Immunophenotypic assessment of clonal plasma cells and B-cells in bone marrow and blood in the diagnostic classification of early stage monoclonal gammopathies: an iSTOPMM study.

Monoclonal gammopathy of undetermined significance (MGUS) is the earliest discernible stage of multiple myeloma (MM) and Waldenström's macroglobulinemia (WM). Early diagnosis of MG may be compromised by the low-level infiltration, undetectable to low-sensitive methodologies. Here, we investigated the prevalence and immunophenotypic profile of clonal (c) plasma cells (PC) and/or cB-lymphocytes in bone marrow (BM) and blood of subjects with a serum M-component from the iSTOPMM program, using high-sensitive next-generation flow cytometry (NGF), and its utility in the diagnostic classification of early-stage MG. We studied 164 paired BM and blood samples from 82 subjects, focusing the analysis on: 55 MGUS, 12 smoldering MM (SMM) and 8 smoldering WM (SWM). cPC were detected in 84% of the BM samples and cB-lymphocytes in 45%, coexisting in 39% of cases. In 29% of patients, the phenotypic features of cPC and/or cB-lymphocytes allowed a more accurate disease classification, including: 19/55 (35%) MGUS, 1/12 (8%) SMM and 2/8 (25%) SWM. Blood samples were informative in 49% of the BM-positive cases. We demonstrated the utility of NGF for a more accurate diagnostic classification of early-stage MG.

Detection of serum M-protein in acetonitrile precipitates by MALDI-TOF mass spectrometry: A novel, low-cost methodology.

BACKGROUND: Several studies have demonstrated the analytical sensitivity of MALDI-TOF mass spectrometry (MALDI-TOF MS) by immunoenrichment for M-protein analysis. We report the results of a novel, low-cost, reagent-based extraction process using acetonitrile (ACN) precipitation to enrich for κ and λ light chains which can be analysed by MALDI-TOF MS. METHODS: Institutional Ethics committee approval was obtained. Serum samples from patients with monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM), plasmacytoma, AL amyloidosis and Waldenström macroglobulinemia (WM) underwent ACN precipitation. The images obtained were overlaid on apparently healthy donor serum samples to confirm the presence of M-protein. A sample was considered positive for M-protein if there was a sharp or broad peak within the κ or λ mass/charge (m/z) range: m/z- [M + 2H]2+: 11,550-12,300 Da and λ m/z- [M + 2H]2+: 11,100-11,500 Da. Images were acquired at a m/z range of 10,000-29,000 Da. Corresponding serum protein electrophoresis (SPEP), serum immunofixation electrophoresis (IFE) and serum free light chain (sFLC) assay by nephelometry were performed for all the samples. RESULTS: Two-hundred-and-two serum samples were included in the study: MM- 184 (91%); AL amyloidosis- 2 (1%); plasmacytoma- 8 (4%); MGUS- 6 (3%) and WM- 2 (1%). All the SPEP positive samples were identified by MALDI-TOF MS. Out of 179 samples positive for M-protein by IFE, MALDI-TOF MS was positive in 176 samples (98%). Compared to IFE, the sensitivity and specificity of M-protein identification by MALDI-TOF MS were 98.3% and 52.2%, respectively. CONCLUSIONS: This study demonstrates the feasibility of qualitatively identifying M-protein without the need for antibody-based immunoenrichment, making the technique cost-effective.

Accuracy of determination of free light chains (Kappa and Lambda) in plasma and serum by Swedish laboratories as monitored by external quality assessment.

BACKGROUND: Free light chain (FLC) measurements are important in diagnosing monoclonal gammopathies. As FLC are heterogeneous, different reagents and instruments for measuring FLC concentrations may give diverging results that affect assessment of patients with monoclonal gammopathies. Here we investigated agreement between different FLC methods using data from the Swedish external quality assurance (EQA) programme. METHODS: The two main FLC assays, N Latex FLC (Siemens) and Serum Freelite (The Binding Site), using four nephelometric or turbidimetric instrument platforms, were compared. Results from 27 EQA rounds distributed to 11-16 Swedish hospital laboratories during 2015-2020 were investigated. RESULTS: The kappa (κ) FLC measurements deviated significantly over time, but when only nephelometry was used, deviation from the mean was lower (median ranges: -5% to 13 %). The CV was significantly higher for the Freelite assay (mean CV = 8.7) than for the N latex assay (mean CV = 5.7) (p < 0.0001). The coefficient of determination between all combinations of reagents and instrument platforms used was generally good (r2 = 0.76-0.87), and the correlation slope acceptable (0.81-1.2). For lambda (λ) FLC measurements, no concordance between combinations of instruments and reagents is apparent, deviating between -40 % to + 48 % from the mean. The CV was significantly higher for the combination with nephelometry and the Freelite assay (CV mean = 13.9 %) than nephelometry and the N latex assay (CV mean = 9.9 %) (p <0.001). The coefficient of determination varied between combinations of reagents and instrument platforms (r2 = 0.59-0.89) and the slope ranged between 0.48 and 1.5. Significant differences between the two reagents used were sometimes noted. CONCLUSIONS: Imprecision in λFLC affects the κFLC/λFLC ratio. This may be important in clinical assessment of patients, especially differentiating between monoclonal and polyclonal gammopathies.

Correlation of plasma cell assessment by phenotypic methods and molecular profiles by NGS in patients with plasma cell dyscrasias.

BACKGROUND: Next-generation sequencing (NGS) detects somatic mutations in a high proportion of plasma cell dyscrasias (PCD), but is currently not integrated into diagnostic routine. We correlated NGS data with degree of bone marrow (BM) involvement by cytomorphology (BMC), histopathology (BMH), and multiparameter flow cytometry (MFC) in 90 PCD patients. METHODS: Of the 90 patients the diagnoses comprised multiple myeloma (n = 77), MGUS (n = 7), AL-amyloidosis (n = 4) or solitary plasmocytoma (n = 2). The NGS panel included eight genes CCND1, DIS3, EGR1, FAM46C (TENT5C), FGFR3, PRDM1, TP53, TRAF3, and seven hotspots in BRAF, IDH1, IDH2, IRF4, KRAS, NRAS. RESULTS: Mutations were detected in 64/90 (71%) of cases. KRAS (29%), NRAS (16%) and DIS3 (16%) were most frequently mutated. At least one mutation/sample corresponded to a higher degree of BM involvement with a mean of 11% pathologic PC by MFC (range, 0.002-62%), and ~ 50% (3-100%) as defined by both BMC and BMH. CONCLUSIONS: The probability of detecting a mutation by NGS in the BM was highest in samples with > 10% clonal PC by MFC, or > 20% PC by BMC/ BMH. We propose further evaluation of these thresholds as a practical cut-off for processing of samples by NGS at initial PCD diagnosis.

Assessment of M-protein quantification using capillary electrophoresis and immunosubtraction-based integration in clinical samples with low M-protein concentrations.

OBJECTIVES: Quantification of monoclonal protein (M-protein) by serum protein electrophoresis (SPE) is indispensable for diagnosing and monitoring monoclonal gammopathies. However, quantification of small and beta migrating M-proteins is challenging because of overlapping non-immunoglobulin and/or polyclonal immunoglobulin protein fractions. We compared a new integration method based on immunosubtraction (IS-CE) using capillary zone electrophoresis (CZE) against the routine method, which includes a combination of perpendicular drop (0.4%), corrected perpendicular drop (1%) and tangent skimming (98.5%). DESIGN & METHODS: The proposed method of M-protein quantification involves calculating the difference in area under the curve between the SPE and a class-specific IS-CE trace. We analyzed the difference in estimated M-protein concentrations obtained with the new method and routine integration methods using 913 samples. For IgA M-proteins at < 10 g/L, the estimated M-protein concentrations were compared with the total IgA concentration. RESULTS: The median M-protein concentration of 913 consecutive samples was 6.2 g/L (IQR 2.1-14.3 g/L). The median and median % difference between the two integration methods was 0.68 g/L (IQR 0.01-1.55 g/L) and 10.9% (IQR 0.18-38.7%), showing a larger estimated M-protein concentration with the new method. More than 25% difference was observed in 38% of the samples and was associated with lower total protein concentration, lower M-protein concentration, IgA and IgM heavy chain isotypes, and beta- or beta-gamma migration. When 161 samples with IgA M-protein < 10 g/L were compared against total IgA concentration, the median bias of the new method was smaller compared to that of the existing method (-0.95 g/L vs. -1.3 g/L, P < 0.0001). CONCLUSIONS: The use of IS based integration using CZE and IS-CE is promising especially for small and beta migrating M-proteins.

Quantitative and qualitative assessment of plasma cell dyscrasias in dual-layer spectral CT.

OBJECTIVES: Virtual non-calcium (VNCa) images could improve assessment of plasma cell dyscrasias by enhancing visibility of bone marrow. Thus, VNCa images from dual-layer spectral CT (DLCT) were evaluated at different calcium suppression (CaSupp) indices, correlating results with apparent diffusion coefficient (ADC) values from MRI. METHODS: Thirty-two patients with initial clinical diagnosis of a plasma cell dyscrasia before any chemotherapeutic treatment, who had undergone whole-body low-dose DLCT and MRI within 2 months, were retrospectively enrolled. VNCa images with CaSupp indices ranging from 25 to 95 in steps of 10, conventional CT images, and ADC maps were quantitatively analyzed using region-of-interests in the vertebral bodies C7, T12, L1-L5, and the iliac bone. Independent two-sample t-test, Wilcoxon-signed-rank test, Pearson's correlation, and ROC analysis were performed. RESULTS: Eighteen patients had a non-diffuse, 14 a diffuse infiltration in conventional MRI. A significant difference between diffuse and non-diffuse infiltration was shown for VNCa-CT with CaSupp indices from 55 to 95, for conventional CT, and for ADC (each p < 0.0001). Significant quantitative correlation between VNCa-CT and MRI could be found with strongest correlation at CaSupp index 65 for L3 (r = 0.68, p < 0.0001) and averaged L1-L5 (r = 0.66, p < 0.0001). The optimum CT number cut-off point for differentiation between diffuse and non-diffuse infiltration at CaSupp index 65 for averaged L1-L5 was -1.6 HU (sensitivity 78.6%, specificity 75.0%). CONCLUSION: Measurements in VNCa-CT showed the highest correlation with ADC at CaSupp index 65. VNCa technique may prove useful for evaluation of bone marrow infiltration if MRI is not feasible. KEY POINTS: • VNCa-CT images can support the evaluation of bone marrow infiltration in plasma cell dyscrasias. • VNCa measurements of vertebral bodies show significant correlation with ADC in MRI. • Averaging L1-L5 at CaSupp index 65 allowed quantitative detection of infiltration comparable to MRI ADC.

Epidemiology, Staging, and Management of Multiple Myeloma.

Multiple myeloma (MM) is a plasma cell disorder that is on the rise throughout the world, especially in the US, Australia, and Western Europe. In the US, MM accounts for almost 2% of cancer diagnoses and over 2% of cancer deaths (more than double the global proportion). Incidence has risen by 126% globally and over 40% in the US since 1990, while global mortality has risen by 94% and US mortality has fallen by 18%. The 5 year survival in the US has more than doubled over the past decades with the introduction of new targeted therapies and transplant techniques. Risk factors for MM include age (average age of diagnosis is 69), race (African Americans are over double as likely to be diagnosed), sex (men are at a 1.5× risk), and family history. Diagnosis includes serum or urine electrophoresis and free light-chain assay but requires bone marrow biopsy. It is distinguished from smoldering myeloma and monoclonal gammopathy of undetermined significance by a high (>3 g/dL) level of M-protein (monoclonal light chains) and the presence of CRAB (Hypercalcemia, Renal failure, Anemia, Bone pain) symptoms, which include hypercalcemia, renal failure, anemia, and bone pain, suggesting an end-organ damage. International staging system staging involves beta 2 microglobulin and albumin levels, while the revised system considers prognostic factors such as lactate dehydrogenase levels and chromosomal abnormalities. Front-line management includes induction regimen, maintenance therapy and hematopoietic cell transplantation for eligible patients and bisphosphonates or bone-stimulating agents for the prevention of skeletal events. Treatment for relapsed disease includes newly approved monoclonal antibodies like the CD38-targeting daratumumab, proteasome inhibitors, immunomodulating agents, and investigational therapies such as B cell maturation antigen Chimeric antigen receptor T cells.

Validation and Implementation of an Ordering Alert to Improve the Efficiency of Monoclonal Gammopathy Evaluation.

OBJECTIVES: To evaluate the use of a provider ordering alert to improve laboratory efficiency and reduce costs. METHODS: We conducted a retrospective study to assess the use of an institutional reflex panel for monoclonal gammopathy evaluation. We then created a clinical decision support (CDS) alert to educate and encourage providers to change their less-efficient orders to the reflex panel. RESULTS: Our retrospective analysis demonstrated that an institutional reflex panel could be safely substituted for a less-efficient and higher-cost panel. The implemented CDS alert resulted in 79% of providers changing their high-cost order panel to an order panel based on the reflex algorithm. CONCLUSIONS: The validated decision support alert demonstrated high levels of provider acceptance and directly led to operational and cost savings within the laboratory. Furthermore, these studies highlight the value of laboratory involvement with CDS efforts to provide agile and targeted provider ordering assistance.

Clinicopathologic Assessment of Monoclonal Immunoglobulin-associated Renal Disease in the Kidney Allograft: A Retrospective Study and Review of the Literature.

BACKGROUND: Monoclonal immunoglobulin (MIg)-associated renal disease (MIgARD) comprises a group of disorders caused by direct deposition of paraproteins in the kidney. Allograft MIgARD is infrequently encountered and poorly characterized. METHODS: First, we assessed our allograft biopsies diagnosed with MIgARD between 2007 and 2018. The cohort included the following 26 patients: proliferative glomerulonephritis with MIg deposits (PGNMID) (n = 13), AL amyloidosis (n = 5), light chain deposition disease (n = 5), light chain proximal tubulopathy (n = 2), and light chain cast nephropathy (n = 1). Second, we conducted a literature review to evaluate the rare non-PGNMID entities. We identified 20 studies describing 29 patients that were added to our cohort (total n = 42). RESULTS: Part 1: Patients' median age was 55 years; 31% were women, and 19% were blacks. Twelve patients (46%) lost their grafts at a median of 8 months after diagnosis. Compared to non-PGNMID, PGNMID patients had lower frequency of detectable paraproteins (31% versus 92%, P = 0.004) and hematologic neoplasms (23% versus 77%, P = 0.02). Within PGNMID group, 6 patients changed their apparent immunofluorescence phenotype between monotypic and polytypic, while all 3 patients with hematologic neoplasms had substructure on electron microscopy. Part 2: Whereas light chain cast nephropathy occurred the earliest and had the worst graft survival, AL amyloidosis occurred the latest and had the best graft survival. CONCLUSIONS: MIgARD in the kidney allograft is associated with poor prognosis. While posttransplant PGNMID can change its apparent clonality by immunofluorescence supporting oligoclonal immune responses, the presence of deposit substructure is an important indicator of underlying hematologic neoplasm. Non-PGNMID are often associated with hematologic neoplasms and varied prognosis.

Noninvasive assessment of corneal alterations associated with monoclonal gammopathy.

Aggregation of monoclonal immunoglobulin can lead to organ damage. However, the necessity of invasive examination such as biopsy has hampered better understanding of the pathophysiology. Corneal crystalline deposition is a rarely reported but known ocular manifestation of multiple myeloma. It is unclear whether the cornea is a common target of monoclonal immunoglobulin deposition. We conducted a prospective clinical case-control study to objectively quantify monoclonal gammopathy-associated corneal changes as well as any therapeutic response. Using an ophthalmic Scheimpflug camera imaging for noninvasive corneal assessments, we quantified densitometry values in 30 patients. Although none had crystalline keratopathy, corneal transparency in monoclonal gammopathy patients was significantly impaired compared to that in age-matched controls, based on noninvasive Scheimpflug camera imaging. Furthermore, treatment for multiple myeloma seemed to eradicate the diffuse aggregation of monoclonal proteins. Our results indicate that exposure to monoclonal immunoglobulin may induce the accumulation of monoclonal immunoglobulin in the cornea, and ophthalmic examinations such as corneal densitometry measurements with a Scheimpflug camera may be useful for noninvasive evaluation of monoclonal immunoglobulin deposition diseases.

The serum heavy/light chain immunoassay: A valuable tool for sensitive paraprotein assessment, risk, and disease monitoring in monoclonal gammopathies.

OBJECTIVE: The heavy/light chain (HLC)-immunoassay quantifies light chain types of each immunoglobulin class in patients with monoclonal gammopathies. METHODS: We assessed 147 consecutive patients with different forms and stages of plasma cell dyscrasias (PCD) who received standard tests (serum and urine protein electrophoresis [SPEP, UPEP], immunofixation [IFE], serum-free light chain [SFLC]), and HLC-immunoassay. Patients with multiple myeloma (MM, n = 102), smoldering MM (SMM, n = 5), monoclonal gammopathy of undetermined significance (MGUS, n = 28), and Waldenström's macroglobulinemia (WM, n = 12) were included. RESULTS: We verified a significant correlation between HLC- and standard monoclonal protein (mp)-parameters, and HLC-increases with higher disease stage and unfavorable remission status. In patients with difficult to quantify mp, more abnormal HLC- than SPEP-, immunoglobulin-, or SFLC-results were found. In WM, a pathological HLC κ/λ-ratio and M-component were observed in 95% and 58%, respectively. In 21/28 MGUS and 5/5 SMM patients, HLC κ/λ-ratios were abnormal. Testing different HLC cutoffs, patients with extreme HLC values showed impaired progression-free survival (PFS). CONCLUSIONS: Despite the fact that different PCD patients were included, the assessment of the HLC-immunoassay in MGUS, SMM, MM, and WM, our comparison with standard mp-assays, and relevant PFS differences may excite future applications, which should be confirmed in prospective multicenter trials.

Teste de cadeia leve livre - relação kappa/lambda para gamopatias monoclonais / Free light chain test - kappa / lambda ratio for monoclonal gammopathies

Contexto: As gamopatias monoclonais (paraproteinemias, disproteinemias ou imunoglobulinopatias), se caracterizam pela proliferação monoclonal de plasmócitos que produzem e secretam imunoglobulinas ou fragmentos de Imunoglobulina monoclonal (proteína monoclonal). A detecção e quantificação do componente monoclonal são necessárias para o diagnóstico. A eletroforese em gel de agarose e a imunofixação séricas e de urina são consideradas técnicas padrão. A pesquisa das cadeias leves livres (FLC) pode ser associada ao diagnóstico, posteriormente visando melhorar a taxa de detecção da doença. Pergunta: O teste de detecção de cadeias leves livres é sensível e específico para a detecção de cadeias leves livres, associado aos testes de eletroforese e imunofixação (imunoeletroforese) em soro e urina para diagnosticar pacientes com suspeita de gamopatia monoclonal, monitorar resposta à farmacoterapia de pacientes diagnosticados com gamopatia monoclonal, identificar recidiva precoce e avaliar prognóstico de pacientes? Evidências científicas: A evidência apresentada não incluiu todas as indicações solicitadas para a utilização do teste Freelite de dosagem de cadeias leves livres conforme descrito na pergunta de pesquisa. A evidência disponível é de baixa qualidade e apresenta limitação metodológica. Demonstra apenas o papel limitado do teste no diagnóstico de pacientes com suspeita de gamopatia monoclonal. Avaliação de Impacto Orçamentário: O demandante apresentou uma estimativa de impacto orçamentário para a utilização do teste de Freelite considerando apenas o diagnóstico de pacientes com suspeita de gamopatias monoclonais. Como o restante das indicações solicitadas, descritas na pergunta de pesquisa, não foram consideradas, nem se considerou os preços dos testes de dosagem de FLC concorrentes, a análise não apresentou valores confiáveis que possam suportar um pedido de incorporação da tecnologia no SUS. Decisão: Não incorporar o teste de cadeia leve livre - relação kappa/lambda para o diagnóstico de Gamopatias Monoclonais, no âmbito do Sistema Único de Saúde ­ SUS, dada pela Portaria SCTIE-MS nº 24 publicada no Diário Oficial da União (D.O.U.) nº 110, de 10 de junho de 2016.

Audit of Use and Overuse of Serum Protein Immunofixation Electrophoresis and Serum Free Light Chain Assay in Tertiary Health Care: A Case for Algorithmic Testing to Optimize Laboratory Utilization.

OBJECTIVES: Overuse of laboratory tests is a persistent issue. We examined the use and overuse of serum immunofixation electrophoresis and serum free light chain assays to develop an algorithm for optimizing utilization. METHODS: A retrospective review of all tests, for investigation of monoclonal gammopathies, for all patients who had any of these tests done from April 24, 2014, through July 25, 2014, was carried out. The test orders were categorized as warranted or not warranted according to criteria presented in the article. RESULTS: A total of 237 patients were tested, and their historical records included 1,503 episodes of testing for one or more of serum protein electrophoresis, serum immunofixation electrophoresis, and serum free light chain assays. Only 46% of the serum immunofixation and 42% serum free light chain assays were warranted. Proper utilization, at our institution alone, would have obviated $64,182.95/year in health care costs, reduced laboratory cost of reagent alone by $26,436.04/year, and put $21,904.92/year of part B reimbursement at risk. CONCLUSIONS: Fewer than half of the serum immunofixation and serum free light chain assays added value. The proposed algorithm for testing should improve utilization. Risk to part B billing may be a disincentive to reducing test utilization.

[The role of the assessment of heavy/light chain pairs of immunoglobulin in monoclonal gammopathies]. / Význam vysetrení páru tezkých/lehkých retezcu imunoglobulinu u monoklonálních gamapatií

The aim of the paper is to inform about the contribution of novel, highly sensitive analytic technique for the assessment of serum immunoglobulins (Hevylite), enabling separate quantitative assessment of heavy/light chain pairs of immunoglobulin (HLC), i. e. the monoclonal ("involved") and polyclonal ("noninvolved") isotype including their ratio (HLC-r) in monoclonal gammopathies. We particularly target the characteristics of this technique, the compari-son of its clinical contribution with standard methods used in the diagnostics, course and the detection of relapse and progression of the disease, as well as the stratification, assessment of therapeutic outcome and prognosis in monoclonal gammopathy of undetermined significance, multiple myeloma, Waldenström´s macroglobulinemia, systemic AL-amyloidosis and some non-Hodgkin lymphomas. Present results show that in comparison with existing routinely used techniques the Hevylite method enriches clinical practice with the assessment of serum levels of "uninvolved" Ig. It enables the evaluation of the depth of "immunoparesis", and the determination of HLC-r index that is needful for the stratification of MM into "risk cohorts". It also contributes to prognostic assessment and improvement of the evaluation of the depth of therapeutic response. In MGUS individuals the HLC-r index provides information about the risk of malignant transformation. We await the results of ongoing validation studies that are expected to provide specific indications for Hevylite technique for MG in routine practice.

Evolving strategies for the management of multiple myeloma: a managed care perspective.

Current challenges in the management of multiple myeloma (MM) include the changing treatment landscape and the need for better care coordination and improved communication. A roundtable meeting involving key stakeholders (physicians, nurses, pharmacists, managed care professionals, pharmaceutical industry professionals, and patient care advocates) was held to discuss challenges in the management of MM and evolving strategies to address these challenges and improve quality of care for patients with MM. Interventions discussed included the use of a treatment pathway to standardize treatment, decrease costs, and possibly increase efficacy by encouraging adherence to treatment guidelines whenever possible, and the use of an oncology medical home (OMH) to facilitate communication among treatment providers. Challenges to the successful implementation of treatment pathways include the rapid introduction of new therapies and the need to balance efficacy and value. It was stressed that treatment pathways must not prioritize profits over the health and welfare of the patient. Considerations related to the implementation of the OMH include the identification of appropriate measures to evaluate quality, value, and outcomes, and the provider implementation costs related to the OMH model.

Optimization of utilization of serum protein analysis: role of the electronic medical record in promoting consultation by pathology.

Screening for monoclonal gammopathies is usually done by serum protein electrophoresis (SPEP) and serum free light chain tests. SPEP may be followed by immunofixation electrophoresis (IFE). IFE may be ordered by the treating physician or be at the discretion of the pathologist. We examined the appropriateness of IFE ordering by treating physicians and report on our findings, follow-up changes to the ordering process, and results of the change. We retrospectively analyzed the data from our laboratory from April 2009 through July 2012. In April 2009, 3 options for test ordering were available for the clinicians: SPEP with reflex IFE, SPEP only, and SPEP with IFE. This test ordering option was limited to SPEP with reflex IFE only in April 2010. We compared the rates of SPEP and IFE performed in the 2 periods (ie, April 2009 through April 2010 and May 2010 through July 2012). There was a substantial drop in the IFE/SPEP ratio from 0.47 to 0.21. Review of electronic medical records by the consultant pathologist was instrumental in improving the utilization and enhancing the value of pathology consultation. Possible impacts on laboratory costs, revenue, and overall health care are also presented.

Treatment of chronic immune-mediated neuropathies: impact of the rare diseases centers network in Italy.

Chronic immune-mediated neuropathies represent a heterogeneous group of mostly demyelinating neuropathies thought to be caused by an autoimmune response to peripheral nerve antigens. They include chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and related variants, multifocal motor neuropathy (MMN) and neuropathy associated with an IgM monoclonal gammopathy with antibody activity against myelin-associated glycoprotein (MAG). Most of these neuropathies respond to immune therapy even though their response to therapy may be different, thereby confirming that their distinct characteristics have relevant clinical implications. While clinicians and scientists are intrigued by the desire to better clarify the cause and pathogenesis of these disorders, the need to allow affected patients to be reimbursed by insurance companies or the national health system can lead to the risk of lumping all these neuropathies under the umbrella term of 'CIDP' to facilitate patients' access to costly therapies.

Assessment of the diagnostic performances of IgA heavy and light chain pairs in patients with IgA monoclonal gammopathy.

OBJECTIVES: Preliminary results of the IgA Hevylite™ assay including the establishment of the 95% reference interval and assessment of the specificity and sensitivity in different populations are reported. DESIGN AND METHODS: The concentrations of IgA heavy and light chains (HLC) enabling to determine an IgAκ/IgAλ ratio were quantified in 119 apparently healthy individuals to generate 95% reference intervals. The specificity of this assay was assessed in 48 patients with an isolated polyclonal IgA increase. In a retrospective analysis of 68 patients with a monoclonal component type IgA (MC-IgA) identified by serum immunofixation (IFE), IgA HLC ratio values were compared with known results for serum protein electrophoresis (SPE) and free light chain (FLC) ratios. RESULTS: The 95% reference range obtained in 119 controls (0.91-2.04) was close to that quoted by the manufacturer (0.80-2.04). Eight of the 48 patients (16.7%) with a polyclonal IgA increase had an IgA HLC ratio above the upper limit of the 95% reference interval. The IgA HLC ratio identified 65 (95.6%) among 68 patients with MC-IgA identified on the basis of IFE. For 34 of these patients (50%), MC-IgA was not detected by SPE due to its co-migration with alpha-2 or beta-globulins. CONCLUSIONS: Compared with serum IFE, the IgA HLC ratio has a sensitivity of 95.6%. Further studies are needed to assess the specificity of the IgA HLC ratio in patients with an isolated polyclonal increase of serum IgA.

Flow cytometry in monoclonal gammopathies.

The technological development of flow cytometry (FC) together with new findings reveal the need for immunophenotyping in research of monoclonal gammopathy (MG) because of its diagnostic, prognostic and predictive significance. The aim of the European Myeloma Network (EMN) is to standardize this analytical method and implement it into routine clinical examination. Since the overall significance and application of FC are still analysed, standardisation could help obtain more clinical relevant information in terms of MG pathophysiology.