation therapy should be further investigated.

Intensive chelation therapy in beta-thalassemia and possible adverse cardiac effects of desferrioxamine.

Combination chelation therapy with desferrioxamine and deferiprone has recently been suggested as a more effective tissue iron-chelating treatment for transfusion-dependent beta-thalassemia patients, although a standard dosage protocol has not yet been established. We describe a thalassemia major patient who had been treated with combination therapy with desferrioxamine and deferiprone and who was referred to us for faintness and dizziness associated with electrocardiographic ST-T changes and arrhythmia. A brief interruption of the treatment and a subsequent decrease in the drug doses caused the reversion of symptoms and findings. This response prompted us to speculate that a causal relationship existed between the observed abnormalities and the intensive chelation therapy. The possibility of this electrical instability as an adverse cardiac event occurring in the context of treatment with these chelating agents raises questions about the time of application of this therapy, the regimen dosages, and follow-up of such patients.

Comparison of echocardiographic (US) volumetry with cardiac magnetic resonance (CMR) imaging in transfusion dependent thalassemia major (TM).

BACKGROUND: Despite advances in survival in patients with thalassemia major (TM) the most common cause of death is cardiac disease. Regular cardiac follow-up is imperative in order to identify and reverse pathology. Cardiac Magnetic Resonance (CMR) and Echocardiography (US) are applied in parallel to TM patients for cardiac evaluation and ongoing monitoring. A comparison between mutual features would be useful in order to assess the accuracy and reliability of the two methods, with a particular focus on routine US application. TM's special attributes offer an excellent opportunity for cardiac imaging research that has universal general purpose applications. METHODS: 135 TM patients underwent US (Teichholz's M-mode formula - rapidly accessible means of measuring volumes and ejection fraction) and CMR volumetry. Paired-samples t-test, Passing & Badlock regression and Bland & Altman plot were used while comparing the common parameters between the CMR and the US. RESULTS: We found that the US volumes were underestimated, especially the end-diastolic volume (p < 0.001). The end-systolic volume showed a borderline two-tailed probability (p approximately 0.05). The correlation for the ejection fraction was acceptable (r = 0.60) without a statistically significant difference (p = 0.37) and the Bland Altman plot range was narrow (25.8%). There was a satisfactory correlation of the US' shortening fraction with CMR's ejection fraction (r = 0.58). CONCLUSION: In cases where cardiac wall movement abnormalities are absent, the US Teichholz's M-mode formula for volume measurements, though less sophisticated in comparison to the high resolution CMR technique, offers an adequate ejection fraction estimation for routine use, especially when monitoring gross alterations in cardiac function over time, and is easy to perform.

Thalassemia intermedia today: should patients regularly receive transfusions?

BACKGROUND: beta-Thalassemia is an inherited hemoglobin disorder characterized by reduced synthesis of beta-globin chain. The severity of clinical course distinguishes this heterogeneous disease in two main subtypes: thalassemia major (TM) and thalassemia intermedia (TI). TI has a later clinical onset with a milder anemia that does not require transfusions at least during the first few years of life. The clinical picture of TI patients who have not received transfusions or have occasionally received transfusions is dominated by the consequences of chronic hemolytic anemia, tissue hypoxia, and their compensatory reactions, such as bone deformities and fractures, extramedullary hemopoiesis, spleen and liver enlargement, hypercoagulability, and pulmonary hypertension. These complications, especially the latter two, are getting more frequent and severe over the years. Nowadays, although TI patients have almost no changes in the course of the disease, well-treated TM patients with regular transfusion-chelation therapy showed suppression of the anemia-related disorders in parallel to prolongation of life. The new oral iron chelators and the magnetic resonance imaging application for early detection of heart iron load are promising for further improvement on survival. CONCLUSIONS: Considering the current cost-benefit balance of regular treatment in TM as well as the frequency and severity of complications in TI, it seems that the majority of TI patients will be benefited if this kind of treatment is applied targeting prevention and not palliation of the anemia-induced complications.

Cardiac magnetic resonance imaging R2* assessments and analysis of historical parameters in patients with transfusion-dependent thalassemia.

Recent advances in magnetic resonance imaging (MRI) techniques allow the assessment of iron overload in tissues 1 especially the heart, 2 in transfusion-dependent thalassemia patients. The R2* value (1/T2*) recorded in the intraventricular septum of the heart indirectly measures the degree of cardiac iron load. Applying this new technology we looked at a number of historical and biochemical parameters in order to determine their relationship to cardiac iron overload and the effect of cardiac iron on functional and structural changes of the heart in transfusion-dependent thalassemics.

Predictive echo-Doppler indices of left ventricular impairment in B-thalassemic patients.

Early detection of cardiac-function impairment by echo-Doppler indices can assist in preventing further cardiac damage by modifying disease progression and treatment. We analyzed our thalassemia major patients database with 10 years cardiac follow-up. Included patients were under constant therapy and should have an initial echo-Doppler study with normal Shortening Fraction (SF > 30%) and reexamination within the last year. We identified patients who developed impaired left ventricular (LV) function in the last Echo and we attempted to find which measured indices could predict LV function impairment. Three hundred fifteen of the 632 database patients were enrolled. Twelve of them developed LV systolic dysfunction. There were no statistically significant differences in mean age, ferritin, and pretransfusion hemoglobin levels of the two groups. LV-systolic-dysfunction group was presenting statistically significantly higher LF end-systolic diameter (LVESD) index, lower SF, higher early transmitral peak flow velocities/late transmitral peak flow velocities (A) ratios, lower A value. All other echocardiographic parameters did not differ significantly. By receiver-operating characteristic analysis, we determined systolic and diastolic indices specificity and sensitivity for LV impairment: LVESD 97% specificity, 11% sensitivity (cutoff value 2.44 cm/m(2) ), SF 92.1 and 33.3% (cutoff value 33%). Regarding diastolic indices, A index was the best criterion (97.7% specificity, 25% sensitivity, cutoff value

Correlation of echocardiography parameters with cardiac magnetic resonance imaging in transfusion-dependent thalassaemia major.

BACKGROUND AND OBJECTIVE: Heart iron load (cardiac Fe) can be indirectly quantified by cardiac magnetic resonance (CMR) T2*. CMR accessibility is limited, whereas echocardiography (Echo) is relatively inexpensive and readily available. The objective was to find Echo parameters that may be useful for predicting cardiac Fe. DESIGN AND METHODS: We compared a number of parameters derived from Echo to cardiac Fe in 142 thalassaemia major patients who had undergone a CMR study. RESULTS: All patients with decreased left ventricular (LV) function had cardiac Fe. After removing those patients from the analysis, the total diameter index (Tdi) >5.57 cms/m2, left atrial diameter index >2.41 cm/m2, and the diastolic parameter E/A > 1.96 were highly specific (91.4%, 97.1% and 96.9% respectively) but had low sensitivity (31.8%, 20.45% and 21.8%) in predicting iron load. A right ventricular index >1.47 cm/m2, LV systolic index >2.26 cm/m2 or Tdi >6.26 cm/m2 discriminated between patients with no, or mild to moderate cardiac Fe from those with heavy load, with specificity of 91%, 98.5%, and 98.5%, respectively, but with low sensitivity. INTERPRETATION AND CONCLUSIONS: Echo parameters for cardiac Fe prediction have restricted value, whereas CMR is essential to assess cardiac Fe. However, patients with decreased LV systolic function should be considered a priori as having cardiac Fe, and chelation therapy should be intensified. This also applies to patients who have the above-described Echo criterion values, even if CMR is not available. Once a patient is found by CMR to have cardiac Fe, then the above Echo criterion values may be useful for ongoing monitoring.

Acute brucellosis: presentation, diagnosis, and treatment of 144 cases.

OBJECTIVES: Brucellosis, whether in an endemic region or not, remains a diagnostic puzzle due to occasional misleading unusual presentations and non-specific symptoms. Presented herein is our 14-year experience with acute brucellosis at Sparta General Hospital, Lakonia, Greece. METHODS: A case series of 144 patients admitted to the internal medicine, pediatrics, and urology departments, through evaluation of history, occupational data, serological tests, cultures of blood and other body fluids, and imaging studies. Patients were treated with a 21-day course of intramuscular streptomycin and a prolonged two-month course of doxycycline with a six-month follow-up. RESULTS: Infected patients had a relevant occupational history in fewer than 20% of cases. Clinical manifestations included non-specific symptoms (fever, malaise, sweats, arthralgias, lower back pain, headache), findings such as splenomegaly (51%), osteoarticular involvement (42%), cervical lymphadenitis (31%), hepatomegaly (25%), genitourinary involvement (13% of men), cholecystitis (2%), breast abscess (0.7%), and acute abdomen (0.7%). Ninety-five percent of the patients had a serological titer > or =1/160 with culture-proven brucellosis. Overall, 82% of blood cultures and 100% of other body fluid cultures (synovial, bile) were positive. Ninety-seven percent of the patients were cured. Relapse in the follow-up period was observed in four patients who had not complied with treatment. CONCLUSIONS: Brucellosis is an infection with multiple presentations, and whether in an endemic region or not, a thorough history of exposure and clinical suspicion are required since thresholds in serological evaluation may lead to misdiagnosis and withholding of adequate treatment.

Extramedullary hematopoiesis-related pleural effusion: the case of beta-thalassemia.

BACKGROUND: Thalassemia intermedia has a later clinical onset and a milder anemia than thalassemia major, characterized by high output state, left ventricle remodeling, and age-related pulmonary hypertension. Bone deformities, extramedullary hematopoiesis (EMH), and spleen and liver enlargement are the consequences of hypoxia and enhanced erythropoiesis. The EMH-related pleural effusion is rarely referred to in the literature of thalassemia. METHODS: We reviewed the thalassemia patients' medical records hospitalized for pleural effusion in our Department, within the last 6 years. RESULTS: Eight (4 men) thalassemia intermedia patients admitted for symptomatic pleural effusion were identified. Common clinical findings on admission were dyspnea and apyrexia. Their mean hemoglobin level was 7.15 +/- 0.64 g/dL. Radiology revealed intrathoracic EMH and pleural effusion in all patients: exudative in seven patients and massive hemothorax in one. Cytologic fluid analysis was negative for malignancy. Fluid and serum cultures, antibodies, and stains were negative for viral, bacterial, and fungal infection. The hemothorax case was successfully treated with repeated aspirations, transfusions, and hydroxyurea. Although repeated thoracentesis and radiation could not control the effusions in the rest of the cases, pleurodesis was successful in 5 patients, without serious adverse events. Treatment was further accomplished with hydroxyurea. No relapses were observed in the mean 30 month follow-up period. CONCLUSIONS: Afebrile, EMH-related pleuritis represents a potentially life-threatening complication in thalassemia. Therapy should be individualized and treatment is emerging. Pleurodesis seems to be an effective and safe therapeutic option for exudative effusions, while transfusion-chelation therapy combined with hydroxyurea may be helpful in suppressing increased erythropoiesis.

Randomized controlled trial of deferiprone or deferoxamine in beta-thalassemia major patients with asymptomatic myocardial siderosis.

Most deaths in beta-thalassemia major result from cardiac complications due to iron overload. Differential effects on myocardial siderosis may exist between different chelators. A randomized controlled trial was performed in 61 patients previously maintained on subcutaneous deferoxamine. The primary end point was the change in myocardial siderosis (myocardial T2(*)) over 1 year in patients maintained on subcutaneous deferoxamine or those switched to oral deferiprone monotherapy. The dose of deferiprone was 92 mg/kg/d and deferoxamine was 43 mg/kg for 5.7 d/wk. Compliance was 94% +/- 5.3% and 93% +/- 9.7% (P = .81), respectively. The improvement in myocardial T2(*) was significantly greater for deferiprone than deferoxamine (27% vs 13%; P = .023). Left ventricular ejection fraction increased significantly more in the deferiprone-treated group (3.1% vs 0.3% absolute units; P = .003). The changes in liver iron level (-0.93 mg/g dry weight vs -1.54 mg/g dry weight; P = .40) and serum ferritin level (-181 microg/L vs -466 microg/L; P = .16), respectively, were not significantly different between groups. The most frequent adverse events were transient gastrointestinal symptoms for deferiprone-treated patients and local reactions at the infusion site for deferoxamine. There were no episodes of agranulocytosis. Deferiprone monotherapy was significantly more effective than deferoxamine over 1 year in improving asymptomatic myocardial siderosis in beta-thalassemia major.

Does heterozygous beta-thalassemia confer a protection against coronary artery disease?

Six hundred and thirty-eight patients who presented with clinical symptoms and/or electrocardiographic findings suggestive of stable angina pectoris were studied; they were also investigated by coronary arteriography. Hemoglobin electrophoresis was performed on all patients to detect the presence of the beta-thalassemia trait. Results were analyzed by logistic regression analysis to determine whether the latter confers any protective effect against advanced coronary artery disease (aCAD; defined as the presence of atheromas in coronary arteries, resulting in stenosis at least 70%). The role of the currently accepted risk factors (smoking, hypertension, hypercholesterolemia, and diabetes) in developing aCAD were reconfirmed, while at the same time it was found that beta-thalassemia heterozygosity is associated with a reduced risk against aCAD (odds ratio 0.39, 95% confidence interval 0.16-0.98). The lipoprotein and blood rheology profile of these individuals may be the underlying causes of this protective effect.

Acute Q fever lobar pneumonia: a case report.

Q fever is a zoonotic disease caused by Coxiella burnetii-an obligate, Gram-negative, intracellular bacteria. Acute febrile illness, hepatitis, and atypical pneumonia are the three most common manifestations, whereas lobar pneumonia is rarely reported among acute Q fever patients. We report a case of acute Q fever with lobar pneumonia and multi-organ involvement.

Identification of echocardiographic indices for the early detection of left-ventricular systolic dysfunction in beta-thalassaemia via Self-Organizing Maps: a data-exploration study.

Congestive heart failure (CHF) remains the primary cause of death in patients suffering from beta-thalassaemia major. Its early detection allows the prompt initiation of aggressive chelation therapy, when the condition can still be reversed. We aimed at identifying echocardiographic indices for the early detection of left ventricular (LV) systolic dysfunction, the physiological abnormality underlying CHF, in these patients. We used Self-Organizing Maps (SOMs)--an artificial neural network--for identifying novel correlations within our Electronic Healthcare Record (EHCR) database on beta-thalassaemia. We sought echocardiographic parameters that are correlated to future deterioration of the LV ejection fraction and therefore constitute early signs of LV systolic dysfunction. At the same time, we evaluated SOMs as tools for exploring clinical datasets and make recommendations on the setup of the SOM algorithm that is appropriate for such tasks. We found that high values of the LV end-systolic diameter index and of the E/A ratio are early indications of LV systolic dysfunction. From a technical point of view, zero-mean unit-variance normalization of the input data, a large initial neighbourhood radius and a rectangular SOM grid produced optimal maps for the purpose of detecting clinical correlations. We have successfully used SOMs for exploring a clinical dataset and for creating novel medical hypotheses. A clinical study has been launched to confirm these hypotheses, and initial results are encouraging.