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Pyoderma gangrenosum (PG) is a neutrophilic dermatosis characterized by ulcerative painful lesions with violaceous undermined borders. Up to 75% of PG cases develop in association with an underlying systemic disease. Monoclonal gammopathy is reportedly a concomitant condition with PG, with studies indicating immunoglobulin (Ig) A gammopathy as the most common. Whether gammopathy is associated with PG or is an incidental finding has been debated. We sought to investigate the association and characteristics of gammopathy in patients with PG. We retrospectively identified PG patients at our institution from 2010 to 2022 who were screened for plasma cell dyscrasia. Of 106 patients identified, 29 (27%) had a gammopathy; subtypes included IgA (41%), IgG (28%), and biclonal (IgA and IgG) (14%). Mean age was similar between those with and without gammopathy (60.7 vs. 55.9 years; P =.26). In addition, hematologic or solid organ cancer developed in significantly more patients with vs. without gammopathy (8/29 [28%] vs. 5/77 [6%]; P =.003). Among the subtypes of gammopathy, IgG monoclonal gammopathy had the highest proportion of patients with subsequent cancer development (4 of 8 patients, 50%). Study limitations include a retrospective, single-institution design with a limited number of patients. Overall, our data show a high prevalence of gammopathy in patients with PG; those patients additionally had an increased incidence of cancer, especially hematologic cancer. [ABSTRACT FROM AUTHOR]

Monoclonal gammopathy of renal significance (MGRS) is where kidney injury occurs due to the accumulation or effects of abnormal monoclonal proteins. These proteins, originating from non-cancerous or pre-cancerous plasma cells or B cells, deposit in specific areas of the kidney. Mechanisms contributing to MGRS include high levels of vascular endothelial growth factor secretion, autoantibodies targeting complement components, and targeting specific receptors leading to nephropathy. Kidney lesions in monoclonal gammopathy of renal significance (MGRS) are classified based on the presence of organized or nonorganized deposits, including fibrillar, microtubular, or crystal inclusions. Kidney biopsy is essential for confirming the diagnosis of MGRS by identifying monoclonal immunoglobulin deposits. Immunofluorescence helps determine the class of light and/or heavy chain involved in MGRS. The treatment approach is clone-directed and hence it depends on the presence of B cell clone or plasma cell clone or any detectable monoclonal protein. Chemotherapy targeting plasma cell or B cell malignancies and autologous hematopoietic cell transplantation may be used to manage MGRS. Kidney outcomes in MGRS patients strongly correlate with the hematologic response to chemotherapy.

Testing of serum-free light chains kappa (κ) and lambda (λ), along with ratio (FLCR) is essential for the diagnosis and management of monoclonal gammopathies. Accurate clinical diagnosis depends upon appropriate local population reference intervals (RIs). This study examined the Saudi population for serum-free light chains and other immunoglobulins to establish RIs and to explore variations in the test results by using the International Federation for Clinical Chemistry and Laboratory Medicine's global protocol for harmonized implementation of RI study. A total of 180 healthy Saudi adults were recruited. All serum samples were assayed using the Freelite reagents from the Binding Site. The variation in reference values attributable to sex, age, BMI, and region was calculated by ANOVA as a standard deviation ratio (SDR). The RIs for the FLCR were derived by the parametric method and validated by using samples from patients with hypo- and hypergammaglobulinemia. The new RIs for free κ and FLCR were shifted to a higher side from the manufacturer-adapted RIs. Based on the SDR cutoff value (>0.4), between-sex partition RIs were not required for all analytes except IgM. Validation using patients with hypo- or hypergammaglobulinemia and without multiple myeloma, was all within the new RI. BMI, smoking, and exercise were not relevant sources of variation for any analyte. Locally derived RIs for free light chains and immunoglobulins analytes specific for Saudis were established after careful consideration of various factors. These RIs were more reliable than those provided as guidance by the manufacturer, or from other countries, for appropriate classification and prediction of disease progression for Saudi patients. [ABSTRACT FROM AUTHOR]

Abstract Background Recurring therapy resistant hives, accompanied by IgM-gammopathy, fever and joint pain can indicate Schnitzler syndrome, a rare autoimmune disorder. There is currently no approved treatment, but complete remission of symptoms can be induced with IL-1 antagonists. Case presentation A patient with a history of chronic urticaria presented frequently at the outpatient clinic with severe hives and was treated unsuccessfully with antihistamines and omalizumab. After several years, additional symptoms such as joint pain, recurrent fever, and IgM-gammopathy developed. After the diagnostic criteria for Schnitzler syndrome were met, treatment with anakinra was initiated and resulted in an improvement of the symptoms. Shortly after the first injection, the patient developed large and painful erythematous lesions at the injection sites, leading to discontinuation of treatment and a rapid recurrence of symptoms. Subsequently, treatment with a longer-acting IL-1 antagonist (canakinumab) was initiated, resulting in a complete remission of symptoms. Conclusion This case report demonstrates that patients with urticarial symptoms that are not relieved by typical treatments should prompt repeated reassessments of the diagnosis, even years later, because gammopathy and other diagnostic criteria for Schnitzler syndrome can occur with a delay.

Simple Summary: This systematic review encompasses the clinical impact of serum paraprotein (PP), in low- and high-grade mature B-cell malignancies (except for myeloma and Waldenstrom Macroglobulinemia). In fact, reports on this topic are sparse and heterogeneous, and an overall view is lacking. Literature analysis shows that, across different entities, PP is consistently associated with high-risk biological and clinical features, as well as with poor outcome. Indeed, screening for serum PP should be included in the diagnostic work-up of all mature B-cell malignancies. The presence of a serum paraprotein (PP) is usually associated with plasma-cell dyscrasias, Waldenstrom Macroglobulinemia/lymphoplasmacytic lymphoma, and cryoglobulinemia. However, PP is also often reported in other high- and low-grade B-cell malignancies. As these reports are sparse and heterogeneous, an overall view on this topic is lacking, Therefore, we carried out a complete literature review to detail the characteristics, and highlight differences and similarities among lymphoma entities associated with PP. In these settings, IgM and IgG are the prevalent PP subtypes, and their serum concentration is often low or even undetectable without immunofixation. The relevance of paraproteinemia and its prevalence, as well as the impact of IgG vs. IgM PP, seems to differ within B-NHL subtypes and CLL. Nonetheless, paraproteinemia is almost always associated with advanced disease, as well as with immunophenotypic, genetic, and clinical features, impacting prognosis. In fact, PP is reported as an independent prognostic marker of poor outcome. All the above call for implementing clinical practice, with the assessment of paraproteinemia, in patients' work-up. Indeed, more studies are needed to shed light on the biological mechanism causing more aggressive disease. Furthermore, the significance of paraproteinemia, in the era of targeted therapies, should be assessed in prospective trials. [ABSTRACT FROM AUTHOR]

Background: Recurring therapy resistant hives, accompanied by IgM-gammopathy, fever and joint pain can indicate Schnitzler syndrome, a rare autoimmune disorder. There is currently no approved treatment, but complete remission of symptoms can be induced with IL-1 antagonists. Case presentation: A patient with a history of chronic urticaria presented frequently at the outpatient clinic with severe hives and was treated unsuccessfully with antihistamines and omalizumab. After several years, additional symptoms such as joint pain, recurrent fever, and IgM-gammopathy developed. After the diagnostic criteria for Schnitzler syndrome were met, treatment with anakinra was initiated and resulted in an improvement of the symptoms. Shortly after the first injection, the patient developed large and painful erythematous lesions at the injection sites, leading to discontinuation of treatment and a rapid recurrence of symptoms. Subsequently, treatment with a longer-acting IL-1 antagonist (canakinumab) was initiated, resulting in a complete remission of symptoms. Conclusion: This case report demonstrates that patients with urticarial symptoms that are not relieved by typical treatments should prompt repeated reassessments of the diagnosis, even years later, because gammopathy and other diagnostic criteria for Schnitzler syndrome can occur with a delay. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is an incurable plasma cell malignancy, which is predominantly a disease of older adults (the median age at diagnosis is 70 years). The slow progression from asymptomatic stages and the late-onset of MM suggest fundamental differences compared to many other hematopoietic system-related malignancies. The concept discussed in this review is that age-related changes at the level of terminally differentiated plasma cells act as the main risk factors for the development of MM. Epigenetic and genetic changes that characterize both MM development and normal aging are highlighted. The relationships between cellular aging processes, genetic mosaicism in plasma cells, and risk for MM and the stochastic processes contributing to clonal selection and expansion of mutated plasma cells are investigated. In line with the DNA damage accumulation theory of aging, in this review, the evolution of monoclonal gammopathy to symptomatic MM is considered. Therapeutic consequences of age-dependent comorbidities that lead to frailty and have fundamental influence on treatment outcome are described. The importance of considering geriatric states when planning the life-long treatment course of an elderly MM patient in order to achieve maximal therapeutic benefit is emphasized. [ABSTRACT FROM AUTHOR]

Light chain deposition disease (LCDD) is a monoclonal immunoglobulin deposition disease characterized by light chain deposition in soft tissues and viscera, causing systemic organ dysfunction with an underlying lymphoproliferative disorder. While the kidney is the most affected organ, cardiac and hepatic involvement is also seen with LCDD. Hepatic manifestation can range from mild hepatic injury to fulminant liver failure. Herein, we are presenting a case of an 83-year-old woman with a monoclonal gammopathy of undetermined significance (MGUS), who presented to our institution with acute liver failure progressing to circulatory shock and multiorgan failure. After an extensive workup, a diagnosis of hepatic LCDD was determined. In conjunction with the hematology and oncology department, chemotherapy options were discussed, but given her poor prognosis, the family decided to pursue a palliative route. Though establishing a prompt diagnosis is important for any acute condition, the rarity of this condition, along with paucity of data, makes timely diagnosis and treatment challenging. The available literature shows variable rates of success with chemotherapy for systemic LCDD. Despite chemotherapeutic advances, liver failure in LCDD indicates a dismal prognosis, where further clinical trials are difficult owing to the low prevalence of the condition. In our article, we will also be reviewing previous case reports on this disease. [ABSTRACT FROM AUTHOR]

Schnitzler syndrome is a rare autoinflammatory disorder characterized by urticarial rash, joint pain, recurrent fever, leucocytosis, elevated C-reactive protein (CRP) and serum amyloid A (SAA), and monoclonal IgM or IgG gammopathy. According to the Strasbourg criteria, both urticarial rash and gammopathy are mandatorily required for the diagnosis of Schnitzler’s syndrome. However, incomplete variants lacking either skin symptoms or monoclonal gammopathy have also been described. Here, we report a case in which the diagnosis of Schnitzler-like syndrome was made despite the absence of gammopathy, based on neutrophilic dermal inflammation, episodic and excessive increase in inflammatory parameters, and prompt response to anakinra, a soluble IL1 receptor antagonist (sIL-1RA). In addition, we detected neutrophil epitheliotropism, which is highly suggestive of autoinflammatory disease. Using whole-exome sequencing, we were unable to find a causative pathogenic mutation but did find several mutations possibly related to the inflammatory processes in this patient. This and other cases highlight that the existing Strasbourg criteria are too strict to capture Schnitzler-like syndromes that may respond well and rapidly to IL1 inhibition. Recurrent episodes of disease with normalization of inflammatory symptoms in the interval, rapid response to anakinra, and neutrophilic epitheliotropism in a lesional skin biopsy may help confirm the diagnosis of Schnitzler-like syndrome.

Background: Hyperglobulinemia is reported in 26% of canine chronic B‐cell lymphocytic leukemia (B‐CLL) cases. However, few cases have been characterized by protein electrophoresis and immunofixation (IF), and the incidence of a monoclonal protein (M‐protein) is unknown using these techniques. Objective: To characterize and determine the proportion of canine B‐CLL cases with an M‐protein using plasma protein electrophoresis (PPE), routine and free light chain (fLC) IF, and to assess if productive B‐CLL cases express MUM1/IRF4 by cell tube block (CTB). Methods: PPE, routine (targeting IgG, IgA, IgM, IgG4, and light chain) and fLC IF were performed using 48 dog B‐CLL plasma samples from patients diagnosed via peripheral blood flow cytometry. CTB was performed on a separate cohort of 15 patients. Results: Hyperproteinemia (>7.5 g/dL) was present in 17/48 cases (35%). An M‐protein was detected in 32/48 cases (67%). Of these, 19/32 cases (59%) had only complete (monoclonal heavy and light chain) M‐proteins detected, 10/32 cases (31%) had both complete and fLC M‐proteins detected, and 3/32 cases (9%) had only an fLC M‐protein detected. IgM was the most common clonal immunoglobulin isotype detected (23 cases). CD21+ cell counts were higher in cases with detectable M‐protein. Plasma fLC IF suggested β‐γ region interference, likely caused by clotting proteins. All B‐CLL cases consistently expressed PAX5 and did not express MUM1/IRF4. Conclusions: Most B‐CLL cases had an M‐protein and were not hyperproteinemic. Most cases with paraproteins had a complete IgM monoclonal gammopathy; a subset had documented fLCs. The prognostic significance of heavy and fLC presence should be evaluated. [ABSTRACT FROM AUTHOR]

Objective : There is currently no evidence of the possible benefit of plasma cell–targeting therapies (PCTT) in immunoglobulin A (IgA) monoclonal gammopathy (MG) associated with IgA vasculitis (IgAV). We report the outcome of different PCTT regimens in a cohort of MG-IgAV. Methods: We used a French network to retrospectively describe the outcome of MG-IgAV patients treated with PCTT. Results: Five patients were included (mean age 65 years). All patients had severe baseline presentation including extensive necrotic purpura (n = 5), gastrointestinal involvement (n = 2), peripheral neuropathies (n = 2), and glomerulonephritis (n = 1). Two patients had IgA indolent multiple myeloma and three had IgA "MG of undetermined significance." Monotypic IgA deposition in the skin vessels wall was highlighted using an immunofluorescence assay. Cases of vasculitis in three patients (n = 3) were refractory to multiple line therapies, including cyclophosphamide (n = 3) or rituximab. Finally, PCTT including bortezomib plus cyclophosphamide and dexamethasone, bortezomib plus melphalan and prednisone, or bortezomib plus lenalidomide and dexamethasone were proposed, allowing complete remission in 4/5 patients without major adverse drug events. Conclusion: This study suggests that the MG-IgAV phenotype might be distinctive of usual IgAV (severe and refractory to conventional immunosuppressive regimens) and supports the benefit of PCTT. This study sheds new light on the overall biology of IgAV, strengthening the pathogenic role of the monoclonal IgA component in IgAV. [ABSTRACT FROM AUTHOR]

Monoclonal gammopathy of renal significance (MGRS) is where kidney injury occurs due to the accumulation or effects of abnormal monoclonal proteins. These proteins, originating from non-cancerous or pre-cancerous plasma cells or B cells, deposit in specific areas of the kidney. Mechanisms contributing to MGRS include high levels of vascular endothelial growth factor secretion, autoantibodies targeting complement components, and targeting specific receptors leading to nephropathy. Kidney lesions in monoclonal gammopathy of renal significance (MGRS) are classified based on the presence of organized or nonorganized deposits, including fibrillar, microtubular, or crystal inclusions. Kidney biopsy is essential for confirming the diagnosis of MGRS by identifying monoclonal immunoglobulin deposits. Immunofluorescence helps determine the class of light and/or heavy chain involved in MGRS. The treatment approach is clone-directed and hence it depends on the presence of B cell clone or plasma cell clone or any detectable monoclonal protein. Chemotherapy targeting plasma cell or B cell malignancies and autologous hematopoietic cell transplantation may be used to manage MGRS. Kidney outcomes in MGRS patients strongly correlate with the hematologic response to chemotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Shankar and Yadla.)

Abstract Background Detection of free light chains (fLC) in animals relies on protein electrophoresis or the Bence‐Jones protein test on urine. Objective To describe the detection of both serum fLC (sfLC) and urine fLC (ufLC) in 8 dogs and 2 cats using a commercially available human immunofixation (IF) kit. Animals Archived serum or urine samples from 27 dogs and 2 cats submitted to the Colorado State University Veterinary Diagnostic Laboratory for routine diagnostics. Methods Retrospective study evaluating the presence of fLC in dogs and cats using agarose gel electrophoresis and routine and fLC IF performed on serum and urine. The performance of the fLC IF reagents was evaluated using samples characterized by routine IF, tandem mass spectrometry, and a combination of fLC IF and western blotting. Free light chains were documented by paired electrophoresis and fLC IF. Results The fLC only myeloma case developed end‐stage renal failure 5 months post initial diagnosis. All electrophoresis‐defined urinary Bence‐Jones proteins were labeled by the anti‐free λ light chain (anti‐fλ) reagent; none were labeled by the anti‐free κ light chain (anti‐fκ); 2 of these were identified as fκ by mass spectrometry. An electrophoretically identical protein restriction that was labeled by the anti‐fλ reagent was present in the paired serum from 5/8 of cases, documenting sfLC. Conclusions and Clinical Importance Commercially available human IF reagents identified sfLC and ufLC in both dogs and cats. Free light chains may be nephrotoxic in dogs.

It is known that eosinophilic fasciitis can be associated with monoclonal gammopathy. There is clinical similarity between eosinophilic fasciitis and morphea profunda, but it is unclear whether morphea profunda might be associated with monoclonal gammopathy. The temporal quantification of gammopathy in morphea profunda has not been well characterized. We describe four patients with morphea profunda that were associated with monoclonal gammopathy. Three were associated with monoclonal IgG protein and one with IgM. No patients in our series developed myeloma. In conclusion, the association of monoclonal gammopathy is not unique to eosinophilic fasciitis and scleromyxedema. Further studies are necessary to characterize further the relationship between the two conditions.

The detection of monoclonal immunoglobulins is a key element in the diagnosis of monoclonal gammopathy. In clinical practice, screening and measurement of monoclonal proteins are commonly performed using capillary zone electrophoresis (CZE). Some exogenous substances, such as iodinated contrast agents, absorb incident UV light at the same wavelengths as the peptide bonds and may therefore interfere with the detection of proteins in CZE. We herein use the description of a case to illustrate that iodinated contrast agents can mask the presence of monoclonal immunoglobulins in CZE and we discuss the strategy needed to confirm this interference. Performing immunofixation, immunosubtraction, or a second CZE at a distance from the first blood sample is not only necessary to confirm the presence of an iodinated contrast media interference but also to ensure the absence of monoclonal proteins. [ABSTRACT FROM AUTHOR]

Sporadic late‐onset nemaline myopathy (SLONM) associated with monoclonal protein (MP) is a rare disease with an aggressive, and often fatal course. Whether SLONM + MP represents a malignancy or dysimmune disease remains unclear. Currently, two main approaches are used to treat SLONM + MP: nonchemotherapy‐based treatment (immunosuppression, intravenous immunoglobulins, plasmapheresis and plasma exchange) or chemotherapy with or without autologous stem cell transplantation. Due to the rare occurrence of the disease, the best treatment modality is unknown. We analyzed treatment and outcomes in a large cohort of 53 patients with SLONM + MP: four our own patients and 49 cases from published literature. Neurological improvement in the nonchemotherapy group (N = 25) was observed in 52% of patients: 8% reached marked improvement, 8% moderate response, 36% mild response; none reached complete remission (CR). In the chemotherapy group (N = 28), neurological improvement was seen in 86% of patients: 46% reached CR, 25% marked response, 11% moderate response and 4% mild response. The best neurological improvement correlated with deep hematological remission. Mean time to best response in the chemotherapy group was 8 months versus 21 months in the nonchemotherapy group (P <.001). Overall survival was higher in patients in the chemotherapy group. A chemotherapy approach should be the preferred treatment for patients with SLOMN + MP with the goal to reach complete hematologic remission. Based on the clinical, morphological peculiarities, aggressive disease course and superior clinical benefits of chemotherapy over nonchemotherapy, SLONM + MP should be considered as a hematological malignancy with the presence of MP of clinical rather than undetermined significance. What's new? Sporadic late‐onset nemaline myopathy (SLONM) associated with monoclonal protein (MP) is a rare aggressive disease. To date, whether SLONM + MP represents a malignancy or dysimmunity and how to treat the disease remain unclear. This study of 53 patients with SLONM + MP shows that a chemotherapy‐based approach is superior to non‐chemotherapy and should be the preferred treatment with the goal to achieve complete hematologic remission. Based on its clinical/morphological peculiarities, aggressive course, and the superior clinical benefits of chemotherapy, SLONM + MP should be considered as a hematological malignancy, with the presence of MP of clinical rather than undetermined significance in SLONM. [ABSTRACT FROM AUTHOR]

Background: Detection of free light chains (fLC) in animals relies on protein electrophoresis or the Bence‐Jones protein test on urine. Objective: To describe the detection of both serum fLC (sfLC) and urine fLC (ufLC) in 8 dogs and 2 cats using a commercially available human immunofixation (IF) kit. Animals Archived serum or urine samples from 27 dogs and 2 cats submitted to the Colorado State University Veterinary Diagnostic Laboratory for routine diagnostics. Methods: Retrospective study evaluating the presence of fLC in dogs and cats using agarose gel electrophoresis and routine and fLC IF performed on serum and urine. The performance of the fLC IF reagents was evaluated using samples characterized by routine IF, tandem mass spectrometry, and a combination of fLC IF and western blotting. Free light chains were documented by paired electrophoresis and fLC IF. Results: The fLC only myeloma case developed end‐stage renal failure 5 months post initial diagnosis. All electrophoresis‐defined urinary Bence‐Jones proteins were labeled by the anti‐free λ light chain (anti‐fλ) reagent; none were labeled by the anti‐free κ light chain (anti‐fκ); 2 of these were identified as fκ by mass spectrometry. An electrophoretically identical protein restriction that was labeled by the anti‐fλ reagent was present in the paired serum from 5/8 of cases, documenting sfLC. Conclusions and Clinical Importance: Commercially available human IF reagents identified sfLC and ufLC in both dogs and cats. Free light chains may be nephrotoxic in dogs. [ABSTRACT FROM AUTHOR]

Cutaneous plasmacytosis is a rare disease that presents clinically with multiple red-brown papules and plaques with minimal to no epidermal change. Histopathologic findings include a perivascular dermal infiltration of polyclonal plasma cells. The etiology of cutaneous plasmacytosis is unknown, but hypothesized to be due to persistent or repeated antigenic stimulation. Ehrlichia represents a family of obligate intracellular bacteria that have been associated with the development of plasma cell dyscrasias in the veterinary literature. We present a case of a 67-year-old male patient with the development of progressively worsening cutaneous plasmacytosis following prolonged hospitalization secondary to ehrlichiosis sepsis. The patient initially presented with isolated cutaneous involvement and normal laboratory findings that eventually progressed to include multiple laboratory abnormalities, including anemia, hyperproteinemia, and elevated serum creatinine. Further diagnostic workup was declined by the patient despite evidence of progression to systemic plasmacytosis or multiple myeloma. [ABSTRACT FROM AUTHOR]

Multiple myeloma is characterized by the presence of M-protein (monoclonal) in blood or urine. These proteins are immunoglobulins which are produced by a clone of abnormally proliferating B-lymphocytes and/or plasma cells. To evaluate M-protein, serum protein electrophoresis (SPEP) is used where a single band, known as M-band is seen. This band is usually seen in the gamma globulin region. However, in rare entities like biclonal gammopathy, two M-bands appear simultaneously at different positions on SPEP which may be attributed to the clonal expansion of two different neoplastic cell lines. Here, we describe an atypical case of IgA-kappa multiple myeloma, where two M-bands (one in the beta region and one in the gamma globulin region) were found during SPEP. This simulated a picture of biclonal gammopathy. However the monoclonal nature of this M-protein was proved by performing immunofixation electrophoresis (IFE). Further, we put across images to explain how IFE helps in differentiating between apparent and true biclonality. [ABSTRACT FROM AUTHOR]

Background: Obesity is an established, modifiable risk factor of multiple myeloma (MM); yet, no lifestyle interventions are routinely recommended for patients with overweight or obesity with MM precursor conditions. Prolonged nightly fasting is a simple, practical dietary regimen supported by research, suggesting that the synchronization of feeding-fasting timing with sleep-wake cycles favorably affects metabolic pathways implicated in MM. We describe the design and rationale of a randomized controlled pilot trial evaluating the efficacy of a regular, prolonged nighttime fasting schedule among individuals with overweight or obesity at high risk for developing MM or a related lymphoid malignancy., Objective: We aim to investigate the effects of 4-month prolonged nightly fasting on body composition and tumor biomarkers among individuals with overweight or obesity with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or smoldering Waldenström macroglobulinemia (SWM)., Methods: Individuals with MGUS, SMM, or SWM aged ≥18 years and a BMI of ≥25 kg/m 2 are randomized to either a 14-hour nighttime fasting intervention or a healthy lifestyle education control group. Participants' baseline diet and lifestyle patterns are characterized through two 24-hour dietary recalls: questionnaires querying demographic, comorbidity, lifestyle, and quality-of-life information; and wrist actigraphy measurements for 7 days. Fasting intervention participants are supported through one-on-one telephone counseling by a health coach and automated SMS text messaging to support fasting goals. Primary end points of body composition, including visceral and subcutaneous fat (by dual-energy x-ray absorptiometry); bone marrow adiposity (by bone marrow histology); and tumor biomarkers, specifically M-proteins and serum free light-chain concentrations (by gel-based and serum free light-chain assays), are assessed at baseline and after the 4-month study period; changes therein from baseline are evaluated using a repeated measures mixed-effects model that accounts for the correlation between baseline and follow-up measures and is generally robust to missing data. Feasibility is assessed as participant retention (percent dropout in each arm) and percentage of days participants achieved a ≥14-hour fast., Results: The PROlonged nightly FASTing (PROFAST) study was funded in June 2022. Participant recruitment commenced in April 2023. As of July 2023, six participants consented to the study. The study is expected to be completed by April 2024, and data analysis and results are expected to be published in the first quarter of 2025., Conclusions: PROFAST serves as an important first step in exploring the premise that prolonged nightly fasting is a strategy to control obesity and obesity-related mechanisms of myelomagenesis. In evaluating the feasibility and impact of prolonged nightly fasting on body composition, bone marrow adipose tissue, and biomarkers of tumor burden, this pilot study may generate hypotheses regarding metabolic mechanisms underlying MM development and ultimately inform clinical and public health strategies for MM prevention., Trial Registration: ClinicalTrials.gov NCT05565638; http://clinicaltrials.gov/ct2/show/NCT05565638., International Registered Report Identifier (irrid): DERR1-10.2196/51368., (©David J Lee, Elizabeth K O'Donnell, Noopur Raje, Cristina Panaroni, Robert Redd, Jennifer Ligibel, Dorothy D Sears, Omar Nadeem, Irene M Ghobrial, Catherine R Marinac. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 11.03.2024.)

Background: Inorganic phosphate in blood is currently determined by the reaction with molybdate. This report aims at reviewing conditions underlying spuriously altered levels of circulating inorganic phosphate. Content: A systematic search of the Excerpta Medica, the National Library Database and the Web of Science database was conducted without language restriction from the earliest publication date available through January 31, 2020. Summary: For the analysis, 80 reports published in English (n = 77), French (n = 1), German (n = 1) and Spanish (n = 1) were retained. Well-documented pseudohyperphosphatemia was observed in individuals exposed to liposomal amphotericin, in patients affected by a gammopathy, in patients with hyperlipidemia and in patients with hyperbilirubinemia. An unexplained elevated inorganic phosphate level sometimes provided a clue to the diagnosis of a gammopathy. Well-documented cases of pseudohypophosphatemia were observed in patients on large amounts of intravenous mannitol. Finally, pseudohypophosphatemia was occasionally observed on treatment with liposomal amphotericin and in patients with a gammopathy. Outlook: In order to avoid unnecessary testing and treatment, the phenomenon of spuriously altered inorganic phosphate should be recognized. An unexplained hyperphosphatemia may provide a clue to the diagnosis of a gammopathy or a severe hyperlipidemia. [ABSTRACT FROM AUTHOR]

Background: Several studies support the evidence of increased incidence of hematological complications in Gaucher disease including monoclonal and polyclonal gammopathies and blood malignancies, especially multiple myeloma. Methods: Serum concentrations of immunoglobulins and PCR analysis of the IGH gene rearrangements were performed. The clonal PCR products were directly sequenced and analyzed with the appropriate database and tools. Serum monoclonal proteins were detected and identified by electrophoresis. Results: Among 27 Gaucher patients, clonal IGH rearrangement was discovered in eight, with 5/8 having also serum monoclonal protein. Elevated immunoglobulins were detected in 9/27 patients. Follow-up data for 17 patients showed that the clonal rearrangement remained the same in four of them, however, in one patient it disappeared after the follow-up period. The remaining 12/17 patients were without previous IGH clonal rearrangement and remained so after the follow-up. Conclusions: Although clonal expansion may occur relatively early in the disease course, at least judging by the IGH gene rearrangements in Gaucher patients, the detected clones may be transient. A careful clinical follow-up in these patients is mandatory, including monitoring for lymphoid neoplasms, especially multiple myeloma.

• Gammopathy is not more frequent on LDSs' patients at diagnosis than in general population. • SPE can be useful to simplify new LSDs' marker discovery projects. Serum protein electrophoresis (SPE) is a well-established technique to identify alterations in plasma protein profiles, caused by diseases as multiple myeloma (MM). In addition, it could be a cost-effective technique to discover new plasma biomarkers. Relation between MM and lysosomal storage diseases (LSDs) as Gaucher disease has been set out but, it has not been evaluated on other LSDs nor the utility of the SPE as first step on LSDs biomarkers discovery projects. Stored plasma samples at diagnosis from several LSDs patients underwent analysis. Quality control was checked prior to the SPE was analyzed by capillary electrophoresis. The analysis for monoclonal spikes and the differences between each fraction on patients' samples vs the control data previously published, were evaluated. Furthermore, immunoprotein quantification and free light chains ratio were done by nephelometry and turbidimetry. Seventy-five samples of LSD patients at diagnosis, were assessed. The frequency of the MGUS on LSDs patients was not higher than in general population whereas one lysosomal acid lipase deficiency infant showed increased IgA and kappa deviation. Regarding to the usefulness of SPE in biomarkers discovery, statistically significant differences were observed on SPE fractions between LSDs and healthy population. The evaluation of SPE fractions can be a useful tool to understand pathophysiologic aspects in LDSs and, to simplify new marker discovery projects. In some of them, the MGUS appearance is a risk factor for the MM development despite its frequency is not increased on the studied LSDs at diagnosis. [ABSTRACT FROM AUTHOR]

This report details 2 different presentations of lymphoma in captive Steller's eiders (Polysticta stelleri). A female Steller's eider, at least 10 years old, developed lameness and lethargy. A complete blood cell count (CBC) revealed a severely elevated total white blood cell (WBC) count with a lymphocytosis. A subsequent liver biopsy confirmed a diagnosis of lymphoma and lymphocytic leukemia. The female Steller's eider was euthanatized 11 days after presentation. On necropsy, neoplastic lymphoid infiltrates were present in multiple tissues, primarily in the skin and subcutis. The results of a CBC from an apparently healthy male Steller's eider, at least 14 years old, also indicated this bird had an increased WBC count with a lymphocytosis. Serum submitted for protein electrophoresis indicated that this bird had a monoclonal gammopathy. Lymphocytes isolated from the male Steller's eider had low levels of proliferation in response to mitogens. The bird survived nearly 2 years without treatment, and the WBC count continued to increase during this time. The male Steller's eider maintained good body condition and exhibited normal behavior throughout the course of the disease until a sudden decline just prior to death. Lymphoma was diagnosed based on histopathology results. Infiltrates of atypical lymphocytes were observed in the bone marrow, proventriculus, ventriculus, heart, and eyes. [ABSTRACT FROM AUTHOR]

Background: Pyoderma gangrenosum (PG) is a devastating neutrophilic dermatosis that may be associated with trauma or systemic diseases. The associations, characteristics, and temporal relationship of PG with hematologic malignancies are not well understood.Objective: We performed a systematic review of PG associated with hematologic malignancies using data from case reports, case series, and retrospective studies.Methods: We searched MEDLINE, EMBASE, Scopus, and Web of Science from each database's inception to December 12, 2018. Two reviewers independently selected studies and extracted data.Results: Two hundred seventy-nine publications met the inclusion criteria (340 cases). Myelodysplastic syndrome (MDS) was the most commonly reported hematologic malignancy associated with PG, followed by monoclonal gammopathy of undetermined significance and acute myeloid leukemia. The mean age of patients was 56.5 years, with males being more common. There was a predominance of the ulcerative PG subtype and multifocal distributions across all hematologic malignancies. The majority of MDS cases preceded PG, which was reversed for MGUS.Limitations: The data were limited by reporting bias because PG subtypes rely on the rendered diagnosis reported. In addition, the classification for hematologic malignancies has evolved since 1978.Conclusion: Patients with PG should be evaluated for hematologic malignancies, with MDS being the most common. [ABSTRACT FROM AUTHOR]

A 13‐year‐old spayed female American Cocker Spaniel was presented for evaluation of a cough and weight loss. Physical exam revealed generalized lymphadenopathy. The patient was diagnosed with marginal zone lymphoma (MZL) on histopathology of an extirpated lymph node. This report demonstrates an unusual case of a pleomorphic neoplastic population documented on cytologic evaluation that had moncytoid features and peripheral blood involvement; a previously undocumented IgG1 monoclonal gammopathy was also an interesting feature of this canine MZL. The patient did not undergo chemotherapy for lymphoma and was euthanized over 4 years after the initial presentation. [ABSTRACT FROM AUTHOR]

Background and purpose: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a heterogeneous autoimmune disorder critically lacking diagnostic biomarkers. Autoantibodies to nodal and paranodal components have recently been described in a small subset of patients. Here, the diagnostic value of immune reactivity toward the myelin compartment was investigated. Methods: Ninety‐four French CIDP patients were retrospectively studied. The reactivity toward the peripheral nerve was investigated. Sural nerve biopsies were examined by electron microscopy and immunofluorescence. Results: Twenty‐one patients (22%) and three patients (3%) presented with a strong immunoglobulin G or immunoglobulin M reactivity respectively against the myelin compartment. The clinical, electrophysiological and morphological features were examined in nine of these patients for whom sural nerve biopsies were available. Seven patients were electrodiagnosed with definite CIDP, one with possible CIDP and one was unclassifiable but sural nerve biopsy argued for CIDP diagnosis. Electron microscopy of sural nerve biopsies demonstrated the presence of macrophage‐mediated demyelination restricted to the internode in all nine patients. Immunolabelling for voltage‐gated sodium channels, myelin and axonal markers confirmed the presence of segmental demyelination and of remyelination. The nodal and paranodal regions, however, were unaffected in these patients. Nerve conduction studies corroborated the multifocal and segmental profile, and seven patients showed increased duration of proximal (1.5–5.1 times) and/or distal (1.2–3.4 times) compound muscle action potential in at least two nerves. Conclusion: Antibody‐ and macrophage‐mediated demyelination appears responsible for conduction alterations in CIDP patients and nerve immunostaining assays may serve as a supportive diagnostic biomarker. [ABSTRACT FROM AUTHOR]

Monoclonal gammopathies complicated by AL amyloidosis can mimic giant cell arteritis (GCA). We hereby present the case of a 63 year old woman in whom symptoms consistent with GCA were the first manifestations of a monoclonal gammopathy of unknown significance (MGUS) associated with amyloidosis. A 63 year old woman was admitted for temporal headache, maseterine claudication, neck and shoulder stiffness. She was recently diagnosed with carpal tunnel syndrome. On physical examination she had prominent temporal arteries, macroglosia and orthostatic hypotension. Muscular strength was normal. She had high ESR and CRP; in this clinical context, GCA was suspected. A gamma spike on serum protein electrophoresis raised the suspicion of monoclonal gammopathy (MG). Immunoelectrophoresis revealed monoclonal bands for IgG and kappa chains. Massive deposits of amyloid and no inflammation were found on temporal artery biopsy. Multiple myeloma and lymphoma were ruled out. A diagnosis of AL amyloidosis complicating MGUS was formulated. She did well on therapy with bortezomib, cyclophosphamide and dexamethasone. Cases published in medical literature reveal amyloidosis mimicking GCA in the setting of established MGUS. As far as we know, this is the first case of MGUS with IgG and kappa chains in which a GCA-like picture induced by amyloidosis was present from the very onset.

Introduction: Our aim was to compare analytical specifications of two assays (monoclonal vs. polyclonal) for free light chains (FLCs) quantification optimized for two different analytical platforms, nephelometer ProSpec (Siemens, Erlangen, Germany) and turbidimetric analyser Optilite (The Binding Site, Birmingham, UK). Materials and methods: The evaluation included verification of the precision, repeatability and reproducibility, estimation of accuracy and method comparison study with 37 serum samples of haematological patients. Kappa and lambda FLC were measured in each sample by both methods and kappa/lambda ratio was calculated. Results: Results show satisfactory precision of both methods with coefficients of variation for ProSpec of CVwr = 2.20% and CVbr = 3.44%, and for Optilite CVwr = 2.82% and CVbr = 4.15%. Estimated bias for FLC lambda was higher on the ProSpec analyser, but bias for FLC kappa was higher on the Optilite analyser. Correlation coefficients were 0.98; P < 0.001 for FLC kappa and 0.97; P < 0.001 for FLC lambda. Considering normal/pathological FLC ratio moderate agreement within assays was detected (κ = 0.621). When the results were categorized according to criteria for progressive disease, 4/37 (0.10) cases were differently classified. Lambda FLC values by Optilite in three samples with monoclonal FLC lambda were more than twelve times higher than by ProSpec. A 25% difference in FLC ratio was detected in 16/37 (0.43) and 50% difference in 13/37 (0.35) patients. Conclusions: All manufacturers' precision claims could not be achieved in the verification study. The comparison of results to biological variations data showed that coefficients of variations are acceptable for both assays. The assays should not be used interchangeably in haematological patients. [ABSTRACT FROM AUTHOR]

Objectives: Testing of serum-free light chains kappa (κ) and lambda (λ), along with ratio (FLCR) is essential for the diagnosis and management of monoclonal gammopathies. Accurate clinical diagnosis depends upon appropriate local population reference intervals (RIs). This study examined the Saudi population for serum-free light chains and other immunoglobulins to establish RIs and to explore variations in the test results by using the International Federation for Clinical Chemistry and Laboratory Medicine's global protocol for harmonized implementation of RI study., Methods: A total of 180 healthy Saudi adults were recruited. All serum samples were assayed using the Freelite reagents from the Binding Site. The variation in reference values attributable to sex, age, BMI, and region was calculated by ANOVA as a standard deviation ratio (SDR). The RIs for the FLCR were derived by the parametric method and validated by using samples from patients with hypo- and hypergammaglobulinemia., Results: The new RIs for free κ and FLCR were shifted to a higher side from the manufacturer-adapted RIs. Based on the SDR cutoff value (>0.4), between-sex partition RIs were not required for all analytes except IgM. Validation using patients with hypo- or hypergammaglobulinemia and without multiple myeloma, was all within the new RI. BMI, smoking, and exercise were not relevant sources of variation for any analyte., Conclusions: Locally derived RIs for free light chains and immunoglobulins analytes specific for Saudis were established after careful consideration of various factors. These RIs were more reliable than those provided as guidance by the manufacturer, or from other countries, for appropriate classification and prediction of disease progression for Saudi patients., (© 2023 the author(s), published by De Gruyter, Berlin/Boston.)

Immunoglobulin E (IgE) gammopathy is a rare disorder, accounting for just 0.1% of all patients with multiple myeloma (MM). Herein, we report a case of IgE monoclonal gammopathy without any biological and clinical symptoms, and we review 63 published cases in the literature. Demographic, biological and clinical presentations and features appear to be similar to those of other subtypes of MM, with a median age of diagnosis of 67 years. There is a slight excess of male patients, and incidence seems to increase with age. The prevalence of renal failure, anaemia and hypercalcaemia at diagnosis was computed to be at 26%, 44% and 18%, respectively, in patients with MM. According to the literature, IgE MM is more aggressive and associated with poorer survival. Nonetheless, cases that are prolonged have also been described. [ABSTRACT FROM AUTHOR]

Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma are precursor conditions of symptomatic multiple myeloma (MM). Diagnostic principles are aimed at excluding MM requiring therapy, other conditions associated with paraproteins that may require different management, and risk stratifying patients for the purposes of tailored follow-up and investigation. The International Myeloma Working Group have recently published a revised definition of MM, which singles out a small group of patients with smoldering multiple myeloma who are at very high risk of progression and organ damage; such patients are now included under the definition of MM and recommended to start anti-myeloma treatment. Furthermore, the recently published National Institute of Health and Care Excellence guideline recommends cross-sectional imaging techniques in place of skeletal survey. These recent recommendations are discussed, and practical guidance for investigation and management are presented. [ABSTRACT FROM AUTHOR]

X-linked severe combined immunodeficiency (X-SCID), caused by defects in the common gamma chain, is typically characterized by T and NK cell defects with the presence of B cells. T cell dysfunction and impaired class-switch recombination of B cells mean that patients typically have defects in class-switched immunoglobulins (IgG, IgA, and IgE) with detectable IgM. Here, we describe two patients with X-SCID with IgG1 gammopathy, in whom we identified maternal T and B cell engraftment. Exclusively, maternal B cells were found among the IgD − CD27 + class-switched memory B cells, whereas the patients' B cells remained naïve. In vitro stimulation with CD40L + IL-21 revealed that peripheral blood cells from both patients produced only IgG1. Class-switched maternal B cells had restricted receptor repertoires with various constant regions and few somatic hypermutations. In conclusion, engrafted maternal B cells underwent class-switch recombination and produced immunoglobulin, causing hypergammaglobulinemia in patients with X-SCID. [ABSTRACT FROM AUTHOR]