Myocarditis, Myositis, and Myasthenia Gravis Overlap Syndrome Associated with Immune Checkpoint Inhibitors: A Systematic Review.

Immune checkpoint inhibitors (ICIs) have significantly transformed cancer treatment, but their use is linked to immune-related adverse events (irAEs), including the rare ICI-associated myocarditis, myositis, and myasthenia gravis (MMM) overlap syndrome. This systematic review aims to highlight MMM's clinical implications in emergency departments. PubMed and Embase were searched using a specific search strategy. Reports were eligible for inclusion if all three conditions were present and associated with the use of an ICI. Data were extracted by independent reviewers using the Rayyan web application for systematic reviews. Descriptive statistics and qualitative synthesis were used to summarize demographic, clinical, and treatment data for the reported cases. Among 50 cases, predominantly associated with melanoma, lung cancer, and renal cancer, the in-hospital mortality rate was 38.0%. The most commonly presenting symptoms were ptosis (58%), dyspnea (48%), diplopia (42%), or myalgia (36%). The median time from ICI initiation to MMM presentation was 21 days (interquartile range: 15-28 days). Corticosteroids were the primary treatment for the irAEs. MMM, a rare but potentially fatal complication of ICI therapy, requires prompt recognition in emergency settings. Corticosteroids should be initiated if suspected, without waiting for confirmation. Multidisciplinary collaboration is vital for diagnosis and treatment planning. Research on MMM's link to specific cancers and ICIs is imperative for better risk assessment and interventions.

Current gaps in emergency medicine core content education for oncologic emergencies: A targeted needs assessment.

Objective: The core content of emergency medicine (EM) residency training includes the management of oncologic emergencies; however, documented knowledge gaps continue to exist in this subtopic. This study represents a targeted needs assessment as indicated by Step 2 of Kern's curriculum design to determine the specific training gaps to be addressed within the oncologic EM curriculum. Methods: A multi-institutional cross-sectional survey of oncologists (surgical and medical) and emergency physicians (attendings and residents) was conducted during 2023 at five institutions. The voluntary survey consisted of general and specialty-specific questions exploring gaps in oncologic emergency-specific training/education topics. Descriptive statistics reported responses as frequencies and percentages. Results: Of the 833 surveys sent across the five sites, 302 (36.3%) were accessed by link; of these, 271 (89.7%) surveys were completed. There were no differences in the responses between early and later respondents and no differences in the characteristics of respondents between sites. A vast majority of the oncologist and EM groups (91.2% and 83.0%, respectively) reported a belief that emergency physicians would benefit from additional oncologic emergency training. Our survey identified 16 important topics for inclusion in an oncologic EM curriculum, including five topics not present on the 2022 Model of Clinical Practice of Emergency Medicine. Conclusions: Based on this needs assessment, an oncologic EM curriculum should include the topics listed under oncologic emergencies in the 2022 Model of the Clinical Practice of Emergency Medicine along with our respondent-identified topics of radiation therapy adverse effects, stem cell transplant complications, and the management of cancer-specific postsurgical complications, pain, and common diseases in patients with cancer.

Cardiovascular events after cancer immunotherapy as oncologic emergencies: Analyses of 610 head and neck cancer patients treated with immune checkpoint inhibitors.

BACKGROUND: Cardio-oncology and emergency medicine are closely collaborative, as many cardiac events in cancer patients require evaluation and treatment in the emergency department (ED). Immune checkpoint inhibitors (ICIs) have become a common treatment for patients with head and neck cancer (HNC). However, the immune-related adverse events (irAEs) from ICIs can be clinically significant. METHODS: We reviewed and analyzed cardiovascular diagnoses among HNC patients who received ICI during the period April 1, 2016-December 31, 2020 in a large tertiary cancer center. Demographics, clinical and cancer-related data were abstracted, and billing databases were queried for cardiovascular disease (CVD)-related diagnosis using International Classification of Disease-version10 (ICD-10) codes. We recorded receipt of care at the ED as one of the outcome variables. RESULTS: A total of 610 HNC patients with a median follow-up time of 12.3 months (median, interquartile range = 5-30 months) comprised our study cohort. Overall, 25.7% of patients had pre-existing CVD prior to ICI treatment. Of the remaining 453 patients without pre-existing CVD, 31.5% (n = 143) had at least one CVD-related diagnosis after ICI initiation. Tachyarrhythmias (91 new events) was the most frequent CVD-related diagnosis after ICI. The time to diagnosis of myocarditis from initiation of ICI occurred the earliest (median 2.5 months, 1.5-6.8 months), followed by myocardial infarction (3.7, 0.5-9), cardiomyopathy (4.5, 1.6-7.3), and tachyarrhythmias (4.9, 1.2-11.4). Patients with myocarditis and tachyarrhythmias mainly presented to the ED for care. CONCLUSION: The use of ICI in HNC is still expanding and the spectrum of delayed manifestation of ICI-induced cardiovascular toxicities is yet to be fully defined in HNC survivors.

Emergency department use by patients who received chimeric antigen receptor T cell infusion therapy.

Background: Chimeric antigen receptor T cell infusion (CAR T) therapy has revolutionized the treatment of hematologic malignancies, but treatment-related toxicities are of concern. Understanding the timing and reasons for which patients present to the emergency department (ED) after CAR T therapy can assist with the early recognition and management of toxicities. Methods: A retrospective observational cohort study was conducted for patients who had undergone CAR T therapy in the past 6 months and visited the ED of The University of Texas MD Anderson Cancer Center between 04/01/2018 and 08/01/2022. The timing of presentation after CAR T product infusion, patient characteristics, and outcomes of the ED visit were examined. Survival analyses were conducted using Cox proportional hazards regression and Kaplan-Meier estimates. Results: During the period studied, there were 276 ED visits by 168 unique patients. Most patients had diffuse large B-cell lymphoma (103/168; 61.3%), multiple myeloma (21/168; 12.5%), or mantle cell lymphoma (16/168; 9.5%). Almost all 276 visits required urgent (60.5%) or emergent (37.7%) care, and 73.5% of visits led to admission to the hospital or observation unit. Fever was the most frequent presenting complaint, reported in 19.6% of the visits. The 30-day and 90-day mortality rates after the index ED visits were 17.0% and 32.2%, respectively. Patients who had their first ED visit >14 days after CAR T product infusion had significantly worse overall survival (multivariable hazard ratio 3.27; 95% confidence interval 1.29-8.27; P=0.012) than patients who first visited the ED within 14 days of CAR T product infusion. Conclusion: Cancer patients who receive CAR T therapy commonly visit the ED, and most are admitted and/or require urgent or emergent care. During early ED visits patients mainly present with constitutional symptoms such as fever and fatigue, and these early visits are associated with better overall survival.

Evaluation and management of acute high-grade immunotherapy-related neurotoxicity.

Immune checkpoint inhibitor monoclonal antibodies allow the host's immune system to attack tumors, which has revolutionized cancer care over the last decade. As the use of immune checkpoint inhibitors has expanded, so have autoimmune-like complications known as immune-related adverse events. These include the infrequent but increasingly more common, potentially deadly neurological immune related adverse events. When feeling acutely ill, patients will often seek care not from their oncologist but from their family physician, clinics, emergency, and urgent care sites, or other available providers. Thus, while assessing acutely ill cancer patients who are experiencing neurological symptoms, non-oncologists should be prepared to recognize, diagnose, and treat neurological immune related adverse events in addition to more familiar conditions. This narrative review is designed to update acute care clinicians on current knowledge and to present a symptom-based framework for evaluating and treating neurological immune related adverse events based on the leading immunotoxicity organizations' latest recommendations.

Characteristics and Outcomes of Patients with Cancer Pain Placed in an Emergency Department Observation Unit.

Pain remains an undertreated complication of cancer, with poor pain control decreasing patients' quality of life. Traditionally, patients presenting to an emergency department with pain have only had two dispositions available to them: hospitalization or discharge. A third emerging healthcare environment, the emergency department observation unit (EDOU), affords patients access to a hospital's resources without hospitalization. To define the role of an EDOU in the management of cancer pain, we conducted a retrospective study analyzing patients placed in an EDOU with uncontrolled cancer pain for one year. Patient characteristics were summarized using descriptive statistics and predictors of disposition from the EDOU and were identified with univariate and multivariate analyses. Most patients were discharged home, and discharged patients had low 72-hour revisit and 30-day mortality rates. Significant predictors of hospitalization were initial EDOU pain score (odds ratio (OR) = 1.12; 95% CI 1.06−1.19; p < 0.001) and supportive care (OR = 2.04; 95% CI 1.37−3.04; p < 0.001) or pain service (OR = 2.67; 95% CI 1.63−4.40; p < 0.001) consultations. We concluded that an EDOU appears to be the appropriate venue to care for a subsegment of patients presenting to an emergency department with cancer pain, with patients receiving safe care as well as appropriate consultation and admission when indicated.

Neuropathic pain prevalence and risk factors in head and neck cancer survivors.

BACKGROUND: Neuropathic pain (NP) is a debilitating symptom among head and neck cancer (HNC) survivors although few large studies report its prevalence and associated risk factors. METHODS: A cross-sectional survey assessing demographic, behavioral, and clinical risk factors for NP. NP was assessed using the Self-administered Leeds Assessment of Neuropathic Symptoms and Signs pain scale (S-LANSS). RESULTS: Forty-five percent (227/505) reported having pain including 13.7% (69/505) who were positive for S-LANSS. Reported pain sites were in the regions of the head and oral cavity (46.2%) and neck and throat (41.5%). Despite a higher self-reported use of analgesic medication (NP+ = 41.2%; NP- = 27.4%; p = 0.020) and alternative pain therapies (NP+ = 19.1%; NP- = 8.4%; p = 0.009), severe pain was more prevalent among those with NP (N+ = 23.2%; NP- = 13.3%; p = 0.004). Adjusted for opioid medications, ethnicity/race, age, surgery, depression, and comorbidities were risk factors for NP. CONCLUSION: NP remains prevalent in HNC survivors highlighting the importance of routine pain surveillance.

Characteristics and predictors of venous thrombosis recurrence in patients with cancer and catheter-related thrombosis.

Background: Central venous catheters raise the risk of catheter-related thrombosis (CRT) in patients with cancer, typically affecting the upper extremity. Management of CRT involves catheter removal and anticoagulation. However, robust evidence is lacking on the optimal timing of anticoagulation relative to catheter removal. Objectives: Our goal is to provide a better understanding of the factors that increase the risk of recurrent venous thromboembolism (VTE) in these patients. Patients and Methods: We conducted a retrospective chart review of all consecutive patients with cancer in our hospital affected by CRT between January 1, 2015, and December 31, 2017. We measured recurrence of VTE as thrombosis in any vascular bed or pulmonary embolism, for up to 2 years after diagnosis. Logistic and competing risk regression analyses were used to determine the association between different clinical factors and any VTE recurrence in patients with cancer and CRT. Results: Of the 257 individuals meeting the inclusion criteria, 80.2% had their catheter removed; of these, 50.5% did not receive anticoagulation before the removal. Patients who did not receive anticoagulation before the removal had increased 3-month and 1-year risks of recurrent VTE (odds ratio, 5.07 [95% confidence interval [CI], 1.53-23.18]; and hazard ratio, 3.47 [95% CI, 1.34-9.01]), respectively. Conclusions: Our study supports the use of anticoagulants before catheter removal in patients with CRT. Randomized clinical trials are recommended to establish stronger evidence pertaining to the long-term risk of VTE recurrence and the effect of catheter reinsertion.

The Value Proposition of Observation Medicine in Managing Acute Oncologic Pain.

PURPOSE OF REVIEW: Despite recommended best practice guidelines, pain remains an ongoing but undertreated symptom in patients with cancer, many of whom require emergency department evaluation for acute oncologic pain. A significant proportion of these patients are hospitalized for pain management, which increases healthcare costs and exposes patients to the risks of hospitalization. We reviewed the literature on observation medicine: an emerging mode of healthcare delivery which can offer patients with acute pain access to a hospital's pain management solutions and specialists without an inpatient hospitalization. Specifically, we appraised the role of observation medicine in acute pain management and its financial implications in order to consider its potential impact on the management of acute oncologic pain. RECENT FINDINGS: Recent evidence shows that observation medicine has the potential to decrease short-stay hospitalizations in cancer patients presenting with various concerns, including pain. Observation medicine is reported to be successful in providing comprehensive and cost-effective care for non-cancer patients with acute pain, making it a promising alternative to short-stay hospitalizations for cancer patients with acute oncologic pain.

A modified emergency severity index level is associated with outcomes in cancer patients with COVID-19.

OBJECTIVE: To evaluate a modified emergency severity index (mESI)-based triage of cancer patients with coronavirus disease 2019 (COVID-19) in the emergency department (ED) and determine the associations between mESI level and ED disposition, hospital length of stay, and overall survival. METHODS: Medical records were retrospectively reviewed for all patients who presented to our institution's ED between March 22, 2020, and March 12, 2021, and tested positive for SARS-CoV-2. RESULTS: A total of 306 cancer patients tested positive for SARS-CoV-2, with 45% of patients triaged to level 2 (emergent) and 55% to level 3 (urgent). Among all patients, 61.8% were admitted to the hospital, 15.7% were admitted to the intensive care unit, 2.9% were sent for observation, and 19.6% were discharged. Although demographic and clinical characteristics did not significantly vary by triage level, we observed significant differences in ED length of stay (urgent = 6.67 h, emergent = 5.97 h; p < 0.01). Hospital and intensive care unit admission rates were also significantly higher among emergent patients than among urgent patients (p < 0.05). There were 75 deaths (urgent = 32; emergent = 43), and the 30-day mortality rate was significantly higher among emergent patients (urgent = 8%, emergent = 15%; p < 0.05). The mESI level persisted as a significant factor associated with overall survival (hazard ratio = 1.7, 95% confidence interval = 1.09-2.81) in multivariable analysis. CONCLUSION: The mESI level is associated with ED disposition, ED length of stay, and overall survival in cancer patients presenting with COVID-19. These results indicate that the mESI triage tool can be effectively used in cancer patients with COVID-19, whose condition can rapidly deteriorate.

Carotid Blowout Syndrome in the Emergency Department: A Case Report and Review of the Literature.

BACKGROUND: Carotid blowout syndrome (CBS) is an infrequent but dangerous oncologic emergency that must be recognized due to a mortality rate that approaches 40% and neurologic morbidity that approaches 60%. Patients present with a variety of symptoms ranging from asymptomatic to frank hemorrhage, and appropriate recognition and management may improve their outcomes. CASE REPORT: A man in his late 60s with squamous cell carcinoma of the oropharynx presented to the emergency department (ED) with hemoptysis and several episodes of post-tussive emesis with large clots. He had been cancer free for multiple years after treatment with chemotherapy and radiation to the neck. Evaluation revealed a necrotic tumor on the posterior pharynx on bedside laryngoscopy and an external carotid pseudoaneurysm that was stented by interventional radiology. The patient experienced recurrent hemorrhage several months later and opted for palliative measures and expired of massive hemorrhage in the ED on a subsequent visit. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: CBS can be fatal, and early suspicion and recognition are key to ensure that a threatened or impending carotid blowout are appropriately managed. Once carotid blowout is suspected, early resuscitation and consultation with interventional radiology and vascular surgery is warranted.

Outcomes of Patients Placed in an Emergency Department Observation Unit of a Comprehensive Cancer Center.

PURPOSE: Emergency department observation units (EDOUs) have been shown to decrease length of stay and improve cost effectiveness. Yet, compared with noncancer patients, patients with cancer are placed in EDOUs less often. In this study, we aimed to describe patients who were placed in a cancer center's EDOU to discern their clinical characteristics and outcomes. METHODS: We performed a retrospective observational study that included all patients age 18 years and older who presented to our emergency department (ED) and were placed in the EDOU between March 1, 2019, and February 29, 2020. The patients' electronic medical records were queried for demographics, comorbidities, diagnosis at the time of placement in the EDOU, length of stay, disposition from the EDOU, ED return within 72 hours after discharge from the EDOU, and mortality outcomes at 14 and 30 days. RESULTS: A total of 2,461 visits were eligible for analysis. Cancer-related pain was the main reason for observation in more than one quarter of the visits. The median length of stay in the EDOU was approximately 23 hours, and 69.6% of the patients were discharged. The ED return rate for unscheduled visits at 72 hours was 1.9%. The 14- and 30-day mortality rates were significantly higher for patients who were admitted than for those who were discharged (14 days: 1.7% v 0.3%, P < .001; 30 days: 5.9% v 1.8%, P < .001). CONCLUSION: Our data suggest that placing patients with cancer in EDOUs is safe, reduces admissions, and reserves hospital resources for patients who can receive the most benefit without compromising care.

Evaluation and Management of Genitourinary Emergencies in Patients with Cancer.

BACKGROUND: Genitourinary emergencies in cancer patients are common. Most cancer treatments are administered in the outpatient setting, and patients with complications often visit the emergency department. However, there is no recent emergency medicine literature review focusing on genitourinary emergencies in the oncologic population. Objective of the review. To increase awareness of common genitourinary emergencies in patients with cancer and enable the prompt recognition and appropriate management of these conditions. Discussion. Genitourinary emergencies in patients with cancer require a multidisciplinary approach to treatment. The most common genitourinary emergencies in patients with cancer are related to infection, obstructive uropathy, hemorrhagic cystitis, and complications associated with urinary diversions. The treatment approach in patients with infections, including viral infections, is similar to those without cancer. Understanding the changes in the anatomy of patients with urinary diversions or fistulas can help with the management of genitourinary emergencies. CONCLUSIONS: Familiarization with the uniqueness of genitourinary emergencies in patients with cancer is important for emergency physicians.

Cardiotoxicity associated with immune checkpoint inhibitors and CAR T-cell therapy.

INTRODUCTION: The expanding use of immunotherapy and the growing population of patients with cancer has led to an increase in the reporting of immune related adverse events (irAEs). The emergency clinician should be aware of these emerging toxicities, some of which can be fatal. In this review we discuss the cardiotoxic side effects of immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell (CAR T-cell) therapy. DISCUSSION: Recognizing the possible presentations of cardiotoxic irAEs is of utmost important as the diagnosis of cardiotoxicity associated with ICI and CAR T-cell can be difficult to make in the emergency department. The emergency clinician will have to presume the diagnosis and treat it without final confirmation in most cases. For this reason, if the diagnosis is suspected, early involvement of the cardiologist and oncologist is important to help guide management. Most irAEs will be treated with glucocorticoids, but in the case of CAR T-cell cardiotoxicity, Tocilizumab should be used as first line. CONCLUSION: Although cardiotoxicity is rare, it is often life-threatening. Treatment should be initiated as soon as the diagnosis is suspected, and early involvement of the cardiologist and oncologist is imperative for optimal treatment.

A Model Oncologic Emergency Medicine Curriculum for Residency Training.

Background Emergency medicine (EM) resident training in oncologic emergencies is limited, and significant gaps have been identified. Although 90% of emergency medicine residency program directors recognize the importance of residency training in oncologic emergencies, there is no standardized oncologic emergency curriculum. Objective We propose a focused oncologic EM curriculum that serves as a complement to existing EM didactics curriculums to prepare EM residents to recognize and manage the most common oncologic emergencies. It will also allow for familiarization with constantly evolving therapies, such as chimeric antigen receptor cellular therapy and immune checkpoint inhibitors.Discussion This curriculum consists of 10 hours of didactic instruction, which can be incorporated into an already existing didactic curriculum. The curriculum encompasses education on the recognition, rapid diagnosis, and management of oncologic emergencies, with the goal of improving the EM resident's understanding of cancer complications. The suggested topics can be delivered in a variety of methods, allowing for flexible integration in an already existing emergency education curriculum. The proposed curriculum should be introduced during the first postgraduate year and then in the second or third year of the residency to reinforce the learning points.Conclusions Our proposal of a focused, standardized 10 hour program curriculum aims to help to fill the gaps in knowledge of oncologic emergencies. To assist in wide dissemination and standardization of these curriculum topics, outlines for each module are given in the article and we also propose creation of open access online lectures and content to be shared for education purposes.

Immune checkpoint inhibitor-associated myasthenia gravis, myositis, and myocarditis overlap syndrome.

INTRODUCTION: Case reports of immune checkpoint inhibitor (ICI) overlap syndrome of myasthenia gravis, myositis and myocarditis, are increasing in the published literature. This is a potentially fatal adverse event of ICIs and emergency physicians need to be familiar with this triad when patients present to the emergency department (ED). METHODS: We performed a retrospective chart review of the electronic medical record between September 1, 2016 to March 9, 2020. We identified patients with the overlap syndrome who presented to our ED. RESULTS: Seven patients were identified. Most were female and treated with a programmed cell death-1 inhibitor. Most patients presented with abnormal vital signs and the most common symptoms were ptosis, diplopia, dyspnea and fatigue. Most required supplemental oxygen and had a prolonged length of stay. All received steroids in addition to other immunomodulators. Two patients died. DISCUSSION: Presence of one of the diagnosis should lead to evaluation for the others. Suspicion should be raised by patients presenting with ptosis, muscular weakness, fatigue and dyspnea. Early recognition of this triad can allow for early administration of high-dose glucocorticoids (1-2 mg/kg of prednisone or equivalent), which is the mainstay of treatment. However, it is likely that patients will need further immunomodulators and therefore, will need hospitalization. CONCLUSION: Emergency physicians should be aware of this potentially lethal triad in cancer patients receiving ICIs. The life-saving interventions in the ED include recognizing the triad, airway support, administration of high-dose glucocorticoids, and early involvement of a multidisciplinary team.

CAR-T and checkpoint inhibitors: toxicities and antidotes in the emergency department.

INTRODUCTION: New cancer treatments with immunotherapy have led to unique toxicities affecting cancer patients. As cancer-related visits to the emergency department increase, the emergency physician and the medical toxicologist should be aware of immunotherapy-related toxicities. In this review we discuss immune related adverse events (irAEs) from chimeric antigen receptor T (CAR-T) cell therapy and immune checkpoint inhibitors (ICI). DISCUSSION: While presentation of the irAEs may mimic common conditions, it is important to recognize them as they may be life-threatening. A thorough history and examination of the patient, including their cancer treatment history in the past year is crucial. Conditions such as cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS), which can occur after CAR-T treatment, can progress rapidly to a fatal outcome if not recognized and managed in a timely manner. ICI can affect any organ system and irAEs may present like a typical autoimmune disease of the affected organ. While most of the irAEs we discuss in this review will benefit from treatment with glucocorticoids, it is important to know the grade of the condition, as it will determine the treatment dose, route and further management considerations. CONCLUSION: Patients experiencing irAEs from ICI and CAR-T can present with subtle symptoms that can rapidly progress if not recognized early. The emergency physician and the medical toxicologist should keep in mind these toxicities and the patient's oncologic history to adequately recognize and manage these conditions.

Sunitinib-associated hyperammonemic encephalopathy.

Sunitinib-associated hyperammonemic encephalopathy has not been previously reported in the emergency medicine literature. As newer treatments for cancer become more widespread and patients live longer, the emergence of previously unreported or rare adverse effects is expected to increase. Here we report the case of a 71-year-old woman with infiltrating ductal carcinoma of the breast with metastasis to the liver who developed hyperammonemic encephalopathy after taking sunitinib for 12 days. She presented to the emergency department (ED) with confusion and the initial workup revealed an elevated ammonia level (202 µmol/L; reference range, 11-51 µmol/L) without evidence of cirrhosis or portal hypertension. The patient was started on lactulose and admitted to the hospital, where her ammonia levels and mental status waxed and waned throughout her 12-day hospitalization. Further workup with magnetic resonance imaging and an electroencephalogram were negative. After 12 days, her ammonia level normalized and she was discharged without re-initiating Sunitinib. The patient was followed for three months post hospitalization without recurrence of symptoms. Patients on sunitinib should have their ammonia levels checked when presenting to the ED with altered mentation for early identification of hyperammonemic encephalopathy and its potential complications, such as seizures, brain edema, and death. Emergent management in the ED should include initiation of lactulose and consultation with the gastroenterology team.