Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids.

The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Through machine learning and multi-omics factor analysis, we compare and contrast the genomic profiles of 116 pulmonary carcinoids (including 35 atypical), 75 large-cell neuroendocrine carcinomas (LCNEC), and 66 small-cell lung cancers. Here we report that the integrative analyses on 257 lung neuroendocrine neoplasms stratify atypical carcinoids into two prognostic groups with a 10-year overall survival of 88% and 27%, respectively. We identify therapeutically relevant molecular groups of pulmonary carcinoids, suggesting DLL3 and the immune system as candidate therapeutic targets; we confirm the value of OTP expression levels for the prognosis and diagnosis of these diseases, and we unveil the group of supra-carcinoids. This group comprises samples with carcinoid-like morphology yet the molecular and clinical features of the deadly LCNEC, further supporting the previously proposed molecular link between the low- and high-grade lung neuroendocrine neoplasms.

Antibodies targeting p63 react specifically in the cytoplasm of breast epithelial cells exhibiting secretory differentiation.

AIMS: The nuclear detection of p63 in myoepithelial cells of the breast has been useful in identifying possibly invasive carcinomas. While examining myoepithelial cells for p63 a very strong cytoplasmic reaction product was noted in secretory cells. The aim was to determine whether this reaction is specific for p63 and indicative of all breast secretory cells. METHODS: Thirty breast specimens were tested immunohistochemically for p63 protein. These included seven with benign secretory changes, 10 secretory carcinomas (nine invasive), one microglandular adenosis, three lobular neoplasias, four invasive ductal carcinomas, three clear cell carcinomas, one squamous cell carcinoma and one mucinous carcinoma. RESULTS: Only cells exhibiting secretory changes or secretory carcinoma were cytoplasmically reactive for p63. The positive reaction was also present as an intraluminal secretory product. This reaction was not seen in cells undergoing apocrine differentiation or in other cells containing secretory vacuoles. CONCLUSIONS: Cells with secretory changes contain p63 protein or an antigenic equivalent. The detection of p63 protein continues to have considerable value for the identification of myoepithelial cells and thus the determination of invasion, but will also have value in the determination of secretory carcinomas of the breast and in understanding their development.

Ductus-dependent fetal cardiac defects contraindicate indomethacin tocolysis.

The hemodynamics of critical aortic stenosis in the fetus make it a ductus-dependent cardiac defect because the ductus arteriosus supplies blood not only to the descending aorta but also to the aortic arch and coronary vessels. In utero closure of the ductus arteriosus has been reported in association with tetralogy of Fallot, truncus arteriosus, maternal use of prostaglandin inhibitors, and as idiopathic events. This is the first report of a ductus-dependent congenital heart defect (critical aortic stenosis) where treatment with indomethacin, a prostaglandin synthetase inhibitor, precipitated premature closure of the ductus and hydrops fetalis. Review of reported cases of premature closure of the ductus show that acute, in utero closure of the ductus in a fetus with limited cardiopulmonary reserves has a worse prognosis than with previously reported cardiac anomalies. This study strongly supports published concerns of increased perinatal morbidity and mortality when fetuses are exposed to prostaglandin inhibitors in utero, and shows that ductus-dependent fetal cardiac defects are contraindications to the maternal use of prostaglandin inhibitors during pregnancy.

A tungsten-supplemented diet delivered by transplacental and breast-feeding routes lowers intestinal xanthine oxidase activity and affords cytoprotection in ischemia-reperfusion injury to the small intestine.

Ischemia-reperfusion injury has been implicated as playing a major role in the development of necrotizing enterocolitis, a major cause of morbidity and mortality in the newborn. A tungsten-supplemented molybdenum-free diet can reduce xanthine oxidase (XO) enzyme activity in the intestine, which in turn reduces the generation of oxygen radicals after an ischemia-reperfusion insult. This study evaluated the ability of this diet to be effective by indirect means, ie, transplacental and breast-feeding routes. XO activity of the intestine was measured in three groups of CD-1 white rats: I, weanlings fed the tungsten diet or standard chow for 1 week; II, 1-day-old rat pups whose mothers were maintained on the tungsten or standard chow for 7 to 10 days prior to term; and III, rat pups at 1 and 3 weeks after birth whose lactating mothers were maintained on the tungsten or standard chow. Some animals from group III also underwent either a 30- or 60-minute episode of occlusion of the superior mesenteric artery (SMA) to evaluate the protective effects of the diet. XO activity was significantly reduced in all groups receiving the tungsten diet (P less than .0001). Blinded histopathologic studies of the entire small bowel showed significantly less villar necrosis (P less than .05) and fibrosis (P less than .0001) in the tungsten-treated group than in the controls. In the 60-minute occlusion study all tungsten-group animals survived, whereas 7 of 12 in the control group died of intestinal infarction within 24 hours (P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Hypersensitivity myocarditis.

Autopsy tissue specimens of 69 cases of hypersensitivity myocarditis were studied to determine drug association, spectrum of histologic findings, distribution of infiltrates, and correlation between degree of infiltrates and cardiac symptoms. Hypersensitivity myocarditis was defined by the presence of eosinophils, a mixed lymphohistiocytic infiltrate along natural planes of separation, and an absence of fibrosis or granulation tissue in areas of infiltrate. Commonly implicated drugs were methyldopa, hydrochlorothiazide, ampicillin, furosemide, digoxin, tetracycline, aminophylline, phenytoin, benzodiazepines, and tricyclic antidepressants. Histiocytes composed the predominant cell type (in addition to eosinophils and lymphocytes). Lymphocytes were predominantly T cells in 12 cases studied immunohistochemically. Small foci of myocyte necrosis were present in 37 cases, and they correlated with the degree of infiltrate. A nonnecrotizing vasculitis was present in 28 cases. The right ventricle was involved in all but three cases. Cardiac arrhythmias or unexplained death occurred in 29 patients and did not correlate with the degree of myocardial infiltrate or presence of necrosis. Eosinophils were present in the livers of 30 of 58 patients, and their presence correlated with the degree of cardiac infiltration. A causative association between histologic findings and drugs is difficult to prove because of the common usage of many of the drugs implicated, multiple drug use, and the absence of clinical criteria of hypersensitivity. Symptoms do not appear related to the degree of infiltrate. In more than half the cases, infiltrates may be missed by endomyocardial biopsy due to focality of lesions.