The Austrian biodatabase for chronic myelomonocytic leukemia (ABCMML) : A representative and useful real-life data source for further biomedical research.

In the Austrian biodatabase for chronic myelomonocytic leukemia (ABCMML) clinicolaboratory real-life data have been captured from 606 CMML patients from 14 different hospitals over the last 30 years. It is the only large biodatabase worldwide in which functional methods such as semisolid in vitro cultures complement modern molecular methods such as next generation sequencing. This provides the possibility to comprehensively study the biology of CMML. The aim of this study was to compare patient characteristics with published CMML cohorts and to validate established prognostic parameters in order to examine if this real-life database can serve as a representative and useful data source for further research. After exclusion of patients in transformation characteristics of 531 patients were compared with published CMML cohorts. Median values for age, leukocytes, hemoglobin, platelets, lactate dehydrogenase (LDH) and circulating blasts were within the ranges of reported CMML series. Established prognostic parameters including leukocytes, hemoglobin, blasts and adverse cytogenetics were able to discriminate patients with different outcome. Myeloproliferative (MP) as compared to myelodysplastic (MD)-CMML patients had higher values for circulating blasts, LDH, RAS-pathway mutations and for spontaneous myelomonocytic colony growth in vitro as well as more often splenomegaly. This study demonstrates that the patient cohort of the ABCMML shares clinicolaboratory characteristics with reported CMML cohorts from other countries and confirms phenotypic and genotypic differences between MP-CMML and MD-CMML. Therefore, results obtained from molecular and biological analyses using material from the national cohort will also be applicable to other CMML series and thus may have a more general significance.

Hyperexpression of NOTCH-1 is found in immature acute myeloid leukemia.

The Notch signaling pathway is a cell program that is active during early development of multicellular organisms and is required for the formation of basic structures in the growing embryo. Scientific evidence which has accumulated during the last years clearly indicates that aberrant pathway activation may also be critical for the pathogenesis of malignant disease. Despite some limited information the exact role of the Notch signaling pathway in acute myeloid leukemia (AML) remains poorly defined. Immunohistochemical staining of paraffin-embedded bone marrow biopsies from 97 patients with AML, treated between February 1994 and May 2011, for NOTCH-1 was performed according to standardized procedures. Immunological, cytological, pathological, molecular and clinical data were obtained from the hospitals database and patient records. Hyperexpression of NOTCH-1 was seen in 7/97 AML specimens, the other patients showed some expression of NOTCH-1. There was a significant correlation between hyperexpression of NOTCH-1 and the morphological subgroup M0/1 - AML without morphologic maturation (p<0.001). Significant correlation between NOTCH-1 hyperexpression and coexpression of CD7, a phenotypic marker of immaturity (p<0.001) was also seen. Patients with hyperexpression of NOTCH-1 were found to have an inferior overall survival in this retrospective study. Our results indicate that a specific subgroup of AMLs may be associated with hyperexpression of components of the Notch signaling pathway. Better knowledge in pathway signaling in AML could help to identify patient subsets that may benefit from administration of pathway inhibitors and could also contribute to tailored treatment.

Monocyte human leukocyte antigen-DR expression-a tool to distinguish intestinal bacterial infections from inflammatory bowel disease?

BACKGROUND: We sought to determine the quantitative expression of human leukocyte antigen-DR (HLA-DR) on monocytes in patients with acute intestinal bacterial infections and inflammatory bowel disease (IBD). METHODS: The quantitative expression of HLA-DR on monocytes was determined by fluorescence-activated cell sorting analysis in patients with IBD, patients with acute intestinal bacterial infections (bact.), and healthy subjects (contr.). RESULTS: The quantitative expression of HLA-DR in patients with bact. (n = 20; 90,000 molecules per monocyte; confidence interval [CI], 79,000-102,000) was significantly higher than that in patients with ulcerative colitis (n = 40, 30,000; CI, 30,000-38,000; P < 0.0001), Crohn disease (n = 80, 31,000; CI, 32,000-39,000; P < 0.0001), or in contr. (n = 28, 39,000; CI, 36,000-46,000; P < 0.0001). In patients with ulcerative colitis and Crohn disease, HLA-DR expression was significantly decreased, as compared with contr. (P < 0.05 and P < 0.01, respectively). With a cutoff point of 50,000, HLA-DR showed a sensitivity of 95% and a specificity of 92% in discriminating between bact. and active IBD. CONCLUSION: The quantitative measurement of HLA-DR expression could serve as a valuable tool to discriminate between bact. and active IBD.

Expression of the high-affinity IgG receptor FcRI (CD64) in patients with inflammatory bowel disease: a new biomarker for gastroenterologic diagnostics.

OBJECTIVES: We sought to determine the quantitative expression of the high-affinity Fc receptor (CD64) on polymorphonuclear neutrophils (PMNs) in inflammatory and functional conditions of the intestine and investigated its correlation with clinical and biological parameters of inflammation. METHODS: The quantitative expression of CD64 was determined by fluorescence-activated cell sorting analysis in patients with active or inactive inflammatory bowel disease (IBD, n=76), infectious enterocolitis, lactose and/or fructose intolerance, and healthy subjects. RESULTS: The quantitative expression of CD64 in patients with active IBD (3,398+/-3,589 molecules per PMN, n=27) was significantly higher than in healthy subjects (607+/-265, n=28, P<0.001) or in patients with lactose/fructose intolerance (531+/-150, n=32, P<0.001). The expression of CD64 correlated significantly with C-reactive protein (CRP, 0.65, P<0.0001), Crohn's disease activity index (CDAI, 0.53, P<0.0001), and colitis activity index (CAI, 0.63, P<0.0001) in patients with IBD. With a cutoff point of 800, CD64 had a sensitivity of 88% and a specificity of 93% in discriminating between lactose/fructose intolerance and active IBD. The quantitative expression of CD64 in patients with infectious enterocolitis (19,190+/-8,920, n=22) was significantly higher than in patients with active IBD (P<0.001). With a cutoff point of 10,000, CD64 showed a sensitivity of 96% and a specificity of 97% in discriminating between infectious enterocolitis and active IBD. CONCLUSIONS: CD64 could serve as a valuable tool to discriminate between IBD, infectious enterocolitis, and functional intestinal disorders.

Passive immunization with the anti-HIV-1 human monoclonal antibody (hMAb) 4E10 and the hMAb combination 4E10/2F5/2G12.

OBJECTIVES: To study the safety, immunogenicity and pharmacokinetics of the human monoclonal antibody (hMAb) 4E10 alone and in combination with the hMAbs 2F5 and 2G12 in HIV-1-infected persons. MATERIALS AND METHODS: Eight healthy volunteers with > or =350 CD4 cells/mm3 and < or =100 000 HIV-1 RNA copies/mL were enrolled, seven finished the study. A single 4E10 infusion was administered on day 0, followed by three doses of the hMAb combination 4E10/2F5/2G12 on days 7, 14 and 21 (total amount 8.5 g). Safety was assessed by physical examination, blood chemistry, complete blood cell count and recording of adverse events. 4E10, 2F5 and 2G12 plasma levels were determined before and at the end of each infusion and during the 7 week follow-up. RESULTS: No drug-related adverse events were observed throughout the study. The median plasma concentrations immediately after the first infusion were 371, 253 and 139 microg/mL for 4E10, 2F5 and 2G12. Multiple infusions resulted in maximum plasma concentrations of 407, 294 and 210 microg/mL for 4E10, 2F5, and 2G12, respectively. The median elimination half-lives (t1/2beta) were 6.6, 3.2 and 14.1 days for 4E10, 2F5 and 2G12. A low level antibody response against 2G12 was found in two patients. CONCLUSION: This Phase I trial showed that the hMAb 4E10 can be safely administered, both alone and in combination with 2F5 and 2G12 to HIV-1-infected patients.

HLA-DR as a marker for increased risk for systemic inflammation and septic complications after cardiac surgery.

OBJECTIVE: This study investigated the predictive value of a decrease in monocyte HLA-DR expression as an early marker for postoperative SIRS and septic complications. We hypothesized that decreased HLA-DR levels in the first 24 h after cardiac surgery is not related to postoperative SIRS/sepsis. We also compared HLA-DR levels of patients with postoperative complications to those with an uncomplicated course. DESIGN AND SETTING: Prospective observational study in a tertiary care postoperative intensive care unit. PATIENTS: Eighty five consecutive patients undergoing cardiac surgery. MEASUREMENTS AND RESULTS: Expression of HLA-DR on monocytes was analyzed by flow cytometry using a new quantitative and well standardized technique. Arterial blood samples were collected before induction of anesthesia, immediately after admission to the ICU, and on the first postoperative day. Postoperative HLA-DR expression was significantly decreased in all patients. There were no significant differences in HLA-DR expression during the first 24 h after surgery in patients with uncomplicated course and those developing SIRS or septic complications. CONCLUSIONS: In patients undergoing cardiac surgery the monitoring of pre- and immediate postoperative HLA-DR levels during the first 24 h does not help to predict increased risk for postoperative SIRS/sepsis or infectious complications.