Differences In Clinical Course Research Articles

Increased levels of anti-glycan antibodies in patients with cystic fibrosis

BackgroundThe prevalence of Crohn's disease (CD) is increased in patients with cystic fibrosis (CF). Anti-Saccharomyces cerevisiae antibodies (ASCA) have been suggested as a screening tool to detect CD in CF. Recently, several new anti-glycan antibodies have been reported in CD.Materials and methodsThe sera of 119 CF patients of various age groups were prospectively screened for ASCA type IgG (gASCA), anti-laminaribioside carbohydrate IgG antibodies (ALCA), anti-chitobioside carbohydrate IgA antibodies (ACCA), and anti-mannobioside carbohydrate IgG antibodies (AMCA). The frequency of these anti-glycan antibodies was then compared in patients with CD, ulcerative colitis, rheumatoid arthritis and healthy volunteers.ResultsA significant number of CF patients were positive for gASCA (51.3% [41.6-60.6]) and up to three other anti-glycan antibodies concurrently. Serum levels of anti-glycan antibodies in CF and CD were not related to parameters of inflammation. Despite the well-documented difference in clinical course between male and female CF patients no gender difference of anti-glycan antibodies was found. In contrast, there was a significant positive correlation between anti-glycan markers and age in CF patients.ConclusionsOur findings demonstrate for the first time the increased frequency of a panel of anti-glycan antibodies in CF and provide a link between the presence of these serological biomarkers and patient's age. Anti-glycan antibody profiling may therefore become a valuable tool in the care of patients with CF.

Familial Pulmonary Capillary Hemangiomatosis Early in Life

Background. Pulmonary capillary hemangiomatosis (PCH) is a rare disease, especially in infancy. Four infants have been reported up to the age of 12 months. So far, no familial patients are observed at this age. Patients. We report three siblings, two female newborns and a foetus of 15-week gestation of unrelated, healthy parents suffering from histologically proven PCH. The first girl presented with increased O2 requirements shortly after birth and patent ductus arteriosus (PDA). She subsequently developed progressive respiratory failure and pulmonary hypertension and died at the age of five months. The second girl presented with clinical signs of bronchial obstruction at the age of three months. The work-up showed a PDA—which was surgically closed—pulmonary hypertension, and bronchial wall instability with stenosis of the left main bronchus. Transient oxygen therapy was required with viral infections. The girl is now six years old and clinically stable without additional O2 requirements. Failure to thrive during infancy and a somewhat delayed development may be the consequence of the disease itself but also could be attributed to repeated episodes of respiratory failure and a long-term systemic steroid therapy. The third pregnancy ended as spontaneous abortion. The foetus showed histological signs of PCH. Conclusion. Despite the differences in clinical course, the trias of PCH, PDA, and pulmonary hypertension in the two life born girls suggests a genetic background.

IGHV-Mutation Status, IGHV-Gene Usage and Chromosomal Aberrations In CLL: Pooled Analysis within First-Line Clinical Trials of the German CLL Study Group (GCLLSG)

AbstractAbstract 3609 Introduction:IGHV mutation status and genomic aberrations are of independent prognostic importance in CLL. Furthermore IGHV-gene usage showed prognostic value for distinct subgroups (e.g. VH3-21). While the introduction of chemoimmunotherapy (i.e. FCR) has led to remarkable improvement of outcome in CLL, it is unclear which of the known genetic markers retain their prognostic value. We therefore performed a pooled analysis of first-line CLL patients from 3 prospective clinical trials of the GCLLSG namely “CLL2M” (R-Bendamustine) “CLL4” (F vs. FC) and “CLL8” (FC vs. R-FC) to evaluate those genetic markers in a large, well characterized CLL cohort.Material and Methods: Genetic characterization was performed in a central laboratory (Ulm). IGHV data was available for 1063 patients. Genomic aberrations (FISH) were generated for 1053 patients. After pooling genetic data from the outlined GCLLSG first-line trials we investigated the impact of IGHV mutation status and VH gene usage within the hierarchical model of genomic abnormalities (deletion 13q (del(13q)) single (n=353), trisomy 12 (n=115), deletion 11q (del(11q)) (n=229), deletion 17p (del(17p)) (n=73)) concerning, progression free survival (PFS events= PD/death) and overall survival (OS). Median follow-up was 39.1 months. Results:For the del(13q) patients, with 56 % carrying a mutated IGHV gene, we found a significant difference in PFS and OS between the del(13q)/IGHV mutated and the IGHV unmutated subgroup (PFS: p-value 0.002; HR: 1.596; OS: p-value 0.002; HR: 2.15; median PFS mut./70.5 months vs. unmut./41.5 months).In the trisomy 12 subgroup 35 % of patients showed a mutated IGHV whereas 65 % showed an unmutated IGHV. For the trisomy12/IGHV unmutated subgroup we could detect a trend towards a shorter PFS and OS compared to the trisomy12/IGHV mutated group although this was not statistically significant (PFS: p-value 0.059; HR: 1.784; OS: p-value 0.079; HR: 3.05; median PFS not reached vs. 36.8 months).In the del(11q) subgroup 17 % were IGHV mutated, whereas 83 % were unmutated. For none of the clinical endpoints (PFS, OS) a significant difference between the 11q-/IGHV mutated group and the 11q-/IGHV unmutated group could be detected (PFS: p-value 0.451; OS: p-value 0.64; median PFS 32.7 months for both subgroups).Finally among the del(17p) pts. with 23 % IGHV-mutated cases we could not find any difference in PFS or OS among the IGHV-mutated or unmutated subgroup (PFS: p-value 0.995; HR: 0.998; OS: p-value 0.584; HR: 0.80, median PFS 8.8 vs. 9.6 months).In contrast to previous findings we detected no significant difference in clinical behaviour of the mutated VH3-23 subgroup in comparison to all non-VH3-23 mutated cases with regard to PFS and OS within the CLL8 cohort. (median PFS not reached vs. 59.7 months).For unmutated VH1-69 cases no significant differences concerning the clinical endpoints in comparison to all non-VH1-69 unmutated cases were detected. Finally the 66 VH3-21 patients in the pooled data set showed a PFS and OS which was surprisingly more comparable to that of IGHV-mutated cases (PFS: p-value 0.488; OS: p-value 0.467; median PFS 51.9 months for VH3-21 vs. 63.6 months for mutated non-VH3-21). However, stereotyped HCDR3 motifs have not been considered in this analysis. Conclusions:The current data were derived from pooled subgroup analyses based on genomic aberrations among patients enrolled in 1st line treatment trials (i.e. patients requiring treatment). It revealed a differential influence of IGHV-mutation status and gene usage in the different genomic subgroups. This might hint to different biological behaviour apart from postulated mechanisms like B cell receptor mediated antigen drive and could also be reflected by differences in clinical course. The impact of VH3-21 usage and potentially other VH genes appears to be less pronounced in this cohort. The prognostic role of distinct IGHV-genes must be further evaluated in different clinical situations also considering stereotyped B-cell receptors. [Display omitted] Disclosures:Bühler:Roche Pharma: Consultancy, Research Funding. Zenz:Roche: Honoraria; Boehringer: Honoraria; GSK: Honoraria; Celgene: Honoraria. Winkler:Roche Pharma AG: Consultancy, Research Funding. Fischer:Roche Pharma AG: Consultancy. Fink:Roche Pharma AG: Consultancy. Wendtner: Celgene, BayerSchering, Roche, Mundipharma: Consultancy, Honoraria. Eichhorst:Roche Pharma AG: Consultancy. Edelmann:Roche Pharma AG: Consultancy, Research Funding. Hallek:Roche Pharma AG: Consultancy. Stilgenbauer:Roche, Bayer, Celgene, GSK, Amgen, Mundipharma: Consultancy, Honoraria, Research Funding.

Prefrontal cortical abnormalities in currently depressed versus currently remitted patients with major depressive disorder

Previous neuromorphometric investigations of major depressive disorder (MDD) have reported abnormalities in gray matter in several regions, although the results have been inconsistent across studies. Some discrepancies in the results across studies may reflect design limitations such as small sample sizes, whereas others may reflect biological variability that potentially manifests as differences in clinical course. For example, it remains unclear whether the abnormalities found in persistently depressed MDD subjects extend to or persist in patients who experience prolonged remission. The aim of the present study was to investigate gray matter (GM) differences in unmedicated, currently-depressed participants (dMDD) and unmedicated, currently-remitted (rMDD) participants with MDD compared to healthy controls (HC).The GM density and volume were compared across groups using voxel-based morphometry, a quantitative neuroanatomical technique, and high-resolution MRI images from 107 HC, 58 dMDD and 27 rMDD subjects.Relative to the HC group the dMDD group had reduced GM in the dorsal anterolateral (DALPFC), the dorsomedial (DMPFC) and the ventrolateral prefrontal cortex (VLPFC). Relative to the rMDD group the dMDD group showed reduced GM in the DALPFC, the VLPFC, the anterior cingulate cortex (ACC), the precuneus and the inferior parietal lobule. No regions were identified in which the rMDD group showed significantly lower GM compared to the HC group after p-values were corrected for the number of comparisons performed.In unmedicated patients in the depressed phase of MDD, we found evidence of morphometric abnormalities in DALPFC and in medial prefrontal cortical regions belonging to the visceromotor network. These findings, along with the absence of GM abnormalities in the remitted sample imply a possible link between greater GM tissue and better clinical outcome. Consistent with other neuroimaging and post-mortem neuropathological studies of MDD, we also found evidence of decreased white matter in patients with dMDD and rMDD.

Roles of an anti-tuberculosis medication and surgery in patients with tuberculous otitis media

Conclusion: The standard treatment for tuberculous otitis media (TOM) without complications consists of anti-tuberculosis (anti-TB) medication, with which we experienced good treatment outcomes. However, surgery is required for recovery of anatomy and hearing function. Objective: To determine the clinical characteristics of TOM that might optimize diagnosis and to evaluate the differences in clinical courses between patients treated with and without surgery. Methods: We analyzed 14 patients (16 ears) who had been diagnosed and treated for TOM. Radiologic findings, laboratory data, and audiometry results were also evaluated. Patients were divided into a chemotherapy group and a surgery group according to treatment modality. Results: Temporal bone CT (TBCT) showed total occupation of the tympanic cavity by soft tissue and little evidence of ossicular erosion. In the chemotherapy group, dry ears were obtained in all but one patient (14 ears) after treatment. Normalized tympanic membrane (TM) was found in 50% in the chemotherapy group and in 75% in the surgery group. The air–bone gap (ABG) changed from 40.3 ± 2.5 dB to 47.0 ± 19.2 dB in the chemotherapy group and from 35.2 ± 7.6 dB to 30.2 ± 11.4 dB in the surgery group. After treatment, ABG improved by > 10 dB in one ear in the chemotherapy group and in four ears in the surgery group.

RISK FACTORS FOR RESPONSE TO CARDIAC RESYNCHRONIZATION THERAPY IN PATIENTS WITH ISCHEMIC AND NONISCHEMIC CARDIOMYOPATHY FROM THE MADIT-CRT STUDY

Methods: We evaluated the risk for the primary end point of death or heart failure event, whichever came first, in patients with IHD (n=1046) and NIHD (n=774) who were enrolled in the MADIT-CRT trial . The Cox model for CRT-D vs. ICD-only hazard ratio was used to evaluate treatment efficacy by disease etiology. The contribution of dichotomized risk variables to the treatment effect was investigated including risk factor-by-treatment interactions. Results: Among patients allocated to ICD-only therapy, IHD was associated with a significant 62% (p=0.02) increase in the risk of the primary end point as compared with NIHD. However, CRT-D therapy was associated with a somewhat more favorable response in NIHD patients (Table). Females, patients with diabetes mellitus, and those with LBBB, derived enhanced efficacy from CRT-D therapy in the NIHD subgroup, with significant risk factor-by-treatment interaction, and LBBB was associated with enhanced efficacy in the IHD subgroup (Table). Conclusions: Our findings demonstrate differences in clinical course and response to preventive CRT-D therapy between IHD and NIHD patients enrolled in MADIT-CRT, suggesting that risk assessment in the 2 subgroups should be carried out separately.

Aberrant Phenotype of Stem Cells as Assessed by Flow Cytometry Discriminates Between Low and High Risk Myelodysplastic Syndromes and Might Be Instrumental in Predicting Leukemic Evolution.

Abstract 3798Poster Board III-734Myelodysplastic syndromes (MDS) can be classified into low risk and high risk categories, with evolution to acute myeloid leukemia (AML) predominantly in the latter cases. In AML, survival of leukemia-initiating cells, often referred to as leukemic stem cells, after chemotherapy is thought to result in minimal residual disease leading to relapse. A larger size of the stem cell compartment in de novo AML is predictive for poor survival [Van Rhenen et al.,Clin Cancer Res 2005,11]. A monoclonal antibody against the cell surface antigen C-type lectin-like molecule-1, CLL-1, together with lineage infidelity markers enables discrimination of normal and malignant stem cells in AML [Van Rhenen et al., Blood 2007, 110; Van Rhenen et al., Leukemia 2007, 21]. Previously, we showed that the size of the total stem cell compartment including both normal and malignant cells, defined as CD45dimCD34+CD38−, were significantly more prevalent within the blast cell fraction in high risk MDS as compared to low risk MDS (median 0.77% (n=15) and 0.25% (n=73), respectively, p=0.040) [Westers et al. Blood 2008, 112, abstract 1661]. This might reflect the differences in clinical course in these patients. It could be hypothesized that aberrant marker expression on MDS stem cells may predict leukemic evolution. Therefore, stem cells in MDS bone marrow samples were analyzed by flow cytometry for expression of CLL-1 and aberrant lineage markers. A reliable number of stem cells (>20) could be examined in 22 low risk and 14 high risk MDS patients; patients were classified by WHO2001 as refractory anemia w/o ring sideroblasts (RS; n=6) or refractory cytopenia with multilineage dysplasia w/o RS (n=16) and 14 refractory anemia with excess of blasts type 1 or 2 (n=14). Median CLL-1 expression on the CD34+CD38− stem cells was 0.0% (range 0-50, 3 out of 22 clearly (>10%) positive cases) in low risk and 2.2% (range 0-27, 3 out of 14 clearly positive cases) in high risk MDS. For comparison, median CLL-1 expression on stem cells in normal controls was 0.0% (range 0-4.7, not significantly different from MDS cases: p=0.55 and 0.20 as compared to low and high risk categories, respectively). Eleven of the low risk MDS cases were tested for aberrant lineage infidelity marker expression on their myeloid blasts and stem cells. In these cases, myeloid blasts expressed either CD5 or CD7 (n=2 and n=7, respectively; median 33% of blast cells). Median expression of these antigens on stem cells was only 1.2% (range 0-47). There was only one case with high expression (47%); the rest was below 7%. Only four of the high risk cases could be analyzed for lineage infidelity marker expression. In these patients, median 51% of the myeloid blasts expressed either CD5 (n=1), CD7 (n=1) or CD56 (n=2). Median expression of these antigens on stem cells in these high risk MDS cases was 44% (range 3-83); three of four cases had high expression (>40%). Overall, expression of CLL-1 and lineage infidelity markers was higher in high risk MDS as compared to the low risk category (p=0.047 and p=0.036 for CLL-1 and lineage infidelity markers, respectively). Of note, the only low risk case with a high percentage (47%) of aberrant stem cells as assessed by flow cytometry rapidly progressed towards AML. To conclude, CLL-1 is virtually absent on stem cells in low and high risk MDS. Nevertheless, expression of lineage infidelity markers, such as CD5, CD7 and CD56, on CD34+CD38− stem cells in some cases strongly suggests that a considerable part of these stem cells was malignant. Aberrant stem cell phenotype as assessed by flow cytometry might discriminate normal from MDS stem cells. This enables further analysis of MDS stem cells and, moreover, makes them amenable for application of targeted therapy. Future analysis might reveal whether the existence of MDS stem cells with an aberrant profile by flow cytometry predicts leukemic evolution. Disclosures:No relevant conflicts of interest to declare.

Radiographic findings of diaphragmatic hernia and hypoplastic lung

Congenital diaphragmatic hernia (CDH) has a poor prognosis, despite intensive management. The prognosis of CDH is correlated with hypoplastic lung, but it is difficult to measure the degree of hypoplasia. The aims of this study were, therefore, to examine the relationship between chest X-ray and prognosis, and to assess whether the radiographic findings were a good indicator of hypoplastic lungs in patients with CDH. Fifty neonates with CDH were classified radiographically into apex and hilar types. To assess the differences in clinical course between these two groups, gestational age, birth weight, prenatal diagnosis, survival rate, requirement of extracorporeal membrane oxygenation (ECMO) therapy and lung area on X-rays were analyzed. In all, 32 cases were of the apex type and 18 were hilar. The survival rate of the hilar group (33%) was significantly worse than that of the apex group (81%) (P<0.001). The hilar group required ECMO therapy more frequently than did the apex group. The present results show a significant correlation between survival rate and the findings of chest X-rays in CDH. Radiographic findings are thus a good clinical indicator of the prognosis of CDH in neonates.

Clinical characteristics of unipolar disorder and bipolar disorder according to the lifetime presence of recurrent panic attacks

The frequent comorbidity of panic and affective disorders has been described in previous studies. However, it is not clear how panic disorder comorbidity in unipolar disorder and bipolar disorder is related to illness course. We compared lifetime clinical characteristics of illness and items of symptomatology in samples of individuals with bipolar I disorder (n = 290) and unipolar disorder (n = 335) according to the lifetime presence of recurrent panic attacks. We found significant differences in clinical course of illness characteristics that were shared across the unipolar and bipolar samples according to the lifetime presence of panic attacks. We also found a number of differences according to the presence of panic attacks that may be specific to the diagnostic group. Distinguishing patients who have mood disorder diagnoses, especially bipolar I disorder, according to the lifetime presence of panic attacks may not only be of use in clinical practice, but may also be informative for aetiological research, such as molecular genetic studies.

Enzyme-Replacement Therapy for Pompe Disease

Pompe disease (α-glucosidase deficiency; also known as glycogen storage disease type II) is the first lysosomal storage disorder for which the biochemical basis was determined. Development of enzyme-replacement therapy for Pompe disease initially involved competing commercial interests and clinical trials using two different enzyme formulations, including one derived from transgenic rabbit’s milk. Further studies have since been conducted with the enzyme generated from transduction of Chinese hamster ovary cells. Therapeutic benefits have been observed in treated patients with either the infantile or late-onset form of Pompe disease; clinical subtypes with marked differences in clinical course and survival. Several factors, including disease duration and antibody formation, appear to influence clinical outcome of enzyme-replacement therapy. Recently, defects of autophagy have been demonstrated; these changes may represent a separate target for therapeutic intervention to optimize outcome. Meanwhile, issues that require further investigation include pathogenesis, ways to improve the means of targeting of recombinant enzyme to skeletal muscle, means to facilitate an early diagnosis and the benefit of early intervention, particularly for the late-onset forms of the disease. Moreover, other therapeutic strategies, such as the use of pharmacologic chaperone and gene therapy, are under investigation.

Differences in clinical course between dementia with Lewy bodies and Alzheimer’s disease

To investigate whether there may be differences in the clinical course and changes in cognitive progression between dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). We compared the time from the first visit to endpoints (discontinuation of visits because of admission, death, or institutionalization) between 56 patients with DLB and 111 patients with AD. Mini-Mental State Examination (MMSE) scores of patients were every 12 months examined up to 60 months. Dementia with Lewy bodies had a significantly shorter time to reaching endpoints than those with AD (median time; 40 months vs. 52 months, P < 0.0001). The proportion of admission (or death) was significantly higher in DLB than in AD (30% vs. 14%, P < 0.05), while the difference in institutionalization in nursing homes did not reach statistical significance (25% vs. 17%). Rates of longitudinal MMSE score decline for DLB and AD groups were equivalent. Dementia with Lewy bodies had a greater risk of admission (or death) because of most commonly fall-related injuries and bronchopneumonia than AD, but the two groups did not differ in rate of cognitive decline.

Expression of C-Type Lectin-Like Molecule-1 (CLL-1) on Stem Cells Might Discriminate De Novo Acute Myeloid Leukemia from Acute Myeloid Leukemia Originating from Myelodysplastic Syndromes

It is generally accepted that myelodysplastic syndromes (MDS) most often originate in a multipotent, myelorestricted progenitor population, although primary transformation may occur at the hematopoietic stem cell level. MDS can be classified into low risk and high risk with evolution to acute myeloid leukemia (AML) predominantly in the latter cases. In AML, survival of leukemia-initiating cells, often referred to as leukemic stem cells, after chemotherapy is thought to lead to minimal residual disease and relapse. Hence, in de novo AML a larger size of the stem cell compartment is predictive for poor survival. [Van Rhenen et al.,Clin Cancer Res 2005,11] The monoclonal antibody against the cell surface antigen C-type lectin-like molecule-1, CLL-1, together with lineage infidelity markers enables discrimination of normal and malignant stem cells. [Van Rhenen et al.,Blood 2007,110; Van Rhenen et al.,Leukemia 2007,21] It could be hypothesized that CLL-1 and aberrant marker expression on MDS stem cells together with size of the stem cell compartment may predict leukemic evolution. Therefore, stem cells, defined as CD45dimCD34+CD38−, were analyzed for expression of CLL-1 and aberrant lineage markers in bone marrow samples from 88 MDS patients classified by WHO as 16 RA w/o RS, 42 RCMD w/o RS, 3 MDS-U, 5 hypoplastic MDS, 6 MDS/MPD and CMML, 15 RAEB-1 and 2, 20 AML patients with a known MDS history and 26 healthy controls. Analysis of the CD34+CD38− frequency in all MDS patients and normal controls revealed no significant differences (median 0.0061% vs. 0.0074%, respectively), whereas the frequency of CD34+CD38− cells was 17-fold higher in high risk MDS (RAEB-1 and 2, median: 0.076%) as compared to low risk MDS (median: 0.0046%, p<0.001). Similar as in AML, stem cells were significantly more prevalent within the blast cell fraction (CD45dimSSCint/low) of high risk MDS as compared to low risk MDS (median 0.77% and 0.25%, respectively), reflecting the differences in clinical course in these patients (p=0.040). Regarding CLL-1 expression, a reliable number of stem cells (>20) could be tested in 11/15 high risk RAEB-1 and 2 cases and in 16/73 of the remaining low risk MDS cases. In these cases, median CLL-1 expression on the CD34+CD38− cells was 1.6% (range 0–50) in low risk and 2.0% (range 0–27) in high risk MDS. Median CLL-1 expression on stem cells was 0.0% (range 0–4.7) in normal controls. Nevertheless, expression of lineage infidelity markers, such as CD5, CD7 and CD56, on CD34+CD38− stem cells in MDS strongly suggests that a considerable part of these stem cells is malignant (median 35% in 7/16 patients tested). Our data show that CLL-1 is virtually absent on stem cells in MDS. Remarkably, median CLL-1 expression on stem cells in AML cases that evolved from MDS (7%, range 0–53, n=9) was manifold lower than in de novo AML (median 45% when excluding non de novo AML [Van Rhenen et al.,Blood 2007,110], p=0.034). Detailed analysis of CLL-1 expression in AML had already revealed that CLL-1 expression increases with differentiation (CD34− > CD34+CD38− > CD34+CD38+). [Bakker et al.,Cancer Res 2004,64;Van Rhenen et al.,Blood 2007,110] Thus, our data suggest that the CD34+CD38− cells in high risk MDS and AML with antecedent MDS are more immature than in most de novo AML, which might explain poor prognosis of AML cases with MDS history. To conclude, our data indicate that CLL-1 is a specific marker of de novo AML, while CLL-1-negative AML may have been evolved from a MDS pre-phase that is further characterized by an increasing size of the stem cell compartment upon progression towards AML.

High Resolution Karyotyping of Large Granular Lymphocyte Leukemia by SNP Arrays Reveals Clonal Defects Leading to LOH at Loci Integral to Lymphocyte Function.

Large granular lymphocyte leukemia (LGL leukemia) is a semiautonomous clonal lymphoproliferation of cytotoxic T cells associated with various immune cytopenias. Within the spectrum of acquired immune-mediated bone marrow failure states, LGL leukemia can serve as monoclonal model of usually polyclonal T cell-mediated pathology. Mechanisms of unopposed clonal expansion of LGL cells in many aspects resemble true lymphoma and are not well understood. In addition to its reactive character, intrinsic clonal defects may be present in some patient with LGL, in particular those with more pronounced lymphoproliferative features. However, unlike in B-cell lymphomas, recurrent chromosomal abnormalities have not been frequently identified in LGL leukemia using traditional metaphase karyotyping techniques. We have applied Affymetrix 250K single nucleotide polymorphism-arrays (SNP-A) and 6.0 SNP-A in 28 patients with LGL leukemia, to elicit a far higher resolution of chromosomal content through genomic mapping of individual SNP and respective copy number analysis in LGL leukemia. SNP-A based cytogenetics have been applied successfully to MDS patients and has increased prognostic reliability. Blood mononuclear cells containing high proportion of clonal cells as determined by TCR Vβ flow cytometry were used as a source of DNA. For comparison, a large number of control blood and marrow specimens (N=119 for 6.0 and 124 for 250K SNP arrays) were analyzed. Data were processed using Genotyping Console v2.1 software (Affymetrix, Santa Clara, CA). After exclusion of known copy number variants (CNV) referenced in public databases and our own set of 178 normal controls, we found distinct chromosomal changes in 16/28 (57%) of LGL leukemia patients. Consensus regions of deletion/gain or uniparental disomy (UPD) were identified. The most common abnormalities included either UPD or copy number loss of chromosome 3q21.2–q21.31, which was identified in 6 (21%) patients. This region harbors CD86, the gene encoding the B7.2 protein responsible for T cell activation and regulation through costimulatory mechanisms. Copy number loss/UPD was also identified at chromosome 1p31.1–p32.3 in 4 (18%) patients. Interestingly, copy number gain in this same region was identified in 2 (9%) patients suggesting that this region may correspond to either a new, infrequent germ line encoded CNV or represents a somatic microdeletion. Recent studies indicated a role for SIL/SCL, which resides at this locus, in V(D)J recombination, lymphocyte development, and maturation. Additional conserved chromosomal abnormalities included copy number gains in 14q (11%) and copy number loss at 11p15 (14%), all possibly representing germ line or somatic CNV physiologically acquired during lymphocyte ontogenesis. We compared chromosomal lesions identified in our LGL cohort with clinical features including age, presence of neutropenia, anemia, thrombocytopenia, splenomegaly, immunophenotype, and degree of clonal expansion. No difference in clinical course was found between patients with and without cytogenetic abnormalities with regard to type and severity of cytopenias or size of the LGL clone. However, patients with 1p31.1–p32.3 deletions were found to have lesser degree of neutropenia compared to patients without 1p31.1–p32.3 deletions (p<0.001). While these data may reflect chromosomal variants and random somatic abnormalities, the recurrent loss of heterozygosity and gains within several loci with known regulatory function for lymphocyte biology suggests the involvement of these defects in the mechanism of clonal evolution.

Inhaled nitric oxide for acute chest syndrome in people with sickle cell disease.

Acute chest syndrome has been defined as a new infiltrate visible on chest radiograph associated with one or more symptoms, such as fever, cough, sputum production, tachypnea, dyspnea, or new-onset hypoxia. Symptoms and complications of this syndrome, whether of infectious or non-infectious origin, vary quite widely in people with sickle cell disease. Lung infection tends to predominate in children, whilst infarction appears more common in adults. However, these are often interrelated and may occur concurrently. The differences in clinical course and severity are suggestive of multiple causes for acute chest syndrome. Successful treatment depends principally on high-quality supportive care. The syndrome and its treatment have been extensively studied, but the response to antibiotics, anticoagulants, and other conventional therapies remains disappointing. The potential of inhaled nitric oxide as a treatment option has more recently provoked considerable interest. Nitric oxide appears to play a major role in both the regulation of vascular muscle tone at the cellular level and in platelet aggregation (clumping). Much of the pathophysiology of sickle cell disease is consistent with a mechanism of nitric oxide depletion and although there has been extensive research on the pathophysiology of acute chest syndrome, the possible therapeutic role of inhaled nitric oxide for acute chest syndrome in sickle cell disease is still to be determined. To assess the effectiveness of inhaled nitric oxide for treating acute chest syndrome by comparing improvement in symptoms and clinical outcomes against standard care. We searched The Group's Haemoglobinopathies Trials Register, which comprises references identified from comprehensive electronic database searches and handsearching of relevant journals and abstract books of conference proceedings. In July 2007 the following clinical trials registers were searched: ClinicalTrials.gov (www.clinicaltrials.gov/); the WHO International Clinical Trials Registry Platform (www.who.int/trialsearch/); Current Controlled Trials (www.controlled-trials.com/) and CLINICALTRIALS.COM (www.clinicaltrials.com/). Most recent search of the Trials Register: November 2007. All randomised or quasi-randomised controlled trials of people with sickle cell disease suffering from acute chest syndrome, comparing the use of inhaled nitric oxide to placebo or standard care for any single or multiple treatment and over any time period. No studies identified were eligible for inclusion. No studies identified were eligible for inclusion. There is a need for well-designed, adequately-powered randomised controlled trial to assess the benefits and risks of this form of treatment as an adjunct to established therapies.

Sporadic Cutaneous Angiosarcomas: A Proposal for Risk Stratification Based on 69 Cases

Angiosarcomas have traditionally been considered high-grade lesions for which histologic features and grading have played no role in prognostication and, consequently, they have been excluded from the American Joint Committee on Cancer staging system. We have, therefore, analyzed 69 cutaneous angiosarcomas seen in consultation and not associated with lymphedema or prior radiation therapy to determine if a combination of histologic and clinical parameters could be used to differentiate indolent from aggressive tumors. The clinical features analyzed included patient age, location, size, depth, and focality of the lesion; the histologic features studied included pattern of growth (vasoformative vs. solid), nuclear grade (high vs. low), necrosis (present/absent), cell type (epithelioid or spindled), extent of inflammatory infiltrate (minimal vs. marked), and mitotic rate. Lesions occurred on the head/neck (49), extremities (15), and trunk (5) of adults (21 to 94 y) and predominated in males (41 males; 28 females). Tumors ranged in size from 0.3 to 15 cm (average 3.1 cm) and involved the papillary (n=9), reticular (n=16), or deep dermis/ subcutis (n=30). They could be predominantly vasoformative (n=28) to solid (greater than 50% solid, n=41). Most lesions were of high (n=65) as opposed to low (n=4) nuclear grade, were mitotically active (0 to 99/10 high power fields), and occasionally displayed necrosis (n=14) and epithelioid features (n=21). Inflammatory infiltrates were minimal in most cases. Follow-up information was obtained for all patients. Recurrences developed in 18 patients (26%) and metastasis in 15 (22%) to the following sites: lung (6), lymph node (7), liver (2), bone (2), and parotid gland (1). Forty-seven patients died (30 of disease) and 22 were alive at last known follow-up (range, 16 to 158 mo; mean, 65; median, 36). Five-year disease-specific survival was 48%. By univariate analysis only older age, anatomic site, necrosis, and epithelioid features correlated with increased mortality. Tumors were stratified into low (n=41) or high (n=28) risk groups based on necrosis and/or epithelioid features. By multivariable analysis, high-risk group (hazard ratio 4.07, P=0.0004) and age >70 (hazard ratio 2.79, P=0.012) were associated with increased mortality, and tumor depth (P=0.048) correlated with the risk of local recurrence. The high-risk group had a significantly worse prognosis than the low-risk group with 3-year survival of 24% and 77%, respectively. No patients with high-risk features survived 5 years. In conclusion, we report that a combination of clinical and histologic features allows stratification of angiosarcoma patients into 2 risk groups that are strongly associated with marked differences in clinical course. These features seem to diminish in importance with increased tumor size and are probably most useful in tumors less than 5 cm in maximum dimension.

Obsessive-Compulsive Spectrum Disorders:Cross-national and Ethnic Issues

Epidemiological and clinical data from a variety of cultural and geographic settings on obsessive-compulsive disorder (OCD), and many of the obsessive-compulsive spectrum disorders, suggest that this is a group of disorders with a good degree of transcultural homogeneity. However, the content and themes that predominate in patients with these disorders, and the course of illness, can be shaped by cultural, ethnic, and religious experiences. Across cultures, OCD is commonly comorbid with mood, anxiety, and impulse-control disorders. However, little is known about the mechanisms by which culture and ethnicity may affect the expression of OCD and related disorders. Cross-national comparative studies exploring culturally influenced differences in clinical course, treatment outcome, including ethnogenetic differences in drug response, and prognosis are needed.

Hemoglobin E Syndromes

Hemoglobin (Hb) E is one of the world's most common and important mutations. It results in a heterogeneous group of disorders whose phenotype range from asymptomatic to severe. Hb E trait and Hb EE are mild disorders. The combination of Hb E and Hb S (Hb SE) results in a sickle cell disease syndrome similar to sickle beta(+) thalassemia. It is important to distinguish Hb E disorders diagnostically because of this marked difference in clinical course among different genotypes. Screening tests, including hemoglobin electrophoresis and high-pressure liquid chromatography (HPLC), may suggest other mutations, unless one is familiar with the findings. E beta-thalassemia, the most serious form of E syndromes, affects a million people worldwide and is increasing in North America. Its phenotype ranges from mild anemia to severe transfusion-dependent thalassemia major. Several genetic modifiers affect the phenotype, including the type of beta-thalassemia mutation, Hb F levels, and co-inheritance of alpha-thalassemia. However, the cause of the phenotypic variability is largely unknown. A prospective natural history study of E beta-thalassemia in Sri Lanka suggests that environmental modifiers are prognostically important. The clinical course of E beta-thalassemia is punctuated by acute and chronic complications that may cause serious morbidity and mortality. Recent studies indicate these patients are at high risk for thromboembolism secondary to a hypercoagulable state increased by splenectomy. Morbidity from iron overload in nontransfused patients secondary to increased gastrointestinal iron absorption is common. Cardiopulmonary disease, including pulmonary hypertension, requires ongoing monitoring and is secondary to iron overload, thromboembolism, and hemolysis-induced nitric oxide deficiency. These patients are excellent candidates for Hb F-modulating agents because moderate changes in hemoglobin may result in marked improvement in phenotype. Recent studies with hydroxyurea indicate 40% of patients will clinically improve with hydroxyurea.

Training program design of a screen based simulator for neonatal cerebral function monitoring.

The cerebral function monitor (CFM) is a device to monitor the cerebral function of newborns at the neonatal intensive care unit (NICU). This relatively new device is used by nurses, residents and doctors of the neonatology department. Their experience in these types of signals is limited and training is needed for an optimal use of the monitor in performance and interpretation of the signals. In the training program design of this screen based simulator, we address subsequently a theoretical introduction, placement of the electrodes, the quality of the signal, recognition of artefacts and interpretation of signals of specific pathologies. In each section the trainee will be tested by his/her actions and by multiple choice questions. Positive feedback and explanations of answers will be given by the program. The scenarios included in the program are birth asphyxia and movements that could be seizures. In addition, attention will be paid to differences in clinical course of disease and effects of medication, with respect to the occurrence of seizures and change in back ground pattern. Different types of artefacts are included as well. The program features different levels of skills for doctors and nurses as well as a review mode where the theoretical introduction, placement of electrodes and the questions will be left out. Using this program, we aim to improve the adequate use of the CFM and hence increase the quality of care in the NICU.

Scope and significance of non-uniform classification practices in breast cancer with non-inflammatory skin involvement: a clinicopathologic study and an international survey

The study evaluates the scope of non-uniform classification practices concerning breast carcinomas with non-inflammatory skin involvement. We compared the clinical course of patients with histologically proven non-inflammatory skin involvement: 119 (65.4%) with clinically obvious 'classical' skin changes (Group A) and 63 (34.6%) with no or only discreet changes (Group B). A questionnaire was circulated to pathology departments in 24 countries to assess the practice concerning the placement of skin- involved breast carcinomas in the TNM classification. Patients in Group B showed a significantly better disease specific survival (P=0.0002). Eighty-six respondents (70.5%) of the survey preferred the 'histological view' and classified tumors with only histological proven skin involvement as T 4 b/stage IIIB. The opposing classification principle ('clinical view'), which dictates that T 4 b breast cancer is a clinical diagnosis and the classical signs must be present, was supported by 31 respondents (25.4%). A large number of breast cancer patients with non-inflammatory skin involvement are only histologically proven and show, compared with cases exhibiting the classical clinical signs, significant differences in clinical course and prognosis. In general, both subsets were aggregated in one T category/stage (T 4 b/IIIB). This results in a considerable distortion of the reported statistical data.

Minimal Access via Lower Partial Sternotomy for Congenital Heart Defects

To evaluate the invasiveness of a minimal access approach for simple congenital heart defects, and determine whether it can be regarded as a standard operation, 83 patients with an atrial septal defect and 73 with a ventricular septal defect underwent repair through a minimal skin incision and lower partial median sternotomy. There were no operative deaths, severe intraoperative complications, or conversion to full sternotomy. The clinical course of 106 patients was compared with that of 21 treated using a full sternotomy by the same surgeon; there were no significant differences, except in the operative time for ASD patients. The clinical courses of 2 minimal access subgroups (50 patients operated on by residents and 106 treated by the staff surgeon were compared; operative time, bypass time, ventricular fibrillation time (ASD repair), and cardiac arrest time (VSD repair) were significantly shorter in those operated on by the staff surgeon, but there was no difference in clinical course. The minimal access approach produced good cosmetic results, its invasiveness was similar to that of a full sternotomy, and it may be considered a standard operation for pediatric patients with septal defects.