PNMA2 forms immunogenic non-enveloped virus-like capsids associated with paraneoplastic neurological syndrome.

The paraneoplastic Ma antigen (PNMA) proteins are associated with cancer-induced paraneoplastic syndromes that present with an autoimmune response and neurological symptoms. Why PNMA proteins are associated with this severe autoimmune disease is unclear. PNMA genes are predominantly expressed in the central nervous system and are ectopically expressed in some tumors. We show that PNMA2, which has been co-opted from a Ty3 retrotransposon, encodes a protein that is released from cells as non-enveloped virus-like capsids. Recombinant PNMA2 capsids injected into mice induce autoantibodies that preferentially bind external "spike" PNMA2 capsid epitopes, whereas a capsid-assembly-defective PNMA2 protein is not immunogenic. PNMA2 autoantibodies in cerebrospinal fluid of patients with anti-Ma2 paraneoplastic disease show similar preferential binding to spike capsid epitopes. PNMA2 capsid-injected mice develop learning and memory deficits. These observations suggest that PNMA2 capsids act as an extracellular antigen, capable of generating an autoimmune response that results in neurological deficits.

Hypercalcemia and cancer: Differential diagnosis and treatment.

Incidentally detected hypercalcemia usually presents in an indolent manner and is most likely caused by primary hyperparathyroidism. In contrast, hypercalcemia in the patient with a history of cancer presents in a wide range of clinical settings and may be severe enough to warrant hospitalization. This form of hypercalcemia is usually secondary to hypercalcemia of malignancy and can be fatal. Hypercalcemia of malignancy is most commonly mediated by tumoral production of parathyroid hormone-related protein or by cytokines activating osteoclast degradation of bone. The initial workup, differential diagnoses, confirmatory laboratory testing, imaging, and medical and surgical management of hypercalcemia are described in the patient with cancer.

General features, pathogenesis, and laboratory diagnostics of autoimmune encephalitis.

Autoimmune encephalitis (AE) is a group of inflammatory conditions that can associate with the presence of antibodies directed to neuronal intracellular, or cell surface antigens. These disorders are increasingly recognized as an important differential diagnosis of infectious encephalitis and of other common neuropsychiatric conditions. Autoantibody diagnostics plays a pivotal role for accurate diagnosis of AE, which is of utmost importance for the prompt recognition and early treatment. Several AE subgroups can be identified, either according to the prominent clinical phenotype, presence of a concomitant tumor, or type of neuronal autoantibody, and recent diagnostic criteria have provided important insights into AE classification. Antibodies to neuronal intracellular antigens typically associate with paraneoplastic neurological syndromes and poor prognosis, whereas antibodies to synaptic/neuronal cell surface antigens characterize many AE subtypes that associate with tumors less frequently, and that are often immunotherapy-responsive. In addition to the general features of AE, we review current knowledge on the pathogenic mechanisms underlying these disorders, focusing mainly on the potential role of neuronal antibodies in the most frequent conditions, and highlight current theories and controversies. Then, we dissect the crucial aspects of the laboratory diagnostics of neuronal antibodies, which represents an actual challenge for both pathologists and neurologists. Indeed, this diagnostics entails technical difficulties, along with particularly interesting novel features and pitfalls. The novelties especially apply to the wide range of assays used, including specific tissue-based and cell-based assays. These assays can be developed in-house, usually in specialized laboratories, or are commercially available. They are widely used in clinical immunology and in clinical chemistry laboratories, with relevant differences in analytic performance. Indeed, several data indicate that in-house assays could perform better than commercial kits, notwithstanding that the former are based on non-standardized protocols. Moreover, they need expertise and laboratory facilities usually unavailable in clinical chemistry laboratories. Together with the data of the literature, we critically evaluate the analytical performance of the in-house vs commercial kit-based approach. Finally, we propose an algorithm aimed at integrating the present strategies of the laboratory diagnostics in AE for the best clinical management of patients with these disorders.

Increased prevalence of malignancies in patients with IgG4-related disease: implications for clinical care.

OBJECTIVES: The association between cancer and IgG4-related disease (IgG4-RD) is evolving. The primary aim of this study was to investigate the prevalence of malignancies in IgG4-RD. The secondary aim was to describe the epidemiological and clinical characteristics of IgG4-RD patients with a history of cancer. METHODS: Two hundred and ten patients with IgG4-RD were included in this retrospective study. IgG4-RD phenotypes, clinical and serological variables were analyzed. The prevalence of cancer in IgG4-RD was compared with that in the Italian population using the registry of the Global Cancer Observatory (GCO) of the World Health Organization. The Standardized Incidence Ratio (SIR) for cancer in IgG4-RD was obtained based on the 5-years Limited Duration Prevalence (2015-2020) of tumors in the Italian population. RESULTS: Thirty-seven/210 patients (18%) developed cancer before or after the diagnosis of IgG4-RD. Solid and hematologic tumors were more frequently observed in pancreato-biliary IgG4-RD. The SIR for malignancy in IgG4-RD patients was 2.54 higher than the general Italian population (p= 0.007). The SIR was 2.78 higher for males (p= 0.005) and 1.15 higher for females (p> 0.05). Thirty-two malignancies were diagnosed before and 16 after IgG4-RD diagnosis. Interval "from IgG4-RD to cancer" was shorter than that "from cancer to IgG4-RD". Most tumors occurring after IgG4-RD developed within 36 months from diagnosis of IgG4-RD. CONCLUSIONS: The prevalence of cancer in patients with IgG4-RD is increased compared with the Italian population and mechanistically suggests a possible paraneoplastic association. Close surveillance is warranted for the first 36 months after IgG4-RD diagnosis.

Multi-omics profiling reveals dysregulated ribosome biogenesis and impaired cell proliferation following knockout of CDR2L.

BACKGROUND: Cerebellar degeneration-related (CDR) proteins are associated with paraneoplastic cerebellar degeneration (PCD) - a rare, neurodegenerative disease caused by tumour-induced autoimmunity against neural antigens resulting in degeneration of Purkinje neurons in the cerebellum. The pathogenesis of PCD is unknown, in large part due to our limited understanding of the functions of CDR proteins. To this end, we performed an extensive, multi-omics analysis of CDR-knockout cells focusing on the CDR2L protein, to gain a deeper understanding of the properties of the CDR proteins in ovarian cancer. METHODS: Ovarian cancer cell lines lacking either CDR1, CDR2, or CDR2L were analysed using RNA sequencing and mass spectrometry-based proteomics to assess changes to the transcriptome, proteome and secretome in the absence of these proteins. RESULTS: For each knockout cell line, we identified sets of differentially expressed genes and proteins. CDR2L-knockout cells displayed a distinct expression profile compared to CDR1- and CDR2-knockout cells. Knockout of CDR2L caused dysregulation of genes involved in ribosome biogenesis, protein translation, and cell cycle progression, ultimately causing impaired cell proliferation in vitro. Several of these genes showed a concurrent upregulation at the transcript level and downregulation at the protein level. CONCLUSIONS: Our study provides the first integrative multi-omics analysis of the impact of knockout of the CDR genes, providing both new insights into the biological properties of the CDR proteins in ovarian cancer, and a valuable resource for future investigations into the CDR proteins.

A Pilot Study to Develop Paraneoplastic Cerebellar Degeneration Mouse Model.

Modeling paraneoplastic neurological diseases to understand the immune mechanisms leading to neuronal death is a major challenge given the rarity and terminal access of patients' autopsies. Here, we present a pilot study aiming at modeling paraneoplastic cerebellar degeneration with Yo autoantibodies (Yo-PCD). Female mice were implanted with an ovarian carcinoma cell line expressing CDR2 and CDR2L, the known antigens recognized by anti-Yo antibodies. To boost the immune response, we also immunized the mice by injecting antigens with diverse adjuvants and immune checkpoint inhibitors. Ataxia and gait instability were assessed in treated mice as well as autoantibody levels, Purkinje cell density, and immune infiltration in the cerebellum. We observed the production of anti-Yo antibodies in the CSF and serum of all immunized mice. Brain immunoreaction varied depending on the site of implantation of the tumor, with subcutaneous administration leading to a massive infiltration of immune cells in the meningeal spaces, choroid plexus, and cerebellar parenchyma. However, we did not observe massive Purkinje cell death nor any motor impairments in any of the experimental groups. Self-sustained neuro-inflammation might require a longer time to build up in our model. Unusual tumor antigen presentation and/or intrinsic, species-specific factors required for pro-inflammatory engagement in the brain may also constitute strong limitations to achieve massive recruitment of antigen-specific T-cells and killing of antigen-expressing neurons in this mouse model.

Immune Checkpoint Inhibitor-Related Cerebellar Toxicity: Clinical Features and Comparison with Paraneoplastic Cerebellar Ataxia.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, and the association with immune-related adverse events (irAEs) is well-established. However, cerebellar irAEs are poorly defined and their relationship with paraneoplastic disorders remains unclear. Our aim was (i) to characterize cerebellar irAE; (ii) to compare it with paraneoplastic cerebellar ataxia (PCA). We performed a multicenter, retrospective, cohort study of patients developing new-onset, immune-mediated, isolated/predominant cerebellar dysfunction after ICI administration. In addition, a systematic review following PRISMA guidelines was performed. Cerebellar irAE cases were compared with a consecutive cohort of patients with PCA. Overall, 35 patients were included, of whom 12 were original cases (males: 25/35 (71%), median age: 65 [range: 20-82]). The most frequent tumor was non-small cell lung cancer (12/35, 34%). Anti-PD1 were adopted in 19/35 (54%). Symptoms developed at a median of 11 weeks after ICI onset. Neuronal antibodies were detected in 15/31 patients tested (48%). Cerebrospinal fluid was inflammatory in 25/30 (83%). Magnetic resonance imaging showed cerebellar hyperintensities in 8/35 (23%). Immunotherapy was applied in 33/35 cases (94%), and most patients improved with residual disability (16/35, 46%). When compared with a series of PCA (n = 15), the cerebellar irAE group was significantly more associated with male sex, lung cancer (rather than gynecological/breast cancers), isolated ataxia, and a better outcome. We provide a detailed characterization of cerebellar irAE. Compared to PCA, differences exist in terms of tumor association, clinical features, and outcome. Clinical presentation-antibody-tumor triad in the ICI group only partially reflects the associations described in paraneoplastic disorders.

Paraneoplastic syndromes associated with classic Hodgkin lymphoma, a systematic literature review.

PNS are uncommon manifestations of cancer. The current literature about these syndromes in the setting of cHL is disintegrated. A systematic literature review of all published literature was conducted. One hundred twenty-eight patients from 115 publications met the inclusion/exclusion criteria. Eight-five patients were of the NS subtype (66.4%). The most frequent clinical presentation of the PNS was CNS manifestation (25.8%). The majority of patients were diagnosed with the cHL and PNS simultaneously (42.2%). In 33.6% of patients, the lymphoma diagnosis preceded the PNS diagnosis. In 16.4% of patients, the PNS diagnosis preceded the lymphoma diagnosis. The presence of PNS antibodies was reported in 35 patients (27.3%). Age older than 18 was associated with higher prevalence of PNS. The CR rate of the lymphoma was 77.3%. The complete resolution rate of the PNS was 54.7%. Relapse of lymphoma was reported in 13 patients, and recurrence of the PNS upon relapse was reported in 10/13 patients.

Neurological autoimmunity in patients with non-pulmonary neuroendocrine neoplasms: clinical manifestations and neural autoantibody profiles.

BACKGROUND AND PURPOSE: Paraneoplastic neurological autoimmunity is well described with small-cell lung cancer, but information is limited for other neuroendocrine neoplasms (NENs). METHODS: Adult patients with histopathologically confirmed non-pulmonary NENs, neurological autoimmunity within 5 years of NEN diagnosis, and neural antibody testing performed at the Mayo Clinic Neuroimmunology Laboratory (January 2008 to March 2023) were retrospectively identified. Control sera were available from patients with NENs without neurological autoimmunity (116). RESULTS: Thirty-four patients were identified (median age 68 years, range 31-87). The most common primary tumor sites were pancreas (nine), skin (Merkel cell, eight), small bowel/duodenum (seven), and unknown (seven). Five patients received immune checkpoint inhibitor (ICI) therapy before symptom onset; symptoms preceded cancer diagnosis in 62.1% of non-ICI-treated patients. The most frequent neurological phenotypes (non-ICI-treated) were movement disorders (12; cerebellar ataxia in 10), dysautonomia (six), peripheral neuropathy (eight), encephalitis (four), and neuromuscular junction disorders (four). Neural antibodies were detected in 55.9% of patients studied (most common specificities: P/Q-type voltage-gated calcium channel [seven], muscle-type acetylcholine receptor [three], anti-neuronal nuclear antibody type 1 [three], and neuronal intermediate filaments [two]), but in only 6.9% of controls. Amongst patients receiving cancer or immunosuppressive therapy, 51.6% had partial or complete recovery. Outcomes were unfavorable in 48.3% (non-ICI-treated) and neural autoantibody positivity was associated with poor neurological outcome. DISCUSSION: Neurological autoimmunity associated with non-pulmonary NENs is often multifocal and can be treatment responsive, underscoring the importance of rapid recognition and early treatment.

Research progress of malignant peritoneal mesothelioma with paraneoplastic syndrome: A review.

Malignant peritoneal mesothelioma (MPM) is a rare and invasive tumor, and some patients will develop paraneoplastic syndrome (PS) during the course of the disease. This review summarizes PS associated with MPM, focusing on the clinical characteristics and treatment progress in hematological, endocrine, rheumatic, neurological, urinary, and other systems to decrease missed diagnosis and misdiagnosis, help early diagnosis and prompt treatment, and provide guidance for the clinical decision-making of this kind of patients.

Anti-metabolic glutamate receptor 5 encephalitis with gangliocytoma: a case and review of the literature.

BACKGROUND: There are very limited reports on anti-metabolic glutamate receptor5 (mGluR5) encephalitis, especially lacking of pediatric research. The disease was mostly accompanied by tumors, mainly Hodgkin's lymphoma. No reports of other tumors, such as gangliocytoma have been reported to associate with anti-mGluR5 encephalitis so far. CASE PRESENTATION AND LITERATURE REVIEWS: We reported a case of a 12-year-old boy with anti-mGluR5 encephalitis complicated with gangliocytoma. The patient suffered from mental disorders including auditory hallucination, and sleep disorders. His cranial magnetic resonance imaging (MRI) showed an abnormality in the right insular lobe. Autoimmune encephalitis antibodies testing was positive for mGluR5 IgG antibody both in cerebrospinal fluid and serum (1:3.2, 1:100 respectively). Abdominal CT indicated a mass in left retroperitoneal confirmed with gangliocytoma via pathology. The patient underwent resection of gangliocytoma. After first-line immunotherapy (glucocorticoid, gamma globulin), his condition was improved. Furthermore, we provide a summary of 6 pediatric cases of Anti-mGluR5 encephalitis. Most of them complicated with Hodgkin's lymphoma, except the case currently reported comorbid with gangliocytoma. The curative effect is satisfactory. CONCLUSIONS: We report the first patient with anti-mGlur5 encephalitis complicated with gangliocytoma. It suggests that in addition to paying attention to the common lymphoma associated with anti-mGlur5 encephalitis, we should also screen the possibility of other tumors for early detection of the cause, active treatment and prevention of recurrence.

Paraneoplastic Syndrome After Kidney Transplantation: Frequency, Risk Factors, Differences to Paraneoplastic Occurrence of Glomerulonephritis in the Native Kidney, and Implications on Long-Term Kidney Graft Function.

Posttransplant malignancies are an important complication of solid organ transplantation. Kidney transplant recipients are at particularly high risk of cancer development. The most relevant risk factors of carcinogenesis are the use of immunosuppressive agents and oncogenic viral infections. Additionally, immune dysregulation caused by these factors may predispose to various types of organ damage. Paraneoplastic glomerular diseases are one of the most interesting and understudied cancer manifestations. The appropriate diagnosis of paraneoplastic glomerular damage can be challenging in kidney transplant recipients, due to factors inherent to concomitant medication and common comorbidities. Recent advances in the field of molecular and clinical nephrology led to a significant improvement in our understanding of glomerular diseases and their more targeted treatment. On the other hand, introduction of novel anticancer drugs tremendously increased patients' survival, at the cost of kidney-related side effects. Our review aims to provide insights into diagnosis and treatment of paraneoplastic glomerular diseases, with a special attention to kidney transplant recipients.

Management of Paraneoplastic Syndromes in the Era of Immune Checkpoint Inhibitors.

OPINION STATEMENT: Our understanding of paraneoplastic neurologic syndromes (PNS) has blossomed over the past few decades. Clinicians have access to more robust diagnostic criteria and have a heightened index of suspicion for these disorders. Nonetheless, treatment, which typically includes immunosuppression, and response to treatment, varies. Due to persistent difficulty in making a definitive diagnosis, we favor empiric treatment when a possible diagnosis of PNS is suspected, and other alternative causes have substantially been excluded (e.g., infections, toxic-metabolic derangements, metastasis, or leptomeningeal disease). Treatment of the underlying cancer, if identified, is the first therapeutic step and can prevent disease worsening and in rare cases, can reverse neurologic symptoms. In addition to anti-cancer treatment, first line immunotherapies, which include corticosteroids, intravenous immunoglobulins (IVIG), or plasma exchange (PLEX) are typically used. If partial or no benefit is seen, second line immunotherapeutic agents such as rituximab are considered. Additionally, the severity of the initial presentation and possible risk for relapse influences the use of the latter agents. Symptomatic management is also an important component in our practice and will depend on the syndrome being treated. One of the more novel entities we are facing currently is the management of immune checkpoint (ICI)-induced PNS. In those cases, current American Society of Clinical Oncology (ASCO) guidelines are followed.

Predictive factors of nivolumab plus ipilimumab treatment efficacy in metastatic renal cell carcinoma patients.

OBJECTIVE: Nivolumab plus ipilimumab is a recommended first-line therapy regimen for metastatic renal cell carcinoma. However, it is not clear which patient characteristics are associated with its effectiveness. METHODS: We retrospectively examined 67 metastatic renal cell carcinoma patients treated with nivolumab plus ipilimumab as a first-line therapy in multiple institutions from September 2018 to August 2022. We analyzed the relationships between survival outcomes and patient-related variables, including paraneoplastic symptoms. We also analyzed the relationships between changes in symptoms and parameters and outcomes. RESULTS: Of the 67 patients, 32 patients had paraneoplastic symptoms. The median progression-free survival was 14.9 months and median overall survival was 43.3 months. The objective response rate was 49.25% (33 patients), including two patients with complete response. Patients with cytoreductive nephrectomy, bone metastasis, high C-reactive protein levels and paraneoplastic symptoms were significantly correlated with short progression-free survival in the univariate analysis. Multivariate analysis of these factors showed that the presence of paraneoplastic symptoms at treatment initiation remained an independent predictor of progression-free survival. Of the 32 patients with paraneoplastic symptoms at treatment initiation, 12 patients had symptomatic improvement and 20 did not. The 1-year progression-free survival rates were significantly longer in improved patients compared with those with no improvement. CONCLUSIONS: Patients without cytoreductive nephrectomy and with bone metastasis, liver metastasis, high C-reactive protein levels and paraneoplastic symptoms were significantly correlated with shorter progression-free survival. The presence of paraneoplastic symptoms was an independent predictor of progression-free survival. Improvement in paraneoplastic symptoms may reflect the treatment efficacy of nivolumab plus ipilimumab.

Neuroendocrine neoplasms of the ovary: a review of 63 cases.

OBJECTIVE: To describe the clinicopathological characteristics and survival outcomes of ovarian neuroendocrine neoplasms from a curated registry. METHODS: This is a retrospective cross-sectional study of patients in our registry with confirmed ovarian neuroendocrine neoplasms. We excluded patients with small cell carcinoma not otherwise specified, small cell hypercalcemic type, and those with neuroendocrine 'features' or 'differentiation.' Clinicopathological characteristics were described in two separate groups: patients with carcinoid tumors and patients with neuroendocrine carcinomas. Progression-free and overall survival were estimated with the Kaplan-Meier product-limit estimator in these two groups, and multivariable analysis was done to identify predictors of survival for neuroendocrine carcinomas only. RESULTS: A total of 63 patients met inclusion criteria, 13 (21%) with carcinoid tumors and 50 (79%) with neuroendocrine carcinomas. In the carcinoid tumor group, one patient (8%) was misdiagnosed. Two patients (15%) had a recurrence and the 5-year overall survival rate was 80% (95% CI 45% to 100%), with a lower bound of the median survival of 4.8 years (95% CI). In the neuroendocrine carcinoma group, 23 patients (46%) were misdiagnosed, 16 of whom (69%) received therapy with the presumption of a non-neuroendocrine carcinoma diagnosis. Thirty patients (60%) had a recurrence, and the 5-year overall survival rate was 24% (10%, 38%), with a median survival of 1.6 years (1.3, 3.3). Patients with carcinomas stage III or IV had an increased risk of progression/recurrence (HR=5.6; 95% CI 1.9 to 17.0) and death (HR=8.1; 95% CI 2.2 to 29.7) compared with those with stage I or II. Pure histology was associated with an increased risk of progression/recurrence (HR=2.3; 95% CI 1.0 to 5.2) compared with admixed histology. CONCLUSION: Most patients had neuroendocrine carcinomas, which were associated with a higher recurrence rate and worse survival than carcinoid tumors. A high proportion of patients in both groups were initially misdiagnosed, and a new association with endometrial hyperplasia was observed. Neuroendocrine admixed histology is associated with a higher risk of progression.

Autoimmune retinopathy in a patient with smoldering multiple myeloma: a case report.

PURPOSE: Multiple myeloma (MM) is a plasma cell dyscrasia leading to proliferation of monoclonal plasma cells. Ocular involvement in multiple myeloma is uncommon but can occur. The ocular manifestations of MM may include the cornea, uvea, and retinal vasculature. We present a rare case of autoimmune retinopathy associated with smoldering MM. CASE: A 76-year-old female with no significant past medical or ocular history presented with four months of worsening vision, difficulty with night driving, and loss of peripheral vision. Examination was notable for pallor of the optic nerves and vascular attenuation. Visual field testing demonstrated significant and progressive field loss in both eyes. An electroretinogram was extinguished under all conditions. Serum protein electrophoresis showed a significant elevation of IgG with an M-spike, and a subsequent bone marrow biopsy was performed showing 12.5% plasma cells, consistent with the diagnosis of MM. CAR antibody testing was positive for anti-enolase, anti-GAPDH, and anti-Rab6 antibodies, consistent with autoimmune retinopathy. DISCUSSION: Autoimmune retinopathy associated with MM is exceedingly rare. Management of this condition is challenging, as treatment of the underlying disease does not often lead to improvement in visual symptoms. Ultimately, visual prognosis is very poor, and both patients and clinicians should be aware of the guarded visual potential. CONCLUSION: The association of autoimmune retinopathy with multiple myeloma is rare. It is crucial for physicians to be aware of such manifestations to ensure timely and appropriate diagnosis and management for patients.

Canadian Consensus Guidelines for the Diagnosis and Treatment of Autoimmune Encephalitis in Adults.

Autoimmune encephalitis is increasingly recognized as a neurologic cause of acute mental status changes with similar prevalence to infectious encephalitis. Despite rising awareness, approaches to diagnosis remain inconsistent and evidence for optimal treatment is limited. The following Canadian guidelines represent a consensus and evidence (where available) based approach to both the diagnosis and treatment of adult patients with autoimmune encephalitis. The guidelines were developed using a modified RAND process and included input from specialists in autoimmune neurology, neuropsychiatry and infectious diseases. These guidelines are targeted at front line clinicians and were created to provide a pragmatic and practical approach to managing such patients in the acute setting.

Antineutrophil cytoplasmic antibody-negative pauci-immune glomerulonephritis in a patient with Waldenstrom macroglobulinaemia.

Waldenstrom macroglobulinaemia (WM), the predominant subtype of lymphoplasmacytic lymphoma with bone marrow involvement and serum IgM paraprotein, is a haematological condition commonly associated with renal parenchymal involvement. However, antineutrophil cytoplasmic antibody (ANCA)-negative pauci-immune crescentic glomerulonephritis (PICGN) in kidney infiltrated by lymphoma is very rare, with only two cases described in chronic lymphocytic leukaemia in English literature so far. We herein report the first patient with WM developing ANCA-negative PICGN. He was a 76-year-old male who presented with elevated serum globulin level and bilateral groin lymph node enlargement, subsequently diagnosed to have WM after pathologic examination of the bone marrow and groin lymph node. One month later, he was found to have acute kidney injury and proteinuria. Renal biopsy confirmed the presence of parenchymal involvement by WM accompanied by PICGN; while ANCA testing was negative. He was treated with pulse methylprednisolone followed by oral prednisolone. In addition, six courses of intravenous rituximab and oral cyclophosphamide were given. There was significant improvement in both his renal and haematological conditions. The clinical course of this case suggested that ANCA-negative PICGN may represent a paraneoplastic syndrome and a rare manifestation of WM-associated renal lesion. Early kidney biopsy and prompt treatment may improve the outcome of patients.

Suspected autoimmune encephalitis: A retrospective study of patients referred for therapeutic plasma exchange.

INTRODUCTION: Autoimmune encephalitis (AE) comprises a heterogeneous group of autoantibody-mediated disorders targeting the brain parenchyma. Therapeutic plasma exchange (TPE), one of several first-line therapies for AE, is often initiated when AE is suspected, albeit prior to an established diagnosis. We sought to characterize the role of TPE in the treatment of suspected AE. METHODS: A single-center, retrospective analysis was performed of adults (≥18 years) who underwent at least one TPE procedure for "suspected AE." The following parameters were extracted and evaluated descriptively: clinicopathologic characteristics, treatment course, TPE-related adverse events, outcomes (e.g., modified Rankin scale [mRS]), and diagnosis once investigation was complete. RESULTS: A total of 37 patients (median age 56 years, range 28-77 years, 62.2% male) were evaluated. Autoimmune antibody testing was positive in serum for 43.2% (n = 16) and cerebrospinal fluid for 29.7% (n = 11). Patients underwent a median of five TPE procedures (range 3-16), with 97.3% (n = 36) via a central line and 21.6% (n = 8) requiring at least one unit of plasma as replacement fluid. Fifteen patients (40.5%) experienced at least one TPE-related adverse event. Compared with mRS at admission, the mRS at discharge was improved in 21.6% (n = 8), unchanged in 59.5% (n = 22), or worse in 18.9% (n = 7). Final diagnosis of AE was determined to be definite in 48.6% (n = 18), probable in 8.1% (n = 3) and possible in 27.0% (n = 10). Six (16.2%) patients were ultimately determined to have an alternate etiology. CONCLUSION: Empiric TPE for suspected AE is generally well-tolerated. However, its efficacy remains uncertain in the absence of controlled trials, particularly in the setting of seronegative disease.

Nephrotic syndrome associated with solid malignancies: a systematic review.

BACKGROUND: Nephrotic syndrome (NS) can occur as a paraneoplastic disorder in association with various types of carcinoma. However, paraneoplastic nephrotic syndrome (PNS) is often misdiagnosed as idiopathic nephrotic syndrome or as an adverse effect of oncology treatment, leading to delayed diagnosis and suboptimal treatment. The characteristics of NS associated with solid malignancies are not yet elucidated. We systematically summarized the clinical data for 128 cases of NS combined with solid malignancies with the aim of informing the clinical management of PNS. METHODS: We searched the PubMed database for articles published from the date of inception through to October 2023 using the following keywords: "cancer" or "malignant neoplasms" or "neoplasia" or "tumors" and "nephrotic syndrome", "nephrotic" or "syndrome, nephrotic". All data were extracted from case reports and case series, and the extraction included a method for identifying individual-level patient data. RESULTS: A literature search yielded 105 cases of PNS and 23 of NS induced by cancer therapy. The median age at diagnosis was 60 years, with a male to female ratio of 1.8:1. In patients with PNS, manifestations of NS occurred before, concomitantly with, or after diagnosis of the tumor (in 36%, 30%, and 34% of cases, respectively). Membranous nephropathy (49%) was the most prevalent renal pathology and found particularly in patients with lung, colorectal, or breast carcinoma. Regardless of whether treatment was for cancer alone or in combination with NS, the likelihood of remission was high. CONCLUSION: The pathological type of NS may be associated with specific malignancies in patients with PNS. Prompt identification of PNS coupled with suitable therapeutic intervention has a significant impact on the outcome for patients.