[European dyslipidemia guidelines 2019 : What is new?] / Europäische Leitlinien zu Lipiden 2019 : Was ist neu?

In August 2019 the updated dyslipidemia guidelines of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) were published. Since the last version from 2016, important large randomized trials especially with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and new genetic analyses have become available that show additional reduction of atherosclerotic cardiovascular disease (ASCVD) risk on top of the previously recommended treatments. Based on these data the main concept of the recommendations is achieving an early and as large as possible absolute reduction of low-density lipoprotein cholesterol (LDL-C). As a result of this knowledge and the extended pharmaceutical treatment options the LDL­C goals are amended to lower values. Patients at very high cardiovascular risk are recommended to achieve LDL­C <1.4 mmol/l (55 mg/dl). For patients with high, moderate, and low cardiovascular risks, LDL­C goals are set at <1.8 mmol/l (70 mg/dl), <2.6 mmol/l (100 mg/dl) and <3.0 mmol/l (116 mg/dl), respectively. A new classification of patients with recurrent cardiovascular events despite maximum tolerated statin-based therapy is introduced. For these patients the LDL­C goal is <1.0 mmol/l (40 mg/dl). Novel recommendations comprise a more precise classification of patients at low or moderate risk based on cardiovascular imaging, recommendations for familial hypercholesterolemia, screening for increased lipoprotein(a) and determination of apolipoprotein B as diagnostic and therapeutic goal.

Individualized evaluation of lumbar bone mineral density in children with cerebral palsy.

Lumbar spine bone mineral density (LS-BMD) assessed by dual-energy X-ray absorptiometry (DXA) is used in children with cerebral palsy (CP) to evaluate bone health. LS-BMD results in children with CP are influenced significantly by their height, BMI, and mobility level. An adjustment for these parameters might improve the clinical significance of the method. PURPOSE/INTRODUCTION: DXA evaluation is considered useful in children with CP to assess bone health. For this purpose, LS-BMD is often used. The aim of the study was to estimate the effect of height, BMI, and reduced mobility level of children with CP on LS-BMD and to develop a method to adjust individual results of LS-BMD for these factors. METHODS: We conducted a monocentric retrospective analysis of data collected in children and adolescents with CP, who participated in a rehabilitation program and had no history of recurrent fractures. The DXA scan was part of the routine examination for participants older than 4 years of age. The relationship between height and BMI for age Z-scores and age-adjusted LS-BMD Z-scores was analyzed. RESULTS: LS-DXA scans of 500 children and adolescents with CP (Gross Motor Function Classification System levels I-V) were included in the statistical analysis (217 female). The mean age was 9.4 years (± 3.7 years). Children with moderate to severe CP had significantly (p < 0.001) lower LS-BMD Z-scores than children with mild CP. We provided nomograms to adjust individual LS-BMD results to their height, BMI, and mobility level. CONCLUSIONS: LS-BMD results in children with CP were influenced significantly by their height, BMI, and mobility level. An adjustment of the LS-BMD results to height, BMI, and mobility level might improve the clinical significance of an individual result.

Prevalence of myeloma precursor state monoclonal gammopathy of undetermined significance in 12372 individuals 10-49 years old: a population-based study from the National Health and Nutrition Examination Survey.

We studied the prevalence of monoclonal gammopathy of undetermined significance (MGUS) in younger individuals, age 10-49 years, using samples from the National Health and Nutritional Examination Survey (NHANES) III. NHANES prevalence rates were standardized to the 2000 US total population. Among 12 372 individuals (4073 blacks, 4146 Mexican-Americans, 3595 whites, and 558 others), MGUS was identified in 63 persons (0.34%, 95% CI 0.23-0.50). The prevalence of MGUS was significantly higher in blacks (0.88%, 95% CI 0.62-1.26) compared with whites (0.22%, 95% CI 0.11-0.45), P=0.001. The prevalence of MGUS in Mexican-Americans was at an intermediate level (0.41%, 95% CI 0.23-0.73). The disparity in prevalence of MGUS between blacks and whites was most striking in the 40-49 age-group; 3.26% (95% CI 2.04-5.18) versus 0.53% (95% CI 0.20-1.37), P=0.0013. There was a trend to earlier age of onset of MGUS in blacks compared with whites. MGUS was seen in only two persons in the 10-19 age-group (both Mexican-American), and in three persons in the 20-29-year age-group (all of whom were black). In persons less than 50 years of age, MGUS is significantly more prevalent, with up to 10 years earlier age of onset, in blacks compared with whites.

Quantitation of circulating wild-type alpha-1-antitrypsin in heterozygous carriers of the S and Z deficiency alleles.

BACKGROUND: Alpha-1-antitrypsin (A1AT) deficiency disease results from mutations in the A1AT gene. Controversy exists in regards to treatment of heterozygous carriers of the S and Z deficiency alleles. Quantitation of allelic expression has not been possible with standard laboratory methods. Here we show that the recently described method for liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis of A1AT tryptic peptides can differentiate between mutated (S and Z) and wild-type (non-S and non-Z) proteins allowing for quantitation of circulating allelic expression in heterozygous patients. METHODS: Serum (244 M/M, 61 M/Z, and 63 M/S) was combined with isotopically labeled peptide standards, digested with trypsin, and quantitated by LC-MS/MS. Total and allele-specific A1AT quantitation was performed by comparison of peptide peak height ratios to a standard curve for each peptide. Linear regression was used to compare results and central 95(th) percentile intervals were calculated using parametric analysis. RESULTS: Quantitation of circulating wild-type A1AT based on the proteotypic and allelic (non-S and non-Z) peptides was validated in M/M patients. Proteotypic peptide concentrations correlated linearly with quantitation by non-Z and non-S peptides [slopes (Spearman correlation coefficient) of 1.09 (0.89) and 0.98 (0.80), respectively]. Allele-specific quantitation showed significant differences in wild-type protein expression in M/Z and M/S patients. Although average total A1AT concentration was lower for M/Z patients, the percentage of wild-type protein in M/Z patients was significantly higher at 82 % (55- > 95 %) compared to 63 % (43-83 %) for M/S heterozygotes. In a cohort of M/Z patients with sufficient total A1AT (≥80 mg/dL), half had insufficient wild-type protein that could have clinical implications for pulmonary dysfunction. CONCLUSIONS: For the first time, a method to quantitate A1AT allele protein expression is described. Given the wide range of circulating wild-type protein observed in heterozygous patients, this method has the potential to reveal correlations between allele concentration and development and/or severity of clinical symptoms.

Racial disparities in the prevalence of monoclonal gammopathies: a population-based study of 12,482 persons from the National Health and Nutritional Examination Survey.

Multiple myeloma (MM) incidence is markedly higher in blacks compared with whites, which may be related to a higher prevalence of monoclonal gammopathy of undetermined significance (MGUS). Our objective was to define the prevalence and risk factors of MGUS in a large cohort representative of the US population. Stored serum samples from the National Health and Nutritional Examination Survey (NHANES) III or NHANES 1999-2004 were available for 12,482 individuals of age ⩾50 years (2331 'blacks', 2475 Hispanics, 7051 'whites' and 625 'others') on which agarose-gel electrophoresis, serum protein immunofixation, serum-free light-chain assay and M-protein typing were performed. MGUS was identified in 365 participants (2.4%). Adjusted prevalence of MGUS was significantly higher (P<0.001) in blacks (3.7%) compared with whites (2.3%) (P=0.001) or Hispanics (1.8%), as were characteristics that posed a greater risk of progression to MM. The adjusted prevalence of MGUS was 3.1% and 2.1% for the North/Midwest versus South/West regions of the United States, respectively (P=0.052). MGUS is significantly more common in blacks, and more often has features associated with higher risk of progression to MM. A strong geographic disparity in the prevalence of MGUS between the North/Midwest versus the South/West regions of the United States was found, which has etiologic implications.

Suppression of uninvolved immunoglobulins defined by heavy/light chain pair suppression is a risk factor for progression of MGUS.

We hypothesized that the suppression of uninvolved immunoglobulin in monoclonal gammopathy of undetermined significance (MGUS) as detected by suppression of the isotype-specific heavy and light chain (HLC-pair suppression) increases the risk of progression to malignancy. This approach required quantitation of individual heavy/light chains (for example, IgGλ in IgGκ MGUS patients). Of 1384 MGUS patients from Southeastern Minnesota seen at the Mayo Clinic from 1960 to 1994, baseline serum samples obtained within 30 days of diagnosis were available in 999 persons. We identified HLC-pair suppression in 27% of MGUS patient samples compared with 11% of patients with suppression of uninvolved IgG, IgA or IgM. HLC-pair suppression was a significant risk factor for progression (hazard ratio (HR), 2.3; 95% confidence interval (CI) 1.5-3.7; P<0.001). On multivariate analysis, HLC-pair suppression was an independent risk factor for progression to malignancy in combination with serum M-spike size, heavy chain isotype and free light chain ratio (HR, 1.8; 95% CI, 1.1-3.00; P=0.018). The finding that HLC-pair suppression predicts progression in MGUS and occurs several years before malignant transformation has implications for myeloma biology.

Serum free light chain ratio as a biomarker for high-risk smoldering multiple myeloma.

A markedly elevated serum free light chain (FLC) ratio may serve as a biomarker for malignant transformation in high-risk smoldering multiple myeloma (SMM) and identify patients who are at imminent risk of progression. We retrospectively studied the predictive value of the serum (FLC) assay in 586 patients with SMM diagnosed between 1970 to 2010. A serum involved/uninvolved FLC ratio ≥ 100 was used to define high-risk SMM, which included 15% (n=90) of the total cohort. Receiver operating characteristics analysis determined the optimal FLC ratio cut-point to predict progression to symptomatic multiple myeloma (MM) within 2 years of diagnosis, which resulted in a specificity of 97% and sensitivity of 16%. Fifty-six percent of patients developed progressive disease during median follow-up of 52 months, but this increased to 98% in the subgroup of patients with FLC ratio ≥ 100. The median time to progression in the FLC ratio ≥ 100 group was 15 months versus 55 months in the FLC <100 group (P<0.0001). The risk of progression to MM within the first 2 years in patients with an FLC ratio ≥ 100 was 72%; the risk of progression to MM or light chain amyloidosis in 2 years was 79%. We conclude that a high FLC ratio ≥ 100 is a predictor of imminent progression in SMM, and such patients may be considered candidates for early treatment intervention.

Relationship between elevated immunoglobulin free light chain and the presence of IgH translocations in multiple myeloma.

Elevated immunoglobulin free light chain (FLC) level and abnormal FLC ratio are commonly seen in multiple myeloma (MM) and have prognostic implications. We hypothesized that presence of immunoglobin heavy chain (IgH) translocations leads to unbalanced production of light chains and more extreme abnormalities of FLC, and may explain the prognostic value of FLC. We studied 314 patients with newly diagnosed MM enrolled in a phase III trial, in whom results of fluorescence in situ hybridization testing and data on serum FLC levels were available. Cytogenetic analyses and FLC estimates were performed on stored samples and results were correlated with clinical data. The median ratio (FLC ratio) and the absolute difference (FLC diff) between the involved and uninvolved FLC were higher among those with IgH translocations, especially t(14;16). In multivariate analysis, the prognostic value of FLC estimates on progression-free and overall survival were independent of high-risk IgH translocations t(4;14) and t(14;16). A combination of the risk factors; either abnormal FLC estimate and/or the presence of high-risk IgH translocation, achieved better prognostic stratification. We conclude that patients with IgH translocations have higher FLC levels and abnormal ratios, but the prognostic effect of FLC is only partially explained by translocation status. A system including both these risk factors allows better prediction of outcome.

Prognostic value of the serum free light chain ratio in newly diagnosed myeloma: proposed incorporation into the international staging system.

To determine if the serum free light chain (FLC) ratio has prognostic value in patients with symptomatic multiple myeloma (MM), baseline serum samples from a well-characterized cohort of 790 newly diagnosed MM patients were tested with the FLC assay. FLC ratio was calculated as kappa/lambda (reference range 0.26-1.65). On the basis of the distribution of values, a cutpoint kappa/lambda FLC ratio of <0.03 or >32 was chosen for further analysis. Overall survival was significantly inferior in patients with an abnormal FLC ratio of <0.03 or >32 (n=479) compared with those with an FLC ratio between 0.03 and 32 (n=311), with median survival of 30 versus 39 months, respectively. We incorporated abnormal FLC ratio with the International Staging System (ISS) risk factors (that is, albumin <3.5 g/dl and serum beta(2)-microglobulin >or=3.5 g/l), to create a risk stratification model with improved prognostic capabilities. Patients with 0, 1, 2 or 3 adverse risk factors had significantly different overall survival, with median survival times of 51, 39, 30 and 22 months, respectively (P<0.001). These findings suggest that the serum FLC ratio at initial diagnosis is an important predictor of prognosis in myeloma, and can be incorporated into the ISS for improved risk stratification.

Factors that influence the measurement of prostate cancer DNA ploidy and proliferation in paraffin embedded tissue evaluated by flow cytometry.

DNA ploidy and proliferation have been shown in several studies to be prognostic markers for prostate cancer. Flow cytometry (FCM) is often used in the determination of ploidy and proliferation. However, FCM cannot readily distinguish among benign epithelium, stromal and inflammatory cells, high grade prostatic intraepithelial neoplasia (HGPIN), and cancer cells. In this study, we evaluated H&E histologic features of 322 radical prostatectomy formalin-fixed, paraffin-embedded tissue blocks used for determining DNA ploidy, percent S-phase (%S), and %S + %G2M by FCM. The microscopic findings included Gleason score, extent of cancer and HGPIN in the tissue block, and presence of a needle track. The amount of cancer in the block was expressed as a percentage of the total tissue surface area in quartiles: < or =25%, 26-50%, 51-75%, and > or =76%. The extent of HGPIN was recorded in rough 5% intervals. Needle track effect was defined as a combination of fibrohistiocytic reaction, fibrin clot, granuloma formation, and chronic inflammation. The associations between these histologic features and DNA ploidy and proliferation (%S and %S + %G2M) were assessed. In multivariate analyses, Gleason score, the amount of tumor in the tissue block, and the extent of HGPIN were significantly associated with ploidy. Gleason score was the only parameter significantly associated with the proliferation measure of %S. If we included %G2M as part of the proliferative fraction of the histogram, however, both Gleason score and the amount of tumor in the block were significantly associated with this measure of proliferation. The presence of a needle track was not significantly associated with DNA ploidy, %S, or %S + %G2M. In summary, prostate cancer DNA ploidy and proliferation results assessed by FCM in paraffin-embedded tissue blocks were associated with the Gleason score, amount of cancer in the tissue block, and extent of HGPIN. However, the presence of a needle track was not associated with the FCM results.

Primary lymph node plasmacytomas (plasmacytic lymphomas).

To determine whether primary lymph node plasmacytoma (PLNP) is a distinct entity among other types of plasma cell neoplasia, we analyzed a large series of PLNPs from 2 large lymphoma registries to compare histologic, immunophenotypic, and clinical features of PLNPs, nonnodal extramedullary plasmacytomas, and multiple myeloma. Twenty-five PLNPs (clinical data on 15 cases) were compared with 10 non-lymph node plasmacytomas and 51 cases of multiple myeloma; 36 cases of reactive plasmacytoses were used as controls. The histologic features of PLNP and other extramedullary plasmacytomas were similar. The histologic features of PLNPs were more immature than those of reactive plasmacytoses and less immature than in multiple myeloma. The immunophenotype of PLNPs significantly differed from that of reactive plasmacytoses, other extramedullary plasmacytomas, and multiple myeloma. PLNPs did not progress to multiple myeloma, unlike other extramedullary plasmacytomas, even though survival in PLNPs and other extramedullary plasmacytomas was similar. Our findings suggest that PLNPs may be distinct from other plasma cell dyscrasias.

Image analysis and flow cytometric DNA studies of benign and malignant body cavity fluids: reappraisal of the role of current methods in the differential diagnosis of reactive versus malignant conditions.

Cytologic examination of body fluids is commonly performed in the clinical laboratory. Determination of the presence of malignancy may sometimes be difficult. In this study, we prospectively studied 60 body fluids with a panel of antibodies, including MOC-31, epithelial membrane antigen, carcinoembryonic antigen, B72.3, keratin, desmin, and CA-125. DNA and S-phase studies were performed both by flow cytometry and image analysis. Thirty-seven fluids were classified as benign and 23 were classified as malignant. The sensitivity of the antibodies for identification of carcinoma in descending order of percentage detection rate were MOC-31 (95%), epithelial membrane antigen (93%), B72.3 (84%), and carcinoembryonic antigen (80%). Desmin stained mesothelial cells in all cases. CA-125 gave similar results but was less specific. Flow cytometry detected 14 of 20 malignant fluids and image analysis 17 of 23 by identifying an aneuploid population. Benign reactive mesothelial cells were not aneuploid. Tetraploidy due to reactive mesothelial cells was found in 9 of 37 body fluids. Their S-phase fraction was low (average, 3.2%). Tetraploidy in malignant cells was distinguished from the reactive mesothelial cells by high S-phase (average, 25.95). S-phase had some use as a discriminating factor, because no benign reactive cases had more than 17%. However, 7 of 23 malignant cases had a value below 17%. DNA analysis by image was more sensitive and specific than flow. Either may be used when immunocytochemistry is nondiagnostic or cannot be performed.

Pretreatment assessment of prognostic indicators in endometrial cancer.

OBJECTIVE: The object of this study was to assess the association of histologic, cytokinetic, and molecular variables in preoperative endometrial samples with extrauterine disease, recurrence, and survival among patients with endometrial cancer. STUDY DESIGN: In a case-cohort study of 125 women, ploidy, S-phase fraction, proliferative index, deoxyribonucleic acid index, proliferating cell nuclear antigen, MIB-1 proliferation marker, p53 tumor suppressor gene, and cytoplasmic HER-2/neu oncogene and bcl-2 expressions were quantitated. RESULTS: A model with only one independent term predicted progression-free survival; that variable was p53 (P <. 0001; relative risk, 5.60). A model with two independent terms predicted disease-related survival; these variables were p53 (P =. 0002; relative risk, 7.39) and MIB-1 (P =.03; relative risk, 3.27). Among patients with tumors with both p53 and MIB-1 expression exceeding 33%, a total of 32% had died of disease by 2 years. A model for predicting extrauterine disease selected two independent variables: p53 (odds ratio, 3.20; P =.01) and ploidy (odds ratio, 2. 16; P =.04). An advanced surgical stage was encountered in 26% to 35% of cases in which either the p53 expression exceeded 33% or the deoxyribonucleic acid content was nondiploid and in 53% of cases in which both variables were unfavorable. CONCLUSIONS: Preoperative evaluation of quantifiable cytokinetic and molecular variables can assist in identifying tumor types that are predisposed toward a more aggressive clinical course.

Higher risk of mismatch repair-deficient colorectal cancer in alpha(1)-antitrypsin deficiency carriers and cigarette smokers.

Microsatellite instability (MSI) is a genomic alteration observed in 15-30% of colorectal cancer (CRC). Two MSI phenotypes have been defined for CRC: MSI-H is characterized by MSI at > or =30% of the examined loci and MSI-L by MSI at 1-30% of the loci. An absence of MSI at any examined loci has been defined as a microsatellite stable (MSS) phenotype. Current data suggest the majority of MSI tumors are the result of defective DNA mismatch repair (MMR). In this study, we have determined the alpha(1)-antitrypsin deficiency carrier (alpha(1)ATD-ht) status of 161 CRC patients whose MSI phenotype and protein expression states had previously been determined. Cases were selected to enrich a larger number of MSI-H cases. Among 51 CRC patients with MSI-H tumors, the alpha(1)ATD-ht rate was 21.6%; among 110 patients with MSI-L/MSS tumors, the rate was 9.1% (MSI-H vs MSI-L/MSS, P = 0.02); and among the 191 population-based controls the alpha(1)ATD-ht rate was 9.4% (MSI-H vs controls, P = 0.02). The estimated relative risk of having MSI-H CRC among alpha(1)ATD-ht was 3.1 after adjusting for age, gender, and smoking history. The risk of having MSI-H CRC among current and past smokers was 6.6 and 2.7, respectively. Patients who were alpha(1)ATD-ht and smoked had a 20-fold increased risk of developing an MSI-H CRC compared to nonsmokers who were homozygous normal at the alpha(1)ATD locus. Our findings suggest an etiologic link between alpha(1)ATD alleles and development of CRC with defective MMR, and a synergistic effect between smoking and alpha(1)ATD allele in the development of MSI-H CRC.

Immunophenotypic analysis of peripheral blood and bone marrow in the staging of B-cell malignant lymphoma.

This study evaluated the contributing roles of flow cytometric immunophenotyping of blood and bone marrow and immunohistochemical paraffin section staining of bone marrow biopsies in the staging of B-cell malignant lymphoma. Flow immunophenotyping was performed on a marrow specimen in 175 cases; a corresponding blood specimen was also immunophenotyped in 135 of these cases. Morphologic marrow involvement by lymphoma was found in 59 cases; flow immunophenotyping identified 54 cases with a monoclonal B-cell process: morphology-positive/flow-positive (n = 49), morphology-positive/flow-negative (n = 10), morphology-negative/flow-positive (n = 5), and morphology-negative/flow-negative (n = 111). The 10 morphology-positive/flow-negative cases included 5 follicular and 5 large-cell lymphomas with minimal marrow involvement. All 5 morphology-negative/flow-positive cases were from patients with large-cell lymphomas and bulky clinical disease. Because the blood contained the same B-cell clone in 2 of 2 morphology-negative/flow-positive cases studied, blood contamination of marrow may account for these findings. Blood flow cytometric immunophenotyping studies were positive in 32 cases; 30 had marrow involvement by morphology and were from patients with follicular, mantle cell, lymphoplasmacytic, small lymphocytic, or marginal zone lymphomas. From our results, we conclude that (1) bone marrow flow cytometric immunophenotyping is not a cost-effective replacement for good morphologic evaluation in lymphoma staging and that (2) a positive peripheral blood flow cytometric immunophenotyping study when performed in low-grade lymphomas correlates with marrow involvement.

Flow cytometric DNA analysis of early stage adenocarcinoma of the cervix.

OBJECTIVE: The aim of this study was to determine the utility of DNA flow cytometry as a prognostic indicator for risk of recurrence and overall survival in patients with early stage adenocarcinomas of the uterine cervix. METHODS: DNA flow cytometry was performed to determine ploidy, DNA index, and proliferative index in 66 women with stage IB and IIA pure mucinous adenocarcinomas of the cervix treated by primary surgical therapy with radical hysterectomy and pelvic lymphadenectomy. Fifty-seven of 66 (86.3%) tissue samples were analyzable. Three sections were obtained from paraffin-embedded tissue blocks containing primary tumor. Flow cytometric results, along with other known prognostic variables for risk for recurrent disease and survival, were analyzed using the Cox regression proportional hazards model and survival curves generated by the Kaplan-Meier method. RESULTS: Of 57 interpretable samples, DNA ploidy patterns were 18 (27%) diploid, 8 (12%) tetraploid, and 31 (47%) aneuploid. Thirteen of 66 patients (20%) experienced recurrence with a median time to recurrence of 1.6 years. No significant correlation was noted between DNA ploidy and risk of recurrence (P = 0.429). Multivariate analysis confirmed that positive metastatic lymph nodes were associated with risk of recurrence (P < 0.001). In node-negative patients, a high proliferative index (S% + G(2)M% > 20%), measured as a continuous variable, was the only significant factor for tumor recurrence (P = 0.002). CONCLUSION: DNA ploidy does not predict a patient's risk for tumor recurrence; however, a high proliferative index value warrants further investigation as a potential prognostic indicator for risk of recurrent disease in patients with adenocarcinoma of the uterine cervix.

Flow-cytometric DNA analysis of early stage adenocarcinoma of the cervix.

OBJECTIVE: The purpose of this study was to determine the utility of DNA flow cytometry as a prognostic indicator for risk of recurrence and overall survival in patients with early stage adenocarcinomas of the uterine cervix. METHODS: DNA flow cytometry was performed to determine ploidy, DNA index, and proliferative index in 66 women with stages IB and IIA pure mucinous adenocarcinomas of the cervix treated by primary surgical therapy with radical hysterectomy and pelvic lymphadenectomy. Fifty-seven of 66 (86.3%) tissue samples were analyzable. Three sections were obtained from paraffin-embedded tissue blocks containing primary tumor. Flow-cytometric results, along with other known prognostic variables for risk for recurrent disease and survival, were analyzed using Cox regression proportional hazards model, and survival curves were generated by the Kaplan-Meier method. RESULTS: Of 57 interpretable samples, DNA ploidy patterns were 18 (27%) diploid, 8 (12%) tetraploid, and 31 (47%) aneuploid. Thirteen of 66 patients (20%) experienced recurrence with a median time to recurrence of 1.6 years. No significant correlation was noted between DNA ploidy and risk of recurrence (P = 0.429). Multivariate analysis confirmed that positive metastatic lymph nodes were associated with risk of recurrence (P < 0.001). In node-negative patients, a high proliferative index (S% + G(2)M% > 20%), measured as a continuous variable, was the only significant factor for tumor recurrence (P = 0.002). CONCLUSION: DNA ploidy does not predict a patient's risk for tumor recurrence; however, a high proliferative index value warrants further investigation as a potential prognostic indicator for risk of recurrent disease in patients with adenocarcinoma of the uterine cervix.

Prognostic significance of the S-phase fraction of light-chain-restricted cytoplasmic immunoglobulin (cIg) positive plasma cells in patients with newly diagnosed multiple myeloma enrolled on Eastern Cooperative Oncology Group treatment trial E9486.

The bone marrow plasma cell labeling index (PCLI) as measured by bromodeoxyuridine uptake is a well-established independent prognostic factor for patients with newly diagnosed multiple myeloma, but the test is not easily done in most laboratories. The purpose of this study was to determine if the proliferative activity (% S-phase) as determined by two-color flow cytometry for cytoplasmic immunoglobulin (cIg) light chain and DNA content also had prognostic significance. As part of Eastern Cooperative Oncology Group clinical trial E9486, 500 patients had successful performance of the bone marrow PCLI. Of 349 patients who had flow cIg and DNA content cytometry, 210 had adequate data to reliably calculate S-phase %. Patients with low % S-phase fraction (<2%) had a significant overall survival advantage over patients high % S-phase fraction (>/=2%), median survivals 4.1 vs. 2.9 years (P = 0.032). Measurement of the S-phase % by flow cytometry gives significant prognostic information in patients with newly diagnosed myeloma. However, in multivariate analysis, S-phase % did not add prognostic information when PCLI was in the model. S-phase % added prognostic information only when all cases with flow measurement of S-phase % were included, and when PCLI was excluded from the model. Discriminating a population of only cIg positive cells proved difficult in patients with a low percentage of bone marrow plasma cells. Methodology to measure S-phase % in patients with a low percent plasma cells is needed before this technique can be used for diagnosis and prognosis in myeloma.

Mannose-binding lectin deficiency associated with neutrophil chemotactic unresponsiveness to C5a.

BACKGROUND: Mannose-binding lectin (MBL) plays an important role in host defense by activating the complement cascade. OBJECTIVE: Three children with a history of recurrent infections since infancy were found to have MBL deficiency associated with a neutrophil chemotactic unresponsiveness specific to C5a. We have studied the genomic sequence of the C5a receptor (C5aR) in 2 of the subjects to determine whether this unresponsiveness was due to a genetic mutation or to aberrant complement activation associated with the MBL deficiency. METHODS: MBL genotype analysis was performed by PCR-based methods with use of specific primers and restriction enzymes to detect the 3 previously reported mutations. Expression of C5aR was analyzed by flow cytometry. The C5aR gene was amplified from the patient's genomic DNA by PCR and sequenced by standard procedures. RESULTS: C5aR was found to be expressed normally on the neutrophils of one of the subjects. Sequence analysis of the C5aR gene revealed a point mutation that substituted threonine at position 261 for alanine in one patient but no abnormality in the other, suggesting gene polymorphism. Treatment of 2 patients with granulocyte-colony stimulating factor corrected the neutrophil chemotactic abnormality in vitro and induced a significant clinical improvement. CONCLUSION: MBL deficiency can be associated with neutrophil chemotactic unresponsiveness to C5a and it is clinically manifested by recurrent and chronic infections. Treatment of these patients with granulocyte colony-stimulating factor results in normalization of neutrophil chemotaxis against C5a and significant clearing of infections.