Paraneoplastic neurological syndromes: clinical presentations and management

We provide an overview of the varied presentations of paraneoplastic neurological syndromes. We also review the onconeural antibodies and their particular oncological and neurological associations. Recognition of these syndromes and their oncological associations is crucial, as early diagnosis and management has been associated with better patient outcomes. Specific management strategies and prognosis vary widely depending on the underlying etiology. An understanding of the relevant clinical details, imaging findings, and other diagnostic information can help tailor treatment approaches. We provide an outline of the diagnostic evaluation and treatment of various paraneoplastic neurological disorders, presenting with central and/or peripheral nervous system involvement. We briefly discuss neurologic immune checkpoint inhibitor-related adverse events, which can occasionally present with paraneoplastic neurological syndrome phenotypes.

Download Full-text

Paraneoplastic Neurological Syndromes and Beyond Emerging With the Introduction of Immune Checkpoint Inhibitor Cancer Immunotherapy

Frontiers in Neurology ◽

10.3389/fneur.2021.642800 ◽

2021 ◽

Vol 12 ◽

Author(s):

Cristina Valencia-Sanchez ◽

Anastasia Zekeridou

Keyword(s):

Nervous System ◽

Cancer Immunotherapy ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Neurological Complications ◽

High Dose ◽

Paraneoplastic Neurological Syndromes ◽

Clinical Presentations

Paraneoplastic neurological syndromes are more commonly seen with malignancies such as small cell lung cancer, thymoma, gynecological malignancies, and breast cancer as well as seminoma. With the introduction of immune checkpoint inhibitor (ICI) cancer immunotherapy we see an increase of autoimmune neurological complications in patients with malignancies not traditionally associated with paraneoplastic neurological syndromes, such as melanoma and renal cell carcinoma. Immune checkpoint inhibitors enhance antitumor immune responses resulting often in immune-related adverse effects that can affect any organ, including the central and peripheral nervous system, neuromuscular junction and muscle. Neurological complications are rare; neuromuscular complications are more common than central nervous system ones but multifocal neurological presentations are often encountered. The vast majority of neurological complications appear within 3 months of ICI initiation, but have been described even after ICI cessation. Neural autoantibody testing reveals autoantibodies in approximately half of the patients with CNS complications. Early suspicion and diagnosis is critical to avoid worsening and improve outcomes. Therapeutic strategies depend on the severity of the symptoms and initially typically involve discontinuation of ICI and high dose steroids. Further immunosuppression might be necessary. Outcomes are dependent on patient's characteristics and clinical presentations.

Download Full-text

Evaluation and clinical impact of a pharmacist-led, interdisciplinary service focusing on education, monitoring and toxicity management of immune checkpoint inhibitors

Journal of Oncology Pharmacy Practice ◽

10.1177/10781552211061133 ◽

2021 ◽

pp. 107815522110611

Author(s):

Glenn Myers ◽

Jonathan Stevens ◽

Andrew Flewelling ◽

Jacqueline Richard ◽

Meagan London

Keyword(s):

Adverse Event ◽

Patient Outcomes ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Study Cohort ◽

Control Cohort ◽

Related Adverse Event

Introduction Immune-related adverse events are complications of immune checkpoint inhibitors which require robust patient education and proactive follow-up to ensure timely identification and management. Oncology pharmacist practice models with other anticancer modalities have been well documented, but there is limited evidence assessing the spectrum of pharmacist interventions in patients receiving immune checkpoint inhibitor(s) and the impact of these interventions on patient outcomes. Methods Patients initiated on immune checkpoint inhibitor(s) from 1 January 2016 to 31 August 2019 were included for data collection and analysis. Part 1 featured an intensive pharmacist follow-up cohort (study cohort) and summarized pharmacist interventions. Part 2 compared patient outcomes between the study cohort and a standard of care cohort (control cohort) from a different oncology centre. Patient outcomes included emergency department visits not resulting in admission, hospitalizations due to immune-related adverse event(s), immune checkpoint inhibitor cycles received, treatment discontinuation due to immune-related adverse event(s), completion of finite programmed death-1/death-1 ligand treatment course and completion of ipilimumab. Clinical outcomes were compared using a retrospective, matched cohort design based on age, cancer diagnosis and immune checkpoint inhibitor(s). Results A total of 143 patients were included in Part 1 encompassing 1664 pharmacist recommendations across 11 categories. The matched cohort yielded 92 matches (n = 184) with a higher odds of immune checkpoint inhibitor discontinuation due to immune-related adverse event(s) in the control cohort (odds ratio (OR) (95% confidence interval (CI)) = 5.5 (1.2−24.8); p = 0.022). Conclusion Intensive immune-related adverse event education, proactive follow-up and immune-related adverse event management by pharmacists result in clinically meaningful interventions which correlate to improved patient outcomes, namely lower odds of treatment discontinuation due to immune-related adverse event(s).

Download Full-text

Biomarkers of immune checkpoint inhibitor efficacy in cancer

Current Oncology ◽

10.3747/co.27.5549 ◽

2019 ◽

Vol 27 (S2) ◽

Cited By ~ 2

Author(s):

D. E. Meyers ◽

S. Banerji

Keyword(s):

Patient Outcomes ◽

Immune Checkpoint ◽

Immune Modulation ◽

Urothelial Cancer ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Cell Cancer ◽

Small Cell Lung ◽

Cell Mediated Immune Response

Immune checkpoint inhibitor–based therapies that target ctla-4, PD-1, or the PD-1 ligand PD-L1 have received approval in Canada and many parts of the world for the treatment of melanoma, renal cell cancer, urothelial cancer, classical Hodgkin lymphoma, and non-small-cell lung cancer. However only a small proportion of patients derive long-term clinical benefit. Here, we describe the biomarkers associated with the complex relationship between tumour-related immune stimulus, T cell–mediated immune response, and immune modulation of the microenvironment that can help to predict improved patient outcomes.

Download Full-text

A retrospective chart review of management strategies for lichenoid eruptions associated with immune-checkpoint inhibitor therapy from a single institution

Cancer Treatment and Research Communications ◽

10.1016/j.ctarc.2021.100506 ◽

2022 ◽

pp. 100506

Author(s):

Wylie M. Masterson ◽

Alexandria M. Brown ◽

May A. Al Ameri ◽

Anisha B. Patel

Keyword(s):

Immune Checkpoint ◽

Chart Review ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Management Strategies ◽

Retrospective Chart Review ◽

Inhibitor Therapy ◽

Single Institution ◽

Checkpoint Inhibitor Therapy

Download Full-text

Immune Checkpoint Inhibitor Cardiotoxicity: Understanding Basic Mechanisms and Clinical Characteristics and Finding a Cure

The Annual Review of Pharmacology and Toxicology ◽

10.1146/annurev-pharmtox-010919-023451 ◽

2021 ◽

Vol 61 (1) ◽

pp. 113-134 ◽

Cited By ~ 1

Author(s):

Sarah Waliany ◽

Daniel Lee ◽

Ronald M. Witteles ◽

Joel W. Neal ◽

Patricia Nguyen ◽

...

Keyword(s):

Patient Outcomes ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Cardiovascular Complications ◽

Clinical Aspects ◽

Therapeutic Approaches ◽

Cell Responses ◽

Self Tolerance

Immune checkpoint inhibitors (ICIs) attenuate mechanisms of self-tolerance in the immune system, enabling T cell responses to cancerous tissues and revolutionizing care for cancer patients. However, by loweringbarriers against self-reactivity, ICIs often result in varying degrees of autoimmunity. Cardiovascular complications, particularly myocarditis but also arrhythmias, pericarditis, and vasculitis, have emerged as significant complications associated with ICIs. In this review, we examine the clinical aspects and basic science principles that underlie ICI-associated myocarditis and other cardiovascular toxicities. In addition, we discuss current therapeutic approaches. We believe a better mechanistic understanding of ICI-associated toxicities can lead to improved patient outcomes by reducing treatment-related morbidity.

Download Full-text

CMV coinfection in treatment refractory immune checkpoint inhibitor colitis

BMJ Case Reports ◽

10.1136/bcr-2019-233519 ◽

2020 ◽

Vol 13 (5) ◽

pp. e233519

Author(s):

Kevin B Harris ◽

Pauline Funchain ◽

Brian B Baggott

Keyword(s):

Case Report ◽

Patient Outcomes ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Treatment Refractory ◽

Cmv Colitis ◽

Improve Patient

As immune checkpoint inhibitors (ICIs) are increasingly used, clinicians are more frequently encountering the side effects of these therapies. ICIs have been implicated in numerous adverse effects against healthy tissues. We present a case of a patient who developed treatment refractory checkpoint inhibitor colitis. Following colonoscopy, it was discovered that this patient had cytomegalovirus (CMV) coinfection. This case report highlights the importance of undertaking an appropriate assessment, including endoscopic and histologic investigation, of patients with presumed ICI colitis. Accurately diagnosing a superimposed CMV colitis changes clinical management and can improve patient outcomes.

Download Full-text

Immune checkpoint inhibitor-mediated myasthenia gravis with focal subclinical myocarditis progressing to symptomatic cardiac disease

BMJ Case Reports ◽

10.1136/bcr-2019-232920 ◽

2020 ◽

Vol 13 (5) ◽

pp. e232920 ◽

Cited By ~ 1

Author(s):

Phillip John Leaver ◽

Helena Sung-In Jang ◽

Stephen Thomas Vernon ◽

Suran Loshana Fernando

Keyword(s):

Myasthenia Gravis ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Fatal Complication ◽

Adverse Health Outcomes ◽

Clinical Presentations ◽

Organ Specific ◽

Delayed Recognition

The advent of immune checkpoint inhibitors (ICIs) for cancer therapy has heralded increasing frequency of immune-related adverse events including endocrinopathies, hepatitis, colitis and rarely myocarditis and myasthenia gravis (MG). The heterogeneity in clinical presentations regardless of organ-specific involvement can lead to delayed recognition and management of these events and adverse health outcomes. We describe a case of ICI-induced subclinical focal myocarditis that was recognised and treated in the broader context of MG. It is essential that patients with ICI-induced MG should be screened and monitored for myocarditis, a potentially fatal complication.

Download Full-text

Unleashing the power of immunotherapy and targeted therapy combinations: Advancing cancer care or discovering unknown toxicities?

Journal of Oncology Pharmacy Practice ◽

10.1177/1078155220984235 ◽

2021 ◽

pp. 107815522098423

Author(s):

Daniel J Przybylski ◽

Jason J Bergsbaken ◽

Jennifer K Piccolo

Keyword(s):

Patient Outcomes ◽

Immune Checkpoint Inhibitor ◽

Kinase Inhibitor ◽

Checkpoint Inhibitor ◽

Dual Therapy ◽

Careful Consideration ◽

Future Research ◽

The Past ◽

Tumor Types ◽

Improve Patient

Objective The purpose of this review was to summarize the triumphs and pitfalls of tyrosine kinase inhibitor (TKI) and immune checkpoint inhibitor (ICI) combinations. Data sources: A literature review of PubMed was conducted and studies were included if they were classified as a clinical trial and assessed TKI and ICI combinations for solid tumor malignancies. Dates of literature search included January 1, 1988 through September 22, 2019. Data summary: In the past decade, TKI and ICI monotherapy strategies have changed the management of many advanced solid tumors through their unique mechanisms of action. Preclinical data suggests that TKIs may be able to sensitize tumors to ICI therapy via direct and indirect pathways; however, optimal mechanisms to support various TKI and ICI combinations have yet to be determined. The FDA recently approved TKI and ICI combinations for renal cell carcinoma, endometrial carcinoma, and melanoma. Several other tumor types currently have TKI and immunotherapy combinations under investigation with mixed results. Dual therapy with TKIs and immunotherapy have the potential to be synergistic and improve patient outcomes; however, careful consideration will need to be taken in regard to what TKI and immunotherapy are combined. Conclusions Future research will be needed to determine appropriate sequencing of TKIs and ICIs after progression on combination therapy. Continued research is necessary to determine optimal dual TKI and immunotherapy options.

Download Full-text

Immune Checkpoints in Cancers: From Signaling to the Clinic

Cancers ◽

10.3390/cancers13184573 ◽

2021 ◽

Vol 13 (18) ◽

pp. 4573

Author(s):

Céline Pisibon ◽

Amira Ouertani ◽

Corine Bertolotto ◽

Robert Ballotti ◽

Yann Cheli

Keyword(s):

Immune System ◽

Patient Outcomes ◽

Immune Cells ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Mechanisms Of Action ◽

Immune Checkpoints

The immune system is known to help fight cancers. Ten years ago, the first immune checkpoint inhibitor targeting CTLA4 was approved by the FDA to treat patients with metastatic melanoma. Since then, immune checkpoint therapies have revolutionized the field of oncology and the treatment of cancer patients. Numerous immune checkpoint inhibitors have been developed and tested, alone or in combination with other treatments, in melanoma and other cancers, with overall clear benefits to patient outcomes. However, many patients fail to respond or develop resistance to these treatments. It is therefore essential to decipher the mechanisms of action of immune checkpoints and to understand how immune cells are affected by signaling to be able to understand and overcome resistance. In this review, we discuss the signaling and effects of each immune checkpoint on different immune cells and their biological and clinical relevance. Restoring the functionality of T cells and their coordination with other immune cells is necessary to overcome resistance and help design new clinical immunotherapy strategies. In this respect, NK cells have recently been implicated in the resistance to anti-PD1 evoked by a protein secreted by melanoma, ITGBL1. The complexity of this network will have to be considered to improve the efficiency of future immunotherapies and may lead to the discovery of new immune checkpoints.

Download Full-text