Treatment-specific risk of subsequent malignant neoplasms in five-year survivors of diffuse large B-cell lymphoma.

BACKGROUND: The introduction of rituximab significantly improved the prognosis of diffuse large B-cell lymphoma (DLBCL), emphasizing the importance of evaluating the long-term consequences of exposure to radiotherapy, alkylating agents and anthracycline-containing (immuno)chemotherapy among DLBCL survivors. METHODS: Long-term risk of subsequent malignant neoplasms (SMNs) was examined in a multicenter cohort comprising 2373 5-year DLBCL survivors treated at ages 15-61 years in 1989-2012. Observed SMN numbers were compared with expected cancer incidence to estimate standardized incidence ratios (SIRs) and absolute excess risks (AERs/10 000 person-years). Treatment-specific risks were assessed using multivariable Cox regression. RESULTS: After a median follow-up of 13.8 years, 321 survivors developed one or more SMNs (SIR 1.5, 95% CI 1.3-1.8, AER 51.8). SIRs remained increased for at least 20 years after first-line treatment (SIR ≥20-year follow-up 1.5, 95% CI 1.0-2.2, AER 81.8) and were highest among patients ≤40 years at first DLBCL treatment (SIR 2.7, 95% CI 2.0-3.5). Lung (SIR 2.0, 95% CI 1.5-2.7, AER 13.4) and gastrointestinal cancers (SIR 1.5, 95% CI 1.2-2.0, AER 11.8) accounted for the largest excess risks. Treatment with >4500 mg/m2 cyclophosphamide/>300 mg/m2 doxorubicin versus ≤2250 mg/m2/≤150 mg/m2, respectively, was associated with increased solid SMN risk (hazard ratio 1.5, 95% CI 1.0-2.2). Survivors who received rituximab had a lower risk of subdiaphragmatic solid SMNs (hazard ratio 0.5, 95% CI 0.3-1.0) compared with survivors who did not receive rituximab. CONCLUSION: Five-year DLBCL survivors have an increased risk of SMNs. Risks were higher for survivors ≤40 years at first treatment and survivors treated with >4500 mg/m2 cyclophosphamide/>300 mg/m2 doxorubicin, and may be lower for survivors treated in the rituximab era, emphasizing the need for studies with longer follow-up for rituximab-treated patients.

Bilateral breast cancer, synchronous and metachronous; differences and outcome.

The aims of this study were twofold: to analyze the incidence of patients having synchronous or metachronous bilateral invasive breast cancer (SBBC and MBBC) and to assess the characteristics and outcome compared to those having unilateral breast cancer (UBC). The used data were obtained from our prospective population-based cohort study which had been started in 1983. Bilateral breast cancer (BBC) was categorized as SBBC (≤3 months of the first primary) or MBBC (>3 months after the first primary). The incidence of SBBC was 1% and that of MBBC 7.0 %. Patients with UBC showed more ductal carcinoma compared to patients with BBC. MBBC status was an independent significant predictor of local failure (HR 1.9; 95% CI 1.3-2.7). SBBC status was an independent predictor of distant metastases (HR 2.6; 95% CI 1.4-4.5). Overall survival (OS) was better for MBBC (HR 0.6; 95% CI 0.4-0.8) and worse for SBBC (HR 2.3; 95% CI 1.5-3.6) compared to UBC. We noted: (1) MBBC showed a significant higher local failure compared to UBC, (2) SBBC, compared to MBBC and UBC had a significant higher distant metastases rate, (3) disease-specific survival and OS were significantly worse for SBBC compared to UBC and MBBC, and (4) that the OS for MBBC compared to UBC, was significantly better.

Survey response of oral and maxillofacial surgeons on invasive procedures in patients using antithrombotic medication.

The aim was to evaluate the management strategies of Dutch oral and maxillofacial surgeons when performing invasive dental or oral surgery in patients using oral antithrombotic medication (OAM). In November 2009 a survey was mailed to all 213 members of the Dutch Society for Oral and Maxillofacial Surgery. A response rate of 57% was achieved with 79 surveys returned through mail and 38 surveys answered through the Internet. The results show that many different treatment strategies are advocated by Dutch oral and maxillofacial surgeons, regarding preferred international normalised ratio (INR) value and continuation or discontinuation of OAM prior to invasive dental or oral surgery. The risk of bleeding during or after an invasive dental procedure was overestimated. A need for a practice guideline on this topic was expressed by 73% of respondents.

The M694V mutation in Armenian-Americans: a 10-year retrospective study of MEFV mutation testing for familial Mediterranean fever at UCLA.

Familial Mediterranean fever (FMF), inherited in an autosomal recessive manner, is a systemic auto-inflammatory disorder characterized by recurrent attacks of fever with peritonitis, pleuritis, synovitis and erysipeloid rash. The marenostrin-encoding fever (MEFV) gene, located on chromosome 16p13.3, is the only gene in which mutations are currently known to cause FMF. To correlate specific genotypes with adverse phenotypes of affected populations residing in the Western United States, a retrospective case series review was conducted of all MEFV gene mutation testing completed at UCLA Clinical Molecular Diagnostic Laboratory between February 2002 and February 2012, followed by clinical chart review of all subjects who either have a single or double mutation. All 12 common mutations in the MEFV gene were analyzed and the M694V variant was found to be associated with an adverse FMF clinical outcome in the Armenian-American population, manifested by earlier onset of disease, increased severity of disease, and renal amyloidosis.

The impact of margin status in breast-conserving therapy for lobular carcinoma is age related.

PURPOSE: The aim is to look at the impact of margin status and outcome of invasive lobular carcinoma (ILC) treated with breast-conserving therapy (BCT). METHODS: This manuscript describes an analysis on 330 BCT in 318 patients with ILC. RESULTS: The 12-year local relapse free survival (LRFS) is 89%. In multivariate analysis, positive margin status, age>50 years, contra lateral breast cancer, and adjuvant systemic therapy were significant predictors of local relapse free survival. In a separate analysis limited to a positive margin for invasive carcinoma or carcinoma in situ, only a positive margin for invasive carcinoma was a significant predictor of local relapse free survival. This was limited to women

GnRH agonist and GnRH antagonist in intracytoplasmic injection cycles.

The long agonistic protocol for controlled ovarian hyperstimulation (COH) is effective and used most often, thus is considered the gold standard. Therefore any new regimen has to be compared in its results with those obtained with the long protocol. This report compares the efficacy of GnRH agonist and antagonist in a retrospective study of IVF/ICSI carried out in a tertiary teaching hospital from 2003 to 2006. Only the first COH cycle followed by IVF-ICSI from 200 couples (agonist = 120 and antagonist = 80) were analysed. The end points studied included the number of oocytes recovered, number of mature (MII) oocytes, fertilization, cleavage, morphology based embryo quality, pregnancy rate, quantity and cost of gonadotrophin. The average age of female subjects was 35.1 +/- 4.7 years with 50% being 35 years and above. Major infertility factors were tubal blockage, male factor and endometriosis altogether comprising 68%. GnRH agonist and antagonist cycle parameters were comparable except lesser amount of gonadotrophin was used with lower resultant costs (both p < 0.0005) in antagonistic regime. Antagonist regime produce somewhat more good quality embryos (p = 0.065), an insignificant difference. A clinical pregnancy rate per embryo transfer of 16.3% in agonist and 20.6% in antagonist regime was achieved respectively. In conclusion, GnRH antagonist protocol produced a COH response, embryonic development and pregnancy rates on par to GnRH agonist regime. Moreover GnRH antagonist protocol required a shorter stimulation period plus fewer complications. Hence GnRH antagonist regime provided means for a friendlier, convenient and cost effective protocol for patients.

Affordable ART for developing countries: a cost benefit comparison of low dose stimulation versus high dose GnRH antagonist protocol.

OBJECTIVE: Low dose stimulation (LS) is emerging as an alternative regime in assisted reproductive technology (ART). This study aimed to compare the cost-effectiveness of LS to the high dose GnRH antagonist (Atg) regime. METHODS: An observational prospective study conducted at an academic infertility unit from January to June 2007. Outcome measures included the numbers of follicles, oocytes and embryos, morphological quality of oocytes and embryos, clinical pregnancy (PR) and complication rate. RESULT: Ninety five first attempt ICSI cycles consisting of 54 LS and 41 Atg were analyzed. Subjects in both groups had comparable sociodemographics and reproductive characteristics. LS generated significantly fewer follicles, total oocytes, mature oocytes (all p < 0.0005) and immature oocytes (p = 0.009) than Atg but the number of excellent quality oocytes was similar. Significantly fewer embryos were available in LS although the proportion of usable embryos was higher, 83.2% vs. 67.0% for Atg. Mean embryos per transfer was 2.0 +/- 1.1 vs. 2.6 +/- 1.0 (p = 0.02) for a clinical PR per transfer of 43.2% vs. 50.0% for LS and Atg respectively. LS regime had a shorter gonadotrophin administration period with resultant COH cost one third of the Atg protocol (both, p < 0.0005). The cost per live birth per started cycle worked out to be USD 13,200 and 24,900 for LS and Atg respectively. Furthermore, LS had fewer incidences of OHSS compared to the Atg regime, 3.7% vs. 12.2%. CONCLUSION: LS cost benefits included lower amounts of gonadotrophin used and fewer injections. It is a viable alternative regime in producing comparable clinical PR at lower cost and less complication in ART.

Synchronous, bilateral breast cancer: prognostic value and incidence.

The purpose of this study was to address the question whether patients with bilateral breast cancer (BBC) have a worse prognosis in terms of recurrence and survival than patients with primarily unilateral breast cancer (UBC) following breast-conserving treatment (BCT). From 1983 to 2000, a total of 1760 BCT were registered in the Radiotherapy Department of the Medisch Spectrum Twente. We defined synchronous a BBC as cancer diagnosed in both breasts at the same time or within a period of 3 months of diagnosis of the first tumor. One thousand seven hundred and sixty BCT were performed on 1705 patients, 26 of whom presented with BBC. Of these 26 patients, 18 had BCT for both breasts. A higher proportion of patients with BBC showed more tubular carcinoma (P=0.029) and medially located tumors (P=0.076) than those with UBC did. The 5- and 10-year local recurrence rates (LRRs) were 4.5% and 9.1%, respectively, in BBC patients, as against 3.3% and 7.6% for UBC after BCT. The 5- and 10-year distant metastasis rates were 26.9% and 50.7%, respectively, for BBC as against 13.4% and 21.1% for UBC after BCT (P=0.065 and P=0.014, respectively). The 5- and 10-year disease-specific survival (DSS) rates for the 1705 patients were 82.1% and 41%, respectively, after BBC, and 91.4% and 84% after UBC (P=0.086 and P=0.0045, respectively). Patients with BBC have a higher rate of distant metastasis and a worse DSS than those with UBC. As the LRR is similar for BBC and UBC, BCT is not contraindicated in BBC. The incidence of BBC is low, at 1.5% which makes it difficult to reach any more definitive conclusions on outcome and treatment.

Prognostic factors in transitional cell cancer of the bladder: an emerging role for Bcl-2 and p53.

BACKGROUND AND PURPOSE: In a recent study on patients with transitional cell cancer of the bladder treated with curative radiotherapy following TUR-T, we demonstrated that a low apoptotic index and p53 positivity were associated with poor local control. The purpose of this study was to assess the prognostic significance of additional markers implicated in regulation of cell cycle and apoptosis. PATIENTS AND METHODS: Bcl-2, Bax and p21 positivity were detected immunohistochemically on paraffin-embedded pre-treatment biopsies from 83 patients with invasive transitional cell cancer (TCC) of the bladder, treated with radiotherapy. In addition, markers determined in an earlier analysis, i.e.: p53, apoptotic index, cyclin D1, retinoblastoma protein and Ki-67 were included in the multivariate analysis. A stepwise proportional hazard analysis was performed, adjusting for classic prognostic factors (T-stage, grade, multifocality and macroscopic completeness of the TUR). Positivity was defined as >10% of tumor cells staining positive for Bcl-2, Bax and p21, and >20% for p53. RESULTS: Bcl-2 positivity was found in 63%, Bax was positive in 52% and p21 in 55% of cases. In the PH analysis Bcl-2 positivity was found to be related to poor local control (36 vs. 72% at 3 years; P=0.003), as well as to shorter disease-specific survival (74 vs. 94% at 3 years; P=0.017). Evidence for an adverse effect of p53 positivity was also found (local control: 32 vs. 69% at 3 years;P=0.037, disease-specific survival: 76 vs. 92% at 3 years; P=0.043). In an additional PH analysis, we found poor local control rates for bladder cancers with combined Bcl-2 and p53 positivity (17 vs. 65% at 3 years; P=0.0017), and lower disease specific survival (60 vs. 92%; P=0.0024), disease-free survival (7 vs.35%, P=0.0023) and overall survival (39 vs. 80%; P=0.0018). CONCLUSION: This study provides evidence for a poor outcome in patients treated with radiotherapy for TCC of the bladder expressing both Bcl-2 and p53. This relationship was found for local control and disease-free, disease-specific and overall survival.

Apoptosis, proliferation and p53, cyclin D1, and retinoblastoma gene expression in relation to radiation response in transitional cell carcinoma of the bladder.

PURPOSE: To determine whether the apoptotic index, the Ki67 index, and the expression of the p53, cyclin D1, and retinoblastoma genes correlate with local control, overall survival, and time to distant metastases in invasive bladder cancer treated with external beam radiation. METHODS AND MATERIALS: Paraffin-embedded pretreatment biopsies from 83 patients with invasive transitional cell carcinoma of the bladder were scored morphologically for apoptosis and immunohistochemically for Ki67, p53, cyclin D1, and retinoblastoma gene expression. Survival analysis methods were used to assess overall survival, local control, and freedom from distant metastases. A multiple proportional hazard (PH) regression analysis was performed to study the prognostic value of the abovementioned biologic parameters (all divided into two categories, except Ki67) in addition to classical prognostic factors such as T stage, histologic grade, multifocality of the tumor, and completeness of transurethral resection. All patients were treated with external beam radiation as sole treatment. Median follow-up for the 19 patients still living was 7.5 years. RESULTS: Apoptotic index varied from 0% to 3.4% with a mean of 0.8% and a median of 0.6%. Ki67 index varied from 0% to 60% with a mean of 14% and a median of 12%. P53 protein was detectable in 61% of the tumors. Overexpression of cyclin D1 was observed in 39% of the tumors and loss of retinoblastoma protein in 23% of the tumors. High Ki67 index was found to be significantly associated with p53 expression (p = 0.04) and cyclin D1 overexpression (p = 0.023). Cyclin D1 overexpression was found more often in Rb-positive tumors than in Rb-negative tumors (p = 0.006). Other associations between the markers are less clear. Biologic markers were not correlated with T stage or grade. In the PH analysis local control was found to be significantly better for tumors with wild-type p53 (p = 0.028). Also, tumors with an apoptotic index above the median value (0.6%) had a significantly better local control rate (p = 0.035). Ki67 index (p = 0.35), retinoblastoma gene expression (p = 0.30) and cyclin D1 overexpression (p = 0.61) were not found to have an additional predictive value regarding local tumor control. None of the tested biologic parameters were found to be associated with overall survival. Time to distant metastases was significantly shorter for tumors with high Ki67 index (p = 0.01) and tumors with an apoptotic index less than median (p = 0.009). CONCLUSIONS: The results of our study provide evidence for a prognostic value of p53 expression and apoptotic index with respect to the radiation response in bladder cancer in addition to more conventional prognosticators. The value of these parameters as a predictive assay for radiation response warrants confirmation in larger and prospective studies.

Deaths of children during an outbreak of hand, foot, and mouth disease in sarawak, malaysia: clinical and pathological characteristics of the disease. For the Outbreak Study Group.

From April through June 1997, 29 previously healthy children aged <6 years (median, 1.5 years) in Sarawak, Malaysia, died of rapidly progressive cardiorespiratory failure during an outbreak of hand, foot, and mouth disease caused primarily by enterovirus 71 (EV71). The case children were hospitalized after a short illness (median duration, 2 days) that usually included fever (in 100% of case children), oral ulcers (66%), and extremity rashes (62%). The illness rapidly progressed to include seizures (28%), flaccid limb weakness (17%), or cardiopulmonary symptoms (of 24 children, 17 had chest radiographs showing pulmonary edema, and 24 had echocardiograms showing left ventricular dysfunction), resulting in cardiopulmonary arrest soon after hospitalization (median time, 9 h). Cardiac tissue from 10 patients showed normal myocardium, but central nervous system tissue from 5 patients showed inflammatory changes. Brain-stem specimens from 2 patients were available, and both specimens showed extensive neuronal degeneration, inflammation, and necrosis, suggesting that a central nervous system infection was responsible for the disease, with the cardiopulmonary dysfunction being neurogenic in origin. EV71 and possibly an adenovirus, other enteroviruses, or unknown cofactors are likely responsible for this rapidly fatal disease.

Evaluation of bone strength: correlation between measurements of bone mineral density and drilling force.

Bone drilling is a major part of modern orthopaedic surgery which involves the internal fixation of fractured bones. The investigation of bone drilling described in this paper demonstrates the contribution of automation technology towards the study of bone strength. The aim of this preliminary investigation is to establish a relationship between bone drilling forces and measurements of bone mineral density (BMD) by dual energy X-ray absorptiometry (DXA). A linear relationship with a high coefficient of correlation has been found between average drilling forces and BMD measurements at both the greater trochanter and the femoral head of porcine femurs when drilling in the anterior-posterior (AP) direction (i.e. the direction of the DXA scan). It has also been found that in the normal drilling direction (i.e. in the cervical axis direction), which is orthogonal to the DXA scanning direction, there are similar trends between the drilling forces and BMD levels in regions where bone density is more consistent (e.g. the femoral head). The findings of this investigation indicate that analysis of bone drilling forces has the potential to provide useful information about the strength of bone.

Serum interleukin-6 has no discriminatory role in paraproteinaemia nor a prognostic role in multiple myeloma.

We determined interleukin-6 (IL-6) levels in the serum of 212 well-defined patients with newly diagnosed paraproteinaemia and evaluated its discriminatory value and prognostic role in multiple myeloma (MM). Results were compared with serum neural cell adhesion molecule and beta-2-microglobulin, both established prognostic MM markers. Paraproteinaemia-related diagnoses were: MM (60), other haematological diseases (46), solid tumours (35), autoimmune diseases (17) and monoclonal gammopathy of unknown significance (MGUS) (54). The range of IL-6 levels in all diagnostic groups overlapped widely and did not serve as a discriminatory marker in newly diagnosed paraproteinaemia even when patients with infection or fever (42) were excluded. In MM high IL-6 levels (>/= 50 pg/ml) were not associated with a shorter survival (P = 0.24). We compared our results with 20 published studies on serum IL-6 in paraproteinaemia and/or MM. IL-6 data have to be related to the assay used (bio- or immunoassay) and to the status of MM (newly diagnosed, during therapy, progressive disease). We conclude that serum IL-6 is not specific for paraproteinaemia-related diseases and will not serve as a reliable discriminatory or prognostic marker in paraproteinaemia and MM.

[The risk of a multiple myeloma in patients with paraproteinemia: a myeloma risk score developed in the region of the Comprehensive Cancer Center West]. / De kans op de ziekte van Kahler (multipel myeloom) bij patiënten met een paraproteïnemie: myeloomrisicoscore, ontwikkeld in de regio van het Integraal Kankercentrum West.

Diagnoses in patients with paraproteinaemia are diverse; few (mostly single centre based) studies are known that describe incidence, diagnoses and follow-up in patients with paraproteinaemia. In the region of the Comprehensive Cancer Centre West in the Netherlands (population 1.6 million, 1992) a population-based registry was set up in the period 1991-1993. Patients (n = 1464; median age: 72 years; range: 16-102) were entered by clinical chemists, internists, haematologists, and pathologists. Multiple myeloma and plasmacytoma were diagnosed in 261 patients (18%), paraprotein-related haematological diseases in 159 patients (11%) and paraprotein-related internal diseases in 210 patients (14%). After bone marrow examination monoclonal gammopathy of unknown significance (MGUS) was diagnosed in 207 (14%) patients. No further diagnosis could be made in 627 (43%) patients mostly for lack of supplementary bone marrow and (or) X-ray examinations. Consequently, more than two-thirds of all patients with a newly found paraprotein did not show any sign of a haematological malignancy. Using these data a 'myeloma risk score' was developed to predict the presence of a multiple myeloma based on paraprotein type and concentration, aiding the physician in determining which patients should undergo further bone marrow and skeletal examinations.

Drilling of bone: a robust automatic method for the detection of drill bit break-through.

The aim of this investigation is to devise a robust detection method for drill bit break-through when drilling into long bones using an automated drilling system that is associated with mechatronic assisted surgery. This investigation looks into the effects of system compliance and inherent drilling force fluctuation on the profiles of drilling force, drilling force, drilling between successive samples and drill bit rotational speed. It is shown that these effects have significant influences on the bone drilling related profiles and thus on the detection of drill bit break-through. A robust method, based on a Kalman filter, has been proposed. Using a modified Kalman filter, it is possible to convert the profiles of drilling force difference between successive samples and/or the drill bit rotational speed into easily recognizable and more consistent profiles, allowing a robust and repeatable detection of drill bit break-through.

Developing a population-based registry for patients with paraproteinemias or multiple myeloma.

The development of a population-based registry on paraproteinemia and multiple myeloma is described. A unique feature of this registry is the multidisciplinary approach to obtain and collect new cases. Clinical chemists, internists, hematologists, and pathologists could all enter patients. All patients newly diagnosed in the mid-western part of The Netherlands (1.7 million inhabitants in 1992) with a paraproteinemia or multiple myeloma in 1991, 1992, and 1993 were included. The project was composed of a registry of clinical and laboratory data extracted from the patient's records, storage of 1 ml serum at diagnosis, and a yearly follow-up. A total of 1832 entries was received, of which 83% met the inclusion criteria. Comparison of this database with the Regional Cancer Registry showed that the paraprotein registry was successful as far as registration of myeloma patients was concerned. We conclude that the multidisciplinary approach used in this paraprotein registry is feasible and has resulted in a unique collection of patients for studying potential pre-malignant conditions such as paraproteinemia.

Development of a "Myeloma Risk Score" using a population-based registry on paraproteinemia and myeloma.

Diagnostic systems for monoclonal gammopathies use bone marrow and X-ray examinations to exclude multiple myeloma (MM). Data from a population-based registry of unselected patients with paraproteinemia indicate that these tests are often done only when MM is suspected. We used 441 randomly selected patients to develop a simple four point "Myeloma Risk Score" based on two readily available laboratory tests. One point was given for paraprotein concentration > or = 10 g/l, one point for IgG and IgA, and two points for IgD and light chains only. A score of 0 or 1 indicated a low risk for MM, with scores of 2 and 3 signifying high risks. Sensitivity, specificity, positive and negative predictive value (PV) for the Myeloma Risk Score in the training sample were 92%, 88%, 79%, and 96% respectively. Extrapolating these results to a larger cohort showed that 90% of patients with a monoclonal gammopathy could be classified correctly as having MM or a non-myeloma condition. The Myeloma Risk Score can identify patients with a paraproteinemia at risk for MM, and who are therefore candidates for bone marrow and X-ray examination.

A population-based registry on paraproteinaemia in The Netherlands. Comprehensive Cancer Centre West, Leiden, The Netherlands.

Patients with monoclonal gammopathies comprise a heterogenous group. The few studies on incidence and follow-up are single-centre-based and may reflect referral bias. To avoid this, all patients (n=1275) in midwestern Netherlands with a newly discovered paraproteinaemia in 1991, 1992 and 1993 were included in a population-based registry and divided into four major diagnostic groups: multiple myeloma and plasmacytoma (n=230, 18%), other haematological diseases (n=141, 11%), paraprotein-related internal diseases (n=191, 15%) and monoclonal gammopathy of undetermined significance (MGUS, n=713, 56%). To avoid a possibly erroneous diagnosis, patients who were classified as having MGUS but who did not undergo confirmatory bone marrow examination were included in a separate group 'provisional MGUS' (n=524, 41%), whereas patients who did were classified as having 'definite MGUS' (n=189, 15%). The 'provisional MGUS' patients were relatively older and had more often a poor performance status, but differences between this and the 'definite MGUS' group were otherwise small. Patients complaining of general malaise more often had a full work-up of their paraproteinaemia. Bone pain, hypercalcaemia, high total protein, and high ESR occurred predominantly in the myeloma group, whereas fever or infection was less often seen in these patients. This registry of patients with paraproteinaemias provided valuable data related to all different diseases associated with paraproteinaemia.

Serum neural cell adhesion molecule differentiates multiple myeloma from paraproteinemias due to other causes.

Serum neural cell adhesion molecule (NCAM) has been described as a prognostic marker in multiple myeloma (MM). Both C-reactive protein (CRP) and beta 2-microglobulin (beta 2M) are established prognostic markers in MM. We tested the diagnostic value of these markers in 212 serum samples of patients with paraproteinemia registered prospectively in a population-based registry. Sixty patients had MM and 152 had other monoclonal gammopathies (hematologic diseases [48], paraneoplastic disease [35], autoimmune disease [15], and monoclonal gammopathy of undetermined significance [56]). CRP and beta 2M had wide and overlapping ranges in all diagnostic categories. However, serum neural cell adhesion molecule (NCAM) was low (< 20 U/mL) in all but 4 of 152 nonmyeloma cases and high (> or = 20 U/mL) in 31 (52%) of the 60 MM cases. Two patients with non-Hodgkin's lymphoma, 1 with chronic lymphatic leukemia, and 1 with autoimmune disease had serum NCAM values between 20 and 30 U/mL. In a discriminant analysis in which serum NCAM, CRP, beta 2M, paraprotein type and concentration, hemoglobin, leukocyte and thrombocyte counts, creatinine, corrected calcium, lactate dehydrogenase, and alkaline phosphatase were included, paraprotein type and concentration and serum NCAM turned out to be the best combination of parameters predicting whether a patient had MM, with 89% of cases being correctly classified. Even without bone marrow and x-ray examinations, serum NCAM, in combination with paraprotein type and concentration, can differentiate between MM and nonmyeloma patients.