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Journal For Immunotherapy of Cancer Mar 2024Patients with paraneoplastic syndromes (PNS) are excluded from clinical trials involving immune checkpoint inhibitors (ICIs) due to safety concerns. Moreover, real-world...
BACKGROUND
Patients with paraneoplastic syndromes (PNS) are excluded from clinical trials involving immune checkpoint inhibitors (ICIs) due to safety concerns. Moreover, real-world data on efficacy and safety is scarce.
METHODS
In this retrospective study, data were collected on patients with PNS and solid tumors receiving ICI between 2015 and 2022 at nine institutions. Patients were classified into: Cohort 1 (pre-existing PNS before ICI initiation), cohort 2 (PNS during ICI treatment), and cohort 3 (PNS after ICI discontinuation). Patients with metastatic non-small cell lung cancer (NSCLC) (mNSCLC) from cohort 1 were matched to patients who were PNS-free at each institution up to a 1:3 ratio for age, sex, type of ICI, use of concurrent chemotherapy, and number of lines of systemic therapy prior to ICI initiation. Kaplan-Meier method was used to assess overall survival (OS) and time-to-next treatment (TTNT).
RESULTS
Among 109 patients with PNS treated with ICIs, median age at ICI initiation was 67 years (IQR: 58-74). The most represented cancer type was NSCLC (n=39, 36%). In cohort 1 (n=55), PNS exacerbations occurred in 16 (29%) patients with median time to exacerbation after ICI of 1.1 months (IQR: 0.7-3.3). Exacerbation or de novo PNS prompted temporary/permanent interruption of ICIs in 14 (13%) patients. For cohort 2 (n=16), median time between ICI initiation and de novo PNS was 1.2 months (IQR: 0.4-3.5). Treatment-related adverse events (trAEs) occurred in 43 (39%) patients. Grade ≥3 trAEs occurred in 18 (17%) patients. PNS-directed immunosuppressive therapy was required in 55 (50%) patients. We matched 18 patients with mNSCLC and PNS (cohort 1) to 40 without PNS, treated with ICIs. There was no significant difference in OS or TTNT between patients with mNSCLC with and without PNS, although a trend was seen towards worse outcomes in patients with PNS. TrAEs occurred in 6/18 (33%) and 14/40 (35%), respectively. Grade ≥3 trAEs occurred in 4 (22%) patients with PNS and 7 (18%) patients without PNS.
CONCLUSIONS
Exacerbations of pre-existing PNS occurred in 29% of patients treated with ICIs and both exacerbations and de novo PNS occur early in the ICI course. TrAE from ICIs were similar between patients with and without PNS. Our data suggest that pre-existing PNS should not preclude consideration of ICI therapy although patients may not derive the same clinical benefit compared with patients without PNS.
Topics: Humans; Middle Aged; Aged; Immune Checkpoint Inhibitors; Carcinoma, Non-Small-Cell Lung; Retrospective Studies; Lung Neoplasms; Paraneoplastic Syndromes
PubMed: 38448038
DOI: 10.1136/jitc-2023-008724 -
Journal of the American Academy of... Jul 2024In the second part of this Continuing Medical Education article on paraneoplastic pemphigus/paraneoplastic autoimmune multiorgan syndrome (PNP/PAMS), its diagnostic... (Review)
Review
In the second part of this Continuing Medical Education article on paraneoplastic pemphigus/paraneoplastic autoimmune multiorgan syndrome (PNP/PAMS), its diagnostic criteria, investigative work-up, and management are reviewed. PNP/PAMS is a rare autoimmune blistering disorder associated with high morbidity and mortality. Recognizing PNP/PAMS's key features and its diagnostic criteria is critical in initiating appropriate work-up. Evaluating PNP/PAMS requires knowledge of its findings on histopathology, direct immunofluorescence, indirect immunofluorescence, and enzyme-linked immunosorbent assay. Lastly, treatments for PNP/PAMS are reviewed with suggestions based on case reports and expert opinions in the literature.
Topics: Humans; Pemphigus; Paraneoplastic Syndromes; Autoimmune Diseases; Multiple Organ Failure; Immunosuppressive Agents; Male
PubMed: 37714216
DOI: 10.1016/j.jaad.2023.08.084 -
Best Practice & Research. Clinical... Dec 2023The tumor microenvironment (TMicroE) and tumor macroenvironment (TMacroE) are defining features of classical Hodgkin lymphoma (cHL). They are of critical importance to... (Review)
Review
The tumor microenvironment (TMicroE) and tumor macroenvironment (TMacroE) are defining features of classical Hodgkin lymphoma (cHL). They are of critical importance to clinicians since they explain the common signs and symptoms, allow us to classify these neoplasms, develop prognostic and predictive biomarkers, bioimaging and novel treatments. The TMicroE is defined by effects of cancer cells to their immediate surrounding and within the tumor. Effects of cancer cells at a distance or outside of the tumor define the TMacroE. Paraneoplastic syndromes are signs and symptoms due to effects of cancer at a distance or the TMacroE, which are not due to direct cancer cell infiltration. The most common paraneoplastic symptoms are B-symptoms, which manifest as fevers, chills, drenching night sweats, and/or weight loss. Less common paraneoplastic syndromes include those that affect the central nervous system, skin, kidney, and hematological autoimmune phenomena including hemophagocytic lymphohistiocytosis (HLH). Paraneoplastic signs such as leukocytosis, lymphopenia, anemia, and hypoalbuminemia are prognostic biomarkers. The neoplastic cells in cHL are the Hodgkin and Reed Sternberg (HRS) cells, which are preapoptotic germinal center B cells with a high mutational burden and almost universal genetic alterations at the 9p24.1 locus primarily through copy gain and amplification with strong activation of signaling via PD-L1, JAK-STAT, NFkB, and c-MYC. In the majority of cases of cHL over 95% of the tumor cells are non-neoplastic. In the TMicroE, HRS cells recruit and mold non-neoplastic cells vigorously via extracellular vesicles, chemokines, cytokines and growth factors such as CCL5, CCL17, IL6, and TGF-β to promote a feed-forward inflammatory loop, which drives cancer aggressiveness and anti-cancer immune evasion. Novel single cell profiling techniques provide critical information on the role in cHL of monocytes-macrophages, neutrophils, T helper, Tregs, cytotoxic CD8 T cells, eosinophils, mast cells and fibroblasts. Here, we summarize the effects of EBV on the TMicroE and TMacroE. In addition, how the metabolism of the TMicroE of cHL affects bioimaging and contributes to cancer aggressiveness is reviewed. Finally, we discuss how the TMicroE is being leveraged for risk adapted treatment strategies based on bioimaging results and novel immune therapies. In sum, it is clear that we cannot effectively manage patients with cHL without understanding the TMicroE and TMacroE and its clinical importance is expected to continue to grow rapidly.
Topics: Humans; Hodgkin Disease; CD8-Positive T-Lymphocytes; Reed-Sternberg Cells; Paraneoplastic Syndromes; Biomarkers; Tumor Microenvironment
PubMed: 38092473
DOI: 10.1016/j.beha.2023.101514 -
Autoimmunity Reviews Oct 2023Laminin-332 is an important component of the basement membrane. Recently, autoantibodies to Laminin-332 have been described in several autoimmune diseases. Many of these... (Review)
Review
IMPORTANCE
Laminin-332 is an important component of the basement membrane. Recently, autoantibodies to Laminin-332 have been described in several autoimmune diseases. Many of these autoimmune diseases have a high incidence of malignancy. The importance of Laminin-332 autoantibodies and its relationship to malignancy is highlighted by using Laminin-332 Pemphigoid (LM-332Pg) as a prototype.
OBJECTIVE
To identify several autoimmune diseases that have autoantibodies to Laminin-332 present, and to determine the prevalence of malignancy in them. Using Laminin-332 Pemphigoid (LM-332Pg) as a prototype, to compare clinical profiles of LM-332Pg patients with and without cancer. By identifying the temporal detection of cancer, can the influence of autoantibodies to Laminin-332 on prognosis be determined.
EVIDENCE REVIEW
A literature search was conducted to identify autoimmune and inflammatory diseases in which autoantibodies to Laminin-332 were present. Subsequently, the rate of malignancy in these autoimmune diseases was determined. A search for publications on LM-332Pg patients to determine cancer rates and clinical outcomes to examine if a relationship can be proposed, was performed.
FINDINGS
Autoantibodies to Laminin-332 were detected in recent studies of systemic lupus erythematosus (SLE), psoriasis, bronchiolitis obliterans (BO), graft-vs-host disease (GVH), bullous pemphigoid (BP), lichen planus (LP), epidermolysis bullosa acquisita (EBA), and membranous glomerulonephropathy (MGN). A high incidence of cancer rate was reported in these autoimmune diseases including primary Sjögren's syndrome (pSS), systemic sclerosis (SS), dermatomyositis (DM), multiple sclerosis (MS), immune thrombocytopenia purpura (ITP), and rheumatoid arthritis (RA). Data analysis demonstrated that LM-332Pg patients had a higher risk of developing ovarian, uterine, lung, gastric cancers and leukemia. The incidence for breast cancer was lower, when compared with global cancer rates. Patients diagnosed with cancer after the presence of LM-332Pg had higher rates of mortality and lower rates of remission, compared to those diagnosed with cancer prior to the discovery/diagnosis of LM-332Pg. When studied, levels of Laminin-332 autoantibodies correlated with the presence or absence of malignancy.
CONCLUSIONS AND RELEVANCE
Preliminary analysis suggests that autoantibodies to Laminin-332 are present in multiple autoimmune diseases, which also have a high incidence of malignancy. Detailed analysis of available data highlights that patients who developed LM-332Pg after cancer was diagnosed, had a more favorable prognosis, compared to patients who developed cancer when LM-332Pg was previously present. Preliminary data would suggest that autoantibodies to Laminin-332 could serve as an important biomarker in certain patients, for correlation with possible incidence of malignancy.
Topics: Humans; Pemphigoid, Bullous; Laminin; Pemphigoid, Benign Mucous Membrane; Autoimmune Diseases; Autoantibodies; Paraneoplastic Syndromes; Neoplasms; Mucous Membrane
PubMed: 37673192
DOI: 10.1016/j.autrev.2023.103444 -
Revue Neurologique 2024In autoimmune neurological diseases, the autonomic nervous system can be the primary target of autoimmunity (e.g. autoimmune autonomic ganglionopathy), or, more... (Review)
Review
In autoimmune neurological diseases, the autonomic nervous system can be the primary target of autoimmunity (e.g. autoimmune autonomic ganglionopathy), or, more frequently, be damaged together with other areas of the nervous system (e.g. Guillain-Barré syndrome). Patients with autoimmune encephalitis and paraneoplastic neurological syndromes (PNS) often develop dysautonomia; however, the frequency and spectrum of autonomic signs and symptoms remain ill defined except for those scenarios in which dysautonomia is a core feature of the disease. Such is the case of Lambert-Eaton myasthenic syndrome, Morvan syndrome or anti-NMDAR encephalitis; in the latter, patients with dysautonomia have been reported to carry a more severe disease and to retain higher disability than those without autonomic dysfunction. Likewise, the presence of autonomic involvement indicates a higher risk of death due to neurological cause in patients with anti-Hu PNS. However, in anti-Hu and other PNS, as well as in the context of immune checkpoint inhibitors' toxicities, the characterization of autonomic involvement is frequently overshadowed by the severity of other neurological symptoms and signs. When evaluated with tests specific for autonomic function, patients with autoimmune encephalitis or PNS usually show a more widespread autonomic involvement than clinically suggested, which may reflect a potential gap of care when it comes to diagnosing dysautonomia. This review aims to revise the autonomic involvement in patients with autoimmune encephalitis and PNS, using for that purpose an antibody-based approach. We also discuss and provide general recommendations for the evaluation and management of dysautonomia in these patients.
Topics: Humans; Paraneoplastic Syndromes; Autonomic Nervous System Diseases; Peripheral Nervous System Diseases; Autoimmune Diseases of the Nervous System; Autonomic Nervous System; Paraneoplastic Syndromes, Nervous System; Autoantibodies; Encephalitis; Hashimoto Disease
PubMed: 38142198
DOI: 10.1016/j.neurol.2023.12.001 -
Neurological Sciences : Official... Mar 2024
Topics: Humans; Myasthenia Gravis; Receptors, Cholinergic; Autoantibodies
PubMed: 37875596
DOI: 10.1007/s10072-023-07122-y -
European Journal of Neurology Oct 2023N-methyl-d-aspartate receptor (NMDAR) and leucine-rich glioma-inactivated protein 1 (LGI1) encephalitis are important types of autoimmune encephalitis (AE) with...
BACKGROUND AND PURPOSE
N-methyl-d-aspartate receptor (NMDAR) and leucine-rich glioma-inactivated protein 1 (LGI1) encephalitis are important types of autoimmune encephalitis (AE) with significant morbidity. In this study, we used a proteomic approach in search of novel clinically relevant biomarkers in these types of encephalitides.
METHODS
Swedish and Czech tertiary neuroimmunology centers collaborated in this retrospective exploratory study. Fifty-eight cerebrospinal fluid (CSF) samples of 28 patients with AE (14 definite NMDAR, 14 with definite LGI1 encephalitis) and 30 controls were included. CSF samples were analyzed using proximity extension assay technology (Olink Target 96 Inflammation panel). For each CSF sample, 92 proteins were measured. Clinical variables were retrospectively collected, and correlations with protein levels were statistically analyzed.
RESULTS
Patients and controls differed significantly in the following 18 biomarkers: TNFRSF9, TNFRSF12, TNFRSF14, TNFβ, TNFα, IL7, IL10, IL12B, IFNγ, CD5, CD6, CASP8, MMP1, CXCL8, CXCL10, CXCL11, IL20RA, and sirtuin 2 (SIRT2). In LGI1 encephalitis, no clinically useful association was found between biomarkers and clinical variables. In the NMDAR encephalitis group, SIRT2, TNFβ, and CD5 were significantly associated with ovarian teratoma. For SIRT2, this was true even for the first patients' CSF sample (SIRT2 without vs. with tumor, mean ± SD = 2.2 ± 0.29 vs. 2.88 ± 0.48; p = 0.007, 95% confidence interval = -1.15 to -0.22; r statistic in point-biserial correlation (rpb) = 0.66, p = 0.011). SIRT2 was positively correlated with age (rpb = 0.39, p = 0.018) and total hospital days (r = 0.55, p = <0.001).
CONCLUSIONS
SIRT2 should be investigated as a biomarker of paraneoplastic etiology in NMDAR encephalitis.
Topics: Female; Humans; Infant, Newborn; Anti-N-Methyl-D-Aspartate Receptor Encephalitis; Autoantibodies; Biomarkers; Proteomics; Retrospective Studies; Sirtuin 2
PubMed: 37483157
DOI: 10.1111/ene.15987 -
Urologic Oncology Sep 2023Paraneoplastic syndromes (PNS) are defined as the signs and symptoms attributed to cytokines or hormones released from a tumor or a patient's immune system. PNS have...
BACKGROUND
Paraneoplastic syndromes (PNS) are defined as the signs and symptoms attributed to cytokines or hormones released from a tumor or a patient's immune system. PNS have been reported with many cancers for decades and data supporting their relevance in renal cell carcinoma (RCC) are largely historical. The widespread use of electronic medical record (EMR) systems provides a more robust method to capture data. The objective of this study was to establish contemporary data regarding the incidence and relevance of PNS in patients undergoing nephrectomy for suspected RCC.
METHODS
In this retrospective single-institution study, 851 patients undergoing nephrectomy for suspected RCC between 2011 and 2018 were assessed for the presence or absence of PNS as defined by laboratory abnormalities. Factors associated with PNS and with all-cause mortality were examined.
RESULTS
The incidence of PNS was 33.1% among 851 patients prior to nephrectomy. The most prevalent PNS were anemia (22.4%), thrombocytosis (7.5%), and elevated C-reactive protein (CRP) (7.4%). PNS were more common in women (39.2% vs. 29.4%, p = 0.0032) and higher stage RCC (31.1% of stage I vs. 54.2% of stage IV, p = 0.0036). Factors associated with the presence of PNS in multivariable analysis included female gender, high comorbidity, and stage IV RCC. Prenephrectomy PNS were associated with poorer survival in multivariable analysis (HR: 2.12, p = 0.0002). Resolution of PNS occurred in 52.1% of patients after nephrectomy, including 55.2% with stage I to III and 38.5% with stage IV RCC (p = 0.10).
CONCLUSIONS
Using EMR data, laboratory evidence of PNS was present in one-third of a contemporary cohort of patients undergoing nephrectomy, with >50% of PNS resolving after surgery. Consistent with prior reports, PNS are more common in higher-stage RCC and are associated with poorer survival in RCC patients.
Topics: Humans; Female; Carcinoma, Renal Cell; Kidney Neoplasms; Incidence; Retrospective Studies; Clinical Relevance; Paraneoplastic Syndromes; Nephrectomy; Prognosis
PubMed: 37537025
DOI: 10.1016/j.urolonc.2023.06.015 -
Frontiers in Immunology 2023The development of new autoantigen discovery techniques, like programmable phage immunoprecipitation sequencing (PhIP-Seq), has accelerated the discovery of...
INTRODUCTION
The development of new autoantigen discovery techniques, like programmable phage immunoprecipitation sequencing (PhIP-Seq), has accelerated the discovery of neural-specific autoantibodies. Herein, we report the identification of a novel biomarker for paraneoplastic neurologic syndrome (PNS), Sloan-Kettering-Virus-Family-Transcriptional-Corepressor-2 (SKOR2)-IgG, utilizing PhIP-Seq. We have also performed a thorough clinical validation using normal, healthy, and disease/cancer control samples.
METHODS
Stored samples with unclassified staining at the junction of the Purkinje cell and the granule cell layers were analyzed by PhIP-Seq for putative autoantigen identification. The autoantigen was confirmed by recombinant antigen-expressing cell-based assay (CBA), Western blotting, and tissue immunofluorescence assay colocalization.
RESULTS
PhIP-Seq data revealed SKOR2 as the candidate autoantigen. The target antigen was confirmed by a recombinant SKOR-2-expressing, and cell lysate Western blot. Furthermore, IgG from both patient samples colocalized with a commercial SKOR2-specific IgG on cryosections of the mouse brain. Both SKOR2 IgG-positive patients had central nervous system involvement, one presenting with encephalitis and seizures (Patient 1) and the other with cognitive dysfunction, spastic ataxia, dysarthria, dysphagia, and pseudobulbar affect (Patient 2). They had a refractory progressive course and were diagnosed with adenocarcinoma (Patient 1: lung, Patient 2: gallbladder). Sera from adenocarcinoma patients without PNS (n=30) tested for SKOR2-IgG were negative.
DISCUSSION
SKOR2 IgG represents a novel biomarker for PNS associated with adenocarcinoma. Identification of additional SKOR2 IgG-positive cases will help categorize the associated neurological phenotype and the risk of underlying malignancy.
Topics: Mice; Animals; Humans; Paraneoplastic Syndromes, Nervous System; Biomarkers; Adenocarcinoma; Autoantigens; Immunoglobulin G
PubMed: 37795104
DOI: 10.3389/fimmu.2023.1243946 -
Medicina (Kaunas, Lithuania) Mar 2024Liver cancer poses a significant global health threat, ranking among the top three causes of cancer-related deaths. Patients with hepatocellular carcinoma (HCC) often...
Liver cancer poses a significant global health threat, ranking among the top three causes of cancer-related deaths. Patients with hepatocellular carcinoma (HCC) often present with symptoms associated with neoplasms or unusual clinical features such as paraneoplastic syndromes (PNS), including hypoglycemia, hypercholesterolemia, thrombocytosis, and erythrocytosis. Our study aimed to investigate the prevalence, clinical characteristics, and survival outcomes associated with PNS in HCC patients and assess each PNS's impact on patient survival. We conducted a retrospective analysis of PNS clinical features and survival among consecutive HCC patients diagnosed at our department over seven years, comparing them with HCC patients without PNS. The study involved a retrospective data evaluation from 378 patients diagnosed with HCC between January 2016 and October 2023. We obtained a PNS prevalence of 25.7%, with paraneoplastic hypercholesterolemia at 10.9%, hypoglycemia at 6.9%, erythrocytosis at 4.5%, and thrombocytosis at 3.4%. Patients with PNS tended to be younger and predominantly male. Multivariate analysis revealed a strong correlation between PNS and levels of alpha-fetoprotein and tumor size, with diabetes also showing a significant statistical association ( < 0.05). Subgroup analysis based on specific paraneoplastic syndromes demonstrated shorter survival in patients with PNS, albeit without significant statistical differences, except for hypoglycemia ( < 0.0001). Matched analysis indicated a shorter survival rate for patients with PNS, although no significant statistical differences were observed. PNS are frequently observed in HCC cases and are associated with unfavorable prognoses and decreased survival rates due to their correlation with increased tumor burdens. However, they do not independently predict poor survival. The impact of individual PNS on HCC prognosis varies.
Topics: Humans; Male; Retrospective Studies; Carcinoma, Hepatocellular; Female; Paraneoplastic Syndromes; Middle Aged; Liver Neoplasms; Aged; Prevalence; Adult; Survival Analysis; Hypercholesterolemia; Hypoglycemia; Polycythemia; Aged, 80 and over; Thrombocytosis
PubMed: 38674198
DOI: 10.3390/medicina60040552