Faculty Bibliography

LEARNING OBJECTIVE #1: Discuss the clinical utility and mechanism of action of a widely used novel immunotherapeutic agents. LEARNING OBJECTIVE #2: Highlight the incidence of endocrinopathies associated with Ipilimumab and Nivolumab. CASE: A 70 year old female with metastatic melanoma presented to the emergency department with fatigue and lethargy for one month. She had recently completed 6 cycles of Nivolumab and Ipilimumab and was currently receiving Nivolumab monotherapy. Over the past month she had worsening fatigue associated with nausea and decreased appetite. Lab work one week prior to admission was significant for newly elevated TSH and low T4, and thyroid replacement therapy was initiated. On the day of admission, she had a syncopal episode at home prompting presentation. On arrival, she was hypotensive to 89/57. Lab work was significant for hyponatremia, hypokalemia, and hypochloremia. Due to concern for adrenal insufficiency, she was started on stress dose hydrocortisone. An AM serum cortisol was 1.5 and ACTH level was undetectable. FSH and LH levels were also low. An MRI of the brain was notable for enhancement of the pituitary gland suggestive of hypophysitis, which was likely a side effect of her immunotherapy. IMPACT: Ipilimumab and Nivolumab are novel immunotherapeutic agents used in the treatment of melanoma, with research investigating their use into other malignancies as well. Endocrinopathies are relatively common side effects of these agents, especially when given as combination therapy. Nonspecific complaints, such as fatigue and nausea in our patient, should warrant a thorough investigation for endocrinopathies in patients with treatment exposure to ipilimumab and/or nivolumab. DISCUSSION: Nivolumab and Ipilimumab are novel immunotherapeutic agents that are currently used for metastatic melanoma and squamous lung carcinoma. Nivolumab antagonizes the binding of Programmed Cell Death Ligand 1 to the programmed cell death 1 receptor (PD-1), activation of which would normally promote T-cell apoptosis. Ipilimumab antagonizes the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), preventing down regulation cytotoxic T lymphocytes. Endocrinopathies are relatively common side effects of checkpoint inhibitors and are thought to be result of auto-immune inflammation. They can manifest as primary hyper/hypothyroidism, primary adrenal insufficiency and/or hypophysitis thereby affecting the multiple hormonal systems. A retrospective review from Memorial Sloan Kettering showed an incidence of hypophysitis of 8 and thyroiditis of 6% following treatment with ipilimumab. The incidence of hypophysitis and thyroiditis increased to 9 and 22% respectively in patients who received combination therapy with ipilimumab and nivolumab. Our patient seemingly developed primary hypothyroidism and hypophysitis causing a secondary adrenal insufficiency secondary to her combination therapy. The initiation of levothyroxine therapy likely precipitated her adrenal insufficiency leading to her syncopal event

LEARNING OBJECTIVE #1: Recognize the clinical features and complications of Lemierre's syndrome. CASE: A healthy 25-year-old male presented with 8 days of progressively worsening sore throat, fever and neck swelling which were unresponsive to 2 outpatient courses of clarithromycin. On presentation, he was febrile, tachycardic, hypotensive, tachypneic and hypoxic. Physical examination was significant for a palpable left-sided neck mass, trismus, and muffled voice. Initial labs revealed a white blood cell count of 26k, creatinine of 1.9mg/dL, and serum lactate of 4.5mg/dL. The patient was intubated for airway protection, and started on antibiotics and vasopressors. Ultrasound and CT imaging revealed left tonsillar, peritonsillar, and sublingual abscesses, pulmonary septic emboli, bilateral parapneumonic effusions and left internal jugular (IJ) thrombus. Wound cultures of left tonsillar abscess grew Fusobacterium necrophorum and antibiotics were narrowed to piperacillin-tazobactam. He underwent left IJ ligation and left lower lobe lobectomy, and gradually improved and was discharged home on a prolonged course of antibiotics. IMPACT: Lemierre's syndrome is a potentially fatal disease that can cause rapid decompensation if untreated. When a young adult presents with worsening symptoms of acute pharyngitis, one must have a high suspicion for this disease in order to diagnose and treat it early. DISCUSSION: Lemierre's syndrome is a rare and serious disease entity that primarily affects healthy young adults with an incidence of 1 in 1 million and a mortality rate of 4-12%. It involves oropharyngeal fusobacteriuminfection that can form abscesses and internal jugular thrombophlebitis. IJ thrombophlebitis results in bacteremia with septic emboli, commonly to the lungs and joints. The prevalence of Lemierre's syndrome has been rising in recent years due to more judicious use of antibiotics for acute pharyngitis.2 This is also attributed to rising resistance of fusobacterium to macrolides that are often prescribed for pharyngitis, as illustrated by our patient who was initially treated with clarithromycin