A Case Report of Immunotherapy-Resistant MSI-H Gastric Cancer with Significant Intrapatient Tumoral Heterogeneity Characterized by Histologic Dedifferentiation.

We describe a patient with both gastric adenocarcinoma and metastatic squamous cell carcinoma (SCC) of unknown primary site. The possibility of a single malignant clonal process as opposed to differing primaries was supported by the finding of both histologies exhibiting high microsatellite instability. Despite evidence of tumor microsatellite instability, the patient's disease process did not respond to immune checkpoint inhibition. Our pursuit of whole-exome sequencing and comparing the single-nucleotide variant profiles of both tumors supported a single clonal process with the development of significant intratumoral heterogeneity. High intratumoral heterogeneity has posed a challenge to precision medicine approaches, but we also provide a review of the literature of this phenomenon mediating resistance to immunotherapy strategies.

Multiple autoimmune side effects of immune checkpoint inhibitors in a patient with metastatic melanoma receiving pembrolizumab.

INTRODUCTION: Immune agents including anti-programmed death receptor-1 and anti-cytotoxic T-lymphocyte antigen-4 have been associated with numerous immune-related complications. Pembrolizumab, a programmed death-1 inhibitor, has been associated with a number of immune-related adverse events such as pneumonitis, colitis, hepatitis, hypophysitis, hyperthyroidism, hypothyroidism, nephritis, and type 1 diabetes. CASE REPORT: We present a rare case of an elderly male on pembrolizumab who suffered from four autoimmune toxicities including type 1 diabetes, pneumonitis, hypothyroidism, and polymyalgia rheumatica likely catalyzed by age-related immune activation.Management and outcome: Immunotherapy was indefinitely stopped, and patient was started on steroids for the immune-related adverse events with complete resolution of polymyalgia rheumatica. Thyroid dysfunction resolved once he started thyroid replacement therapy. His diabetes is well controlled with insulin and is followed by endocrinology. He continues on prednisone for immune-mediated pneumonitis with a good response with regular monitoring via computed tomography scans and pulmonary consultation. DISCUSSION: Few cases wherein multiple toxicities are seen within one patient are reported. Aging appears to be a risk factor for immune-related adverse events. Aging is associated with an increased incidence of autoimmunity as programmed death-1 ligand expression represents an important mechanism that tissues use to protect from self-reactive effector T cells. Programmed death-1 blockade breaks this protective mechanism and enhances autoimmune diseases. Therefore, close monitoring and extreme vigilance is warranted while using immune checkpoint inhibitors including pembrolizumab as multiple toxicities can occur within a short span of infusion, especially in elderly individuals. Prompt discontinuation and the use of a multidisciplinary team are prudent to prevent further morbidity and mortality.

Metastatic squamous cell carcinoma to the heart: an unusual cause of ST elevation-a case report.

BACKGROUND: Cardiac tumours are typically secondary in nature, and the most common malignancies metastasizing to the heart are cancers of the lung, breast, oesophagus, melanoma, and lymphoma. We present a unique case of squamous cell carcinoma of the tongue, metastasizing to the heart and manifesting with ST elevation in the inferior-leads on electrocardiogram (ECG). CASE SUMMARY: A 25-year-old woman was initially diagnosed with squamous cell carcinoma of the tongue at the age of 23 and treated with hemi-glossectomy with clear-margins. Sixteen months later, the tumour recurred in the oropharynx and the left upper lobe of the lung. She was treated with chemotherapy; however, the tumour progressed. Thus, she was initiated on immunotherapy and radiation therapy. One month later, she presented with chest pain. Electrocardiogram revealed ST elevation in the inferior-leads. Troponin-I was elevated. Transthoracic echocardiogram revealed focal areas of thickening within the left and right ventricular myocardium with associated hypokinesis. These findings suggested ECG changes were likely secondary to infiltrative metastases and not acute-coronary-syndrome. Cardiac magnetic resonance imaging showed infiltrative masses with increased T2-signal and heterogeneous enhancement on perfusion and delayed enhancement sequences. Imaging also demonstrated numerous extra-cardiac metastases. She was treated with analgesics and discharged to home hospice. DISCUSSION: Head and neck cancers are a rare cause of cardiac metastasis. ST elevation and troponin release are thought to be due to tumour extension into the myocardium. Cardiac metastases usually present in patients with advanced widespread malignancy. In a cancer patient with cardiac symptoms or ECG changes, it is important to consider a broad differential diagnosis and entertain the possibility of cardiac metastasis.

A Case of Immunotherapy-Induced Colitis Complicated by Perforation and Treated with Infliximab Postoperatively.

The advent of checkpoint inhibitor therapy in medical oncology has led to an increase in hospitalizations for immune-related adverse effects. Severe colitis has been reported in approximately 5% of patients treated with cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) inhibitors, such as ipilimumab. Standard management for those with severe colitis includes administration of systemic corticosteroids with the reservation of antitumor necrosis factor (anti-TNF) therapy, such as infliximab, if there has been no improvement. Rarely, immunotherapy-induced colitis can become life-threatening and result in bowel perforation requiring surgical intervention. Yet, there are no specific recommendations for medical management following colectomy in these situations. In cases of severe colitis from Crohn's disease, postoperative treatment with infliximab has been found to be safe when administered shortly after intestinal resection. However, there remains limited data to support administration of infliximab following bowel perforation due to immunotherapy-induced colitis. Our case illustrates management of a severe adverse reaction to checkpoint inhibitor therapy and the need to further evaluate the role of infliximab postoperatively in patients who develop colitis complicated by bowel perforation.

Cerebral Sinus Venous Thrombosis in the Setting of Acute Mastoiditis.

Cerebral sinus venous thrombosis (CSVT) is a rare complication of acute mastoiditis with a declining incidence in the post-antibiotic era. In the adult population its incidence ranges from three to four cases per million. Here we present a case of a 47-year-old female with triple negative breast cancer on chemotherapy who underwent a molar tooth extraction, which was followed two weeks later by the sudden onset of left-sided frontotemporal headache radiating down the face, left ear fullness with associated hearing loss, toothache, and left orbital pain. Imaging studies performed included magnetic resonance imaging (MRI) as well as magnetic resonance venography (MRV), both of which showed thrombosis of the left transverse sinus, sigmoid sinus as well as the internal jugular vein, which was consistent with a diagnosis of cerebral sinus venous thrombosis. Following the diagnosis, the patient was managed with anti-coagulation and antibiotics, which resulted in improvement of her symptoms. This case highlights the need to be vigilant in patients with acute mastoiditis for the above clinical syndrome in order to promptly diagnose this rare complication and avoid life-threatening consequences.