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Purpose: Accurate quantification of monoclonal IgM immunoglobulins is essential for response assessment in patients with Waldenström's macroglobulinaemia (WM). The propensity of IgM to form multimers in serum makes sample evaluation by current laboratory methods particularly challenging., Experimental Design: We assessed the precision and linearity of IgMκ and IgMλ heavy/light chain (HLC, Hevylite) assays, and established reference intervals using 120 normal donor sera. We compared the quantitative performance of HLC assays with serum protein electrophoresis (SPE) and total IgM nephelometry for 78 diagnostic samples and follow-up samples from 25 patients with WM. Comparisons were made between the three methods for diagnostic sensitivity and response assessment., Results: IgMκ and IgMλ HLC assays showed low imprecision and good linearity. There was good agreement between summated HLC (IgMκ + IgMλ) and total IgM (measured nephelometrically; R 2 = 0.90), but only moderate agreement between involved IgM HLC and SPE densitometry (R 2 = 0.49). Analysis of 120 normal donor sera produced the following normal ranges: IgMκ: 0.29-1.82 g/L; IgMλ: 0.17-0.94 g/L; IgMκ/IgMλ ratio: 0.96-2.30. Using these ranges, IgM HLC ratios were abnormal in all WM presentation sera tested, including 15 with non-quantifiable SPE. Despite discordance in quantitation, responses assigned with HLC assays showed excellent agreement to those based on international guidelines using SPE or total IgM; although abnormal HLC ratios indicated residual disease in some patients with negative electrophoresis results., Conclusions: Nephelometric assessment of IgMκ and IgMλ HLC pairs offers a quantitative alternative to traditional laboratory techniques for the measurement of monoclonal IgM and may aid in the management of WM. Clin Cancer Res; 22(20); 5152-8. ©2016 AACR., (©2016 American Association for Cancer Research.)

Background: Accurate quantification of immunoglobulin A (IgA) monoclonal immunoglobulins by serum protein electrophoresis (SPEP) can be difficult and can impact the assessment of response among patients with multiple myeloma (MM). Therefore, there is a need to identify new assays that better reflect disease burden and response to treatment, and correlate with patient outcome. IgA Hevylite (HLC) measures IgA kappa and IgA lambda separately and provides precise quantitative measurements of the monoclonal IgA expression and polyclonal-isotype matched suppression. In the current study, the authors assessed the usefulness of these assays in the diagnosis of IgA MM and sought to comment on the prognostic value of the assays., Methods: A study of 157 patients with IgA MM for whom diagnostic samples were available was performed. HLC measurements were performed on a nephelometer and the results were compared with those of electrophoresis., Results: All presentation sera (100 IgA kappa specimens and 57 IgA lambda specimens) were found to have abnormal IgA HLC ratios (IgA kappa median ratio: 336.2 [range, 8.2-7353] and IgA lambda ratio: 0.011 [range, 0.0003-0.45]). In comparison, SPEP bands were quantifiable in only 105 of 157 samples (67%) (median, 28.5 g/L [range, 2.2 g/L-98 g/L]). Of the total of 157 patients, 12 patients (8%) presented with oligosecretory myeloma (<10 g/L; including 4 patients with nonquantifiable SPEP bands). HLC uniquely allows for the measurement of isotype paired suppression, which was found to be associated with shortened overall survival in the current study., Conclusions: In the current study, IgA HLC ratios were found to be abnormal in all patients and the assay was able to produce quantifiable results in more MM sera than either SPEP or total IgA, potentially representing a solution to the issue of comigration and oligosecretory MM. These preliminary data require confirmation in larger prospective trials to validate the usefulness of IgA HLC., (© 2014 American Cancer Society.)

The combination of pomalidomide and dexamethasone can be safely administered to patients with multiple myeloma (MM) and has significant efficacy, although the optimal regimen remains to be determined. Patients with MM whose disease progressed after multiple lines of therapy have limited treatment options. We designed a multicenter, phase 2 randomized study assessing two different dose regimens of pomalidomide and dexamethasone in advanced MM. Treatment response was assessed centrally. Pomalidomide (4 mg) was given orally on days 1 to 21 (arm 21/28) or continuously (arm 28/28) over a 28-day cycle, plus dexamethasone given weekly. Eighty-four patients (43, arm 21/28 and 41, arm 28/28) were randomized. The median number of prior lines was 5. Overall response rate was 35% (arm 21/28) and 34% (arm 28/28), independent of the number of prior lines and level of refractoriness. Median duration of response, time to disease progression, and progression-free survival was 7.3, 5.4, and 4.6 months, respectively, which was similar across cohorts. At 23 months follow-up, median overall survival was 14.9 months, with 44% of the patients alive at 18 months. Toxicity consisted primarily of myelosuppression, which was manageable. The efficacy and safety data presented here, along with data from other phase 2 trials, suggest that pomalidomide 4 mg per day on days 1 to 21 of 28 with dexamethasone should be investigated in future trials. This trial is registered at ClinicalTrials.gov (No. NCT01053949).

Aims: The present study was designed to build and validate a composite score based on the Global Registry of Acute Coronary Events (GRACE) score and B-type natriuretic peptide (BNP) concentrations to predict outcome in patients with acute coronary syndromes (ACS)., Methods: The GRACE risk score and BNP concentrations were obtained in a retrospective and a prospective cohort. A composite score including the GRACE score and BNP concentrations was first developed in a retrospective cohort of 248 patients with ACS and then validated in a prospective cohort of 575 patients. The primary outcome was 6-month death or myocardial infarction., Results: End points were reached in 34 patients in the retrospective cohort and in 68 patients in the prospective cohort. Both higher BNP concentration and GRACE score were independently associated with outcome in the retrospective cohort (p=0.003 and p<0.0001). The composite score could be obtained as follows: GRACE+BNP/60. The use of the composite score increased the accuracy of the GRACE score, with an increase in the C statistic from 0.810 (0.727 to 0.892) to 0.822 (0.745 to 0.902) in the retrospective cohort and from 0.724 (0.657 to 0.791) to 0.750 (0.686 to 0.813) in the prospective cohort. Finally, 7% of patients in the prospective study population were reclassified from low to high risk or from high to low risk using this composite score., Conclusions: Plasma BNP levels refine the accuracy of the GRACE score. A comprehensive risk score, which includes BNP concentration and the GRACE risk score, might improve ACS risk stratification in clinical practice.

Background: The Prognostic Inflammatory and Nutritional Index (PINI) is a simple scoring system that aggregates two blood markers of inflammatory [C-reactive protein (CRP) and orosomucoid] and of nutritional (albumin and prealbumin) states. It is used in routine practice in geriatric medicine, especially in hospitalized elderly patients. This study was undertaken to evaluate the usefulness of PINI index in multiple myeloma (MM), a malignancy of the elderly., Method: The PINI score was determined in 231 previously untreated patients with MM, of whom 112 were ≥65 yrs old. The serum albumin, prealbumin, orosomucoid (human α1-acid glycoprotein), and hsCRP are measured routinely by immunonephelometry., Results: In the overall population and the elderly subset, PINI ≥ 4 ('high PINI') was correlated with a shorter median survival, 26 vs. 65 months in the high and low PINI groups, respectively. The prognostic impact of PINI index was dramatic in the elderly MM subgroup, 6 and 45 months, respectively. The high PINI index also predicted for shorter survival in various groups with good prognostic, such as low International Staging System (ISS) stages, low b2m, and absence of del17p and t(4;14), further demonstrating its prognostic impact on overall survival. In multivariate analysis, PINI index provided additional survival prognostic information to b2m in a b2m/PINI model., Conclusion: PINI index appears to be a useful and easy-to-perform marker in routine to determine the prognosis of patients with MM, especially in the elderly population. PINI might represent an alternative to ISS score, especially in elderly patients, in the future., (© 2012 John Wiley & Sons A/S.)

Background: Recent studies have demonstrated that aldosterone levels measured in patients with heart failure or acute myocardial infarction (MI) are associated with long-term mortality, but the association with aldosterone levels in patients with coronary artery disease (CAD) outside these specific settings remains unknown. In addition, no clear mechanism has been elucidated to explain these observations. The present study was designed to evaluate the relationship between the level of aldosterone and the risk of death and acute ischaemic events in CAD patients with a preserved left ventricular (LV) function and no acute MI., Methods and Results: In 799 consecutive CAD patients referred for elective coronary angioplasty measurements were obtained before the procedure for: aldosterone (median = 25 pg/mL), brain natriuretic peptide (BNP) (median = 35 pg/mL), hsC-reactive protein (median = 4.17 mg/L), and left ventricular ejection fraction (mean = 58%). Patients with acute MI or coronary syndrome (ACS) who required urgent revascularization were not included in the study. The primary endpoint, cardiovascular death, occurred in 41 patients during a median follow-up period of 14.9 months. Secondary endpoints-total mortality, acute ischaemic events (acute MI or ischaemic stroke), and the composite of death and acute ischaemic events-were observed in 52, 54, and 94 patients, respectively. Plasma aldosterone was found to be related to BMI, hypertension and NYHA class, and inversely related to age, creatinine clearance, and use of beta-blockers. Multivariate Cox model analysis demonstrated that aldosterone was independently associated with cardiovascular mortality (P = 0.001), total mortality (P = 0.001), acute ischaemic events (P = 0.01), and the composite of death and acute ischaemic events (P = 0.004). Reclassification analysis, using integrated discrimination improvement (IDI) and net reclassification improvement (NRI), demonstrated incremental predictive value of aldosterone (P < 0.0001)., Conclusion: Our results demonstrate that, in patients with CAD but without heart failure or acute MI, the level of aldosterone is strongly and independently associated with mortality and the occurrence of acute ischaemic events.

Objective: To determine whether a biological marker of ischemia, ischemia-modified albumin (IMA), alone or normalized to albumin serum concentration, was modified during the course of pregnancy and so could be used for discrimination between normal pregnancy and preeclampsia., Methods: Serum IMA concentrations and IMA to serum albumin ratio (IMA/alb) were compared in 22 nonpregnant healthy women (NP), 19 healthy pregnant women (HP) and 20 pre-eclamptic women (PE). Influence of age of gestation on these markers was also investigated., Results: IMA to albumin ratio (IMA/alb) was significantly increased in HP compared with NP (IMA/alb. HP: 2.60 +/- 0.38 kU/g and IMA/alb. NP: 2.10 +/- 0.22 kU/g; p < 0.05). Both IMA and IMA/alb were significantly elevated during PE compared with HP (IMA HP: 98.4 +/- 9.2 kU/l and IMA PE 116.9 +/- 12.3 kU/l, p < 0.001; IMA/alb HP: 2.60 +/- 0.38 kU/g and IMA/alb PE: 3.79 +/- 0.75 kU/g p < 0.001)). Both IMA and IMA/alb were increased in PE up to delivery. No correlation could be demonstrated between gestational age and maternal IMA both in HP (r = 0.13; p = 0.071) or PE (r = 0.05; p = 0.318)., Conclusions: IMA and IMA normalized to albumin appear to be significantly increased during pathological pregnancies. These results confirm that IMA could be used as a biological marker of preeclampsia. These data need to be confirmed by determining intra-individual IMA change during normal and pathological pregnancy.

In clinically isolated syndrome (CIS), the detection of oligoclonal bands (OCBs) in cerebrospinal fluid (CSF) is critical for space dissemination validation when magnetic resonance imaging (MRI) diagnostic criteria are not fulfilled. However, lumbar puncture for CSF collection is considered relatively invasive. Previous studies have demonstrated applicability of OCB detection in tears to the diagnosis of multiple sclerosis (MS). The objective of the present study was to assess concordance between OCB detection in tears and in CSF. We have prospectively included patients with CIS and compared results of CSF and tear OCB detection by isoelectric focusing (IEF). Tears were collected using a Schirmer strip. We included 82 patients. For 69 of them, samples were analysable. OCBs were detected in CSF for 63.8% and in tears for 42% of patients. All patients with tear OCBs had CSF OCBs. We suggest that tear OCB detection may replace CSF OCB detection as a diagnostic tool in patients with CIS. This would circumvent the practice of invasive lumbar punctures currently used in MS diagnosis.

Background: High-sensitivity C-reactive protein (hs-CRP) elevation is associated with poor clinical outcome in patients with coronary artery disease (CAD). However, the prognostic value of preprocedural hs-CRP elevation before coronary stent implantation remains debated especially regarding restenosis and target vessel revascularization (TVR). Furthermore, whether hs-CRP elevation may predict stent thrombosis (ST) is unknown., Methods: We included 560 consecutive patients, who underwent coronary stent implantation in our institution. Blood samples for hs-CRP determination were obtained immediately before the procedure. During a median follow-up of 12.5 months, cardiovascular events including death, myocardial infarction (MI), TVR, and ST were systematically included., Results: Median hs-CRP was 3.10 [25-75th percentile: 1.36-8.63] mg/l. There were 27 (4.8%) deaths, 17 (3.1%) nonfatal MI, 58 (10.5%) TVR, and 12 (2.1%) ST. The composite criteria death-MI occurred in 44 (7.9%) patients. Independent predictors of the composite death-MI were hs-CRP level [hazard ratio (HR)=1.33 (95% CI: 1.05-1.70); P=.021], diabetes (P=.003), and multivessel CAD (P=.011). The composite death-MI occurred in 31 (13.3%) of the 233 patients with hs-CRP >4.63 mg/l vs. 13 (4.0%) of the 327 patients with hs-CRP <4.63 mg/L (P<.001). By contrast, hs-CRP predicted neither TVR [HR=0.88 (0.73-1.08); P=.23] nor ST [HR=1.15 (0.77-1.71); P=.49]., Conclusion: High hs-CRP levels before coronary stent implantation are associated with risk of death or MI, but are not related to TVR or ST. These data suggest that preprocedural hs-CRP is more a predictor of global cardiovascular risk than a predictor of stent-related complications.

Aims: The metabolic syndrome (MS) is associated with an increased cardiovascular risk. Patients with the MS have endothelial dysfunction, decreased circulating adiponectin, and a high expression of angiogenic inhibitors such as plasminogen activator inhibitor-1 (PAI-1). We hypothesized that such patients, in the event of a coronary occlusion, might exhibit a less developed collateral circulation., Methods and Results: Three hundred and eighty-seven consecutive patients with at least one coronary occlusion of a major coronary vessel at diagnostic angiography were prospectively enrolled. Collateral development was graded with validated angiographic methods. The MS was defined according to the ATP-III definition. Fasting glucose, adiponectin, insulin concentrations, and PAI-1 were measured at the time of angiography. MS was associated with less developed collateral vessels (P = 0.005). In multivariable analysis adjusting for potential confounding factors including the duration of coronary occlusion (P = 0.0001), fasting glycaemia (P = 0.0007), low adiponectin concentration (P = 0.01), insulin-resistance (HOMA-IR; P = 0.01), high circulating PAI-1 concentration (P = 0.01), and hypertension (P = 0.008) were independently associated with poor coronary collateral vessel development., Conclusion: This study shows that in patients with coronary occlusion, collateral circulation is impaired in patients with the MS. This association is partly related to fasting glycaemia and to key parameters linked to insulin resistance.

The serum IgM level has been utilised as a marker of tumor progression and to assess response to therapy in patients with Waldenstrom macroglobulinemia (WM). However, there are many limitations to the IgM protein level. The objective of this study was to evaluate the association of known tumor burden markers and prognostic factors with serum free light chain (sFLC) in 98 patients with WM. We demonstrated that sFLC measurement accurately differentiated IgM-MGUS compared with WM reflecting a measurement of tumor burden. In univariate and multivariate analysis, median sFLC at the cut-off at 60 mg/L was higher for WM patients with low hemoglobin and high beta2M, when we applied the WM-IPSS cut-offs, but showed no association with IgM level. This study demonstrates that sFLC is a new marker in WM disease. Further analysis is required to prospectively study the role of sFLC in monitoring response to therapy and as a prognostic marker in WM patients.

Objectives: Waldenstrom Macroglobulinemia (WM) is a B-cell neoplasm characterised by secretion of IgM by lymphoplasmacytic bone marrow cells and by cytopenias and hypogammaglobulinemia in a subset of patients. Beta-2 microglobulin (b2m) is a major prognostic factor in WM and the heavy chain of HLA class I molecules, which are known to have immunosuppressive properties and have been implicated in the pathogeny of several malignancies., Methods: We assessed the serum levels of the total soluble HLA-I molecules and the HLA-Gs molecules in 105 patients with IgM-related disorders [WM (n = 42) and IgM MGUS (n = 63)], and compared the results to 41 healthy subjects., Results: We found higher levels of HLA-Is in WM, compared to IgM MGUS and healthy donors. HLA-Gs levels were similar in WM and in IgM MGUS, but higher than in healthy donors. The association between HLA-Is at the cut-off of 1.8 microg/mL and known markers of poor prognosis was then evaluated among WM patients using univariate and multivariate methods. Based on this, high HLA-Is level was strongly associated with high serum beta2M level >3 mg/L [OR = 2, (CI 95% 1.1-5.7); P = 0.04], age > 65 yrs [OR = 1.5, (CI 95% 0.5-4.1), P = 0.06] and haemoglobin < or =11.5 g/dL [OR = 3.3, (CI 95% 1.2-9.7); P = 0.03]. High levels of serum HLA-Is were also found in patients with cryoglobulinemia, however irrespectively of WM or IgM-MGUS status., Conclusion: Together our results suggest a possible role for soluble MHC class I molecules in WM disease. Further investigations are necessary to further demonstrate the prognostic impact of soluble MHC class I molecules in Waldenstrom Macroglobulinemia.

Aims: To evaluate, in patients referred for elective percutaneous coronary revascularization (PCR) without heparin pre-treatment, the relationship between baseline serum levels of the angiogenic growth factors, vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF), and clinical outcome., Methods and Results: In 488 consecutive patients undergoing elective coronary angioplasty, hsC-reactive protein, HGF, and VEGF levels were measured before heparin administration. The primary endpoint, a composite of death and myocardial infarction, occurred in 44 patients at a median follow-up of 14.9 months. At baseline, VEGF levels were related to C-reactive protein levels and inversely related to age; HGF levels were related to C-reactive protein levels, diabetes, and recent clinical instability. In the univariate analysis, HGF had a significant positive relationship (P=0.003) with the primary endpoint. A similar trend was observed for VEGF (P=0.11). The only three variables significantly associated with the primary endpoint in the multivariable Cox model were HGF (P=0.004), C-reactive protein (P=0.007), and diabetes (P=0.04)., Conclusion: Our results demonstrate that in patients, without heparin pre-treatment, referred for PCR, a high serum level of HGF is an independent predictor of clinical events during follow-up and is correlated with other surrogate measures of the activity of atherosclerosis.

Aims: To determine the potential adjunct of high-sensitivity (hs) C-reactive protein for risk stratification in patients with stable congestive heart failure (CHF)., Methods and Results: We studied 546 consecutive patients clinically stable with an ejection fraction <45% who were referred to our centre for evaluation of left ventricular dysfunction. hs C-reactive protein levels were determined on blood samples obtained on entry into the study. Clinical follow-up (median 972 days) was obtained for 545 patients. Cardiovascular mortality was significantly increased (P=0.001) in patients with hs C-reactive protein >3 mg/L. By multivariable analysis, including clinical, biological, and echocardiographic variables, hs C-reactive protein >3 mg/L was an independent predictor of cardiovascular mortality [HR=1.78 (1.17-2.72); P=0.008]; the strongest predictive parameter in this model was B-type natriuretic peptide (BNP) (P=0.005). When peak VO(2) was included into the model, hs C-reactive protein >3 mg/L remained an independent predictor of cardiovascular mortality [HR=1.55 (1.02-2.38); P=0.04]; the strongest predictive parameter in this model was peak VO(2) (P<0.0001). In patients with ischaemic CHF, cardiovascular mortality was significantly increased in patients with hs C-reactive protein >3 mg/L (P=0.001), whereas in patients with non-ischaemic CHF, hs C-reactive protein >3 mg/L was not associated with cardiovascular mortality (P=0.098). By multivariable analysis, hs C-reactive protein >3 mg/L was an independent predictor of cardiovascular mortality in ischaemic patients [HR=2.16 (1.23-3.78)] but not in non-ischaemic patients [HR=1.05 (0.52-2.11)]., Conclusion: Cardiovascular mortality is increased in CHF patients with hs C-reactive protein >3 mg/L. The impact of hs C-reactive protein is independent of usual prognostic parameters, in particular BNP and peak VO(2). The interest of hs C-reactive protein determination appears to be especially marked in patients with ischaemic cardiomyopathy.

Serum beta2-microglobulin, the light chain of the HLA class I molecular complex, remains one of the best survival prognostic factors in multiple myeloma, but other HLA class I molecules might be of interest in monoclonal gammopathies. In this study, we evaluate total soluble HLA class I (HLA-Is) and soluble HLA-G (HLA-Gs) in 103 patients with newly diagnosed multiple myeloma, 30 patients with monoclonal gammopathy of undetermined significance (MGUS), and 30 healthy subjects, studying their prognostic value in multiple myeloma. In multiple myeloma patients, HLA-Is and HLA-Gs median values were 0.8 microg/mL and 28 ng/mL, respectively. Median HLA-Is concentration was higher in stage II and III multiple myeloma patients than in stage I multiple myeloma, MGUS, and control patients. Median HLA-Gs was significantly lower in healthy controls than in MGUS and multiple myeloma patients. A high level of HLA-Is (> or =2.1 microg/mL) was predictive of short survival (P = 0.017). For each given level of beta2-microglobulin, the relative risk of death was higher for patients with HLA-Is > or = 2.1 microg/mL than in patients with a lower level (P = 0.047). HLA-Gs, a marker of monoclonal gammopathy, was of no prognostic value, but the addition of HLA-Is to beta2-microglobulin produced an efficient prognostic score (P < 0.0001). HLA-Is is a new marker of multiple myeloma tumor load and provides additional survival prognostic information to beta2-microglobulin.

Three different approaches were used in an attempt to characterize the KB-cell receptor for adenovirus: affinity chromatography, immunoadsorption and cross-linking with a cleavable bifunctional reagent. The first system used an affinity gel consisting of adenovirus-fibre projection linked to Sepharose matrix by an intermediate bis(aminopropyl)amine arm, the amino groups of the fibre ligand being preserved by prior citraconylation. The second system consisted of adenovirus complete penton capsomere attached to anti-(penton base) antibody and cross-linked to polyacrylamide particles with glutaraldehyde. In this latter affinity model, the penton-fibre projection was appropriately oriented outwards, as in the virus particle. Both affinity systems permitted isolation from a KB-cell plasma-membrane extract of fibre-binding and penton-fibre-binding protein material, which inhibited adenovirus attachment. The penton-immunoadsorbent appeared more efficient and more specific than the affinity column of fibre-bis(aminopropyl)amino-Sepharose gel in specific activity of inhibition of adenovirus attachment. The third method consisted of reversibly cross-linking KB-cell receptor proteins with adenovirus particles by means of a cleavable di-imidoester and isolation of the complexes by sucrose-density-gradient centrifugation. Polypeptide analysis on sodium dodecyl sulphate/polyacrylamide gel of labelled KB-cell surface proteins, selected by the different procedures, showed that three major protein subunits of 78000, 42000 and 34000mol.wt. were common to the three selection systems. A possible model for the structure and function of the KB-cell receptor for adenovirus is discussed.