Distinct genomic landscapes of gastroesophageal adenocarcinoma depending on PD-L1 expression identify mutations in RAS-MAPK pathway and TP53 as potential predictors of immunotherapy efficacy.

BACKGROUND: The impact of molecular alterations on programmed death-ligand 1 (PD-L1) combined positive score (CPS) is not well studied in gastroesophageal adenocarcinomas (GEAs). We aimed to characterize genomic features of tumors with different CPSs in GEAs. PATIENTS AND METHODS: Genomic alterations of 2518 GEAs were compared in three groups (PD-L1 CPS ≥ 10, high; CPS = 1-9, intermediate; CPS < 1, low) using next-generation sequencing. We assessed the impact of gene mutations on the efficacy of immune checkpoint inhibitors (ICIs) and tumor immune environment based on the Memorial Sloan Kettering Cancer Center and The Cancer Genome Atlas databases. RESULTS: High, intermediate, and low CPSs were seen in 18%, 54% and 28% of GEAs, respectively. PD-L1 positivity was less prevalent in women and in tissues derived from metastatic sites. PD-L1 CPS was positively associated with mismatch repair deficiency/microsatellite instability-high, but independent of tumor mutation burden distribution. Tumors with mutations in KRAS, TP53, and RAS-mitogen-activated protein kinase (MAPK) pathway were associated with higher PD-L1 CPSs in the mismatch repair proficiency and microsatellite stability (pMMR&MSS) subgroup. Patients with RAS-MAPK pathway alterations had longer overall survival (OS) from ICIs compared to wildtype (WT) patients [27 versus 13 months, hazard ratio (HR) = 0.36, 95% confidence interval (CI): 0.19-0.7, P = 0.016] and a similar trend was observed in the MSS subgroup (P = 0.11). In contrast, patients with TP53 mutations had worse OS from ICIs compared to TP53-WT patients in the MSS subgroup (5 versus 21 months, HR = 2.39, 95% CI: 1.24-4.61, P = 0.016). CONCLUSIONS: This is the largest study to investigate the distinct genomic landscapes of GEAs with different PD-L1 CPSs. Our data may provide novel insights for patient selection using mutations in TP53 and RAS-MAPK pathway and for the development of rational combination immunotherapies in GEAs.

Mothers with HIV/AIDS and their children: disclosure and guardianship issues.

For many mothers living with HIV/AIDS, whether, when, and how to disclose their HIV diagnosis to their children and arranging for future care are important although agonizing issues. Due to the increasing number of children who lose their mothers to AIDS and the dearth of empirical information about them, these issues are increasingly important to research. This study of 188 HIV-positive mothers and their 267 children of minor age in New York City revealed that only half the mothers had disclosed their HIV diagnosis to at least one of their children and only 57% had made formal plans for the children's care. As expected, older children were more likely to be informed than younger children. Contrary to some previous research, maternal disclosure was not related to ethnicity, advanced illness, improved psychological well-being, or greater or more satisfying social support resources. Implications for future research and provision of services to this group of women are discussed.

Five-year follow-up of 589 patients treated with amiodarone.

Between 1977 and 1986, 589 patients (age, 57 +/- 13 years; 464 men and 125 women) received amiodarone for ventricular fibrillation (VF; 147 patients), sustained (VT-S; 242 patients) or nonsustained (VT-NS; 80 patients) ventricular tachycardia, or supraventricular tachycardia (SVT; 120 patients). Mean left ventricular ejection fraction was 36 +/- 17%, with 23% in New York Heart Association functional class I, 49% in class II, 25% in class III, and 3% in class IV. Sixty-two percent had ischemic heart disease. Follow-up was 32 +/- 27 months (mean +/- SD). Life table analysis revealed that patients with VF, VT-S, and VT-NS had a cumulative incidence of sudden death of 9% at 1 year, increasing by about 3% per year. By years 2 and 5, the cumulative incidence of sudden death, VF, or VT-S recurrence was 26% and 38% and the percent of patients still taking amiodarone was 54% and 32%. For patients with SVT at years 2 and 5, the cumulative incidence of sudden death was 1% and 3%, and of sudden death or SVT recurrence the cumulative incidence was 20% and 29%. The percent of patients still taking amiodarone was 67% and 43%. Of 14 clinical variables assessed, New York Heart Association functional class was the best predictor of sudden death and arrhythmic failure and no other variable added independent predictive power. Older age and lower left ventricular ejection fraction were independent predictors of drug failure (sudden death or arrhythmic failure or need to discontinue amiodarone because of side effects). We conclude that despite its side effect profile, amiodarone is an effective and reasonably well-tolerated antiarrhythmic drug.

Coronary artery pseudothrombus: angiographic filling defects caused by competitive collateral flow.

Two cases are described of intraluminal coronary artery filling defects resembling thrombus caused by nonopacified collateral blood flow mixing with injected contrast just distal to a severe coronary artery stenosis. The term pseudothrombus is ascribed to this appearance to emphasize this differential diagnosis of intraluminal filling defects.

External compression by metastatic squamous cell carcinoma: a rare cause of left main coronary artery narrowing.

A 69-year-old male with carcinoma of the lung developed unstable angina pectoris during his last few months of life. At necropsy, the coronary arteries were free of atherosclerotic plaque, but the left main artery was severely narrowed by external compression from neoplastic metastases. Persistent anterior ST-segment elevation without evolutionary changes of myocardial infarction was a clue to cardiac involvement by tumor. Direct and indirect effects of metastatic tumors upon the coronary arteries include tumor or thrombi, emboli, wall invasion, or extrinsic wall compression. Extrinsic compression of the left main coronary artery is rare among congenital and acquired conditions producing severe left main disease.

Cardiac manifestations of noncardiac tumors. Part II: Direct effects.

Cardiac manifestations of secondary tumors of the heart exert their effects directly by endocardial, myocardial, epicardial or cavitary deposits (metastatic lesions); indirectly via tumor products such as carcinoma; or mediated by therapy (chemotherapy, radiation) to treat the primary neoplasm. Part II of this review summarizes certain direct effects of noncardiac tumors on the heart including superior and inferior vena cava syndromes, pulmonary artery and vein obstruction or compression, myocardial implants, and intracavitary metastases. Many of these direct effects may be noninvasively diagnosed by computed tomography, magnetic resonance imaging and/or two-dimensional echocardiography.

Cardiac manifestations of noncardiac tumors. Part I: Direct effects.

Cardiac manifestations of secondary tumors of the heart may exert their effects directly by endocardial, myocardial, epicardial, or cavitary deposits (metastatic lesions), indirectly via tumor products such as in carcinoma, or mediated by therapy (chemotherapy, radiation) to treat the primary neoplasm. Part I of this review summarizes the frequency of metastatic cardiac involvement by various tumors and discusses pericardial manifestations (effusion, tamponade, constriction), one of the most common consequences of direct cardiac involvement by secondary tumors.