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Plasma cell‐rich acute rejection (PCAR), a relatively rare subtype of acute allograft rejection, is usually associated with a significantly lower treatment response rate and a higher graft failure rate. PCAR is characterized by the presence of more than 10% of plasma cells out of all graft infiltrating cells, with approximately 40%–60% of PCAR resulting in graft failure within a year. Currently, there is no gold standard for the effective treatment of PCAR. This case report demonstrates the potential treatment effect of bortezomib in PCAR. A 37‐year‐old woman with reflux nephropathy received a kidney transplant from a brain‐dead kidney donor. The patient presented with an acute kidney injury with a serum creatinine level over 4 mg/dL 4 months after the surgery. The allograft biopsy showed acute T cell–mediated rejection (TCMR), Grade IIA, plasma cell‐rich variant. There were diffuse polyclonal plasma cells infiltrating the renal parenchyma with marked tubulitis and focal endarteritis. She received a methylprednisolone pulse of 500 mg daily x3, followed by thymoglobulin (rATG) at 4.2 mg/kg. However, a repeated biopsy after 2 months showed persistent plasma cells infiltrate with increased interstitial fibrosis with tubular atrophy. Then, the patient was given one cycle of bortezomib with a total of four subcutaneous injections and continued immunosuppressants of tacrolimus, mycophenolate mofetil, and prednisone. Following the treatment, the patient's serum creatinine level trended down to 2 mg/dL, and a second repeat biopsy after 4 months showed a significant treatment effect with complete resolution of interstitial inflammation and decreased chronicity. Bortezomib is a proteasome inhibitor that prevents cell proliferation by inducing apoptosis in plasma cells and has shown great promise as a therapeutic agent for multiple myeloma. Our case suggests that bortezomib can also be used as a potential therapeutic intervention for patients with PCAR. [ABSTRACT FROM AUTHOR]

Summary Monoclonal Immunoglobulin deposition disease (MIDD) is characterised by deposits of intact monoclonal light chains in the kidney leading to renal dysfunction. In this study, we retrospectively investigated the underlying plasma cell cytogenetic abnormalities in MIDD. CyclinD1 (11;14) translocation was identified in 12/27 (45%) patients. Among the patients without translocation, del13q and hyperdiploidy were the most common abnormalities. Patients in the non‐t (11;14) group had a higher baseline light‐chain ratio, higher proteinuria and lower eGFR as compared to patients with t (11;14). Haematological VGPR or higher was seen in 58% of t (11;14), and 30% without t (11;14), possibly related to higher use of Daratumumab‐based therapy in the t (11;14) group. With a median follow‐up of 750 days, 30% (8/24) progressed to end stage renal disease (ESRD). eGFR <20 mL/min (HR 25, 95% CI 2.09–298, p = 0.01) and 24 urine protein >3 g/24 h (HR 9, 95% CI 1.27–63.90, p = 0.02) at diagnosis were significantly associated with progression to ESRD. Renal survival was better in t (11;14) as compared to the non‐t (11;14) group (HR 0.11, p = 0.06). Translocation (11;14) is a common abnormality in MIDD and affects the presentation and outcomes. Identification of this abnormality should lead to exploration of BCL2 inhibitors in this disease. [ABSTRACT FROM AUTHOR]

Castleman disease (CD), also known as giant lymph node hyperplasia or angiofollicular lymph node hyperplasia, is a rare and indeterminate group of chronic lymphoproliferative disorders. CD is highly heterogeneous, classified into unicentric Castleman disease (UCD) and multicentric Castleman disease (MCD) based on lesion distribution, and further categorized into three pathological types: hyaline vascular type (HV), plasma cell type (PC), and mixed type (Mix). This paper describes a rare case of solitary mediastinal Castleman disease with transparent vessels in the anterior sacrum, presenting as the HV type. Surgical excision of the mass was performed following coccygectomy for treatment. The patient recovered well postoperatively. During a 6-month follow-up period, there were no signs of recurrence, and the patient's quality of life significantly improved. [ABSTRACT FROM AUTHOR]

This post hoc analysis of the randomized, placebo‐controlled N‐MOmentum study (NCT02200770) of inebilizumab in neuromyelitis optica spectrum disorder (NMOSD) evaluated relationships between circulating B‐cell subsets and aquaporin‐4 immunoglobulin G (AQP4‐lgG) titers and attacks. Among participants receiving placebo, CD20+ and CD27+ B‐cell counts were modestly increased from the pre‐attack visit to attack; plasmablast/plasma cell gene signature was increased from baseline to the pre‐attack visit (p = 0.016) and from baseline to attack (p = 0.009). With inebilizumab treatment, B‐cell subset counts decreased and did not increase with attacks. No difference in change of AQP4‐IgG titers from baseline to time of attack was observed. [ABSTRACT FROM AUTHOR]

Introduction: Thyroid-associated ophthalmopathy (TAO) is considered to be an organ-specific autoimmune disease. Polymorphonuclear neutrophils (PMN) have been implicated in the pathogenesis of TAO. However, little is known about the role of PMN in the development of TAO, much less the relationship between PMN with B cells and CD4+T cells in TAO. Objective: This study aims to investigate the phenotypic characteristics of PMN and the relationship between PMN with CD4+T cell and B cell subsets in the pathogenesis of TAO. Methods: Blood routine information was collected from 135 TAO patients, 95 Grave's disease without TAO (GD) patients, and 116 normal controls (NC), while surface marker expression of PMN and the level of CD4+T cell and B cell subsets in peripheral blood from 40 TAO patients, 17 GD patients, and 45 NC was assessed by flow cytometry. Result: The level of PMN, CD62L+PMN, CD54+PMN, CD4+T cells, and Th17 cells displayed an increase in TAO patients than NC, while Treg cells were lower in the TAO group compared to NC. There was no statistical difference in Th1 and plasma cells among the groups. PMN were positively correlated with Th17 cells, but not the Th1, Treg, and plasma cells. Conclusion: In the present study, we found that the percentage of PMN and PMN subset cells was significantly higher in TAO than in NC, and PMN were positively correlated with Th17 cells. It suggests that PMN may be involved in the immunopathogenesis of TAO and modulate the Th17 cell response during this process. [ABSTRACT FROM AUTHOR]

Backgrounds: Homeobox C6 (HOXC6) is a gene that encodes for a transcription factor involved in various cellular processes, including development and differentiation, and regulates cancer progression. However, the carcinogenesis and effect of HOXC6 in lung adenocarcinoma (LUAD) still need further investigation. Methods: The differential HOXC6 expression levels at the mRNA and protein level were explored in multiple public datasets, including The Cancer Genome Atlas (TCGA) and Human Protein Atlas (HPA) dataset. Gene Expression Omnibus (GSE31210), International Cancer Genome Consortium (ICGC) datasets and the LUAD sample from Affiliated Hospital of Guangxi Medical University. We also investigated the relation between HOXC6 expression and clinicopathologic indexes. Furthermore, the correlation of immune infiltration, drug responsiveness and HOXC6 were explored. Results: The upregulated HOXC6 expressions at mRNA and protein levels were found in LUAD tissues compared to the normal lung tissues. Besides, the relatively shorter overall survival time, worse T and N stages, and lower immune scores were found in the high-expression HOXC6 subgroup. Notably, T cells regulatory (Tregs), Macrophages M0, and Plasma cells had the higher infiltration levels in the high-HOXC6 expression subgroup, while NK cells activated, Monocytes, Dendritic cells resting, and Mast cells resting had the lower infiltration levels. In drug sensitivity analysis, we revealed that LUAD patients with high-HOXC6 expression may be more susceptible to Camptothecin, Cytarabine, Docetaxel, Elesclomol, Rapamycin, Sorafinib, Temsirolimus, and Vorinostat. Conclusions: Taken together, there is a great potential for HOXC6 to become a prognosis biomarker and contribute to develop treatment strategies for LUAD patients. Further mechanism exploration and drug development for HOXC6 are needed. [ABSTRACT FROM AUTHOR]

Background and Aim: Autotaxin (ATX) is an extracellular lysophospholipase D that catalyzes the hydrolysis of lysophosphatidylcholine into lysophosphatidic acid (LPA). Recent accumulating evidence indicates the biological roles of ATX in malignant tumors. However, the expression and clinical implications of ATX in human cholangiocarcinoma (CCA) remain elusive. Methods: In this study, the expression of ATX in 97 human CCA tissues was evaluated by immunohistochemistry. Serum ATX levels were determined in CCA patients (n = 26) and healthy subjects (n = 8). Autotaxin expression in cell types within the tumor microenvironment was characterized by immunofluorescence staining. Results: High ATX expression in CCA tissue was significantly associated with a higher frequency of lymph node metastasis (p = 0.050). High ATX expression was correlated with shorter overall survival (p = 0.032) and recurrence‐free survival (RFS) (p = 0.001) than low ATX expression. In multivariate Cox analysis, high ATX expression (p = 0.019) was an independent factor for shorter RFS. Compared with low ATX expression, high ATX expression was significantly associated with higher Ki‐67‐positive cell counts (p < 0.001). Serum ATX levels were significantly higher in male CCA patients than in healthy male subjects (p = 0.030). In the tumor microenvironment of CCA, ATX protein was predominantly expressed in tumor cells, cancer‐associated fibroblasts, plasma cells, and biliary epithelial cells. Conclusions: Our study highlights the clinical evidence and independent prognostic value of ATX in human CCA. [ABSTRACT FROM AUTHOR]

Serum B-cell maturation antigen (sBCMA) levels can serve as a sensitive biomarker in multiple myeloma (MM). In the research setting, sBCMA levels can be accurately detected by enzyme-linked immunosorbent assay (ELISA), but the approach has not been approved for clinical use. Here, we used a novel chemiluminescence method to assess sBCMA levels in 759 serum samples from 17 healthy donors and 443 patients with plasma cell (PC) diseases including AL amyloidosis, POEMS syndrome, and MM. Serum BCMA levels were elevated 16.1-fold in patients with newly diagnosed MM compared to healthy donors and rare PC diseases patients. Specifically, the sBCMA levels in patients with progressive disease were 64.6-fold higher than those who showed partial response or above to treatment. The sBCMA level also correlated negatively with the response depth of MM patients. In newly diagnosed and relapsed MM patients, survival was significantly longer among those subjects whose sBCMA levels are below the median levels compared with those above the median value. We optimized the accuracy of the survival prediction further by integrating sBCMA level into the Second Revised International Staging System (R2-ISS). Our findings provide evidence that the novel chemiluminescence method is sensitive and practical for measuring sBCMA levels in clinical samples and confirm that sBCMA might serve as an independent prognostic biomarker for MM. Chemiluminescence method was first established to measure serum BCMA and proved to be sensitive and practical for in clinical samples. Serum BCMA is an important parameter for treatment efficacy evaluation and prognosis prediction in MM, especially in some special subpopulations, such as non-secretory MM, IgD-MM, and patients with BCMA-CAR-T therapy. The accuracy of the survival prediction of MM was further optimized by integrating sBCMA level into the R2-ISS. Graphical Abstract [ABSTRACT FROM AUTHOR]

Light chain deposition disease (LCDD) is a rare, clonal plasma cell proliferative condition. The deposition of nonamyloid monoclonal immunoglobulin light chains predominantly affects the kidneys, which may lead to end-stage renal disease, eventually requiring renal replacement therapy. The present study reported a rare case of LCDD that was confirmed after renal transplantation. A 49-year-old man initially presented with heavy proteinuria, hypoproteinemia, hyperlipidemia and renal insufficiency. The patient was diagnosed with nephrotic syndrome and pathological examination revealed fibrillary glomerulonephritis in 2014. Treatment was started with prednisolone. About 5 years later, the patient began to receive continuous hemodialysis due to worsening serum creatinine levels. Renal allograft transplantation was performed in 2020 and dialysis independence was achieved. Laboratory findings before renal transplantation revealed that serum and urine immunofixation electrophoresis was negative. Allograft kidney biopsy established the pathological diagnosis of LCDD at >1 year after renal transplantation for renal dysfunction. The treatment is challenging due to the lack of generally accepted standard treatment practices. Administration of bortezomib combined with dexamethasone was started. As anemia and renal failure developed progressively, the treatment was switched to anti-CD38 antibody and continuous hemodialysis was restarted. The best response achieved was hematological partial response and relief of anemia. However, the patient's renal function did not improve and he remains to have end-stage kidney disease. LCDD is easily missed in cases in which serum and urine immunofixation electrophoresis is negative. Hence, early recognition of LCCD based on kidney biopsy is important. To the best of our knowledge, the use of anti-CD38 antibody therapy in patients with LCDD is rarely reported. Anti-CD38 antibody is effective in treating LCDD, but it may not reverse the marked deterioration of renal function. [ABSTRACT FROM AUTHOR]

This article presents a case study of a patient with a rare vascular tumor called epithelioid hemangioendothelioma (EHE). The study describes the characteristics of EHE cells and discusses the challenges in diagnosing this tumor due to its variability and lack of specific markers. The article also compares EHE with other malignancies and emphasizes the importance of using vascular markers and molecular studies to confirm the diagnosis. The prognosis for EHE in the lungs or pleura is generally poor, and treatment usually involves surgery with or without chemoradiation. [Extracted from the article]

Emperipolesis is a cell-within-cell phenomenon distinct from phagocytosis more often described in Rosai-Dorfman disease, where usually lymphocytes or other bone marrow cells (plasma cells, erythroblasts or neutrophils) are entirely surrounded but not engulfed by macrophages as the host cell, but occasionally megakaryocytes and neoplastic could be. Mesothelial cell has been described in a couple of cases of lymphomas affecting serous membranes, but never described in pleuritis. In the present work, the first case of emperipolesis by mesothelial cells in a patient with self-limited pleural effusion was demonstrated by immunohistochemistry and Electron Microscopy studies. [ABSTRACT FROM AUTHOR]

TEMPI syndrome is a rare, acquired disorder with multisystemic manifestations. It is classified as a plasma cell disorder and is characterized by telangiectasias, erythrocytosis, monoclonal gammopathy, perinephric fluid collections and intrapulmonary shunt. Even though TEMPI's pathophysiology remains elusive, it responds to anti-myeloma therapy indicating that the monoclonal protein or clone plays a key role. We present a challenging case of a 73-year-old man with erythrocytosis and deteriorating renal function with nephrotic-range proteinuria in whom after extensive work up, the diagnosis of TEMPI syndrome was made. He was received treatment with daratumumab-bortezomib-cyclophosphamide and dexamethasone (Dara-VCD) and achieved a hematological and clinical response. We also report preliminary data on a multiplex assay for cytokines and growth factors for two patients with TEMPI syndrome and note lower levels for non-specific innate immunity related cytokines. A direct link between renal impairment and TEMPI syndrome is not currently established; cytokine deregulation could potentially be involved in the ischemic changes observed in the renal biopsy of our patient. [ABSTRACT FROM AUTHOR]

We aimed to evaluate if circulating plasma cells (CPC) detected by flow cytometry could add prognostic value of R2-ISS staging. We collected the electronic medical records of 336 newly diagnosed MM patients (NDMM) in our hospital from January 2017 to June 2023. The median overall survival (OS) for patients and R2-ISS stage I-IV were not reached (NR), NR, 58 months and 53 months, respectively. There was no significant difference in OS between patients with stage I and patients with stage II (P = 0.309) or between patients with stage III and patients with stage IV (P = 0.391). All the cases were re-classified according to R2-ISS stage and CPC numbers ≥ 0.05% (CPC high) or<0.05% (CPC low) into four new risk groups: Group 1: R2-ISS stage I + R2-ISS stage II and CPC low, Group 2: R2-ISS stage II and CPC high + R2-ISS stage III and CPC low, Group 3: R2-ISS stage III and CPC high + R2-ISS stage IV and CPC low, Group 4: R2-ISS stage IV and CPC high. The median OS were NR, NR, 57 months and 32 months. OS of Group 1 was significantly longer than that of Group 2 (P = 0.033). OS in Group 2 was significantly longer than that of Group 3 (P = 0.007). OS in Group 3 was significantly longer than that of Group 4 (P = 0.041). R2-ISS staging combined with CPC can improve risk stratification for NDMM patients. [ABSTRACT FROM AUTHOR]

Plasmacytomas are malignant tumours characterised by abnormal monoclonal proliferation of plasma cells. They may be osseous or may arise from soft tissues. Extramedullary plasmacytoma (EMP) accounts for only 1% of all head and neck malignancies. Septal plasmacytomas are extremely rare. Here, we report a case of an 80-year-old male patient with alocalised plasmacytoma arising from the nasal septum, which was resected endoscopically, with post-op radiotherapy and no recurrence in 1 year of follow-up. A multidisciplinary approach is required for the optimal diagnosis and management. It is essential to exclude any systemic involvement before arriving at a diagnosis of solitary plasmacytoma. Depending on lesion resectability, a combined therapy is the treatment of choice. [ABSTRACT FROM AUTHOR]

Background: At present, immunotherapy has become a powerful treatment for advanced gastric cancer (AGC), but not all patients can benefit from it. According to the latest research, the impact of B cell subpopulations on the immune microenvironment of gastric cancer (GC) is unknown. Exploring whether the interaction between B cells and tumor cells in GC affects the effectiveness of immunotherapy has attracted our interest. Methods: This study involved the re-analysis of single-cell RNA (scRNA) and spatial transcriptomics (ST) data from publicly available datasets. The focus was on investigating the subpopulations and differentiation trajectories of B cells in the gastric cancer (GC) tumor immune microenvironment (TIME). Spatial transcriptomics (ST) and multiple immunofluorescence (mIF) revealed a clear co-localization pattern between B cells and tumor cells. Multiple immunotherapy datasets were collected to identify unique immunotherapy biomarkers. The unique immunotherapeutic potential of targeting CCL28 was validated through a mouse gastric cancer model. In addition, flow cytometry revealed changes in the tumor immune microenvironment targeting CCL28. Results: The re-analysis of ST data from multiple cancer types revealed a co-localization pattern between B cells and tumor cells. A significant number of IgA plasma cells were identified in the GC TIME. Five different tumor-infiltrating B cell subpopulations and two unique B cell differentiation trajectories were characterized, along with seven GC-related states. By analyzing the communication between GC cells and B cells, it was further discovered that tumor cells can influence and recruit plasma cells through CCL28-CCR10 signaling. Additionally, there was a crosstalk between GC cells and B cells. Finally, we identified the LAMA/CD44 signaling axis as a potential prognostic marker for immunotherapy through a large amount of immunotherapy data. We also validated through various animal tumor models that targeting CCL28 can significantly promote CD8+T cell infiltration and function in the TME by regulating B cell and plasma cell functions, and has the ability to synergize immunotherapy. Conclusion: The co-localization and crosstalk between GC cells and B cells significantly affect the efficacy of immunotherapy, and inhibiting the CCL28-CCR10 signal axis is a potential immunotherapy target for GC. Meanwhile, LAMA/CD44 pair may be a potential adverse indicator for immunotherapy and tumor prognosis. [ABSTRACT FROM AUTHOR]

ABSTRACT Hodgkin‐like lymphoma (HLL) is a rare neoplasm in cats that shares characteristics with the human disease. The hallmark of HLL is the presence of Reed‐Sternberg (RS) cells expressing CD30 and CD20. This study aimed to elucidate the clinicopathologic features, immunophenotype and clonality patterns of feline HLL. A comprehensive retrospective review of clinicopathologic and molecular data of nodal lymphomas over a 6‐year period was conducted in MyLav laboratory. Twenty‐four cases were identified. All cats presented with submandibular or retropharyngeal lymphadenopathy. Histopathologic examination revealed a multifocal to diffuse proliferation of medium‐to‐large lymphoid cells with low mitotic activity, interspersed RS cells, and a heterogeneous inflammatory infiltrate comprising T‐cells, plasma cells and neutrophils. In addition, extensive necrosis was a consistent finding. Immunohistochemistry showed a variable membranous CD20 and nuclear PAX5 expression in neoplastic cells, while RS cells displayed only mild to moderate CD20 positivity and were negative to PAX5. In 21/24 cases (87.5%), RS cells were diffusely CD30‐positive. PARR analysis demonstrated clonal B‐cell expansion in 60% of cases, with the remaining 40% exhibiting polyclonality. For the 10 cats with available follow‐up, the prognosis was generally favourable, with only two cats succumbing to progressive disease. In conclusion, diagnosing feline HLL is challenging. The expression of CD30 and CD20 by RS cells should be considered a hallmark of the disease, but only after excluding differential diagnoses such as anaplastic B‐cell lymphoma and granulomatous lymphadenopathy. [ABSTRACT FROM AUTHOR]

Multiple myeloma is a haematological malignancy typically characterised by neoplastic plasma cell infiltration of the bone marrow. Treatment for multiple myeloma consists of multi-line chemotherapy with or without autologous stem cell transplantation and has been rapidly evolving in recent years. However, clinical trials are unable to provide patients and clinicians with long-term prognostic information nor policymakers with the full body of evidence needed to perform economic evaluation of new therapies or make reimbursement decisions. To address these limitations of the available evidence, this study aimed to develop and validate the EpiMAP Myeloma model, a discrete-event simulation model of multiple myeloma disease outcomes and treatment pathways. Risk equations were estimated using the Australian and New Zealand Myeloma & Related Diseases Registry after multiple imputation of missing data. Risk equation coefficients were combined with multiple myeloma patients at diagnosis from the Registry to perform the simulation. The model was validated with 100 bootstraps of an out-of-sample prediction analysis using a 70/30 split of the 4,121 registry patients diagnosed between 2009 and 2023, resulting in 2,884 and 1,237 patients in the training and validation cohorts, respectively. For 90% of the 120 months in the 10-year post-diagnosis period, there was no significant difference in overall survival between the validation and simulated cohorts. These results highlight that the EpiMAP Myeloma model is robust at predicting multiple myeloma disease outcomes and treatment pathways in Australia & New Zealand. In the future, clinicians will be able to use the EpiMAP Myeloma model to provide personalised estimates of life expectancy to patients based on their specific characteristics, disease stage, and response to treatment. Policymakers will also be able to use the model to perform economic evaluation, to forecast the number of patients receiving treatment at different stages, and to determine the downstream impact of listing new, effective therapies. [ABSTRACT FROM AUTHOR]

In 2022, two updated classification systems for lymphoid neoplasms were published by the World Health Organization (WHO Classification of Haematolymphoid Tumours, 5th edition, referred to hereafter as WHO-HAEM5) and the International Consensus Conference (ICC) (Alaggio et al. in Leukemia 36(7):1720–1748, 2022; Campo et al. in Blood 140(11):1229–1253, 2022). Both classifications were conceived by both pathologists and clinicians with expertise in the field. The reasons for this have been reviewed previously (Arber et al. in Virchows Arch 482(1):1–9, 2023; Cree in Leukemia 36(7):1701–1702, 2022, Leukemia 36(11):2750, 2022). Given that both groups were using data-driven processes and consensus and used the revised 4th edition of the WHO Classification of Haematolymphoid Tumours (WHO-HAEM4R) as a starting point, it is not entirely surprising that the resulting classifications are quite similar. However, they are not identical and reflect preferences or approaches for certain unsettled areas as well as preferred terminology. In this review, we will compare nomenclature of the WHO-HAEM5 and ICC classifications, focusing on lymphoid neoplasms and lymphoproliferative disorders (LPDs). [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article on the classification of mature B, T, and NK-cell neoplasms. The original article had errors in Table 1, which have been corrected in this document. The corrected table compares the classification of different types of lymphomas according to various classifications. The document provides a comprehensive overview of the different types of lymphomas, including subtypes of large B-cell lymphomas and other types associated with immune deficiency and dysregulation. It aims to provide accurate information for library patrons conducting research on these specific topics. [Extracted from the article]

Background: Autoimmune hemolytic anemia (AIHA) is a rare disease due to increased destruction of erythrocytes by autoantibodies, with or without complement activation. Summary: AIHA is usually classified in warm AIHA (wAIHA) and cold agglutinin disease (CAD), based on isotype and thermal amplitude of the autoantibody. The direct antiglobulin test (DAT) or Coombs test is the cornerstone of AIHA diagnosis, as it is positive with anti-IgG in wAIHA, and with anti-C3d/IgM antisera plus high titer cold agglutinins in CAD. Therapy is quite different, as steroids and rituximab are effective in the former, but have a lower response rate and duration in the latter. Splenectomy, which is still a good option for young/fit wAIHA, is contraindicated in CAD, and classic immunosuppressants are moving to further lines. Several new drugs are increasingly used or are in trials for relapsed/refractory AIHAs, including B-cell (parsaclisib, ibrutinib, rilzabrutinib), and plasma cell target therapies (bortezomib, daratumumab), bispecific agents (ianalumab, obexelimab, povetacicept), neonatal Fc receptor blockers (nipocalimab), and complement inhibitors (sutimlimab, riliprubart, pegcetacoplan, iptacopan). Clinically, AIHAs are highly heterogeneous, from mild/compensated to life-threatening/fulminant, and may be primary or associated with infections, neoplasms, autoimmune diseases, transplants, immunodeficiencies, and drugs. Along with all these variables, there are rare forms like mixed (wAIHA plus CAD), atypical (IgA or warm IgM driven), and DAT negative, where the diagnosis and clinical management are particularly challenging. Key Messages: This article covers the classic clinical features, diagnosis, and therapy of wAIHA and CAD, and focuses, with the support of clinical vignettes, on difficult diagnosis and refractory/relapsing cases requiring novel therapies. [ABSTRACT FROM AUTHOR]

Rationale: Food allergy is a prevalent disease in the U.S., affecting nearly 30 million people. The primary management strategy for this condition is food avoidance, as limited treatment options are available. The elevation of pathologic IgE and over-reactive mast cells/basophils is a central factor in food allergy anaphylaxis. This study aims to comprehensively evaluate the potential therapeutic mechanisms of a small molecule compound called formononetin in regulating IgE and mast cell activation. Methods: In this study, we determined the inhibitory effect of formononetin on the production of human IgE from peripheral blood mononuclear cells of food-allergic patients using ELISA. We also measured formononetin's effect on preventing mast cell degranulation in RBL-2H3 and KU812 cells using betahexosaminidase assay. To identify potential targets of formononetin in IgE-mediated diseases, mast cell disorders, and food allergies, we utilized computational modeling to analyze mechanistic targets of formononetin from various databases, including SEA, Swiss Target Prediction, PubChem, Gene Cards, and Mala Cards. We generated a KEGG pathway, Gene Ontology, and Compound Target Pathway Disease Network using these targets. Finally, we used qRT-PCR to measure the gene expression of selected targets in KU812 and U266 cell lines. Results: Formononetin significantly decreased IgE production in IgE-producing human myeloma cells and PBMCs from food-allergic patients in a dose-dependent manner without cytotoxicity. Formononetin decreased betahexosaminidase release in RBL-2H3 cells and KU812 cells. Formononetin regulates 25 targets in food allergy, 51 in IgE diseases, and 19 in mast cell diseases. KEGG pathway and gene ontology analysis of targets showed that formononetin regulated disease pathways, primary immunodeficiency, Epstein- Barr Virus, and pathways in cancer. The biological processes regulated by formononetin include B cell proliferation, differentiation, immune response, and activation processes. Compound target pathway disease network identified NFKB1, NFKBIA, STAT1, STAT3, CCND1, TP53, TYK2, and CASP8 as the top targets regulated at a high degree by formononetin. TP53, STAT3, PTPRC, IL2, and CD19 were identified as the proteins mostly targeted by formononetin. qPCR validated genes of Formononetin molecular targets of IgE regulation in U266 cells and KU812 cells. In U266 cells, formononetin was found to significantly increase the gene expression of NFKBIA, TP53, and BCL-2 while decreasing the gene expression of BTK TYK, CASP8, STAT3, CCND1, STAT1, NFKB1, IL7R. In basophils KU812 cells, formononetin significantly increased the gene expression of NFKBIA, TP53, and BCL-2 while decreasing the gene expression of BTK, TYK, CASP8, STAT3, CCND1, STAT1, NFKB1, IL7R. Conclusion: These findings comprehensively present formononetin's mechanisms in regulating IgE production in plasma cells and degranulation in mast cells. [ABSTRACT FROM AUTHOR]

B-cell malignancies, such as chronic lymphocytic leukemia (CLL) and multiple myeloma (MM), remain incurable, with MM particularly prone to relapse. Our study introduces a novel mouse model with active RANK signaling and the TCL1 oncogene, displaying both CLL and MM phenotypes. In younger mice, TCL1 and RANK expression expands CLL-like B1-lymphocytes, while MM originates from B2-cells, becoming predominant in later stages and leading to severe disease progression and mortality. The induced MM mimics human disease, exhibiting features like clonal plasma cell expansion, paraproteinemia, anemia, and kidney and bone failure, as well as critical immunosurveillance strategies that promote a tumor-supportive microenvironment. This research elucidates the differential impacts of RANK activation in B1- and B2-cells and underscores the distinct roles of single versus combined oncogenes in B-cell malignancies. We also demonstrate that human MM cells express RANK and that inhibiting RANK signaling can reduce MM progression in a xenotransplantation model. Our study provides a rationale for further investigating the effects of RANK signaling in B-cell transformation and the shaping of a tumor-promoting microenvironment. [ABSTRACT FROM AUTHOR]

The clinical significance of an abnormal free light chain (FLC) test, performed due to unspecific complains in the absence of a known plasma cell dyscrasia (PCD) or lymphoproliferative disease (LPD), is not fully elucidated. We investigated the importance of an abnormal FLC ratio (FLC-R) in this setting. Patients registered in the Maccabi Healthcare Services database, tested for FLC during 2007–2023 without previously documented PCD/LPD or increased total protein (TP) level, were reviewed. Demographics, co-morbidities, and laboratory tests were recorded. FLC-R was defined as normal (0.26–1.65) or slightly (slAb 0.1–0.26/1.65–4), moderately (mAbn 0.1–0.05/4–8) and significantly abnormal (sigAb- < 0.05 or > 8). Factors associated with PCD/LPD and overall survival were identified. In total, 8,661 patients, 2,215 (25.6%) with abnormal FLC-R [2,090 (24.1%)-slAb, 65 (0.75%)-mAbn and 60 (0.7%)-sigAb], were analyzed. Almost none had anemia nor acute renal failure. 14% had concomitant increased immunoglobulins. Within a median follow-up of 52 months, 943 were diagnosed with PCD (816-MGUS, 127-MM/Amyloidosis/plasmacytoma) and 48 with LPD. Median time to PCD and LPD were 19 and 28 months. Multivariate analysis found slAb (HR = 1.8, CI95%:1.53–2.12, p < 0.001), mAbn (HR = 6.3, CI95%:4.16–9.53, p < 0.001), and sigAb FLC (HR = 10.4, CI95%:7.0–15.35, p < 0.001), to be associated with PCD/LPD diagnosis. Decreased IgG, increased IgA, and concomitant comorbidities predicted PCD, whereas increased IgM predicted LPD. Older age, male gender, anemia, decreased albumin, increased IgG and concomitant comorbidities, predicted shorter survival. Our large study emphasizes the independent clinical significance of abnormal FLC-R as a predictor of PCD/LPD diagnosis even in patients with normal TP level, promoting early detection of PCD/LPD. [ABSTRACT FROM AUTHOR]

AbstractPlasma cell neoplasms (PCN) have infrequently been reported in patients with myelodysplastic syndrome (MDS) and even more rarely in those with myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN). We report the clinicopathologic features of 26 patients with bone marrow myelodysplasia accompanied by PCN, including 21 patients with MDS and 5 with MDS/MPN. The clinicopathologic features of the MDS/MPN-PCN were compared to those of the MDS-PCN group and 68 cases of MDS/MPN without PCN, respectively. The MDS/MPN-PCN group was notable for increased reticulin fibrosis > grade 1 when compared to both the MDS/MPN (p = 0.007) and MDS-PCN (p = 0.02) groups. MDS/MPN-PCN was associated with worse overall survival when compared with MDS-PCN (p = 0.03) and but not with MDS/MPN. Notably, hemoglobin level <8 g/dl (p = 0.008), and IDH2 somatic mutation (p = 0.003) were independent predictors of poor overall survival in all patients with MDS/MPN. Analysis of larger cohorts is required to confirm these associations and provide an insight into the pathogenesis. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a hematological cancer marked by plasma cell accumulation in the bone marrow. Despite treatment advancements, MM remains incurable in most patients. MM-associated immune dysregulation fosters disease progression, prompting research into immunotherapy to combat the disease. An area of immunotherapy investigation is the design of myeloma vaccine therapy to reverse tumor-associated immune suppression and elicit tumor-specific immune responses to effectively target MM cells. This article reviews vaccine immunotherapy for MM, categorizing findings by antigen type and delivery method. Antigens include idiotype (Id), tumor-associated (TAA), tumor-specific (TSA), and whole tumor lysate. Myeloma vaccination has so far shown limited clinical efficacy. However, further studies are essential to optimize various aspects, including antigen and patient selection, vaccine timing and sequencing, and rational combinations with emerging MM treatments. [ABSTRACT FROM AUTHOR]

Objective: Rare coexistence of disease or pathology Background: Fluid overload-associated large B-cell lymphoma (FO-LBCL) is a recently described malignant lymphoma that presents with serous effusions in the pleura, peritoneum, and/or pericardium but without an identifiable lymphoma mass. This report describes the case of an 80-year-old man who presented with a pleural effusion and describes the approach to diagnosis and management of FO-LBCL. Case Report: We present a case of an 80-year-old man who presented with right pleural effusion and shortness of breath at work. Initial radiological assessment suggested a pleural effusion on the right side, without an identifiable mass, given the patient’s symptoms and imaging characteristics. Subsequently, he underwent a pleural fluid puncture and biopsy. Based on the initial pathological assessment, malignant lymphoma, a non-epithelial tumor, was considered likely, but differentiation from reactive proliferative cells was difficult, given the patient’s symptoms and cytologic characteristics. Postoperatively, histopathological examination and immunohistochemistry confirmed a diagnosis of FO-LBCL. After 1 year of follow-up, the condition had progressed and the patient died due to recurrence. Conclusions: This report has presented a case of FO-LBCL in an elderly man with pleural effusion and described how this rare and recently described lymphoma was diagnosed and managed. [ABSTRACT FROM AUTHOR]

Objectives: This prospective study evaluated whether endometriosis is associated with chronic endometritis (CE) and affects the uterine endometrium microbiome (UEM) in women with repeated implantation failure (RIF). Methods: Forty-three women with RIF were divided into 12 with endometriosis (EM) and 31 without endometriosis (non-EM). The UEM was examined by 16S ribosomal RNA (rRNA) sequencing, and CE was determined by CD 138 staining (plasma cells > 5.15/10 mm2) simultaneously. Results: The EM group had a higher bacterial number (EM vs. non-EM; median [range], 6.5 vs. 3 [3–11, 1–16], p = 0.009), while the frequency of Lactobacillus species did not change. The rates of presence of Dialister (41.7% [5/12] vs. 3.3% [1/31], p = 0.004) and Streptococcus species (58.3% [7/12] vs. 16.1% [5/31], p = 0.017) were higher in the EM group. The prevalence of CE did not differ between the two groups. Multivariable logistic regression analysis revealed that the presence of Dialister species (odds ratio, 10.97, 95% confidence interval, 1.17–249.37, p = 0.036) was associated with endometriosis. In the EM group, five women with Dialister species had a higher number of bacterial species (10 vs. 5 [6–11, 3–7], p = 0.021) and higher Shannon diversity index (0.50 vs. 0.20 [0.19–1.39, 0.03–0.46], p = 0.026) than seven without Dialister species. Conclusions: Dialister and Streptococcus species, and the increased number of bacterial species in UEM may be related to the pathogenesis of RIF complicated by endometriosis. [ABSTRACT FROM AUTHOR]

Background: The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) has been increasing in recent years, becoming a cause of community-acquired infection. Interestingly, its role in malignancy recently started to be considered after a noticed increase in reported cases and studies discussing the potential association. Case Report: In the present case, the patient had known and uncontrolled diabetes mellitus and a history of multiple abscesses that were previously treated by incision and drainage. The patient received a diagnosis of severe pneumonia, and MRSA was found in blood cultures. Further tests for HIV, hemagglutinin type 1, and neuraminidase type 1 (H1N1) were negative. The D test was also performed for macrolide-inducible resistance and was negative, indicating the need for intravenous administration of clindamycin. An echocardiogram ruled out endocarditis. Subsequently, the patient experienced progressive back pain and weakness involving the lower limbs. A pathological fracture was discovered, along with nerve root compression. An urgent posterior spine fixation was then performed by a neurosurgeon. A biopsy was collected at the site of the pathological fracture, and histopathological tests indicated a plasma cell neoplasm. Conclusions: MRSA is known to cause serious and dangerous infections, including necrotizing pneumonia. Furthermore, a link between MRSA and plasma cell dyscrasia has been considered in several reports. This necessitates the need for further studies to clarify this hidden association, which may help in the course and prognosis of these patients. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is the second most prevalent hematological malignancy, characterized by infiltration of the bone marrow by malignant plasma cells. Extramedullary disease (EMD) represents a more aggressive condition involving the migration of a subclone of plasma cells to paraskeletal or extraskeletal sites. Liquid biopsies could improve and speed diagnosis, as they can better capture the disease heterogeneity while lowering patients' discomfort due to minimal invasiveness. Recent studies have confirmed alterations in the proteome across various malignancies, suggesting specific changes in protein classes. In this study, we show that MALDI-TOF mass spectrometry fingerprinting of peripheral blood can differentiate between MM and primary EMD patients. We constructed a predictive model using a supervised learning method, partial least squares-discriminant analysis (PLS-DA) and evaluated its generalization performance on a test dataset. The outcome of this analysis is a method that predicts specifically primary EMD with high sensitivity (86.4%), accuracy (78.4%), and specificity (72.4%). Given the simplicity of this approach and its minimally invasive character, this method provides rapid identification of primary EMD and could prove helpful in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Risk stratification in multiple myeloma (MM) patients is crucial, and molecular genetic studies play a significant role in achieving this objective. Enrichment of plasma cells for next-generation sequencing (NGS) analysis has been employed to enhance detection sensitivity. However, these methods often come with limitations, such as high costs and low throughput. In this study, we explore the use of an error-corrected ultrasensitive NGS assay called positional indexing sequencing (PiSeq-MM). This assay can detect somatic mutations in MM patients without relying on plasma cell enrichment. Method: Diagnostic bone marrow aspirates (BMAs) and blood samples from 14 MM patients were used for exploratory and validation sets. Results: PiSeq-MM successfully detected somatic mutations in all BMAs, outperforming conventional NGS using plasma cells. It also identified 38 low-frequency mutations that were missed by conventional NGS, enhancing detection sensitivity below the 5% analytical threshold. When tested in an actual clinical environment, plasma cell enrichment failed in most BMAs (14/16), but the PiSeq-MM enabled mutation detection in all BMAs. There was concordance between PiSeq-MM using BMAs and ctDNA analysis in paired blood samples. Conclusion: This research provides valuable insights into the genetic landscape of MM and highlights the advantages of error-corrected NGS for detecting low-frequency mutations. Although the current standard method for mutation analysis is plasma cell-enriched BMAs, total BMA or ctDNA testing with error correction is a viable alternative when plasma cell enrichment is not feasible. [ABSTRACT FROM AUTHOR]

POEMS syndrome, characterized as a rare multisystem paraneoplastic syndrome, arises from plasma cell abnormalities. Coined by Bardwick in 1980, the acronym POEMS delineates the distinctive features of the syndrome: Peripheral nerve Lesions, Organomegaly, Endocrinopathy, Monoclonal gammopathy, and Skin changes. The prevalence of POEMS syndrome stands at approximately 0.3 per 100,000 individuals. Owing to its low prevalence and the paucity of prospective studies, current treatment approaches largely hinge on retrospective studies and revolve around the use of plasma cell-directed therapy typically used in multiple myeloma treatments. This article presents the pioneering case of utilizing a fourdrug combination regimen of DKRd (daratumumab, carfilzomib, lenalidomide, and dexamethasone) as a first-line treatment. This is succeeded by induction therapy and subsequently, autologous hematopoietic stem cell transplantation. A comprehensive review of related literature is conducted. [ABSTRACT FROM AUTHOR]

The two primary types of non-puerperal mastitis (NPM) are granulomatous lobular mastitis (GLM) and plasma cell mastitis (PCM). Existing research indicates that immune inflammatory response is considered to be the core of the pathogenesis of GLM and PCM, and both innate and adaptive immune responses play an important role in the pathophysiology of PCM and GLM. However, the regulatory balance between various immune cells in these diseases is still unclear. Consequently, we present a comprehensive summary of the immune-related variables and recent advances in GLM and PCM. [ABSTRACT FROM AUTHOR]

Lymphoplasmacytic lymphoma (LPL) is an incurable low-grade lymphoma with no standard therapy. Nine asymptomatic patients treated with a first-in-human, neoantigen DNA vaccine experienced no dose limiting toxicities (primary endpoint, NCT01209871). All patients achieve stable disease or better, with one minor response, and median time to progression of 72+ months. Post-vaccine single-cell transcriptomics reveal dichotomous antitumor responses, with reduced tumor B-cells (tracked by unique B cell receptor) and their survival pathways, but no change in clonal plasma cells. Downregulation of human leukocyte antigen (HLA) class II molecules and paradoxical upregulation of insulin-like growth factor (IGF) by the latter suggest resistance mechanisms. Vaccine therapy activates and expands bone marrow T-cell clonotypes, and functional neoantigen-specific responses (secondary endpoint), but not co-inhibitory pathways or Treg, and reduces protumoral signaling by myeloid cells, suggesting favorable perturbation of the tumor immune microenvironment. Future strategies may require combinations of vaccines with agents targeting plasma cell subpopulations, or blockade of IGF-1 signaling or myeloid cell checkpoints. Lymphoplasmacytic lymphoma is a B-cell low-grade lymphoma with no approved standard therapy. Here the authors report a non-randomized phase 1 clinical trial performing early intervention with personalized neoantigen vaccines in asymptomatic patients and associating clinical efficacy with successful perturbation of the tumor immune microenvironment. [ABSTRACT FROM AUTHOR]

Introduction: Immunoglobulin G (IgG) is important in mediating humoral immunity and in the maintenance of immune homeostasis in the intestinal mucosa. Oregano essential oil (OEO) is a natural herbal extract that possesses antimicrobial, antioxidant, anti-inflammatory, and immunomodulatory properties. As the effects of OEO on intestinal mucosal immunity in Holstein dairy bulls remained unclear, we investigated the effect of dietary supplementation of OEO on IgG levels and IgG+ cells residing in the intestinal tract in Holstein dairy bulls. Methods: Twelve Holstein bulls in good health of approximately 10 months of age were selected for the experiment and randomly equally divided into two groups. The control (CK) group was fed a basal ration, and in the OEO group, the basal ration was supplemented with OEO (20 g/head/day). After 300 days of feeding, tissue samples of the jejunum, ileum, and colon of the bulls in each group were collected for histopathological analysis, immunohistochemistry, and enzyme-linked immunosorbent assays, respectively. Results: The jejunum, ileum, and colon of bulls in the CK group had obvious pathological damage, whereas the structure of each intestinal segment was clear and intact. In the OEO group, pathological damage was significantly reduced. IgG+ plasma cells were diffusely distributed in the lamina propria of the jejunum, ileum, and colon in the CK and OEO groups, with no significant difference between the groups. OEO supplementation significantly reduced the number of IgG+ plasma cells in each intestinal segment, with the highest decrease rate being noted for the ileum (22.87%), followed by the colon (19.45%) and jejunum (8.52%). ELISA test results and immunohistochemical results were mutually verified. The change in IgG content was consistent with the trend of change in the number of IgG+ plasma cells. Discussion: Our findings suggest that OEO supplementation does not alter the diffuse spatial distribution of IgG+ plasma cells in the intestines of Holstein dairy bulls, but lowers immunoglobulin levels to normal levels, significantly reduces intestinal damage, and may enhance mucosal immune defence barrier function by inhibiting inflammatory reactions. [ABSTRACT FROM AUTHOR]

Autophagy is a regulated intracellular catabolic process by which invading pathogens, damaged organelles, aggregated proteins, and other macromolecules are degraded in lysosomes. It has been widely appreciated that autophagic activity plays an important role in regulating the development, fate determination, and function of cells in the immune system, including B lymphocytes. Autophagy encompasses several distinct pathways that have been linked to B cell homeostasis and function. While B cell presentation of major histocompatibility complex (MHC) class II-restricted cytosolic antigens to T cells involves both macroautophagy and chaperone-mediated autophagy (CMA), plasma cells and memory B cells mainly rely on macroautophagy for their survival. Emerging evidence indicates that core autophagy factors also participate in processes related to yet clearly distinct from classical autophagy. These autophagy-related pathways, referred to as noncanonical autophagy or conjugation of ATG8 to single membranes (CASM), contribute to B cell homeostasis and functions, including MHC class II-restricted antigen presentation to T cells, germinal center formation, plasma cell differentiation, and recall responses. Dysregulation of B cell autophagy has been identified in several autoimmune and autoinflammatory diseases such as systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel disease. In this review, we discuss recent advances in understanding the role of canonical and noncanonical autophagy in B cells, including B cell development and maturation, antigen processing and presentation, pathogen-specific antibody responses, cytokine secretion, and autoimmunity. Unraveling the molecular mechanisms of canonical and noncanonical autophagy in B cells will improve our understanding of B cell biology, with implications for the development of autophagy-based immunotherapies. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a chronic autoimmune condition that can affect multiple organ systems and is heterogenous in its presentation and response to therapy. When diagnosed in childhood, SLE is associated with increased morbidity and mortality compared to adult SLE, often requiring substantial immunosuppression with the risk of significant side effects. There remains a significant unmet need for new therapies that can improve disease control and reduce glucocorticoid and other toxic medication exposure for patients with severe or refractory disease. The pathogenesis of SLE involves B cell dysregulation and autoantibody production, which are a hallmark of the disease. Currently approved B cell directed therapies often result in incomplete B cell depletion and may not target long-lived plasma cells responsible for SLE autoantibodies. It is hypothesized that by persistently eliminating both B cells and plasmablasts, CAR T therapy can halt autoimmunity and prevent organ damage in patient's refractory to current B cell-depleting treatments. Herein we summarize the current preclinical and clinical data utilizing CAR T cells for SLE and discuss the future of this treatment modality for lupus. [ABSTRACT FROM AUTHOR]

Diseases in which cutaneous plasma cell infiltrates predominate are rare and usually of unknown etiology, including those that transition from benign to malignant, such as cutaneous plasmacytosis, multicentric Castleman disease, and extramedullary plasmacytoma. These diseases may present as purplish, reddish‐brown cutaneous plaques or nodules. Here, we report an exceptional case of lichen planus (LP) in which the patient had classic histopathological features, but the infiltrating inflammatory cells were plasma cells with restricted light chain expression. The patient presented with severe rashes, including purplish‐red plaques and nodules, erythema, and erosions in the palmoplantar area, verrucous hyperplasia of the oral mucosa, and anonychia of the toes. These findings suggest a possible role of plasma cells with restricted light chain expression in the LP. Clinicians should closely follow patients for changes in their rash, perform repeat biopsies if necessary, and regularly conduct multisystemic evaluations. [ABSTRACT FROM AUTHOR]

Multiple myeloma is a hematological malignancy arising from immunoglobulin-secreting plasma cells. It remains poorly understood how chromatin rewiring of regulatory elements contributes to tumorigenesis and therapy resistance in myeloma. Here we generate a high-resolution contact map of myeloma-associated super-enhancers by integrating H3K27ac ChIP-seq and HiChIP from myeloma cell lines, patient-derived myeloma cells and normal plasma cells. Our comprehensive transcriptomic and phenomic analyses prioritize candidate genes with biological and clinical implications in myeloma. We show that myeloma cells frequently acquire SE that transcriptionally activate an oncogene PPP1R15B, which encodes a regulatory subunit of the holophosphatase complex that dephosphorylates translation initiation factor eIF2α. Epigenetic silencing or knockdown of PPP1R15B activates pro-apoptotic eIF2α-ATF4-CHOP pathway, while inhibiting protein synthesis and immunoglobulin production. Pharmacological inhibition of PPP1R15B using Raphin1 potentiates the anti-myeloma effect of bortezomib. Our study reveals that myeloma cells are vulnerable to perturbation of PPP1R15B-dependent protein homeostasis, highlighting a promising therapeutic strategy. The role of chromatin rewiring of regulatory elements in multiple myeloma (MM) remains poorly understood. Here, the authors identify a super-enhancer driven gene, PPP1R15B whose perturbation confers vulnerability in MM cells and suggest it as a therapeutic target. [ABSTRACT FROM AUTHOR]

Eosinophilic angiocentric fibrosis (EAF) is a rare, benign fibroinflammatory condition primarily affecting the sinonasal and upper respiratory tract, with a few cases reported beyond these regions. Primary intracranial EAF is rare. To date, only one case of intracranial EAF has been reported; ours is the second. This case report presents a case of EAF in a 55‐year‐old man, initially misdiagnosed as meningioma based on clinical and radiological features. The patient complained of a persistent dull headache for six months without associated neurological symptoms. Brain magnetic resonance imaging revealed a dural‐based lesion with characteristics suggestive of meningioma. However, histopathological examination post‐surgical resection revealed a nodular vascular lesion with concentric angiocentric fibrosis, a distinctive onion skin pattern, and an inflammatory infiltrate rich in eosinophils, plasma cells, and histiocytes. Immunohistochemistry ruled out IgG4‐related disease, and other systemic disorders were ruled out based on combined clinical and histological features. This case underscores the need for considering EAF in the differential diagnosis of dural‐based lesions. Awareness of its potential mimicking of meningioma is crucial for accurate diagnosis and appropriate management, emphasizing the importance of histopathological examination in challenging cases. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a hematologic malignancy characterized by abnormal plasma cell proliferation in the bone marrow. Recent advancements in anti-CD38 monoclonal antibody therapies, such as daratumumab and isatuximab, have significantly improved MM patient survival. However, the lack of predictive factors of response to these therapies remains a challenge. Notably, anti-CD38 antibodies can interfere with laboratory tests, complicating response assessment. We conducted a retrospective study to evaluate the association between the appearance of positive IgGk (therapeutic antibody) on immunofixation/immunosubtraction (IF) and clinical parameters in 87 non-IgGk MM patients treated with anti-CD38 therapy. Positive IgGk IF was observed in 42 patients after a median of three treatment courses. Patients with positive IgGk IF had higher rates of complete/very good partial responses (p = 0.03) and improved progression-free survival (median not reached vs. 21.83 months, p < 0.01). High BMI (p = 0.03), higher hemoglobin (p = 0.02), lower CRP (p = 0.04), and lower monoclonal protein levels (p = 0.03) were associated with positive IgGk IF. Our findings suggest that monitoring therapeutic antibody appearance on IF may predict and optimize anti-CD38 therapy in MM. Potential explanations include the impact of patient factors (e.g. BMI) on drug pharmacokinetics, the relationship between antibody levels and immune response, and the influence of tumor biology. Further research is needed to elucidate the underlying mechanisms and clinical utility of this biomarker. Nonetheless, our results highlight the importance of considering therapeutic antibody detection when interpreting laboratory tests and managing MM patients receiving anti-CD38 therapies. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is an incurable malignancy of plasma cells. Epidemiological studies indicate a substantial heritable component, but the underlying mechanisms remain unclear. Here, in a genome-wide association study totaling 10,906 cases and 366,221 controls, we identify 35 MM risk loci, 12 of which are novel. Through functional fine-mapping and Mendelian randomization, we uncover two causal mechanisms for inherited MM risk: longer telomeres; and elevated levels of B-cell maturation antigen (BCMA) and interleukin-5 receptor alpha (IL5RA) in plasma. The largest increase in BCMA and IL5RA levels is mediated by the risk variant rs34562254-A at TNFRSF13B. While individuals with loss-of-function variants in TNFRSF13B develop B-cell immunodeficiency, rs34562254-A exerts a gain-of-function effect, increasing MM risk through amplified B-cell responses. Our results represent an analysis of genetic MM predisposition, highlighting causal mechanisms contributing to MM development. Multiple myeloma (MM) is an incurable blood malignancy. Here, the authors report 35 MM risk loci and two causal mechanisms for genetic MM risk: longer telomeres and elevated plasma B-cell maturation antigen (BCMA) and interleukin−5 receptor alpha (IL5RA) levels. [ABSTRACT FROM AUTHOR]

In the earliest days, the idea that surviving a single infection often resulted in lifelong immunity to the infecting pathogen was recorded and then led to the discovery of vaccination. We have now confirmed that such protection is primarily based on the generation of immunological memory in antibody response. With the wide implementation of more and more vaccines around the world, it is well documented that different vaccines have different potential regarding to the duration of antibody response. In clinical observations, live-attenuated vaccines often elicit long-term immunity but are also accompanied with risks in safety that are hard to avoid. In order to develop novel vaccines with both excellent potential in eliciting antibody memory and low safety risk, it is critical to further investigate the mechanism of antibody memory in the perspective of immunology. Antibody memory is mediated by certain longlived B cells: long-lived plasma cell can secret antibody to maintain serum antibody titer while memory B cell contributes to the rapid immune response during the secondary encounter of pathogens. Cellular and molecular processes that drive the production of long-lived plasma cells and memory B cells are subjects of intensive research and have important implications for global health. Several factors in the vaccine would indeed affect and regulate these processes, including the antigen valency, vaccine kinetics and the signal integration of both antigen and danger molecules. Many studies have focused on strategies to manipulate these factors to improve or develop new vaccines. Here, we will summarize our current knowledge on how the component in vaccines will affect their potential in generating and sustaining antibody memory, and also point out the challenges we face in the route of developing a "perfect" vaccine. [ABSTRACT FROM AUTHOR]

Summary: Multiple myeloma (MM) is an incurable plasma cell cancer in the bone marrow. Immunomodulatory drugs, such as lenalidomide (LEN) and pomalidomide, are backbone agents in MM treatment, and LEN resistance is commonly seen in the MM clinic. In this study, we presented that heterogeneous nuclear ribonucleoprotein U (hnRNPU) affected MM resistance to LEN via the regulation of target mRNA translation. hnRNPULow MM cells exhibited upregulated CRBN and IKZF1 proteins, stringent IKZF1/3 protein degradation upon LEN addition and increased sensitivity to LEN. RNA pulldown assays and RNA electrophoretic mobility shift assays revealed that hnRNPU bound to the 3′‐untranslated region of CRBN and IKZF1 mRNA. A sucrose gradient assay suggested that hnRNPU specifically regulated CRBN and IKZF1 mRNA translation. The competition of hnRNPU binding to its target mRNAs by small RNAs with hnRNPU‐binding sites restored MM sensitivity to LEN. hnRNPU function in vivo was confirmed in an immunocompetent MM mouse model constructed by the inoculation of Crbn‐humanized murine 5TGM1 cells into CrbnI391V/+ mice. Overall, this study suggests a novel mechanism of LEN sensitivity in which hnRNPU represses CRBN and IKZF1 mRNA translation. [ABSTRACT FROM AUTHOR]

Purpose: Melanoma is widely utilized as a prominent model for the development of immunotherapy, thought an inadequate immune response can occur. Moreover, the development of apoptosis-related therapies and combinations with other therapeutic strategies is impeded by the limited understanding of apoptosis's role within diverse tumor immune microenvironments (TMEs). Methods: Here, we constructed an apoptosis-related tumor microenvironment signature (ATM) and employ multi-dimensional analysis to understand the roles of apoptosis in tumor microenvironment. We further assessed the clinical applications of ATM in nine independent cohorts, and anticipated the impact of ATM on cellular drug response in cultured cells. Results: Our ATM model exhibits robust performance in survival prediction in multiple melanoma cohorts. Different ATM groups exhibited distinct molecular signatures and biological processes. The low ATM group exhibited significant enrichment in B cell activation-related pathways. What's more, plasma cells showed the lowest ATM score, highlighting their role as pivotal contributors in the ATM model. Mechanistically, the analysis of the interplay between plasma cells and other immune cells elucidated their crucial role in orchestrating an effective anti-tumor immune response. Significantly, the ATM signature exhibited associations with therapeutic efficacy of immune checkpoint blockade and the drug sensitivity of various agents, including FDA-approved and clinically utilized drugs targeting the VEGF signaling pathway. Finally, ATM was associated with tertiary lymphoid structures (TLS), exhibiting stronger patient stratification ability compared to classical "hot tumors". Conclusion: Our findings indicate that ATM is a prognostic factor and is associated with the immune response and drug sensitivity in melanoma. [ABSTRACT FROM AUTHOR]

Lichen myxedematosus (LM) is a chronic cutaneous mucinosis that can present as a localized skin lesion or as a generalized systemic disease termed scleromyxedema. The differential diagnosis is determined by a combination of clinical presentation, serological studies, and histopathological examination. Currently, well‐established and accepted histopathological features to distinguish localized LM from scleromyxedema have not been elucidated. Our recent publication, together with a retrospective literature review, suggests that the presence of groups of light chain‐restricted plasma cells represents a distinct histopathological clue for the diagnosis of localized LM. In this report, we provide two additional cases of localized LM with lambda light chain‐restricted plasma cells, together with clinical and histopathological findings that are similar to our previous publication. These cases support our theory that the light chain‐restricted plasmacytic microenvironment is primarily attributed to the pathogenesis of localized LM. Therefore, we consider these cases to constitute a clinically and pathologically new variant of localized LM and name it primary localized cutaneous LM with light chain‐restricted plasma cells. [ABSTRACT FROM AUTHOR]

The term "idiopathic lymphoplasmacellular mucositis" (ILPM) refers to a set of conditions marked by extensive lymphocyte and plasma cell infiltrates in the submucosa which can involve the oral cavity, upper respiratory tract and the genital epithelium. There is no recognized cause of ILPM, and the diagnosis is mostly done on an exclusion basis. Herein, we report a 32-year-old man presented with an erosive ulcerated lesion on the hard palate and review the literature regarding the possible differential diagnosis including squamous cell carcinoma. We also reviewed the previously reported cases of ILPM with palatal involvement to summarise clinical presentation, treatment, and outcome of the entity to date. [ABSTRACT FROM AUTHOR]

This letter to the editor discusses the potential use of venetoclax, a BCL-2 inhibitor, as a treatment option for primary plasma cell leukemia (PCL) with high BCL-2 expression. PCL is a rare and aggressive form of plasma cell dyscrasias, and current treatments have limited success. The letter presents a case study of a patient who achieved a durable, complete response to venetoclax-based therapy without a stem cell transplant. The letter suggests that venetoclax may be a promising alternative for PCL patients who cannot undergo or choose not to have a stem cell transplant. The effectiveness of venetoclax in patients with t(11;14) was also studied, showing increased progression-free survival compared to standard treatment. However, further research is needed to confirm these findings. [Extracted from the article]

Background: Antibody‐mediated rejection is one of the most significant risk factors for allograft dysfunction and failure in children and adolescents with kidney transplants, yet optimal treatment remains unidentified. To date, there are mixed findings regarding the use of Bortezomib, a plasma cell apoptosis inducer, as an adjunct therapy in the treatment of antibody‐mediated rejection. Methods: In a retrospective single center study, we reviewed the efficacy and tolerability of bortezomib as adjunct therapy for treatment‐refractory antibody‐mediated rejection. Results: Six patients with a median age of 14.6 years (range 6.9–20.1 years) received bortezomib at a mean of 71 months (range 15–83 months) post‐kidney transplant. Four patients experienced decline in estimated glomerular filtration rate (eGFR) from 4% to 42%. One patient started bortezomib while on hemodialysis and did not recover graft function, and another patient progressed to hemodialysis 6 months after receiving bortezomib. Although DSA did not completely resolve, there was a statistically significant decline in DSA MFI pre and 12‐months post‐BZ (p =.012, paired t‐test) for the subjects who were not on dialysis at the time of bortezomib. Chronic Allograft Damage Index (CADI) score of ≥3 was seen in all six subjects at their biopsy prior to therapy. No adverse effects were reported. Conclusions: Bortezomib was well tolerated and resulted in improvements in MFI of DSA among four pediatric subjects without allograft failure, although no effects were observed on eGFR trajectory. Further studies are needed to clarify whether earlier intervention with bortezomib could prevent renal failure progression. [ABSTRACT FROM AUTHOR]

Background: Anti‐IgE immunotherapy with monoclonal antibodies represents a breakthrough in treatment of severe allergic diseases. However, drawbacks such as short half‐life and high price are not negligible. Our objective is to develop an anti‐IgE vaccine based on virus‐like particles (VLPs) which can induce long‐lasting neutralizing IgG anti‐IgE antibodies reducing allergic responses without causing intrinsic mast cell activation due to IgE cross‐linking. Methods: The vaccines were made by chemically coupling three synthetic mouse IgE‐Fc fragments to plant‐derived immunologically optimized CuMVTT VLPs. The immunogenicity of the vaccines was tested by immunizing naive or allergic mice either with the coupled vaccines or the VLP control followed by systemic or local allergen challenge. Results: Mice immunized with the vaccines exhibited high titers of anti‐IgE antibodies in the sera and high levels of anti‐IgE secreting plasma cells in lymphoid organs. Moreover, free IgE in serum were reduced by the induced anti‐IgE antibodies; therefore, less IgE was bound to FcεRI on the surface of basophils. In line with these reduced IgE levels on effector cells after vaccination, immunized mice were protected from challenge with allergens. Importantly, despite presence of anti‐IgE antibodies, no signs of acute or chronic allergic response were seen in immunized allergic mice. Conclusion: The generated vaccines can effectively induce anti‐IgE antibodies that did not cause allergic responses in sensitized mice but were able to decrease the level of free and cell bound IgE and protected sensitized animals from allergic responses upon allergen challenge. [ABSTRACT FROM AUTHOR]

This article discusses a case study of a patient with a rare condition called Russell body oral mucositis. Russell bodies are abnormal collections of immunoglobulins within plasma cells, and they can be seen in various chronic inflammatory conditions and autoimmune diseases. The patient in this case study had a large ulcerative lesion on the tongue, which was diagnosed as Mott cell-rich lymphoplasmacytic infiltrate. The lesion healed completely after 2 months of follow-up. The article also mentions similar cases of Russell body formation in the gastrointestinal tract and emphasizes the importance of recognizing this condition due to its prognostic impact. [Extracted from the article]