Antiepileptic therapy approaches in KCNQ2 related epilepsy: A systematic review.

BACKGROUND: KCNQ2 related disorders comprise both benign seizure disorders and early onset epileptic encephalopathies. Especially within the latter group, patients suffer from refractory seizures to standard antiepileptic drugs and developmental delay. Besides the hope of personalized medical approaches to treat the recently unraveled large amount of genetic channelopathies, there are sparse systematic data on treatment responses in KCNQ2 related epilepsy in larger cohorts. METHODS: We searched PubMed using the free text term search 'KCNQ2 AND Epilepsy' and identified additional records using PubMed Medical Subject Headings (MeSH). Based on patients' clinical information about their therapy they were assigned to one of four groups: 'seizure freedom', 'responder', 'successful therapy', and 'unsuccessful therapy'. RESULTS: Out of 52 studies, 217 subjects were eligible for further data analyses. 133 patients were classified as 'benign' seizure disorders whereas 84 patients were classified as 'Early Onset Epileptic Encephalopathy (EOEE)'. In the 'benign' group, 92.5% of patients became seizure free while 3.8% did not respond to treatment. In contrast 65.5% of patients in the 'EOEE' group were reported seizure free, while 14.3% showed no treatment success (p = 0.003). Spontaneous seizure remission (without medication) was 30.1% in the 'benign' group. Phenobarbital and sodium channel blockers most often lead to seizure freedom in patients with a 'benign' course. In patients with 'EOEE' seizure freedom was more likely achieved when receiving sodium channel blockers. CONCLUSIONS: Seizures associated with mutations within the voltage gated potassium channel KCNQ2 are well controlled by medical treatment in patients with 'benign' courses and moderately well in patients with the 'EOEE' group. A significant number of patients in the 'benign' group may experience seizure freedom spontaneously. Phenobarbital might be considered in benign courses, while sodium channel blockers seem appropriate for both 'benign' and 'EOEE' patients.

The Validity of a New Structured Assessment of Gastrointestinal Symptoms Scale (SAGIS) for Evaluating Symptoms in the Clinical Setting.

BACKGROUND: The clinical assessments of patients with gastrointestinal symptoms can be time-consuming, and the symptoms captured during the consultation may be influenced by a variety of patient and non-patient factors. To facilitate standardized symptom assessment in the routine clinical setting, we developed the Structured Assessment of Gastrointestinal Symptom (SAGIS) instrument to precisely characterize symptoms in a routine clinical setting. AIMS: We aimed to validate SAGIS including its reliability, construct and discriminant validity, and utility in the clinical setting. METHODS: Development of the SAGIS consisted of initial interviews with patients referred for the diagnostic work-up of digestive symptoms and relevant complaints identified. The final instrument consisted of 22 items as well as questions on extra intestinal symptoms and was given to 1120 consecutive patients attending a gastroenterology clinic randomly split into derivation (n = 596) and validation datasets (n = 551). Discriminant validity along with test-retest reliability was assessed. The time taken to perform a clinical assessment with and without the SAGIS was recorded along with doctor satisfaction with this tool. RESULTS: Exploratory factor analysis conducted on the derivation sample suggested five symptom constructs labeled as abdominal pain/discomfort (seven items), gastroesophageal reflux disease/regurgitation symptoms (four items), nausea/vomiting (three items), diarrhea/incontinence (five items), and difficult defecation and constipation (2 items). Confirmatory factor analysis conducted on the validation sample supported the initially developed five-factor measurement model ([Formula: see text], p < 0.0001, χ 2/df = 4.6, CFI = 0.90, TLI = 0.88, RMSEA = 0.08). All symptom groups demonstrated differentiation between disease groups. The SAGIS was shown to be reliable over time and resulted in a 38% reduction of the time required for clinical assessment. CONCLUSIONS: The SAGIS instrument has excellent psychometric properties and supports the clinical assessment of and symptom-based categorization of patients with a wide spectrum of gastrointestinal symptoms.

RIG-I-like helicases induce immunogenic cell death of pancreatic cancer cells and sensitize tumors toward killing by CD8(+) T cells.

Pancreatic cancer is characterized by a microenvironment suppressing immune responses. RIG-I-like helicases (RLH) are immunoreceptors for viral RNA that induce an antiviral response program via the production of type I interferons (IFN) and apoptosis in susceptible cells. We recently identified RLH as therapeutic targets of pancreatic cancer for counteracting immunosuppressive mechanisms and apoptosis induction. Here, we investigated immunogenic consequences of RLH-induced tumor cell death. Treatment of murine pancreatic cancer cell lines with RLH ligands induced production of type I IFN and proinflammatory cytokines. In addition, tumor cells died via intrinsic apoptosis and displayed features of immunogenic cell death, such as release of HMGB1 and translocation of calreticulin to the outer cell membrane. RLH-activated tumor cells led to activation of dendritic cells (DCs), which was mediated by tumor-derived type I IFN, whereas TLR, RAGE or inflammasome signaling was dispensable. Importantly, CD8α(+) DCs effectively engulfed apoptotic tumor material and cross-presented tumor-associated antigen to naive CD8(+) T cells. In comparison, tumor cell death mediated by oxaliplatin, staurosporine or mechanical disruption failed to induce DC activation and antigen presentation. Tumor cells treated with sublethal doses of RLH ligands upregulated Fas and MHC-I expression and were effectively sensitized towards Fas-mediated apoptosis and cytotoxic T lymphocyte (CTL)-mediated lysis. Vaccination of mice with RLH-activated tumor cells induced protective antitumor immunity in vivo. In addition, MDA5-based immunotherapy led to effective tumor control of established pancreatic tumors. In summary, RLH ligands induce a highly immunogenic form of tumor cell death linking innate and adaptive immunity.