Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series.

Background: We have previously developed and confirmed a pragmatic molecular classifier for endometrial cancers; ProMisE (Proactive Molecular Risk Classifier for Endometrial Cancer). Inspired by the Cancer Genome Atlas, ProMisE identifies four prognostically distinct molecular subtypes and can be applied to diagnostic specimens (biopsy/curettings) enabling earlier informed decision-making. We have strictly adhered to the Institute of Medicine (IOM) guidelines for the development of genomic biomarkers, and herein present the final validation step of a locked-down classifier before clinical application. Patients and methods: We assessed a retrospective cohort of women from the Tübingen University Women's Hospital treated for endometrial carcinoma between 2003 and 2013. Primary outcomes of overall, disease-specific, and progression-free survival were evaluated for clinical, pathological, and molecular features. Results: Complete clinical and molecular data were evaluable from 452 women. Patient age ranged from 29 to 93 (median 65) years, and 87.8% cases were endometrioid histotype. Grade distribution included 282 (62.4%) G1, 75 (16.6%) G2, and 95 (21.0%) G3 tumors. 276 (61.1%) patients had stage IA disease, with the remaining stage IB [89 (19.7%)], stage II [26 (5.8%)], and stage III/IV [61 (13.5%)]. ProMisE molecular classification yielded 127 (28.1%) MMR-D, 42 (9.3%) POLE, 55 (12.2%) p53abn, and 228 (50.4%) p53wt. ProMisE was a prognostic marker for progression-free (P = 0.001) and disease-specific (P = 0.03) survival even after adjusting for known risk factors. Concordance between diagnostic and surgical specimens was highly favorable; accuracy 0.91, κ 0.88. Discussion: We have developed, confirmed, and now validated a pragmatic molecular classification tool (ProMisE) that provides consistent categorization of tumors and identifies four distinct prognostic molecular subtypes. ProMisE can be applied to diagnostic samples and thus could be used to inform surgical procedure(s) and/or need for adjuvant therapy. Based on the IOM guidelines this classifier is now ready for clinical evaluation through prospective clinical trials.

Electrocardiographic changes during electrographic seizures.

The occurrence of high-risk cardiac arrhythmias during electrographic seizures has been proposed as a possible cause for sudden unexpected death in patients with epilepsy. Several anecdotal case reports have documented various cardiac irregularities during seizures. We reviewed simultaneous 24-hour electroencephalographic - electrocardiographic studies obtained by ambulatory cassette electroencephalography in 45 patients who experienced 106 electrographic seizures. An increase in heart rate was seen in 96% of seizures, while in four seizures, the rate was unchanged. Heart rate increase measured from 1 minute preictally to intraictal peak ranged from 0% to 160% (mean, 60%). The onset of tachycardia was usually within several seconds (before or after) of the seizure onset, and often persisted for several minutes after termination of the discharge. No difference was found in patients with lateralized vs generalized seizures. Neither ventricular ectopia, conduction defects, or bradycardia were observed during the ictal episodes. We conclude that ictal tachycardia is the rule during electrographic seizures, and that high-risk cardiac arrhythmias are uncommon.

ECG abnormalities in patients with epilepsy.

Some investigators believe that patients with epilepsy are at increased risk of sudden death, perhaps because of cardiac arrhythmias. We studied 338 patients with epilepsy referred for simultaneous ambulatory EEG/ECG monitoring. High-risk cardiac arrhythmias were detected in 18 (5.3%) patients while low-risk arrhythmias or negative studies were found in the others. Fifty-six electrographic seizures were seen in 17 patients, but no associated ventricular arrhythmias or conduction defects were identified. We conclude that the incidence of serious cardiac arrhythmias predisposing to sudden death is not increased in patients with epilepsy.

Ambulatory cassette EEG in absence epilepsy.

Absence epilepsy is associated with bursts of generalized 3 Hz spike-and-wave activity. Even very brief bursts may cause an alteration in the level of consciousness and impaired reaction time. We studied 15 patients, ages 5-16 years, with absence epilepsy using 8 channel ambulatory cassette electroencephalography. All patients demonstrated multiple paroxysms of generalized spike-and-wave discharges, most of which were asymptomatic. Because patients with absence epilepsy may not accurately report seizure frequency, periodic long-term monitoring may be required which is accomplished easily on an outpatient basis with ambulatory cassette electroencephalography.