Judy Zhong

A 53-year-old woman presenting with irregular vaginal bleeding was treated with hysterectomy and diagnosed with a pT1b pN0, stage IB, FIGO grade III endometrial adenocarcinoma, high-grade endometrioid type, with extensive necrosis, lymphovascular invasion, and myometrial invasion. A peritumoral lym-Antibodies that target the immune checkpoint receptor programmed cell death protein 1 (PD-1) have resulted in prolonged and beneficial responses toward a variety of human cancers. However, anti-PD-1 therapy in some patients provides no benefit and/or results in adverse side effects. The factors that determine whether patients will be drug sensitive or resistant are not fully understood; therefore, genomic assessment of exceptional responders can provide important insight into patient response. Here, we identified a patient with endometrial cancer who had an exceptional response to the anti-PD-1 antibody pembrolizumab. Clinical grade targeted genomic profiling of a pretreatment tumor sample from this individual identified a mutation in DNA polymerase epsilon (POLE) that associated with an ultramutator phenotype. Analysis of The Cancer Genome Atlas (TCGA) revealed that the presence of POLE mutation associates with high mutational burden and elevated expression of several immune checkpoint genes. Together, these data suggest that cancers harboring POLE mutations are good candidates for immune checkpoint inhibitor therapy.

Background: Myocardial infarction with nonobstructive coronary arteries (MINOCA) occurs in 6% to 15% of myocardial infarctions (MIs) and disproportionately affects women. Scientific statements recommend multimodality imaging in MINOCA to define the underlying cause. We performed coronary optical coherence tomography (OCT) and cardiac magnetic resonance (CMR) imaging to assess mechanisms of MINOCA. Methods: In this prospective, multicenter, international, observational study, we enrolled women with a clinical diagnosis of myocardial infarction. If invasive coronary angiography revealed <50% stenosis in all major arteries, multivessel OCT was performed, followed by CMR (cine imaging, late gadolinium enhancement, and T2-weighted imaging and T1 mapping). Angiography, OCT, and CMR were evaluated at blinded, independent core laboratories. Culprit lesions identified by OCT were classified as definite or possible. The CMR core laboratory identified ischemia-related and nonischemic myocardial injury. Imaging results were combined to determine the mechanism of MINOCA, when possible. Results: Among 301 women enrolled at 16 sites, 170 were diagnosed with MINOCA, of whom 145 had adequate OCT image quality for analysis; 116 of these underwent CMR. A definite or possible culprit lesion was identified by OCT in 46.2% (67/145) of participants, most commonly plaque rupture, intraplaque cavity, or layered plaque. CMR was abnormal in 74.1% (86/116) of participants. An ischemic pattern of CMR abnormalities (infarction or myocardial edema in a coronary territory) was present in 53.4% (62/116) of participants undergoing CMR. A nonischemic pattern of CMR abnormalities (myocarditis, takotsubo syndrome, or nonischemic cardiomyopathy) was present in 20.7% (24/116). A cause of MINOCA was identified in 84.5% (98/116) of the women with multimodality imaging, higher than with OCT alone ( P <0.001) or CMR alone ( P =0.001). An ischemic cause was identified in 63.8% of women with MINOCA (74/116), a nonischemic cause was identified in 20.7% (24/116) of the women, and no mechanism was identified in 15.5% (18/116). Conclusions: Multimodality imaging with coronary OCT and CMR identified potential mechanisms in 84.5% of women with a diagnosis of MINOCA, 75.5% of which were ischemic and 24.5% of which were nonischemic, alternate diagnoses to myocardial infarction. Identification of the cause of MINOCA is feasible and has the potential to guide medical therapy for secondary prevention. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02905357.