POLE exonuclease domain mutation predicts long progression-free survival in grade 3 endometrioid carcinoma of the endometrium

Objective

POLE exonuclease domain mutations were recently found to occur in a subset of endometrial carcinomas and result in defective proof-reading function during DNA replication. The aim of this study is to further characterize the clinical and pathologic significance of POLE exonuclease domain mutations in high-grade endometrial carcinomas.

Methods

We assessed for mutations in the exonuclease domain of POLE by Sanger sequencing in 53 grade 3 endometrioid, 25 serous, 16 clear cell and 5 dedifferentiated carcinomas. We correlated POLE mutation status with clinicopathologic features and molecular parameters. Univariate and multivariate survival analyses were performed using Kaplan–Meier and cox regression analyses.

Results

POLE exonuclease domain mutations were identified in 8 of 53 (15%) grade 3 endometrioid carcinomas and not in any other histotypes examined. Only 1 of the 8 grade 3 endometrioid carcinomas with POLE exonuclease domain mutation displayed deficient mismatch repair protein expression by immunohistochemistry (MSH6 loss), compared to 21 of 45 grade 3 endometrioid carcinomas with wild-type exonuclease domain. When analyzed together with published grade 3 endometrioid carcinomas by The Cancer Genome Atlas, the presence of POLE exonuclease domain mutation was associated with significantly better progression-free survival in univariate (p = 0.025) and multivariate (p = 0.010) analyses, such that none of the patients with POLE mutated tumors experienced disease progression

Conclusions

POLE exonuclease domain mutations occur in a subset of grade 3 endometrioid carcinomas and are associated with good clinical outcome. It can serve as an important prognostic molecular marker to guide the management of patients with grade 3 endometrioid carcinomas.     

Cortical spreading depression reversibly disrupts convulsive motor seizure expression in amygdala-kindled rats.

To determine the role of the frontal cortex in the generalization of limbic seizures, we first produced unilateral cortical spreading depression to reversibly suppress neuronal activity in the motor cortex and then triggered an amygdala-kindled seizure. Three minutes following induction of unilateral spreading depression, stimulation of the ipsilateral kindled amygdala produced only a brief electrographic seizure, and completely failed to produce the bilateral electrographic and clonic convulsive seizures that were normally present during control trials. A very different outcome occurred when unilateral spreading depression was induced in the cortex contralateral to the kindled amygdala. In these cases, the electrographic amygdala seizures were normal and bilateral like control trials, yet the clonic convulsive seizures were lateralized and appeared to be controlled by the non-depressed, kindled hemisphere. These lateralized convulsions were identical to those observed following forebrain commissurotomy, when direct communication between the frontal cortices was permanently severed. The results of the present study further define the pathways of temporal lobe seizure propagation, and highlight the important contribution frontal cortical regions provide to both the electrographic and convulsive expression of amygdala-kindled seizures by amplifying local seizures and projecting them into downstream brainstem and spinal cord circuits.     

Nociceptive flexion reflex thresholds and pain during rest and computer game play in patients with hypertension and individuals at risk for hypertension

Supraspinal pain modulation may explain hypertensive hypoalgesia. We compared nociceptive flexion reflex (NFR) thresholds and pain during rest and computer game play in hypertensives and normotensives (Experiment 1) and normotensives with and without hypertensive parents (Experiment 2). The game was selected to modulate activity in pain pathways. NFR thresholds did not differ between groups during rest or game play. Pain ratings never differed between hypertensives and normotensives, whereas individuals with hypertensive parents reported less pain during the first two NFR assessments, compared to those without. NFR thresholds and pain were reduced by game play compared to rest. The failure of game play to differentially modulate NFR thresholds or associated pain reports between groups argues against enhanced supraspinal modulation of nociception and pain in hypertensives and those at increased risk for hypertension.     

Racial variation in wanting and obtaining mental health services among women veterans in a primary care clinic

Epidemiologic studies suggest that African-American women may be less likely to obtain mental health services. Racial differences were explored in wanting and obtaining mental health services among women in an equal access primary care clinic setting after adjusting for demographics, mental disorder symptoms, and a history of sexual trauma. Participating in the study were women veterans at a primary care clinic at the Durham Veterans Affairs Medical Center. Consecutive women patients (n = 526) between the ages of 20 and 49 years were screened for a desire to obtain mental health services. Patients were given the Primary Care Evaluation of Mental Disorders questionnaire (PRIME-MD) and a sexual trauma questionnaire. Mental health service utilization was monitored for 12 months. The median age of the women was 35.8 years; 54.4% of them were African-American. African-American women expressed a greater desire for mental health services than whites, yet mental health resources at the clinic were similarly used by both racial groups. African-American women may want more mental health services; however, given an equal access system, there were no racial differences in mental health use.     

Medical and substance-related comorbidity in bipolar disorder: translational research and treatment opportunities

It is well established that individuals with bipolar disorder are differentially affected by substance-related as well as medical disorders (ie, cardiometabolic disorders, respiratory disorders, neurological disorders, and infectious diseases). Emerging evidence indicates that some comorbid conditions (eg, diabetes mellitus) in bipolar individuals may be subserved by overlapping neurobiological networks. Disturbances in glucocorticoid/insulin signaling and immunoinflammatory effector systems are points of pathophysiological commonality between bipolar disorder and "stress-sensitive" medical disorders. Subphenotyping bipolar disorder as a function of comorbidity and temporality of onset may provide an opportunity for refining disease pathophysiological models and developing innovative disease-modifying therapies.     

Spontaneous intramural rupture of the oesophagus.

The clinical, endoscopic, and radiological features of seven patients with an uncommon oesophageal injury characterised by long lacerations of the oesophageal mucosa with haematoma formation but without perforation are reported. The injuries were not related to forceful vomiting or any other definable cause but were similar to those previously described as intramural oesophageal rupture. Upper gastrointestinal endoscopy undertaken to identify the cause of haematemesis in six patients proved safe and useful. When dysphagia and odynophagia occurred early in the clinical course to alert the clinician to possible oesophageal injury, radiological contrast studies were used to exclude perforation. One patient in this study had oesophageal cavernocapillary haemangiomatosis which may have caused intramural oesophageal bleeding and submucosal dissection but in the remainder the aetiology of intramural oesophageal rupture remains uncertain. Conservative management was successful in all patients.     

Metabolic profiling for water-soluble metabolites in patients with schizophrenia and healthy controls in a Chinese population: A case-control study

Abstract

Objectives: Objective measures integrated with clinical symptoms may improve early prevention and detection of schizophrenia. Herein we aim to evaluate potential water-soluble metabolic biomarkers in schizophrenia.

Methods: We recruited adults with schizophrenia (n?=?113) who had not received pharmacological treatment for at least 1 month prior to enrollment and 111 age- and sex-matched healthy subjects from Weifang, Shandong province, China. All serum samples were analysed using liquid chromatography-tandem mass spectrometry coupled with a hydrophilic interaction liquid chromatography column.

Results: Eleven metabolites, namely carnitines (oleoylcarnitine, l-palmitoylcarnitine, 9-decenoylcarnitine and 2-trans,4-cis-decadienoylcarnitine), polar lipids (lysophosphatidylcholine (LPC)(P-16:0), LPC (16:0), LPC (15:0) and LPC(14:0)), amino acids (taurine and l-arginine), and organic acid (2,5-dichloro-4-oxohex-2-enedioate), separated the patients and healthy controls. Compared with healthy controls, taurine, l-palmitoylcarnitine and oleoylcarnitine levels were higher, whereas the remaining eight metabolites were lower in patients with schizophrenia. A combination of four metabolites, i.e., oleoylcarnitine, 9-decenoylcarnitine, LPC (15:0) and LPC (14:0), provided the most robust between-group separation.

Conclusions: This study appears to distinguish between groups of patients and controls, which should be considered as a contribution to putative potential biomarkers. The water-soluble metabolites were determined to be significantly different between the groups in the current study, and were primarily related to cellular bioenergetics, notably oxidative stress.     

PIK3CA mutational status and overall survival in patients with cervical cancer treated with radical chemoradiotherapy

ObjectiveMutational activation of PIK3CA is associated with poor prognosis in patients with solid tumors, and may predict favorable response to PI3K/AKT/mTOR pathway inhibitors. However, PIK3CA mutational status has not previously been evaluated in patients with cervical carcinoma treated with radical chemoradiotherapy (CRT). The aims of this study were (1) to evaluate the frequency of PIK3CA mutations in patients with cervical cancer treated with radical CRT and (2) to examine the effect of tumor PIK3CA mutational status in pre-treatment biopsies on overall survival (OS) and progression-free survival (PFS).MethodsPatients with cervical cancer, treated at a single institution with radical CRT, from 1999 to 2008, were eligible for this retrospective study. Pre-treatment tumor biopsies (n = 157) were retrieved. Genomic DNA was extracted from tumor blocks, and exons 9 and 20 of the PIK3CA gene were sequenced for mutations.ResultsEighty-two tumors were sequenced for both exon 9 and exon 20. 19/82 (23%) tumors were PIK3CA mutation positive; of these 84% were squamous cell carcinomas. 79% of mutations were in exon 9. PIK3CA mutation status was strongly associated with overall survival (OS) in FIGO stage IB/II patients, unadjusted HR 6.0 (95% CI 2.1–17.5), p = 0.0002, but not stage III/IVA patients, unadjusted HR 1.0 (95% CI 0.32–3.1), p = 0.98.ConclusionsIn cervical cancer patients treated with CRT, tumor PIK3CA mutation status was associated with overall survival in FIGO stage IB/II cervix cancers. Further evaluation with a larger dataset will be required to validate these findings to inform potential clinical trials designs involving PI3K/AKT/mTOR pathway inhibitors.     

Incompatibility of contrast agents with intravascular medications. Work in progress

In vitro and in vivo precipitation of iodinated contrast agents when ioxaglate and papaverine are given together has been reported. To verify these reports and to investigate other medications not previously tested, the authors analyzed mixtures of contrast agents and medications in vitro with a light spectrophotometer and observed them for visible precipitates for up to 120 minutes. Previously reported incompatibilities between ionic or low-osmolality contrast media and medications were verified, and several new incompatibilities were discovered. No incompatibilities were found when the drugs tested were mixed with the new nonionic contrast media.     

Management of Postoperative Lower Urinary Tract Symptoms (LUTS) After Pelvic Organ Prolapse (POP) Repair

Purpose of Review

Pelvic organ prolapse (POP) is a common condition for which approximately 200,000 US women annually undergo surgical repair [Am J Obstet Gynecol 188:108–115, 2003]. After surgical correction, persistent or new lower urinary tract symptoms (LUTS) can be present. We provide guidance on the current tools to predict, counsel, and subsequently handle postoperative LUTS. The current literature is reviewed regarding LUTS diagnosis and management in the setting of prolapse surgery with an emphasis on newer developments in this area.

Recent Findings

1. 1.
   More severe stages of prolapse are positively correlated with obstructive symptoms [Am J Obstet Gynecol 185:1332–1337, 2001], but not with other LUTS [Adv Urol 2013:5673753, 2013, Eur J Obstet Gynecol Reprod Biol 177:141–145, 2014, Am J Obstet Gynecol 199:683, 2008, Int Urogynecol J 21:1143–1149, 2010].
    
2. 2.
   One-week ambulatory pessary trial is an effective way to approximate postoperative results—one study correctly predicted persistent urgency and frequency in addition to occult stress urinary incontinence in 20% of study population [Obstet Gynecol Int 2012:392027, 2012].
    
3. 3.
   No preoperative overactive bladder (OAB) symptom was the best predictor for the absence of de novo OAB symptoms postoperatively [Int Urogynecol J 21:1143–1149, 2010].
    
4. 4.
   Urge incontinence patients respond favorably to sacral neuromodulation [Neurourol Urodyn 26: 29–35, 2007], botulinum toxin, and anticholinergic therapy [Res Rep Urol 8:113–122, 2016 , N Engl J Med, 367:1803–1813, 2012].
    
5. 5.
   Primary bladder outlet obstruction (BOO) can be treated effectively with alpha antagonists or anticholinergics, timed voiding, and pelvic physiotherapy as first-line therapy.
    

Summary

Counseling regarding postoperative LUTS is key when planning POP surgery. A thorough understanding of patient history is crucial to successful repair. Patients with significant preoperative symptoms, history of neurologic disease, pelvic floor dysfunction, bladder neck obstruction, or higher stages of anterior wall prolapse may be higher risk for postoperative LUTS. UDS with or without reduction and an ambulatory pessary trial can help prognosticate. Patients will likely maintain a positive therapeutic relationship postoperatively for LUTS if counseled preoperatively.