Patients In Early Stages Of Disease Research Articles

Quality of life in Chilean breast cancer survivors

Quality of Life (QOL) assessment may evaluate the impact of diseases and their treatment on the overall well-being of patients. To assess QOL in Chilean breast cancer survivors. Ninety one female breast cancer patients aged 60 ± 10 years, who finished their oncologic treatment at least a year prior to the assessment, who were disease free and in medical follow-up were included in the study. They completed the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 core questionnaire and the breast cancer module QLQ-BR23. Forty eight percent of respondents were long term survivors (more than five years). Global QOL scores were high (73.6 ± 18.2), emotional scale had the lowest scores in QLQ-C30 functional scales (72.1). Symptoms with the highest scores were: Insomnia (= 21.2), pain (= 20.8), and fatigue (= 19.1). Body image, sexual function, and concern about the future were the most relevant problems. Body image was superior in patients with breast-conserving surgery (p = 0.008), and cognitive function was better in patients in early disease stage (p = 0.03) and in those with more than five years of survival (p = 0.04). Even when global QOL scores were high, some symptoms were prevalent. Awareness about these problems and symptoms should improve their diagnosis and treatment.

Tissue damage within normal appearing white matter in early multiple sclerosis: assessment by the ratio of T1- and T2-weighted MR image intensity.

Histopathological and magnetic resonance imaging (MRI) studies have shown white matter (WM) damage in early stages of multiple sclerosis (MS) beyond the apparent T2-hyperintense lesions. These changes in normal appearing WM (NAWM) are important with regard to the clinical picture and prognosis. However, the detection of changes within NAWM has so far required special imaging techniques commonly not available in clinical routine and, hence, at large scale. The purpose of this study was to detect MS-related damage of NAWM by conventional MRI. As, within NAWM, the myelin content mainly drives the T1-weighted (T1w) signal, we scaled it by the T2w signal. We tested the hypothesis that the mean T1w/T2w ratio of NAWM is decreased in MS compared to healthy controls (HC) and that it correlates with clinical measures. We developed a pipeline to determine the individual mean values of this ratio within NAWM. We studied 244 patients in early disease stages of MS (mean age 37±10years, mean disease duration 3.1±2.3, Expanded Disability Status Scale 1.3±1), and 78 HC (mean age 31±8years). Compared to HC, the mean T1w/T2w ratio was lowered in the patient group (P<0.001). The difference remained significant after restricting the analysis to patients with a disease duration of 5years or less and without disease modifying drugs. Our measures also correlated with clinical scores. We believe that the mean T1w/T2w ratio is a promising candidate to assess MS-related tissue damage within NAWM at large scale.

Long-term outcomes of patients with esthesioneuroblastomas: A cohort from a single institution

Esthesioneuroblastoma is a rare cancer. The purpose of this study was to review the long-term outcomes of patients with esthesioneuroblastomas (ENBs) who were treated at a single institution. One hundred thirteen patients with biopsy-proven ENBs between June of 1979 and November of 2014 were retrospectively reviewed. There was 1 patient at stage A, 23 stage B and 89 stage C according to Kadish classifications. The initial treatments included pre-operative radiotherapy (RT) followed by surgery in 11 patients, surgery followed by post-operative RT in 51, primary RT in 47, and surgery in 3, and only a single patient was treated with palliative chemotherapy alone. The median follow-up was 75months, 5-year overall survival (OS), loco-regional control rate (LRC) and distant metastasis-free survival were 65%, 73% and 67%, respectively. The OSs at 5years were 91% in the pre-operative RT group, 82% in the post-operative RT group, and 50% in the primary RT group (p<0.001). Regarding the patients in early disease stages (Kadish A/B), no survival differences were observed between primary RT and combination treatment. Regarding the node-negative Kadish C disease patients, combination of surgery and RT elicited superior survival, and pre-operative RT yielded the best prognoses. Distant failure rate is over 60% for N-positive disease, chemotherapy may play a more important role. The optimal treatment policy for ENBs remains the combination of surgery and radiotherapy. When choosing the most adequate therapy for ENBs, disease stage, age and lymph nodes status should be taken into consideration.

International validation of the Chinese university prognostic index for staging of hepatocellular carcinoma: a joint United Kingdom and Hong Kong study.

The outcome of hepatocellular carcinoma (HCC) patients significantly differs between western and eastern population centers. Our group previously developed and validated the Chinese University Prognostic Index (CUPI) for the prognostication of HCC among the Asian HCC patient population. In the current study, we aimed to validate the CUPI using an international cohort of patients with HCC and to compare the CUPI to two widely used staging systems, the Barcelona Clinic Liver Cancer (BCLC) classification and the Cancer of the Liver Italian Program (CLIP). To accomplish this goal, two cohorts of patients were enrolled in the United Kingdom (UK; n = 567; 2006-2011) and Hong Kong (HK; n = 517; 2007-2012). The baseline clinical data were recorded. The performances of the CUPI, BCLC, and CLIP were compared in terms of a concordance index (C-index) and were evaluated in subgroups of patients according to treatment intent. The results revealed that the median follow-up durations of the UK and HK cohorts were 27.9 and 29.8 months, respectively. The median overall survival of the UK and HK cohorts were 22.9 and 8.6 months, respectively. The CUPI stratified the patients in both cohorts into three risk subgroups corresponding to distinct outcomes. The median overall survival of the CUPI low-, intermediate-, and high-risk subgroups were 3.15, 1.24, and 0.29 years, respectively, in the UK cohort and were 2.07, 0.32, and 0.10 years, respectively, in the HK cohort. For the patients who underwent curative treatment, the prognostic performance did not differ between the three staging systems, and all were suboptimal. For those who underwent palliative treatment, the CUPI displayed the highest C-index, indicating that this staging system was the most informative for both cohorts. In conclusion, the CUPI is applicable to both western and eastern HCC patient populations. The performances of the three staging systems differed according to treatment intent, and the CUPI was demonstrated to be optimal for those undergoing palliative treatment. A more precise staging system for early-stage disease patients is required.

Health-related quality of life and chronic obstructive pulmonary disease in early stages - longitudinal results from the population-based KORA cohort in a working age population.

BackgroundIt is widely recognized that health-related quality of life (HRQL) is impaired in patients with Chronic Obstructive Pulmonary Disease (COPD), but there is a lack of research on longitudinal associations of COPD and HRQL. This study examined the effects of COPD in early stages of disease on HRQL over ten years in a working-age general population setting in Southern Germany while considering the influence of common comorbidities.MethodsIn the population-based KORA F4 study (2006–08) 1,321 participants aged 41–61 years performed spirometry and reported information on HRQL (measured by the generic SF-12) and comorbidities. For the same participants, HRQL information was available seven years before and three years after the lung function test from the previous S4 (1999–2001) and the F4L follow-up study (2010). Using linear mixed models, the physical and mental component summary scores (PCS-12 / MCS-12) of the SF-12 were compared over time between COPD groups.Results7.8% of participants were classified as having COPD (according to the LLN definition and the Global Lungs Initiative), 59.4% of them in grade 1. Regression models showed a negative cross-sectional association of COPD grade 2+ with PCS-12 which persisted when comorbidities were considered. Adjusted mean PCS-12 scores for the COPD grade 2+ group were reduced (−3.5 (p = 0.008) in F4, −3.3 (p = 0.014) in S4 and −4.7 (p = 0.003) in F4L) compared to the group without airflow limitation. The size of the COPD effect in grade 2+ was similar to the effect of myocardial infarction and cancer. Over ten years, a small decline in PCS-12 was observed in all groups. This decline was larger in participants with COPD grade 2+, but insignificant. Regarding MCS-12, no significant cross-sectional or longitudinal associations with COPD were found.ConclusionDespite small HRQL differences between COPD patients in early disease stages and controls and small changes over ten years, our results indicate that it is important to prevent subjects with airflow limitation from progression to higher grades. Awareness of HRQL impairments in early stages is important for offering early interventions in order to maintain high HRQL in COPD patients.

Telomere dysfunction accurately predicts clinical outcome in chronic lymphocytic leukaemia, even in patients with early stage disease.

Defining the prognosis of individual cancer sufferers remains a significant clinical challenge. Here we assessed the ability of high-resolution single telomere length analysis (STELA), combined with an experimentally derived definition of telomere dysfunction, to predict the clinical outcome of patients with chronic lymphocytic leukaemia (CLL). We defined the upper telomere length threshold at which telomere fusions occur and then used the mean of the telomere 'fusogenic' range as a prognostic tool. Patients with telomeres within the fusogenic range had a significantly shorter overall survival (P<0·0001; Hazard ratio [HR]=13·2, 95% confidence interval [CI]=11·6-106·4) and this was preserved in early-stage disease patients (P<0·0001, HR=19·3, 95% CI=17·8-802·5). Indeed, our assay allowed the accurate stratification of Binet stage A patients into those with indolent disease (91% survival at 10years) and those with poor prognosis (13% survival at 10years). Furthermore, patients with telomeres above the fusogenic mean showed superior prognosis regardless of their IGHV mutation status or cytogenetic risk group. In keeping with this finding, telomere dysfunction was the dominant variable in multivariate analysis. Taken together, this study provides compelling evidence for the use of high-resolution telomere length analysis coupled with a definition of telomere dysfunction in the prognostic assessment of CLL.

Anti-CD3 monoclonal antibody as a possible therapeutic alternative in HAM/TSP

Anti-CD3 antibody therapy is used to treat transplant rejection and has been applied in several autoimmune diseases, such as type I diabetes and ulcerative colitis, but its potential in HAM/TSP has not been investigated. Therefore, we explored the effect of ex vivo treatment (24-96h) of PBMCs from HAM/TSP patients (n=15) and healthy controls (n=20, all from Salvador-Bahia, Brazil) with an anti-CD3 monoclonal antibody approved for in vivo treatment post-transplantation (produced under GMP conditions). In contrast to normal donors and patients in early disease stages, anti-CD3 treatment did not increase lymphoproliferation in PBMCs from advanced HAM/TSP patients (EDSS>4), but strongly induced apoptosis. In addition, anti-CD3 treatment did not induce a pro-inflammatory cytokine storm, either at the protein or mRNA level. Therefore, anti-CD3 treatment ex vivo might eliminate pathogenic T cells through activation-induced cell death. Since we have previously shown that pro-apoptotic capacity decreases over time in HAM/TSP patients, both defective (Fas-mediated) apoptosis and excessive lymphoproliferation, more pronounced in patients with advanced disease progression, can be restored by anti-CD3 treatment. Using microarray analysis, we found that treatment of HAM/TSP PBMCs with anti-CD3 mAb had a pronounced effect on gene expression, significantly (p<0.001) down-regulating 1918 genes (including pro-inflammatory genes) and up-regulating 1926 genes, including cell cycle-related and immunoregulatory genes, such as CTLA4. In conclusion, our results suggest anti-CD3 monoclonal antibody might be a possible therapeutic alternative in HAM/TSP, due to its immunomodulatory effect, by inducing apoptosis, reducing exacerbated lymphoproliferation and stimulating anti-inflammatory gene expression and/or proliferation of cells with immunoregulatory capacity.

Was ist gesichert in der Therapie der axialen Spondyloarthritis?

The new term axial spondyloarthritis (axSpA) includes classic ankylosing spondylitis and non-radiographic (nr-) axSpA. The definition was introduced in 2009 as part of the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axSpA, where-apart from chronic back pain starting before the age of 45years and the presence of HLA-B27-magnetic resonance imaging demonstrated bone marrow edema of the sacroiliac joints (osteomyelitis) or structural changes on x-rays may play an important role. These criteria can also be used for diagnosis. A major advantage of the new criteria is the identification of patients in early disease stages. In addition to physical therapy, drug treatment with steroidal anti-inflammatory agents (NSAIDs), corticosteroid injections, and biologics [blocker of tumor necrosis factor (TNF)] have all been shown to be effective, while conventional disease modifying drugs (DMARDs) such as sulfasalazine and methotrexate seem to work mainly for peripheral arthritis but not for enthesitis. Biologics are indicated when NSAIDs in optimal dosage have failed. Both these drugs have the potential to improve pain, stiffness, and function but they may also have an influence on new bone formation (syndesmophytes). NSAIDs need to be given continuously and biologics for longer periods of time. Patients with elevated C-reactive protein levels benefit most when treated consequently.

TLTF in Cerebrospinal Fluid for Detection and Staging of T. b. gambiense Infection

BackgroundTrypanosome-derived lymphocyte triggering factor (TLTF) is a molecule released by African trypanosomes that interacts with the host immune system, resulting in increased levels of IFN-γ production.Methodology/Principal findingsTLTF and anti-TLTF antibodies were assessed in sera and cerebrospinal fluid (CSF) from patients infected with Trypanosoma brucei gambiense (T. b. gambiense) in an attempt to identify alternative markers for diagnosis and stage determination of human African trypanosomiasis or sleeping sickness. Seventy-four serum and sixty-one CSF samples from patients with parasitologically confirmed infection and known disease stage along with 13 sera and CSF from uninfected controls were tested. In serum the levels of anti-TLTF antibodies were unrelated to the disease stage. In contrast, levels of anti-TLTF antibodies in CSF were higher in intermediate/late stages than in early stage disease patients. Specificity of the detected antibodies was assessed by inhibition of TLTF bioactivity as represented by its ability to induce IFN-γ production. Additionally, TLTF was detected in CSF from late stage patients by Western blotting with the anti-TLTF specific monoclonal antibody MO3.Conclusions/SignificanceThese findings suggest a new possibility for disease diagnosis with focus on involvement of the CNS through detection of TLTF and anti-TLTF antibodies in the CSF.

Dendritic Cell-Based Vaccination for Renal Cell Carcinoma: Challenges in Clinical Trials

After decades of research, dendritic cell (DC)-based vaccines for renal cell carcinoma have progressed from preclinical rodent models and safety assessments to Phase I/II clinical trials. DC vaccines represent a promising therapy that has produced measurable immunological responses and prolonged survival rates. However, there is still much room to improve in terms of therapeutic efficacy. The key issues that affect the efficiency and reliability of DC therapy include the selection of patients who will respond best to treatment, the proper preparation and administration of DC vaccines, and a combination of DC vaccination with other immune-enhancing therapies (e.g., removal of Tregs, CTLA-4 blockade and lymphodepletion). Additional antiangiogenic agents will hopefully lead to greater survival benefits for patients in early disease stages. This review focuses on the different approaches of DC-based vaccination against renal cell carcinoma and potential strategies to enhance the efficacy of DC vaccination.

Analysis of baseline parameters in the HALT polycystic kidney disease trials

HALT PKD consists of two ongoing randomized trials with the largest cohort of systematically studied patients with autosomal dominant polycystic kidney disease to date. Study A will compare combined treatment with an angiotensin-converting inhibitor and receptor blocker to inhibitor alone and standard compared with low blood pressure targets in 558 early-stage disease patients with an eGFR over 60 ml/min per 1.73 m(2). Study B will compare inhibitor-blocker treatment to the inhibitor alone in 486 late-stage patients with eGFR 25-60 ml/min per 1.73 m(2). We used correlation and multiple regression cross-sectional analyses to determine associations of baseline parameters with total kidney, liver, or liver cyst volumes measured by MRI in Study A and eGFR in both studies. Lower eGFR and higher natural log-transformed urine albumin excretion were independently associated with a larger natural log-transformed total kidney volume adjusted for height (ln(HtTKV)). Higher body surface area was independently associated with a higher ln(HtTKV) and lower eGFR. Men had larger height-adjusted total kidney volume and smaller liver cyst volumes than women. A weak correlation was found between the ln(HtTKV) and natural log-transformed total liver volume adjusted for height or natural log liver cyst volume in women only. Women had higher urine aldosterone excretion and lower plasma potassium. Thus, our analysis (1) confirms a strong association between renal volume and functional parameters, (2) shows that gender and other factors differentially affect the development of polycystic disease in the kidney and liver, and (3) suggests an association between anthropomorphic measures reflecting prenatal and/or postnatal growth and disease severity.

Prognostic Significance of Telomere Length in Chronic Lymphocytic Leukemia Patients in Early Stage Disease,

Abstract 3890Chronic lymphocytic leukemia (CLL) is a genetically heterogeneous disease with a variable outcome. The identification of factors that could predict the clinical course of early-stage CLL represents a crucial objective. Although previous studies indicated that telomere length may be a useful independent prognostic factor in the risk stratification of CLL, limited information has been reported in asymptomatic early stage patients (Binet stage A). We investigate the association of telomere length with the major biological and cytogenetic markers known to predict clinical outcome in CLL. The global DNA methylation levels of Alu and LINE sequences, was also investigated. Correlation with disease progression, measured as the time elapsed from diagnosis to first treatment, was evaluated. We measured relative telomere length (RTL) by real-time PCR in a panel of highly purified (>90%) peripheral mononuclear CD19+ cells from 7 healthy donors and 77 untreated CLLs. All the cases were characterized by FISH for the most frequent chromosomal aberrations (Fabris et al. GCC, 2008). Molecular markers including mutation status of the heavy chain variable regions of immunoglobulin genes (IGVH), the expression of the 70-kd zeta-chain T-cell receptor-associated protein kinase (ZAP-70) and CD38 cell surface antigen protocols were previously reported (Cutrona et al., Haematologica, 2008). A quantitative bisulfite-PCR Pyrosequencing method was used to evaluate methylation of Alu and LINE-1. We found a significantly lower RTL values in CLLs (median RTL=0.4 IQR 0.3–0.6) as compared with controls (median RTL=1.0 IQR 0.9–1.3) (P <0.001). A progressive and significant RTL decrease in low (13q- and normal karyotype), intermediate (+12) and high (11q- and 17p-) cytogenetic risk categories (P for trend =0.008) was observed. Patients with IGVH mutated genes had longer telomeres than patients with unmutated genes (P <0.001). No significant association between telomere length and either CD38 or ZAP-70 expression was found. Telomere shortening was significantly correlated with hypomethylation of Alu (P =0.048) and LINE-1 (P =0.001), indicating a contribution to chromosome instability. Finally, follow-up analysis showed a significantly higher risk of starting treatment for patients with shorter telomeres (P =0.0037). Our results extended previous evidence that telomere length could be used as marker for the identification of CLLs with a different prognostic risk. Disclosures:No relevant conflicts of interest to declare.

Abstract 1229: Prognostic significance of telomere length in B-chronic lymphocytic leukemia patients in early stage disease

Abstract BACKGROUND: Cell chronic lymphocytic leukemia (CLL) is a genetically heterogeneous disease with a variable outcome. The identification of factors that could predict the clinical course of early-stage CLL represents a crucial objective in this malignancy. Although previous studies indicated that telomere length may be a useful independent prognostic factor in the risk stratification of CLL patients, limited information has been reported in asymptomatic early stage patients (Binet stage A). OBJECTIVES: The present study was aimed at investigating the association of telomere length with the major biological and cytogenetic markers known to predict clinical outcome in CLL. The global DNA methylation of repeat sequences, Alu and LINE-1, both associated with chromosomal instability, was also studied. Finally, correlation with disease progression, measured as the time elapsed from diagnosis to first treatment, was evaluated. METHODS: We measured relative telomere length (RTL) by real-time PCR in a panel of highly purified (&amp;gt;90%) peripheral mononuclear CD19+ cells from 7 healthy donors and 77 untreated CLL patients. All cases were characterized by FISH for the most frequent chromosomal aberrations, namely trisomy of chromosome 12 and deletions at 17p13.1, 11q22.3 and 13q14.3 loci (Fabris et al. GCC, 2008). Molecular markers including mutation status of the heavy chain variable regions of immunoglobulin genes (IGVH), the expression of the 70-kd zeta-chain T-cell receptor-associated protein kinase (ZAP-70) and CD38 cell surface antigen protocols were previously reported (Cutrona et al. Haematologica, 2008). A quantitative bisulfite-PCR Pyrosequencing method was used to evaluate methylation of Alu and LINE-1. RESULTS: We found a significantly lower RTL values in CLLs (median RTL=0.4 IQR 0.3-0.6) as compared with controls (median RTL=1.0 IQR 0.9-1.3) (P &amp;lt; 0.001). A progressive and significant RTL decrease in low (13q- and normal karyotype), intermediate (+12) and high (11q- and 17p-) cytogenetic risk categories (P for trend =0.008) was observed. Patients with IGVH mutated genes had longer telomeres than patients with unmutated genes (P&amp;lt;0.001). No significant association between telomere length and either CD38 or ZAP70 expression was found. In line, telomere shortening was significantly correlated with hypomethylation of Alu (P=0.048) and LINE-1 (P=0.001), indicating a contribution to chromosome instability. Finally, follow-up analysis, available for 63 patients, showed a significantly higher risk of starting treatment for patients with shorter telomeres (P=0.037) CONCLUSIONS: Our results extended previous evidence that telomere length could be used as marker for the identification of different CLL prognostic subgroups. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1229. doi:10.1158/1538-7445.AM2011-1229

Minimale Resterkrankung beim Magenkarzinom - eine Übersicht

Despite recent developments in therapy for gastric cancer, the prognosis of this disease remains poor in advanced stages. In many cases even curatively treated patients without any residual tumour develop metachronous metastases. As in other solid tumours, adjuvant therapies can reduce the metastatic risk, which implies that some of these patients harbour isolated tumour cells or micrometastases (minimal residual disease, MRD) that are undetectable by radiological imaging and conventional histopathology but can still be the cause of tumour recurrence. Therefore, reliable methods for diagnosing MRD would be desirable for individually tailoring therapy for these patients. Unfortunately, testing methods for MRD and interpretation of their results are not standardised and studies published on this topic are difficult to interpret due to methodological differences and small sample sizes. As of now, testing for MRD has not become relevant in clinical routine for any of the anatomic compartments lymph nodes, peritoneal lavage fluid, peripheral blood, and bone marrow in the Western hemisphere. Most reliable data on MRD in gastric cancer patients have been reported for peritoneal lavage fluid. In some centres in Japan, this test is routinely being used for making therapeutic decisions, e. g., on the use of intraperitoneal chemotherapy. MRD in resected lymph nodes will be further evaluated in the context of the sentinel lymph node concept and possibly be employed for designing individualised therapy for patients in early disease stages who are not routinely candidates for multimodal treatment. As for tumour cells in peripheral blood and in bone marrow, studies suggest that these cells are only able to form metastases in the presence of certain molecular factors. Therefore, rather than simply confirming the existence of isolated tumour cells in blood or bone marrow, future studies should concentrate on defining their molecular characteristics and the conditions required for their metastatic potential. This may gain relevance in diagnostics and prognostic evaluation of individual patients as well as in the development of targeted therapies directly interfering with the metastatic process.

Increased activity and improved outcome in unrelated donor haemopoietic cell transplants for acute myeloid leukaemia in Australia, 1992–2005

Numbers of unrelated donor allogeneic haemopoietic cell transplants (HCT) for acute myeloid leukaemia have increased in Australia in recent years. The aims of this study were to investigate the components of this change and find contributing factors to changes in outcome. The study method was a retrospective analysis of 213 consecutive first unrelated donor HCT for acute myeloid leukaemia performed within Australia for adult patients during the years of 1992-1997 (n= 43) and 1998-2005 (n= 170). The proportion of patients transplanted in first or second complete remission (CR) increased markedly from 21% in 1992-1997 to 52% in 1998-2005. The cumulative incidence of relapse at 1 year post HCT was significantly lower for the later cohort (22% vs 30%, P= 0.04) and for patients transplanted in CR compared with those not in CR (16% vs 31%, P= 0.01). The overall survival probability was significantly better at 5 years post HCT for patients transplanted in 1998-2005 compared with 1992-1997 (40% vs 21%, P= 0.04). Multivariate analysis identified five independent significant favourable factors for survival among the whole patient group: age under 40 years, transplant in CR1, CR2 or first relapse, patient CMV seronegativity, good performance status and year of transplant within 1998-2005. The later cohort of patients had improved survival even after allowing for the effects of age, remission status and other factors, which suggests a general improvement in the safety of the procedure over time, particularly for patients in early disease stages at transplant.

Abstract 181: Biological and clinical relevance of quantitative global methylation in repetitive DNA sequences in B-cell chronic lymphocytic leukemia

Abstract Background: B-cell chronic lymphocytic leukemia (B-CLL) is characterized by highly clinical heterogeneity; the identification of reliable prognostic factors useful in predicting patient outcome and planning therapeutic strategies represent a crucial task. Global DNA hypomethylation affecting repeat sequences, such as long interspersed nuclear elements-1 (LINE-1), Alu and satellite α DNA (SAT-α DNA), has been reported in different cancer types and associated with chromosomal instability. Aim: In order to investigate the role of global DNA methylation in B-CLL we quantified the methylation levels of Alu, LINE-1 and SAT-α repetitive in B-CLL patients and correlated them with the major cytogenetic and molecular features and clinical relevance in predicting therapy-free survival (TFS). Patients and methods: A quantitative bisulfite-PCR Pyrosequencing method was used to evaluate methylation of Alu, LINE-1, and SAT-α in a panel of highly purified (&amp;gt;90%) peripheral mononuclear CD19+ cells from 7 healthy donors and 77 B-CLL untreated well-characterized patients in early stage disease (Binet stage A). Results: Forty-eight patients had unmutated IgVH genes; ZAP-70 and CD38 were positive in 28 and 35 cases, respectively; 13q14.3 deletion was present as a sole abnormality in 21/33 patients while in the remaining cases it was combined with 17p13.1 (4 pts) or 11q22.3 deletions (7 pts) or both (1 pt). The 11q22.3 and 17p13.1 deletions were detected as sole abnormality in 6 and 7 patients, respectively. Trisomy 12 occurred in 17 patients, as a sole abnormality in all cases. Methylation levels (median %5mC) were lower in B-CLLs compared with controls (21.4 vs. 25.9; 66.8 vs. 85.7; and 84.0, vs. 88.2; for Alu, LINE-1 and SAT-α, respectively). A significant association was observed with 17p13.1 deletion (15.4 vs. 22.4; 42.9 vs. 68.5; 32.7 vs. 85.0, for Alu, LINE-1 and SAT-α) but not with other major genetic lesions, IgVH mutation status, CD38 or ZAP-70 expression. Notably, lower SAT-α methylation levels appeared to be an independent prognostic marker significantly associated with a shorter TFS. Conclusion: Our study extended limited evidence in methylation of repetitive sequences in B-CLL suggesting an important biological and clinical relevance in the disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 181.

HIV‐infected long‐term nonprogressors display a unique correlative pattern between the interleukin‐7/interleukin‐7 receptor circuit and T‐cell homeostasis

We hypothesized that there may be a correlation between the interleukin-7 (IL-7)/IL-7 receptor (IL-7R) regulatory system and parameters of T-cell homeostasis in HIV-infected long-term nonprogressors (LTNPs) as compared with patients with disease progression. The possibility of a correlation between T-cell homeostatic parameters and IL-7/IL-7R was investigated in 22 LTNPs (CD4 count > or =500 cells/microL for >10 years) vs. HIV-positive patients at different disease stages [12 early: CD4 count > or =400 cells/microL ; 15 late (AIDS-presenters): CD4 count < or =150 cells/microL ]. Compared with early-stage HIV-positive patients, LTNPs displayed a higher circulating IL-7 concentration (P=0.05), which was positively associated with higher IL-7Ralpha expression and a higher T-cell receptor excision circle (TREC) content specifically within CD4 cells (P<0.05). Compared with late-stage disease patients, early-stage disease patients displayed a lower IL-7 concentration (P<0.01) and higher percentages of IL-7Ralpha+ CD4 and CD8 cells (P=0.05). IL-7 was positively correlated with the percentage of TREC+ CD4 cells (P<0.01), which translated into a higher percentage of naïve CD4 cells in early-stage disease patients than in late-stage disease patients; however, the CD4 cells in early-stage disease patients were less enriched in recent thymic emigrants (RTEs) compared with LTNPs (P<0.05). In late-stage AIDS-developing patients, substantially increased IL-7 was correlated with a decreased percentage of IL-7Ralpha+ CD4 cells (P=0.01), which resulted in these patients having a significantly lower percentage of naïve T cells (P<0.01) and a significantly lower content of TREC (P<0.01) than the other patients. The maintenance of high CD4 cell counts in LTNPs was associated with a specific IL-7/IL-7R pattern characterized by increased IL-7 and highest IL-7Ralpha-expressing CD4 cells relative to other patients. Compared with patients with late-stage disease, LTNPs displayed a phenotypically naïve, less activated CD4 cell pool highly enriched in RTEs, suggesting the existence of a compensatory IL-7-mediated pathway specifically sustaining peripheral CD4 counts.

Genexpressionsprofile in der onkologischen Diagnostik

Tumorerkrankungen stellen in Deutschland nach wie vor die zweithaufigste Tordesursache dar. Neben der Entwicklung wirksamer primarer und sekundarer Praventionsmasnahmen sind vor allem Methoden zur Verbesserung der Diagnose und Subklassifikation sowie zur Prognoseeinschatzung der einzelnen Tumorentitaten dazu geeignet, die krebsbedingte Letalitat langfristig zu senken. Die klassische Diagnose eines Tumors stutzt sich vielfach auf seine histomorphologische Charakterisierung, wohingegen die prognostische Einschatzung zusatzlich durch das Stadium der Erkrankung bei Diagnose bestimmt wird. Nach der Etablierung von Hochdurchsatzmethoden zur Erstellung von Genexpressionsprofilen von Tumorbiopsien wurde im vergangenen Jahrzehnt untersucht, ob die molekulare Charakterisierung von Tumoren die diagnostische Sicherheit zusatzlich erhohen und die Einschatzung der Prognose verbessern kann. Hierzu wurden vor allem Studien beim Mamma-, Lungen- und Kolonkarzinom durchgefuhrt mit dem Ziel, in der adjuvanten Situation bei Vorliegen eines fruhen Stadiums feststellen zu konnen, welche Patientenkollektive tatsachlich von einer Chemotherapie profitieren wurden. Ferner wurden Genexpressionsprofile dazu genutzt, Tumoren mit unklarem Primarius ihrem Ursprungsgewebe zuzuordnen. Daruber hinaus wurde mittels Genexpressionsanalyse eine erganzende molekulare Klassifikation sowohl von B-Zell-Non-Hodgkin-Lymphomen als auch von lymphatischen und myeloischen Leukamien ermoglicht, wodurch moglicherweise sowohl die Diagnostik als auch die Einschatzung der Prognose dieser Erkrankungen langfristig verbessert werden konnen. Obwohl mittlerweile zahlreiche Signaturen und Pradiktoren zu einzelnen Neoplasien veroffentlicht wurden, fand in Deutschland bisher keiner der Tests Eingang in die leitlinienbasierte Diagnostik und Therapie einer malignen Erkrankung. Dies ist vor allem darauf zuruckzufuhren, dass die vielversprechenden Ergebnisse zunachst in grosen prospektiven klinischen Studien evaluiert werden mussen. Erst nach Abschluss dieser Studien wird zu entscheiden sein, ob und welche Testverfahren tatsachlich geeignet sind, den Verlauf einer bestimmten Tumorerkrankung signifikant zu verbessern.

Autologous hematopoietic stem cell transplantation: the glass seems to be half full for aggressive, early forms of MS and half empty for advanced MS

Sir, We would like to respond to the above submitted correspondence by Nash et al. on our article ‘Autologous stem cell transplantation fails to stop demyelination and neurodegeneration’. Both Nash et al. and we seem to agree that HSCT might be an effective therapy for multiple sclerosis (MS) patients in the so-called inflammatory stage of the disease. These patients appear to benefit from the intense immunosuppression and the reprogramming of their immune system (Muraro et al. , 2003; Martin, 2007). The benefit for these patients has been clinically shown and is documented in MRI studies. Thus the most promising MS population for a therapy study with HSCT might be patients in early disease stages with an aggressive disease course who do not …

Haploidentical haematopoietic stem cell transplantation for acute leukaemia in adults: experience in Europe and the United States

Work on one haplotype-mismatched transplants has been proceeding for over 20 years all over the world and novel transplant techniques have been developed. Some centres have focused on the conditioning regimens and post transplant immune suppression; others have concentrated on manipulating the graft. Haploidentical transplant modalities are based mainly on high-intensity conditioning regimen, but reduced intensity regimens have recently been introduced. The graft may be a megadose of extensively T cell-depleted or unmanipulated progenitor cells. Excellent engraftment rates are associated with a very low incidence of GVHD- and regimen-related mortality even in patients who are over 50 years old. Overall, event-free survival and transplant-related mortality compare favourably with reports on transplants from sources of stem cells other than the matched sibling. Improvements will come with successful implementation of strategies to accelerate and strengthen post transplant immune reconstitution as well as transplantation of patients in early stage disease.