Paraneoplastic Research Articles

Neurological Adverse Events Related to Immune Checkpoint Inhibitors: A Practical Review.

The increasing use of immune checkpoint inhibitors (ICI) in cancer therapy has brought attention to their associated neurotoxicities, termed neurological immune-related adverse events (n-irAEs). Despite their relatively rare incidence, n-irAEs pose a significant risk, potentially leading to severe, long-lasting disabilities or even fatal outcomes. This narrative review aims to provide a comprehensive overview of n-irAEs, focusing on their recognition and management. The review addresses a spectrum of n-irAEs, encompassing myositis, myasthenia gravis, various neuropathies, and central nervous system complications, such as encephalitis, meningitis, and demyelinating diseases. The key features of n-irAEs are emphasized in this review, including their early onset after initiation of ICIs, potential association with non-neurological irAEs and/or concurrent oncological response, the significance of ruling out other etiologies, and the expected improvement upon discontinuation of ICIs and/or immunosuppression. Furthermore, this review delves into considerations for ICI re-challenge and the intricate nature of n-irAEs within the context of pre-existing autoimmune and paraneoplastic syndromes. It underscores the importance of a multidisciplinary approach to diagnosis and treatment, highlighting the pivotal role of severity grading in guiding treatment decisions.

A malignancy phantom: a rare clinical case report of metastatic renal cell carcinoma with no evidence of a primary lesion presenting as cerebellar ataxia

Background: Anti-Ma2 antibody associated paraneoplastic syndrome (PNS) usually presents as limbic encephalitis in the context of testicular tumors. We report a rare case of anti-Ma2 positive PNS with deviation from the classic scenario, thus expanding the phenotype of anti-ma2 associated PNS. Case presentation: This is a 53-year-old male who presented with what was later diagnosed as anti-Ma2 antibody positive cerebellar ataxia. Further workup revealed retroperitoneal lymphadenopathy which, using biopsy, was identified as metastatic clear cell renal cell carcinoma (RCC). However, imaging did not reveal a primary renal lesion. Conclusion: Physicians should be aware of non-classic presentations of paraneoplastic syndromes, especially given that they commonly precede and point towards an underlying, many times undiagnosed, malignancy.

Significant improvement in paraneoplastic neurological syndromes without identifiable anti-neural antibodies in patients with breast cancer after breast surgery.

Paraneoplastic neurological syndromes (PNS) are neurological disorders that occur in close association with tumors without direct metastasis or invasion of the tumors and in which anti-neural antibodies may be present. Cerebellar ataxia is a common form of PNS in patients with breast cancer. However, reports of symptom improvement with breast cancer treatment are more common in patients with positive anti-neural antibodies and are rarely seen in those with negative anti-neural antibodies. In addition, there have been few quantitative evaluations of symptom improvement. We report a case in which neurological symptoms significantly improved after surgical treatment for breast cancer. The patient was a 78-years-old woman with subacute progressive cerebellar ataxia. A subsequent diagnosis of breast cancer led to the diagnosis of "PNS probable". A comprehensive search for anti-neural antibodies was negative in all cases. The quantitative index of the Scale for the Assessment and Rating of Ataxia (SARA) score, a standard evaluation method for ataxia in spinocerebellar degeneration, improved after breast cancer surgery. This case may provide a rationale for treating breast cancer patients negative for anti-neural antibodies, with the possibility of improving neurological symptoms.

Patients with Anti-Hu/ANNA1 Paraneoplastic Neurological Syndromes Develop Progressive Disability but Have Increased Survival Compared to SCLC Patients Without Paraneoplastic Syndromes (S38.008)

Patients with Anti-Hu/ANNA1 Paraneoplastic Neurological Syndromes Develop Progressive Disability but Have Increased Survival Compared to SCLC Patients Without Paraneoplastic Syndromes (S38.008)

Paraneoplastic Neurologic Syndromes Associated with Testicular Germ Cell Tumors: Clinical and Serological Characteristics (S38.005)

Paraneoplastic Neurologic Syndromes Associated with Testicular Germ Cell Tumors: Clinical and Serological Characteristics (S38.005)

Identification of SKOR2 IgG as a Novel Biomarker of Paraneoplastic Neurologic Syndrome (N1.001)

Identification of SKOR2 IgG as a Novel Biomarker of Paraneoplastic Neurologic Syndrome (N1.001)

Focal Breast Microcalcifications: The Only Finding in a Patient with Extensive Breast Malignancy-Induced Paraneoplastic Syndrome

Focal Breast Microcalcifications: The Only Finding in a Patient with Extensive Breast Malignancy-Induced Paraneoplastic Syndrome

Spectrum of Neuroradiological Findings in Novel High-risk Paraneoplastic Syndromes (P1-14.017)

Spectrum of Neuroradiological Findings in Novel High-risk Paraneoplastic Syndromes (P1-14.017)

Pathological characteristic of the eye changes within dogs ophthalmopathy associated with paraneoplastic syndrome

Ophthalmopathy associated with parneoplastic syndrome is a poorly studied pathology of the dogs eye. They occur as a result of the malignant neoplasm’s systematic exposure on the animal's body. They appear in the form of non-specific clinical signs. Main objective of the study – to study the pathomorphological changes in the dog’s eyes with malignant neo-plasms. The material for the study were 30 eyeballs enucleated in dogs in the terminal stage of cancer. Autopsy material obtained from animals was subjected to standard histological processing. As a result of histological studies, pathomorphological changes in eyeball structures associated with Patnaik G2 and G3 mastocytomas (28.6% of cases), liver and kidney carcinomas (28.6%), lymphoma (28.6%) and spleen hemangiosarcoma (14.2%) were revealed in 46.7% of cases. The main histopathological changes were thickening of the iris due to inflammatory cellular infiltration (57.1%) and vasodilation of blood vessels (42.9%), the presence of fibrinous hemorrhagic exudate in the anterior chamber of the eye (28.6%), edema and inflammatory infiltration of the vascular membrane proper (42.9%), thinning, loss of layering and weak retinal atrophy (42.9%). The revealed histological changes indicate the predominant involvement in the pathological process of the vascular membrane of the eye with a violation of the hematophthalmic barrier, as the main pathogenetic mechanism for the development of endogenous uveitis against the background of malignant neoplasm in the animal body.

Liver-Directed Locoregional Therapies for Neuroendocrine Liver Metastases: Recent Advances and Management.

Neuroendocrine tumors (NETs) are a heterogeneous class of cancers, predominately occurring in the gastroenteropancreatic system, which pose a growing health concern with a significant rise in incidence over the past four decades. Emerging from neuroendocrine cells, these tumors often elicit paraneoplastic syndromes such as carcinoid syndrome, which can manifest as a constellation of symptoms significantly impacting patients' quality of life. The prognosis of NETs is influenced by their tendency for metastasis, especially in cases involving the liver, where the estimated 5-year survival is between 20 and 40%. Although surgical resection remains the preferred curative option, challenges emerge in cases of neuroendocrine tumors with liver metastasis (NELM) with multifocal lobar involvement, and many patients may not meet the criteria for surgery. Thus, minimally invasive and non-surgical treatments, such as locoregional therapies, have surfaced. Overall, these approaches aim to prioritize symptom relief and aid in overall tumor control. This review examines locoregional therapies, encompassing catheter-driven procedures, ablative techniques, and radioembolization therapies. These interventions play a pivotal role in enhancing progression-free survival and managing hormonal symptoms, contributing to the dynamic landscape of evolving NELM treatment. This review meticulously explores each modality, presenting the current state of the literature on their utilization and efficacy in addressing NELM.

Hematological manifestations of paraneoplastic syndromes in dogs

Hematological paraneoplastic syndromes are common but poorly studied complications in veterinary oncology, manifested by a variety of hematological changes associated with the system effects of malignant neoplasms on the animal's body. The article presents the results of studying hematological paraneoplastic syndromes, the research involves 131 dogs with spontaneous malignant neoplasms. We used a comprehensive methodological approach, including clinical, instrumental, morphological and hematological research methods. During the morphological study we found out that carcinomas were diagnosed in 33.6% of cases in dogs, of which breast carcinoma was registered in 24.4%, in other cases lung, liver, kidney and abdominal lesions were noted. We also discovered: sarcomas in 22.1% of cases, including hemangiosarcoma of the spleen in 7.6%; and gastrointestinal lymphoma in 16.8% of cases and lymph nodes; in 16.8% of mastocytomas. in 4.6% of melanomas of the skin and mucous membranes; squamous cell carcinoma in 6.1% of cases. As a result of hematological studies, it was revealed that anemia syndrome (18.4%), lymphopenia (16.8%) and thrombocytopenia (15.4%) are the most frequent changes in clinical blood analysis in dogs with oncological diseases. Neutrophilic leukocytosis, leukopenia and thrombocytosis had an identical incidence, which was 12.2% of cases. Monocytosis and lymphocytosis were diagnosed less frequently, in 4.6% of cases. Leukogram changes were observed in 75.4% of cases: in 66.2%, an increase in the percentage of neutrophils was found, with a shift to the left in 38.5% of cases, a decrease in the percentage of lymphocytes in 18.5% of cases, monocytes in 6.2% of cases, eosinophils in 4.6% of cases. The frequency of hematological changes in the general clinical blood analysis of dogs depended on the histogenesis of the tumor. Hematological paraneoplastic syndromes can be used as an early marker of the oncological process, and they can also prevent timely prescription of treatment. Anemia and thrombocytopenia are absolute contraindications for chemotherapy and radiation therapy.

Non-Hodgkin’s Lymphoma of the Central Nervous System with N-Methyl-D-Aspartate Receptor Antibody Positivity - A Case Report

Purpose: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, among the paraneoplastic syndromes, is a recently characterized autoimmune encephalitis most commonly associated with antibodies against subunits of the NMDAR in the central nervous system. As a paraneoplastic syndrome, anti-NMDAR encephalitis is commonly associated with ovarian teratomas, small cell lung carcinomas and testicular germ cell tumors. To our knowledge, there have been no cases with primary central nervous system lymphoma (PCNSL), a rare type of extranodal non-Hodgkin’s lymphoma, without lymph node involvement associated with anti-NMDAR encephalitis. Case Report: A 58-year-old right-handed male patient with complaints of instability in walking for two months, progressively smaller handwriting, hallucinations when falling asleep or waking up, decreased memory, inability to maintain attention was admitted to our hospital for further diagnosis and treatment. Lumbar puncture was performed with the diagnosis of possible encephalitis after many further examinations and CSF studies revealed NMDAR antibody positivity, leading to the initial diagnosis of anti - NMDAR encephalitis. He was treated with high dose methylprednisolone and intravenous immunoglobulin. Due to the continuation of the patient’s presenting symptoms and cranial magnetic resonance imaging findings, a stereotactic brain biopsy was performed from the area with contrast enhancement and the diagnosis was revised as PCNSL associated with NMDAR antibody positivity. Conclusion: This report emphasizes the importance of anti-NMDAR encephalitis as a paraneoplastic syndrome in previously undiagnosed PCNSL. Therefore, it is crucial to be aware of anti-NMDAR encephalitis as a paraneoplastic neurological syndrome that can present with non-Hodgkin’s lymphoma. It is necessary to continually observe the evolution of the disease and perform further diagnostic tests for early identification.

Disentangling the Diagnoses of Psychotic Depression, Catatonia, Neurocognitive Disorders, and Delirium: A Multidisciplinary Approach

An ambiguous clinical presentation can create diagnostic uncertainty, leading to delays in effective interventions and increasing the likelihood of adverse clinical outcomes. Unfortunately, many psychiatric conditions share overlapping clinical symptoms. Psychotic depression, catatonia, neurocognitive disorders, and delirium are all examples of distinct clinical conditions with overlapping symptomatology, and all require decidedly different therapeutic interventions. While much literature is devoted to the diagnostic criteria and management of these clinical conditions, little is dedicated to the challenge of disentangling these diagnoses when faced with a complex clinical presentation.We present here a complicated psychiatric inpatient hospitalization of a 77-year-old male who exemplified this diagnostic challenge. He primarily presented with severely depressed mood and decreased functionality, remaining in bed for much of the day with little attention to basic hygiene and oral intake. While records from a recent outside hospitalization carried a historical diagnosis of catatonia, his moderate level of engagement with providers and somatic delusion of disseminated prostate cancer suggested an alternate diagnosis of psychotic depression. However, before a diagnostic conclusion could be reached, other clinical characteristics surfaced. Following a singular administration of olanzapine shortly after his initial assessment, he developed Lilliputian hallucinations, prominent parkinsonism, and significantly altered mentation.Neuroleptic sensitivity raised clinical suspicion for an underlying neurocognitive disorder such as dementia with Lewy bodies, and a consult was placed to the neuropsychology service. While dementia could not be fully ruled out, they did recommend additional workup to rule out herpes simplex encephalitis, autoimmune limbic encephalitis, and paraneoplastic syndromes. After his MRI imaging revealed moderate microvascular ischemic changes, a true multidisciplinary approach to care was taken, as neurology was consulted to also help narrow the differential. An EEG was unremarkable and a serum encephalitis panel was also unremarkable. Olanzapine was discontinued with significant improvement in parkinsonism and cognition; however, severe neurovegetative symptoms and somatic and nihilistic delusions persisted. While antipsychotics remained clinically indicated for a suspected depression with psychotic features, caution was taken due to established neuroleptic sensitivity, subtle catatonic features, and the related risks of neuroleptic malignant syndrome. Ultimately, low-dose quetiapine was initiated with some benefit; however, he continued to remain acutely depressed and withdrawn with prominent negativism. Trials with benzodiazepines for these catatonic features were also approached with caution to avoid potential risks of delirium.Over time, a multidisciplinary approach to psychopharmacologic interventions and medication trials led the team to a principal diagnosis of major depressive disorder with psychotic features and subtle catatonia. The abrupt changes observed early in the hospital course were determined to be related to olanzapine-induced anticholinergic delirium. With greater diagnostic certainty, the team was able to counsel the patient and family about the importance of pursuing electroconvulsive therapy (ECT). The patient's cardiovascular risk factors and known microvascular changes were considered in the determination of the appropriateness for ECT. After starting ECT, he was immediately noted to have objective improvement, and following his fifth treatment, he was deemed appropriate for discharge after exhibiting significant improvement in depression and functionality and reporting near-resolution of somatic delusions. He was able to complete ECT on an outpatient basis and follow-up visits note durable improvements in mood, functionality, and quality of life, continuing to enjoy an active lifestyle of socializing with family and playing tennis. We use this case to further explore the clinical challenges that stem from the symptomatic similarity between psychotic depression, catatonia, neurocognitive disorders, and delirium and discuss optimal therapeutic approaches when the presentation appears complex and equivocal.

Neuropathology of Inflammatory and Autoimmune-Mediated Diseases

Herein, the author summarize the basic findings on the neuropathology of inflammatory and autoimmune central nervous system (CNS) diseases. Current knowledge on infectious, demyelinating, and autoimmune diseases have also been reported. Further, I emphasize the importance of considering the neuropathology of meningitis, encephalitis, and abscesses as infectious diseases; multiple sclerosis and neuromyelitis optica as demyelinating diseases; and vasculitis, paraneoplastic neurological syndrome, and collagen diseases as autoimmune diseases.

The current state of the paraneoplastic neurological syndromes problem

Paraneoplastic syndromes (PS) are immune-mediated manifestations of a distant oncological process, which is a reaction of autoantibodies against antigens expressed by the tumor. These syndromes are divided into neurological, endocrine, hematological, and dermatological. PS can be diagnosed before or in parallel with tumor detection and often masquerade as neurological or psychiatric disorders. The review discusses the updated 2021 diagnostic criteria, which include revisions to diagnostic levels since 2004, as well as new classifications of antibodies based on the pathogenetic mechanisms of nerve cell damage and their frequency of detection in patients. The phenotypes of high-, medium-, and low-risk paraneoplastic neurological syndromes (PNS) are highlighted, with a special emphasis on the clinical features of high-risk phenotypes. Particular attention is paid to limbic encephalitis, its clinical signs, specific antibodies, instrumental and laboratory studies, and associated oncological diseases. Encephalomyelitis and subacute cerebellar degeneration are also discussed, detailing pathological changes, key antibodies and neoplasia, emphasizing the need for differential diagnosis and immunosuppressive treatment. General features about opsoclonus myoclonus syndrome, its clinical manifestations and causes, as well as Lambert—Eaton myasthenic syndrome are provided, in particular, its association with small cell lung cancer is emphasized, and the features of diagnosis, differential diagnosis with myasthenia gravis and treatment are highlighted. Based on the updated diagnostic criteria, the data analysis will provide clinicians with guidelines for identifying specific phenotypes of PNS and associated antibodies, which are key to improving diagnostic processes and selecting an effective treatment strategy.

Paraneoplastic Syndromes in Hepatocellular Carcinoma, Epidemiology, and Survival: A Retrospective Seven Years Study.

Background and Objectives: 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. Materials and Methods: 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. Results: 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 (p < 0.05). Subgroup analysis based on specific paraneoplastic syndromes demonstrated shorter survival in patients with PNS, albeit without significant statistical differences, except for hypoglycemia (p < 0.0001). Matched analysis indicated a shorter survival rate for patients with PNS, although no significant statistical differences were observed. Conclusions: 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.

Altered serum metabolome as an indicator of paraneoplasia or concomitant cancer in patients with rheumatic disease

ObjectivesA timely diagnosis is imperative for curing cancer. However, in patients with rheumatic musculoskeletal diseases (RMDs) or paraneoplastic syndromes, misleading symptoms frequently delay cancer diagnosis. As metabolic remodelling characterises both...

Interest of rare autoantibodies in autoimmune encephalitis and paraneoplastic neurological syndromes: the utility (or futility) of rare antibody discovery.

The increasing recognition and diagnosis of autoimmune encephalitis (AE) and paraneoplastic neurological syndromes (PNS) is partly due to neural autoantibody testing and discovery. The past two decades witnessed an exponential growth in the number of identified neural antibodies. This review aims to summarize recent rare antibody discoveries in the context of central nervous system (CNS) autoimmunity and evaluate the ongoing debate about their utility. In the last 5 years alone 15 novel neural autoantibody specificities were identified. These include rare neural antibody biomarkers of autoimmune encephalitis, cerebellar ataxia or other movement disorders, including multifocal presentations. Although the clinical applications of these rare antibody discoveries may be limited by the low number of positive cases, they still provide important diagnostic, prognostic, and therapeutic insights.

Recurrent severe hypocalcemia following chemotherapy regimen changes in advanced breast cancer: two case reports

BackgroundAs an oncologic emergency related to abnormalities in calcium metabolism, hypercalcemia associated with paraneoplastic syndrome and bone metastases is well known. Meanwhile, the incidence of hypocalcemia is low, except in cases associated with bone-modifying agents used for bone metastases. Hypocalcemia induced by bone-modifying agents typically occurs early after the initial administration, and its incidence can be significantly reduced by preventive administration of calcium and vitamin D3 supplements.Case reportWe report two cases of recurrent severe hypocalcemia occurring during chemotherapy for metastatic breast cancer with multiple bone metastases.Case 1: A 35-year-old Japanese woman developed metastases in the bone, liver, and ovaries during postoperative endocrine therapy for invasive lobular carcinoma of the breast. She underwent chemotherapy and treatment with denosumab. She experienced recurrent episodes of severe hypocalcemia subsequent to a change in the chemotherapy regimen. Case 2: A 65-year-old Japanese woman encountered multiple bone metastases after postoperative anti-human epidermal growth factor receptor 2 therapy and during endocrine therapy for invasive ductal carcinoma of the breast. She underwent anti-human epidermal growth factor receptor 2 therapy and treatment with denosumab. She experienced recurrent severe hypocalcemia subsequent to a change in the chemotherapy regimen to letrozole + lapatinib, trastuzumab emtansine, and lapatinib + capecitabine.ConclusionsWe observed two cases of recurrent severe hypocalcemia in patients with advanced breast cancer and bone metastases after modifications to their therapy regimens. These cases differed from the typical hypocalcemia induced by bone-modifying agents. It is possible that antitumor drugs affect calcium and bone metabolism associated with bone metastases. While these cases are rare, it is crucial for oncologists to be aware of hypocalcemia not only at the initiation of bone-modifying agents but also throughout the entire antitumor therapy, as hypocalcemia can lead to fatal outcomes.

Neurological Paraneoplastic Syndromes in most Common Cancers in Poland

INTRODUCTION: Paraneoplastic Neurological Syndromes (PNS) represent a heterogeneous group of diseases associated with the presence of neoplasm. The appearance of PNS can precede cancer diagnosis. The estimated frequency amongst cancer patients is about 1%. Malignant tumors represent a serious health problem and are the second leading cause of death in Poland. The aim of this study is to collect information about PNS focusing on cancers mostly diagnosed in Polish adults. REVIEW METHODS: The analysis was conducted based on information regarding PNS gathered from PubMed and Google Scholar within the context of selected cancers. THE STATE OF KNOWLEDGE: PNS develop from an autoimmune reaction in which onconeural antibodies are produced. The recent classification divides PNS to high risk, indicating a likely paraneoplastic origin and intermediate risk, if this association is less evident. Diagnosis is difficult and usually relies on exclusion methods. The symptoms described are non-specific and the diagnostic process may require the involvement of various specialists. The main approaches include cancer treatment, especially tumor removal and immunotherapy, which in certain may prove to be effective. SUMMARY: Although PNS is relatively rare, its detectability has recently increased. Many syndromes are especially associated with lung cancer (mainly small cell carcinoma). Breast and prostate cancers have also shown associations with certain syndromes. They can present with nonspecific symptoms related to different organ systems. Awareness and understanding of this phenomenon can be helpful amongst many specialists.