Gepants, calcitonin gene-related peptide antagonists, for abortive treatment of migraine: current status

Migraine is a neurovascular disorder characterized by unilateral, recurrent, pulsating, throbbing, and moderate to severe headache. Triptans use is often limited by their poor efficacy, reports of poor responders, and contraindicated in patients with cardiovascular disorders. Calcitonin gene-related peptide (CGRP), a neuropeptide, regulates vascular tonicity as well as potent pain mediator, and both the mechanisms involved in development of migraine headache. Gepants are non-peptide, small molecules, highly selective, and potent CGRP antagonists. These novel drugs have been approved for abortive treatment of acute migraine with or without aura. These are being evaluated for their effectiveness and showing promising results in the prevention of migraine. Gepants do not have vasoconstrictive properties, are safe to use in patients with cardiovascular risk, and best alternative to triptan therapy. These are available in tablet, orally disintegrating tablet, and nasal forms to improve patient compliance. Ubrogepant and rimegepant are the two oral CGRP antagonists approved whereas atogepant and zavegepant are at late stage of development for approval

Effects of Process Variables and Size Scale on Solidification Microstructure in Laser-Based Solid Freeform Fabrication of Ti-6Al-4V

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c-FOS drives reversible basal to squamous cell carcinoma transition.

While squamous transdifferentiation within subpopulations of adenocarcinomas represents an important drug resistance problem, its underlying mechanism remains poorly understood. Here, using surface markers of resistant basal cell carcinomas (BCCs) and patient single-cell and bulk transcriptomic data, we uncover the dynamic roadmap of basal to squamous cell carcinoma transition (BST). Experimentally induced BST identifies activator protein 1 (AP-1) family members in regulating tumor plasticity, and we show that c-FOS plays a central role in BST by regulating the accessibility of distinct AP-1 regulatory elements. Remarkably, despite prominent changes in cell morphology and BST marker expression, we show using inducible model systems that c-FOS-mediated BST demonstrates reversibility. Blocking EGFR pathway activation after c-FOS induction partially reverts BST in vitro and prevents BST features in both mouse models and human tumors. Thus, by identifying the molecular basis of BST, our work reveals a therapeutic opportunity targeting plasticity as a mechanism of tumor resistance

Long-term seizure and psychosocial outcomes of vagus nerve stimulation for intractable epilepsy

Vagus nerve stimulation (VNS) is a widely used adjunctive treatment option for intractable epilepsy. Most studies have demonstrated short-term seizure outcomes, usually for up to 5 years, and thus far, none have reported psychosocial outcomes in adults. We aimed to assess long-term seizure and psychosocial outcomes in patients with intractable epilepsy on VNS therapy for more than 15 years. We identified patients who had VNS implantation for treatment of intractable epilepsy from 1997 to 2013 at our Comprehensive Epilepsy Program and gathered demographics including age at epilepsy onset and VNS implantation, epilepsy type, number of antiepilepsy drugs (AEDs) and seizure frequency before VNS implantation and at the last clinic visit, and the most recent stimulation parameters from electronic medical records (EMR). Phone surveys were conducted by research assistants from May to November 2014 to determine patients\u27 current seizure frequency and psychosocial metrics, including driving, employment status, and use of antidepressants. Seizure outcomes were based on modified Engel classification (I: seizure-free/rare simple partial seizures; II: \u3e90% seizure reduction (SR), III: 50-90% SR, IV:50% SR)=favorable outcome). A total of 207 patients underwent VNS implantation, 15 of whom were deceased at the time of the phone survey, and 40 had incomplete data for medical abstraction. Of the remaining 152, 90 (59%) were contacted and completed the survey. Of these, 51% were male, with the mean age at epilepsy onset of 9.4 years (range: birth to 60 years). There were 35 (39%) patients with extratemporal epilepsy, 19 (21%) with temporal, 18 (20%) with symptomatic generalized, 5 (6%) with idiopathic generalized, and 13 (14%) with multiple types. Final VNS settings showed 16 (18%) patients with an output current \u3e2 mA and 14 (16%) with rapid cycling. Of the 80 patients with seizure frequency information, 16 (20%) had a modified Engel class I outcome, 14 (18%) had class II, 24 (30%) had class III, and 26 (33%) had class IV. Eighty percent said having VNS was worthwhile. Among the 90 patients, 43 patients were ≥ 18 years old without developmental delay in whom psychosocial outcomes were further analyzed. There was a decrease in the number of patients driving (31% vs 14%, p=0.052) and working (44% vs 35%, p=0.285) and an increase in the number of patients using antidepressant medication (14% vs 28%, p=0.057) at the time of survey compared to before VNS. In this subset, patients with \u3e50% SR (60%) were taking significantly fewer AEDs at the time of survey compared to patients with unfavorable outcomes (median: 3 vs 4, p=0.045). The associations of \u3e50% SR with the psychosocial outcomes of driving, employment, and antidepressant use were not significant, although 77% of this subset said VNS was worthwhile. This is the first study that assesses both seizure and psychosocial outcomes, and demonstrates favorable seizure outcomes of \u3e50% SR in 68% of patients and seizure freedom in 20% of patients. A large majority of patients (80%) considered VNS therapy worthwhile regardless of epilepsy type and psychosocial outcomes

Recurrence of intestinal metaplasia and early neoplasia after endoscopic eradication therapy for Barrett’s esophagus: A systematic review and meta-analysis

Abstract Background Conflicting data exist with regard to recurrence rates of intestinal metaplasia (IM) and dysplasia after achieving complete eradication of intestinal metaplasia (CE-IM) in Barrett’s esophagus (BE) patients. Aim (i) To determine the incidence of recurrent IM and dysplasia achieving CE-IM and (ii) to compare recurrence rates between treatment modalities [radiofrequency ablation (RFA) with or without endoscopic mucosal resection (EMR) vs stepwise complete EMR (SRER)]. Methods A systematic search was performed for studies reporting on outcomes and estimates of recurrence rates after achieving CE-IM. Pooled incidence [per 100-patient-years (PY)] and risk ratios with 95 %CI were obtained. Heterogeneity was measured using the I 2 statistic. Subgroup analyses, decided a priori, were performed to explore heterogeneity in results. Results A total of 39 studies were identified (25-RFA, 13-SRER, and 2 combined). The pooled incidence of any recurrence was 7.5 (95 %CI 6.1 – 9.0)/100 PY with a pooled incidence of IM recurrence rate of 4.8 (95 %CI 3.8 – 5.9)/100 PY, and dysplasia recurrence rate of 2.0 (95 %CI 1.5 – 2.5)/100 PY. Compared to the SRER group, the RFA group had significantly higher overall [8.6 (6.7 – 10.5)/100 PY vs. 5.1 (3.1 – 7)/100 PY, P = 0.01] and IM recurrence rates [5.8 (4.3 – 7.3)/100 PY vs. 3.1 (1.7 – 4)/100 PY, P &lt; 0.01] with no difference in recurrence rates of dysplasia. Significant heterogeneity between studies was identified. The majority of recurrences were amenable to repeat endoscopic eradication therapy (EET). Conclusion The results of this study demonstrate that the incidence rates of overall, IM, and dysplasia recurrence rates post-EET are not inconsiderable and reinforce the importance of close surveillance after achieving CE-IM.</jats:p

Effect of seizure timing on long-term survival in patients with brain tumor

OBJECTIVE: Seizures often occur in patients with primary brain tumor (BT). The aim of this study was to determine if there is an association between the time of occurrence of seizures during the course of BT and survival of these patients. METHODS: This retrospective cohort study at Henry Ford Hospital, an urban tertiary referral center, included all patients who were diagnosed with primary BTs at Henry Ford Health System between January 2006 and December 2014. Timing of seizure occurrence, if occurred at presentation or after the tumor diagnosis during follow-up period, in different grades of BTs, and survival of these patients were analyzed. RESULTS: Of the 901 identified patients, 662 (53% male; mean age: 56 years) were included in final analysis, and seizures occurred in 283 patients (43%). Patients with World Health Organization (WHO) grade III BT with seizures as a presenting symptom only had better survival (adjusted hazard ratio (HR): 0.27; 95% confidence interval (CI), 0.11-0.67; P = 0.004). Seizures that occurred after tumor diagnosis only (adjusted HR: 2.11; 95% CI, 1.59-2.81; P \u3c 0.001) in patients with WHO grade II tumors (adjusted HR: 3.41; 95% CI, 1.05-11.1; P = 0.041) and WHO grade IV tumors (adjusted HR: 2.14; 95% CI, 1.58-2.90; P \u3c 0.001) had higher mortality. Seizures that occurred at presentation and after diagnosis also had higher mortality (adjusted HR: 1.34; 95% CI, 1.00-1.80; P = 0.049), in patients with meningioma (adjusted HR: 6.19; 95% CI, 1.30-29.4; P = 0.021) and grade III tumors (adjusted HR: 6.19; 95% CI, 2.56-15.0; P \u3c 0.001). CONCLUSION: Seizures occurred in almost half of the patients with BTs. The association between seizures in patients with BT and their survival depends on the time of occurrence of seizures, if occurring at presentation or after tumor diagnosis, and the type of tumor. Better survival was noted in patients with WHO grade III BTs who had seizures at presentation at the time of diagnosis, while higher mortality was noted in WHO grade II tumors who had seizure at presentation and after tumor diagnosis, and in grade IV tumors after tumor diagnosis

A comparison between endoscopic ultrasound-guided rendezvous and percutaneous biliary drainage after failed ERCP for malignant distal biliary obstruction

Background and study Aims: Selective biliary cannulation is unsuccessful in 5 % to 10 % of patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) for malignant distal biliary obstruction (MDBO). Percutaneous biliary drainage (PBD) has been the gold standard, but endoscopic ultrasound guided rendezvous (EUSr) have been increasingly used for biliary decompression in this patient population. Our aim was to compare the initial success rate, long-term efficacy, and safety of PBD and EUSr in relieving MDBO after failed ERC Patients and methods: A retrospective study involving 50 consecutive patients who had an initial failed ERCP for MDBO. Twenty-five patients undergoing EUSr between 2008 – 2014 were compared to 25 patients who underwent PBD immediately prior to the introduction of EUSr at our center (2002 – 2008). Comparisons were made between the two groups with regard to technical success, duration of hospital stay and adverse event rates after biliary decompression. Results: The mean age at presentation was 66.5 (± 12.6 years), 28 patients (54.9 %) were female. The etiology of MDBO was pancreaticobiliary malignancy in 44 (88 %) and metastatic disease in 6 (12 %) cases. Biliary drainage was technically successful by EUSr in 19 (76 %) cases and by PBD in 25 (100 %) (P = 0.002). Median length of hospital stay after initial drainage was 1 day in the EUSr group vs 5 days in PBD group (P = 0.02). Repeat biliary intervention was required for 4 patients in the EUSr group and 15 in the PBD group (P = 0.001). Conclusions: Initial technical success with EUSr was significantly lower than with PBD, however when EUSr was successful, patients had a significantly shorter post-procedure hospital stay and required fewer follow-up biliary interventions. Meeting presentations: Annual Digestive Diseases Week 201

Friction stir welding of SS 316 LN and Nitronic 50 jacket sections for application in superconducting fusion magnet systems

Article explores the possibility of using friction stir welding (FSW) to join jacket web sections of two nitrogen-containing stainless steels for housing internally cooled superconducting cables which are utilized to generate magnetic fields in tokamak type fusion reactor systems. It has been shown that the FSW fabricated SS 316 LN jackets possessed the required strength and magnetic properties critical to this application