Impact of Balanced or Unbalanced Karyotype At Diagnosis On Prognosis of CML: Long-Term Observation From 1346 Patients of the Randomized CML Study IV

Introduction: Acquired genetic instability in chronic myeloid leukemia (CML) as a consequence of the translocation t(9;22)(q34;q11) and the resulting BCR-ABL fusion causes the continuous acquisition of additional chromosomal aberrations and mutations and thereby progression to accelerated phase (AP) and blast crisis (BC). At least 10% of patients in chronic phase (CP) CML show additional alterations at diagnosis. This proportion rises during the course of the disease up to 80% in BC. Acquisition of chromosomal changes during treatment is considered as a poor prognostic indicator, whereas the impact of chromosomal aberrations at diagnosis depends on their type. Patients with major route additional chromosomal alterations (major ACA: +8, i(17)(q10), +19, +der(22)t(9;22)(q34;q11) have a worse outcome whereas patients with minor route ACA show no difference in overall survival (OS) and progression-free survival (PFS) compared to patients with the standard translocation, a variant translocation or the loss of the Y chromosome (Fabarius et al., Blood 2011). However, the impact of balanced vs. unbalanced (gains or losses of chromosomes or chromosomal material) karyotypes at diagnosis on prognosis of CML is not clear yet. Patients and methods: Clinical and cytogenetic data of 1346 evaluable out of 1544 patients with Philadelphia and BCR-ABL positive CP CML randomized until December 2011 to the German CML-Study IV, a randomized 5-arm trial to optimize imatinib therapy by combination, or dose escalation and stem cell transplantation were investigated. There were 540 females (40%) and 806 males (60%). Median age was 53 years (range, 16-88). The impact of additional cytogenetic aberrations in combination with an unbalanced or balanced karyotype at diagnosis on time to complete cytogenetic and major molecular remission (CCR, MMR), PFS and OS was investigated. Results: At diagnosis 1174/1346 patients (87%) had the standard t(9;22)(q34;q11) only and 75 patients (6%) had a variant t(v;22). In 64 of 75 patients with t(v;22), only one further chromosome was involved in the translocation; In 8 patients two, in 2 patients three, and in one patient four further chromosomes were involved. Ninety seven patients (7%) had additional cytogenetic aberrations. Of these, 44 patients (3%) lacked the Y chromosome (-Y) and 53 patients (4%) had major or minor ACA. Thirty six of the 53 patients (2.7%) had an unbalanced karyotype (including all patients with major route ACA and patients with other unbalanced alterations like -X, del(1)(q21), del(5)(q11q14), +10, t(15;17)(p10;p10), -21), and 17 (1.3%) a balanced karyotype with reciprocal translocations [e.g. t(1;21); t(2;16); t(3;12); t(4;6); t(5;8); t(15;20)]. After a median observation time of 5.6 years for patients with t(9;22), t(v;22), -Y, balanced and unbalanced karyotype with ACA median times to CCR were 1.05, 1.05, 1.03, 2.58 and 1.51 years, to MMR 1.31, 1.51, 1.65, 2.97 and 2.07 years. Time to CCR and MMR was longer in patients with balanced karyotypes (data statistically not significant). 5-year PFS was 89%, 78%, 87%, 94% and 69% and 5-year OS 91%, 87%, 89%, 100% and 73%, respectively. In CML patients with unbalanced karyotype PFS (p<0.001) and OS (p<0.001) were shorter than in patients with standard translocation (or balanced karyotype; p<0.04 and p<0.07, respectively). Conclusion: We conclude that the prognostic impact of additional cytogenetic alterations at diagnosis of CML is heterogeneous and consideration of their types may be important. Not only patients with major route ACA at diagnosis of CML but also patients with unbalanced karyotypes identify a group of patients with shorter PFS and OS as compared to all other patients. Therefore, different therapeutic options such as intensive therapy with the most potent tyrosine kinase inhibitors or stem cell transplantation are required.

Chylothorax in children: guidelines for diagnosis and management.

STUDY OBJECTIVE: To establish guidelines for the diagnosis and management of chylothorax in children. DESIGN: Retrospective study. PATIENTS: Fifty-one patients with a diagnosis of chylothorax. Twelve patients were excluded because of incomplete data or incorrect diagnosis. The following parameters were analyzed: triglyceride level, total cell number, and lymphocyte percentage; amount of pleural effusion on day of diagnosis, day 5, and day 14; and total time of pleural effusion. Prospectively, the same parameters were analyzed in a control group of 10 patients with pleural drainage. INTERVENTION: Patients with chylothorax were treated primarily with fat-free oral nutrition; if chyle did not stop, total parenteral nutrition with total enteric rest was started. If conservative therapy was not successful, pleurodesis was performed. RESULTS: In children with chylothorax triglyceride, triglyceride content ranged from 0.56 to 26.6 mmol/L; all values except one were > 1.1 mmol/L. In 36 of 39 patients (92%), the cell count was > 1,000 cells/microL. In 33 of 39 patients (85%), lymphocytes were > 90%. In patients without chylothorax triglyceride, triglyceride levels ranged from 0.1 to 0.71 mmol/L (median, 0.38 mmol/L) and cell count was from 20 to 1400 cells/microL (median, 322 cells/microL), with a maximum of 60% lymphocytes. With fat-free nutrition, chyle disappeared in 29 of 39 patients. Five patients died, and five required pleurodesis. CONCLUSIONS: Pleural effusion in children is chyle when it contains > 1.1 mmol/L triglycerides (with oral fat intake) and has a total cell count > or 1,000 cells/microL, with a lymphocyte fraction > 80%. Chylous effusions usually last long; however, after 6 weeks, the majority of the effusions (29 of 39 patients) had ceased. Late surgical interventions reduce the number of thoracotomies substantially, but can lead to very long hospitalization times. Early surgical interventions (after < 3 weeks) lead to a high number of thoracotomies, but certainly reduce hospitalization time.

The psychosocial impacts caused by diagnosis and treatment of Coeliac Disease

Abstract OBJECTIVE To comprehend the psychosocial effects that Coeliac Disease diagnosis entails. METHOD Qualitative study, achieved through semi-structured interviews, analyzed in accordance to the Association of ideas map Technique. A total 12 recently-diagnosed patients from the Centro de diagnóstico, tratamento e apoio ao paciente com doença celíaca (Coeliac Disease Prevention, Support and Treatment Diagnose Centre) from the Hospital Universitário de Brasília (University Hospital of Brasilia) were enrolled for the study, between the years of 2013 and 2014. RESULTS The interviewed patients presented negative impacts in three categories: psychoaffective, family and social relationships, indicating issues with social readaptation once the treatment had started, as well as difficulty coping with a gluten free diet. CONCLUSION Coeliac Disease holds substantial impact on psychological functions, family and social relationships to diagnosed patients, requiring a clinical biopsychological assistance for better adherence to treatment and patients quality of life.

Cerebrospinal fluid in the diagnosis of multiple sclerosis: a consensus report.

The Committee of the European Concerted Action for Multiple Sclerosis (Charcot Foundation) organised five workshops to discuss CSF analytical standards in the diagnosis of multiple sclerosis. This consensus report from 12 European countries summarises the results of those workshops. It is hoped that neurologists will confer with their colleagues in clinical chemistry to arrange the best possible local practice. The most sensitive method for the detection of oligoclonal immunoglobulin bands is isoelectric focusing. The same amounts of IgG in parallel CSF and serum samples are used and oligoclonal bands are revealed with IgG specific antibody staining. All laboratories performing isoelectric focusing should check their technique at least annually using "blind" standards for the five different CSF and serum patterns. Quantitative measurements of IgG production in the CNS are less sensitive than isoelectric focusing. The preferred method for detection of blood-CSF barrier dysfunction is the albumin quotient. The CSF albumin or total protein concentrations are less satisfactory. These results must be interpreted with reference to the age of the patient and the local method of determination. Cells should be counted. The normal value is no more than 4 cells/microliters. Among evolving optional tests, measurement of the combined local synthesis of antibodies against measles, rubella, and/or varicella zoster could represent a significant advance if it offers higher specificity (not sensitivity) for identifying chronic rather than acute inflammation. Other tests that may have useful correlations with clinical indices include those for oligoclonal free light chains, IgM, IgA, or myelin basic protein concentrations.

Impact of navigator timing on free-breathing submillimeter 3D coronary magnetic resonance angiography.

The purpose of this study was to investigate the impact of navigator timing on image quality in navigator-gated and real-time motion-corrected, free-breathing, three-dimensional (3D) coronary MR angiography (MRA) with submillimeter spatial image resolution. Both phantom and in vivo investigations were performed. 3D coronary MRA with real-time navigator technology was applied using variable navigator time delays (time delay between the navigator and imaging sequences) and varying spatial resolutions. Quantitative objective and subjective image quality parameters were assessed. For high-resolution imaging, reduced image quality was found as a function of increasing navigator time delay. Lower spatial resolution coronary MRA showed only minor sensitivity to navigator timing. These findings were consistent among volunteers and phantom experiments. In conclusion, for submillimeter navigator-gated and real-time motion-corrected 3D coronary MRA, shortening the time delay between the navigator and the imaging portion of the sequence becomes increasingly important for improved spatial resolution.

Fluoreszenzdiagnostik bei Patienten mit nicht muskelinvasivem Harnblasenkarzinom: Ergebnisse einer Metaanalyse [Fluorescence diagnosis in patients with non-muscle invasive bladder cancer: results of a metaanalysis]

Purpose: Heterogeneous results of single studies with photodynamic diagnosis (PDD) in bladder cancer have been reported. A metaanalysis of prospective studies has now been performed. Material and Methods: The effect of PDD in addition to WLC on a) the diagnosis and b) the therapeutic outcome of primary or recurrent non-muscle invasive bladder cancer (NMIBC) investigated by cystoscopy or transurethral resection was analysed. An electronic database search was performed. Trials were included if they prospectively compared WLC with PDD in bladder cancer. Primary endpoints were additional detection rate, residual tumour at second resection and recurrence-free survival. Results: Significantly more tumour-positive patients were detected with PDD in all patients with non-muscle invasive tumours (= 20%) [95% confidence interval (CI): 8 to 35%] and in CIS patients (= 39%) (CI: 23 to 57%). Residual tumour was significantly less often found after PDD (odds ratio 0.28, CI: 0.15 to 0.52, p<0.0001). Recurrence-free survival was significantly higher at 12 and 24months in the PDD groups than in WLC only groups. Conclusions: More bladder tumour-positive patients are detected by PDD. Best results were found in CIS patients. Diagnosis with PDD results in a more complete resection and a longer recurrence-free survival.

Hexyl Aminolevulinate-Guided Fluorescence Cystoscopy in the Diagnosis and Follow-up of Patients with Non-Muscle-invasive Bladder Cancer: A Critical Review of the Current Literature.

CONTEXT: Controversy exists regarding the therapeutic benefit and cost effectiveness of photodynamic diagnosis (PDD) with 5-aminolevulinic acid (5-ALA) or hexyl aminolevulinate (HAL) in addition to white-light cystoscopy (WLC) in the management of non-muscle-invasive bladder cancer (NMIBC). OBJECTIVE: To systematically evaluate evidence regarding the therapeutic benefits and economic considerations of PDD in NMIBC detection and treatment. EVIDENCE ACQUISITION: We performed a critical review of PubMed/Medline, Embase, and the Cochrane Library in October 2012 according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. Identified reports were reviewed according to the Consolidated Standards of Reporting Trials (CONSORT) and Standards for the Reporting of Diagnostic Accuracy Studies (STARD) criteria. Forty-four publications were selected for inclusion in this analysis. EVIDENCE SYNTHESIS: Included reports used 5-ALA (in 26 studies), HAL (15 studies), or both (three studies) as photosensitising agents. PDD increased the detection of both papillary tumours (by 7-29%) and flat carcinoma in situ (CIS; by 25-30%) and reduced the rate of residual tumours after transurethral resection of bladder tumour (TURBT; by an average of 20%) compared to WLC alone. Superior recurrence-free survival (RFS) rates and prolonged RFS intervals were reported for PDD, compared to WLC in most studies. PDD did not appear to reduce disease progression. Our findings are limited by tumour heterogeneity and a lack of NMIBC risk stratification in many reports or adjustment for intravesical therapy use in most studies. Although cost effectiveness has been demonstrated for 5-ALA, it has not been studied for HAL. CONCLUSIONS: Moderately strong evidence exists that PDD improves tumour detection and reduces residual disease after TURBT compared with WLC. This has been shown to improve RFS but not progression to more advanced disease. Further work to evaluate cost effectiveness of PDD is required.

Free-breathing black-blood coronary MR angiography: initial results

The authors developed a free-breathing black-blood coronary magnetic resonance (MR) angiographic technique with a potential for exclusive visualization of the coronary blood pool. Results with the MR angiographic technique were evaluated in eight healthy subjects and four patients with coronary disease identified at conventional angiography. This MR angiographic technique accurately depicted luminal disease in the patients and permitted visualization of extensive continuous segments of the native coronary tree in both the healthy subjects and the patients. Black-blood coronary MR angiography provides an alternative source of contrast enhancement.

Improved coronary artery definition with T2-weighted, free-breathing, three-dimensional coronary MRA.

BACKGROUND: Three-dimensional (3D) navigator-gated and prospectively corrected free-breathing coronary magnetic resonance angiography (MRA) allows for submillimeter image resolution but suffers from poor contrast between coronary blood and myocardium. Data collected over >100 ms/heart beat are also susceptible to bulk cardiac and respiratory motion. To address these problems, we examined the effect of a T2 preparation prepulse (T2prep) for myocardial suppression and a shortened acquisition window on coronary definition. METHODS AND RESULTS: Eight healthy adult subjects and 5 patients with confirmed coronary artery disease (CAD) underwent free-breathing 3D MRA with and without T2prep and with 120- and 60-ms data-acquisition windows. The T2prep resulted in a 123% (P<0. 001) increase in contrast-to-noise ratio (CNR). Coronary edge definition was improved by 33% (P<0.001). Acquisition window shortening from 120 to 60 ms resulted in better vessel definition (11%; P<0.001). Among patients with CAD, there was a good correspondence with disease. CONCLUSIONS: Free-breathing, T2prep, 3D coronary MRA with a shorter acquisition window resulted in improved CNR and better coronary artery definition, allowing the assessment of coronary disease. This approach offers the potential for free-breathing, noninvasive assessment of the major coronary arteries.

The prognostic value of semi-quantitative i-123 mibg scintigraphy at diagnosis in high risk neuroblastoma: validation of the siopen score method

Purpose: SIOPEN scoring of 123I mIBG imaging has been shown to predict response to induction chemotherapy and outcome at diagnosis in children with HRN.Method: Patterns of skeletal 123I mIBG uptake were assigned numerical scores (Mscore) ranging from 0 (no metastasis) to 72 (diffuse metastases) within 12 body areas as described previously. 271 anonymised, paired image data sets acquired at diagnosis and on completion of Rapid COJEC induction chemotherapy were reviewed, constituting a representative sample of 1602 children treated prospectively within the HR-NBL1/SIOPEN trial. Pre-and post-treatment Mscores were compared with bone marrow cytology (BM) and 3 year event free survival (EFS).Results: Results 224/271 patients showed skeletal MIBG-uptake at diagnosis and were evaluable forMIBG-response. Complete response (CR) on MIBG to Rapid COJEC induction was achieved by 66%, 34% and 15% of patients who had pre-treatment Mscores of <18 (n¼65, 29%), 18-44 (n¼95,42%) and Y ´ 45 (n¼64, 28.5%) respectively (chi squared test p<.0001). Mscore at diagnosis and on completion of Rapid COJEC correlated strongly with BM involvement (p<0.0001). The correlation of pre score with post scores and response was highly significant (p<0.001). Most importantly, the 3 year EFS in 47 children with Mscore 0 at diagnosis was 0.68 (A ` 0.07), by comparison with 0.42 (A` 0.06), 0.35 (A` 0.05) and 0.25 (A` 0.06) for patients in pre-treatment score groups <18, 18-44 and Y ´ 45, respectively (p<0.001). AnMscore threshold ofY ´ 45 at diagnosis was associated with significantly worse outcome by comparison with all other Mscore groups (p¼0.029). The 3 year EFS of 0.53 (A` 0.07) of patients in metastatic CR (mIBG and BM) after Rapid Cojec (33%) is clearly superior to patients not achieving metastatic CR (0.24 (A ` 0.04), p¼0.005).Conclusion: SIOPEN scoring of 123I mIBG imaging has been shown to predict response to induction chemotherapy and outcome at diagnosis in children with HRN.

Diagnosis and treatment of follicular lymphoma.

Follicular lymphoma is a slow-growing disease exhibiting a heterogeneous clinical course, with a subset of patients experiencing a rapid disease course in the first two years and some developing disease transformation to a more aggressive phenotype. The advent of highly effective therapies has resulted in an increasing number of patients who achieve long-term progression-free survival alongside a good quality of life. Monoclonal antibodies, such as rituximab, either alone or in combination with chemotherapy regimens or radioimmunotherapy have been used with significant improvements in outcome. New treatment strategies such as new antibodies, biologic agents or vaccination therapy are also under investigation for the treatment of relapsed or refractory disease, further expanding the available options for patients and physicians alike. This article presents an overview of the current therapeutic strategies for the management of follicular lymphoma, focusing on the issues encountered in clinical practice.

Free microvascular iliac crest flap for extensive talar necrosis--case report with a 16-year long-term follow up.

Atraumatic osteonecrosis of the talus can be extremely painful and lead to significant functional impairment. Although clinical, radiographic, and demographic characteristics of atraumatic osteonecrosis of the talus have been well documented, the diagnosis is frequently missed or delayed; the most common causes are use of corticosteroids and the presence of immune disorders. Operative treatment of large osteochondral lesions of the talus is difficult because the blood supply is poor in the talar dome. Microvascular reconstruction of the talar dome with iliac crest autografts is a complex but functionally excellent therapeutic option. We present a 48-year-old man, who developed an extensive atraumatic avascular necrosis of the talar dome without collapse. Except for insulin dependent diabetes mellitus no further comorbidities were known. A microvascular iliac crest bone flap was inserted into the talus. A follow-up 16 years postoperatively showed a clinically as well as radiographically stable reconstruction of the talar dome and an excellent mobility of the ankle joint. The AOFAS hindfoot scale had improved from initially 33 points to 100 on the last follow-up. Free microvascular bony reconstruction of the talar dome should not only be considered in younger patients but also for middle aged active patients, since our follow-up shows an excellent long term result. Early reconstruction can prevent collapse of the talar bone.

Circulating EM66 is a highly sensitive marker for the diagnosis and follow-up of pheochromocytoma.

We have previously demonstrated that measurement of tissue concentration of the novel secretogranin II-derived peptide EM66 may help to discriminate between benign and malignant pheochromocytomas. The aim of the present study was to characterize EM66 in plasma and urine of healthy volunteers and pheochromocytoma patients, in order to further evaluate the usefulness of this peptide as a circulating marker for the management of the tumors. HPLC analysis of plasma and urine samples demonstrated that the EM66-immunoreactive material coeluted with the recombinant peptide. In healthy volunteers, plasma and urinary EM66 levels were, respectively, 2.6 (1.9-3.7) ng/ml and 2.9 (1.9-4.6) ng/ml. In patients with pheochromocytoma, plasma EM66 levels were 10-fold higher than those of healthy volunteers (26.9 (7.3-44) ng/ml), and returned to normal values after removal of the tumor. In contrast, urinary EM66 levels were not significantly different from those of healthy volunteers (3.2 (2.2-3.9) ng/ml). Measurement of total or free plasma metanephrines and 24 hr urinary metanephrines in our series of patients revealed that these tests, taken separately, are less sensitive than the EM66 determination. Pheochromocytes in primary culture secreted high levels of EM66, suggesting that the chromaffin tumor was actually responsible for the increased plasma peptide concentrations in the patients. These data indicate that EM66 is secreted in the general circulation and that elevated plasma EM66 levels are correlated with the occurrence of pheochromocytoma. Thus, EM66 is a sensitive plasma marker that should be considered as a complementary tool in the management of pheochromocytoma.

Diagnostic contribution of cardiac magnetic resonance in patients with acute coronary syndrome and culprit-free angiograms.

BACKGROUND: In spite of robust knowledge about underlying ischemic myocardial damage, acute coronary syndromes (ACS) with culprit-free angiograms raise diagnostic concerns. The present study aimed to evaluate the additional value of cardiac magnetic resonance (CMR) over commonly available non-CMR standard tests, for the differentiation of myocardial injury in patients with ACS and non-obstructed coronary arteries. MATERIAL/METHODS: Patients with ACS, elevated hs-TnT, and a culprit-free angiogram were prospectively enrolled into the study between January 2009 and July 2013. After initial evaluation with standard tests (ECG, echocardiography, hs-TnT) and provisional exclusion of acute myocardial infarction (AMI) in coronary angiogram, patients were referred for CMR with the suspicion of myocarditis or Takotsubo cardiomyopathy (TTC). According to the result of CMR, patients were reclassified as having myocarditis, AMI, TTC, or non-injured myocardium as assessed by late gadolinium enhancement. RESULTS: Out of 5110 patients admitted with ACS, 75 had normal coronary angiograms and entered the study; 69 of them (92%) were suspected for myocarditis and 6 (8%) for TTC. After CMR, 49 patients were finally diagnosed with myocarditis (65%), 3 with TTC (4%), 7 with AMI (9%), and 16 (21%) with non-injured myocardium. The provisional diagnosis was changed or excluded in 23 patients (31%), with a 9% rate of unrecognized AMI. CONCLUSIONS: The study results suggest that the evaluation of patients with ACS and culprit-free angiogram should be complemented by a CMR examination, if available, because the initial work-up with non-CMR tests leads to a significant proportion of misdiagnosed AMI.

Analytical interference of 4-hydroxy-3-methoxymethamphetamine with the measurement of plasma free normetanephrine by ultra-high pressure liquid chromatography-tandem mass spectrometry.

OBJECTIVES: The diagnosis of pheochromocytoma relies on the measurement of plasma free metanephrines assay whose reliability has been considerably improved by ultra-high pressure liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). Here we report an analytical interference occurring between 4-hydroxy-3-methoxymethamphetamine (HMMA), a metabolite of 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy"), and normetanephrine (NMN) since they share a common pharmacophore resulting in the same product ion after fragmentation. DESIGN AND METHODS: Synthetic HMMA was spiked into plasma samples containing various concentrations of NMN and the intensity of the interference was determined by UPLC-MS/MS before and after improvement of the analytical method. RESULTS: Using a careful adjustment of chromatographic conditions including the change of the UPLC analytical column, we were able to distinguish both compounds. HMMA interference for NMN determination should be seriously considered since MDMA activates the sympathetic nervous system and if confounded with NMN may lead to false-positive tests when performing a differential diagnostic of pheochromocytoma.