AGA Clinical Practice Update on Diagnosis and Management of Cyclic Vomiting Syndrome: Commentary.

DESCRIPTION: The purpose of this American Gastroenterological Association (AGA) Institute Clinical Practice Update (CPU) is to review the available evidence and provide expert advice regarding the diagnosis and management of cyclic vomiting syndrome. METHODS: This CPU was commissioned and approved by the AGA Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the CPUC and external peer review through standard procedures of Gastroenterology. This expert commentary incorporates important as well as recently published studies in this field, and it reflects the experiences of the authors who are experts in treating patients with cyclic vomiting syndrome.

Prophylactic treatment of FSGS recurrence in patients who relapsed in a previous kidney graft.

BACKGROUND AND HYPOTHESIS: Recurrence of focal segmental glomerulosclerosis (FSGS) is common after kidney transplantation and is classically associated with a significant decrease in graft survival. A major risk factor is a prior history of FSGS recurrence on a previous graft. This analysis reports the impact of a prophylactic treatment of FSGS recurrence in very high-risk patients who experienced a recurrence on a previous graft. METHODS: We performed a retrospective multicentre observational study in 25 French transplantation centres. The inclusion criteria were patients aged more than 18 years who had undergone kidney transplant between December 31, 2004, and December 31, 2020, and who had a history of FSGS recurrence on a previous graft. RESULTS: We identified 66 patients: 40 received prophylactic treatment (PT+), including intravenous cyclosporine and/or rituximab and/or plasmapheresis, and 26 did not receive any prophylactic treatment (PT-). The time to progression to end-stage kidney disease was similar between groups. The PT + group was younger at FSGS diagnosis and at the time of kidney retransplantation and lost their previous graft faster. The overall recurrence rate was 72.7% (76.9% in the PT- group and 70.0% in the PT + group, P = 0.54). At least partial remission was achieved in 87.5% of patients. The 5-year graft survival was 67.7% (95% CI: 53.4 to 78.4%): 65.1% (95%CI: 48.7 to 77.4%) in patients with FSGS recurrence vs. 77.3% (95% CI: 43.8 to 92.3%) in patients without recurrence (P = 0.48). CONCLUSION: Our study suggests that prophylactic treatment should not be used routinely in patients receiving a second transplantation after recurrence of FSGS on a previous graft. The recurrence rate is high regardless of the use of prophylactic treatment. However, the 5-year graft survival remains satisfactory.

Efficacy of oral and non-oral migraine prophylactic treatment on self-reported subjective sleep quality in migraine patients with sleep problems: A review and meta-analysis.

This study aims to investigate the effects of oral and non-oral migraine prophylaxis on subjective sleep quality in migraine patients with sleep problems. A bidirectional relationship between migraine and sleep is presumed, although this relationship is not fully clarified. Possibly, prophylactic treatment of migraine aiming at a reduction of migraine attack frequency can also positively affect the quality of sleep for patients with migraine with sleep problems. PubMed, Cochrane, Embase and CINAHL databases were searched in March 2022 for studies evaluating prophylactic treatment of migraine and the impact on perceived sleep quality (Pittsburgh Sleep Quality Index or Insomnia Severity Index). A systematic review using the McMaster Tool and a random-effects meta-analysis (effect size Cohen's d) were conducted. Seven studies were identified, including 989 participants, of which 844/989 (85.3%) female, with a mean (SD) age of 41.3 (12.1) years. In 6/7 (85.7%) studies, monthly migraine days improved (p < 0.002). Five out of six (83.3%) studies presented a relevant improvement in quality of sleep (p < 0.05), and one study reported a clinically meaningful improvement in the treatment group (Insomnia Severity Index change >7, in >50% of participants). The meta-analysis showed a large effect size of 1.09 (95% confidence interval 0.57-1.62; overall p < 0.001; Cochran's Q < 0.0001) for migraine prophylaxis on improving sleep quality. In conclusion, prophylactic migraine treatment improves sleep quality in patients with migraine and sleep problems, as measured with self-reported questionnaires Pittsburgh Sleep Quality Index and Insomnia Severity Index. Unfortunately, some included studies used prophylactic treatment that is not in current (international) guidelines. The evidence for this improvement in quality of sleep is strong, and seems a generic effect of migraine prophylaxis.

Reliability, validity, and responsiveness of the Arabic version of HIT-6 questionnaire in patients with migraine indicated for preventive therapy: A multi-center study.

BACKGROUND: The Headache Impact Test (HIT-6) is an important patient-reported outcome measure (PROM) in migraine prevention trials. OBJECTIVES: This study aimed to (i) assess the reliability and validity of the Arabic version of HIT-6 in Arabic-speaking patients experiencing migraine, and (ii) evaluate the responsiveness of HIT-6 following migraine preventive therapy. METHODS: In this prospective study, patients with migraine (n = 145) were requested to fill out a headache diary, the Arabic version of HIT-6, and Migraine Disability Assessment Scale (MIDAS) at two time points (baseline and 3 months after initiation of prophylactic treatment). Some respondents (n = 73) were requested to fill out HIT-6 again 1 week from the baseline for test-retest reliability. The intensity of migraine headache attacks was evaluated using the Visual Analogue Scale (VAS). An anchor-based method was used to establish the minimal important change (MIC) value and responsiveness of HIT-6. RESULTS: The total scores of HIT-6 were significantly correlated to a fair degree with MIDAS (r = 0.41), as well as VAS (r = 0.53), and monthly migraine days (r = 0.38) at the baseline while at the follow-up (after 3 months), the correlations were of moderate degree with MIDAS scores (r = 0.62) and monthly migraine days (r = 0.60; convergent validity). Reliability estimates of the Arabic HIT-6 were excellent (Cronbach's α = 0.91 at baseline and 0.89 at follow-up). The average measure interclass correlation coefficient (ICC) value for the test-retest reliability was 0.96 (95% confidence interval = 0.94-0.98, p < 0.001). The HIT-6 total score is sensitive to change, being significantly reduced after prophylactic treatment compared to before (effect size = 1.5, standardized response mean = 1.3). A reduction from baseline of 4.5 on HIT-6 showed the highest responsiveness to predict improvement with an area under the curve equal to 0.66, sensitivity of 80%, specificity of 45%, and significance at 0.021. Changes in the HIT-6 total score were positively correlated with changes in monthly migraine days (r = 0.40) and VAS scores (r = 0.69) but not with changes in the score of MIDAS (r = 0.07). CONCLUSION: The Arabic version of HIT-6 is valid, reliable, and sensitive to detect clinical changes following migraine prophylactic treatment with a MIC of 4.5 points.

Risk Factors of Cetuximab-Induced Hypomagnesemia and the Effect of Magnesium Prophylaxis in Patients with Head and Neck Cancer: A Retrospective Study.

Hypomagnesemia is a characteristic adverse event of cetuximab in patients with head and neck cancer (HNC). However, there is limited information about its prevalence, risk factors, and preventive strategies. This study aimed to investigate the risk factors of hypomagnesemia and examine the preventive effects of prophylactic magnesium (Mg) administration. We initially investigated HNC patients treated with cetuximab between 2013 and 2019. Our institute started prophylactic Mg treatment (20-mEq Mg sulfate administration before cetuximab) in practice during this period. We retrospectively assess the preventive efficacy by comparing patients before and after its implementation. In total, 109 patients were included. In 60 patients without prophylaxis, all-grade and grade ≥2 hypomagnesemia at 3 months occurred in 61.7 and 15.0% of patients. The incidence of hypomagnesemia was not affected by regimens and concomitant medications. In 49 patients treated with prophylactic Mg treatment, there was no significant decrease in the cumulative incidence of hypomagnesemia. However, the preventive Mg treatment eliminated the need for additional Mg repletion to maintain Mg levels in patients treated with paclitaxel + cetuximab. A risk factor in patients without prophylaxis was a low Mg level at pre-treatment (≤2.0 mg/dL) (odds ratio: 6.03, 95% confidence interval: 1.78-20.4, p = 0.004), whereas that in patients with prophylaxis was the number of cetuximab doses (≥10) (odds ratio: 5.50, 95% confidence interval: 1.52-19.87, p = 0.009). In conclusion, a low pre-treatment Mg level was the only risk factor that could be avoided by prophylactic Mg administration. This preventive intervention is recommended for managing cetuximab-induced hypomagnesemia.

Genome-wide DNA methylation analysis in an antimigraine-treated preclinical model of cortical spreading depolarization.

BACKGROUND: Cortical spreading depolarization, the cause of migraine aura, is a short-lasting depolarization wave that moves across the brain cortex, transiently suppressing neuronal activity. Prophylactic treatments for migraine, such as topiramate or valproate, reduce the number of cortical spreading depression events in rodents. OBJECTIVE: To investigate whether cortical spreading depolarization with and without chronic treatment with topiramate or valproate affect the DNA methylation of the cortex. METHODS: Sprague-Dawley rats were intraperitoneally injected with saline, topiramate or valproate for four weeks when cortical spreading depolarization were induced and genome-wide DNA methylation was performed in the cortex of six rats per group. RESULTS: The DNA methylation profile of the cortex was significantly modified after cortical spreading depolarization, with and without topiramate or valproate. Interestingly, topiramate reduced by almost 50% the number of differentially methylated regions, whereas valproate increased them by 17%, when comparing to the non-treated group after cortical spreading depolarization induction. The majority of the differentially methylated regions lay within intragenic regions, and the analyses of functional group over-representation retrieved several enriched functions, including functions related to protein processing in the cortical spreading depolarization without treatment group; functions related to metabolic processes in the cortical spreading depolarization with topiramate group; and functions related to synapse and ErbB, MAPK or retrograde endocannabinoid signaling in the cortical spreading depolarization with valproate group. CONCLUSIONS: Our results may provide insights into the underlying physiological mechanisms of migraine with aura and emphasize the role of epigenetics in migraine susceptibility.

Acute symptomatic seizures after stroke: A scoping review on primary prevention, treatment with antiseizure medications and drug discontinuation.

AIM: To evaluate and synthesize the evidence and knowledge gaps on primary prevention and treatment of post-stroke acute symptomatic seizures (ASSs) using antiseizure medications (ASMs). METHODS: We systematically searched of EMBASE, MEDLINE (accessed from PubMed), and the Cochrane Central Register of Controlled Trials (CENTRAL) to include randomized, double- or single-blinded trials (RCTs) on primary prophylaxis and treatment of post-stroke ASSs with ASMs. The risk of bias in the included studies was assessed according to the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions. RESULTS: Two placebo-controlled RCTs (totaling 114 participants) evaluating valproate or levetiracetam as primary prophylaxis of ASSs due to hemorrhagic stroke were included. In one RCT, post-stroke ASS occurred in 1/36 patients (2.7%) on valproate and in 4/36 patients (7%) on placebo (p = 0.4). In the other RCT, ASSs were only electrographic and occurred in 3/19 (16%) with levetiracetam and in 10/23 (43%) with placebo (p = 0.043). We found no RCTs on the treatment of post-stroke ASSs or discontinuation of ASMs administered for the treatment of post-stroke ASSs. CONCLUSION: Evidence to support primary prophylaxis of ASSs is sparse and of very low quality and is insufficient to recommend it routinely. Secondary prevention of post-stroke ASSs is usually not recommended except in selected cases (the most relevant being acute symptomatic status epilepticus, which carries a high risk of subsequent poststroke seizures (PSE)). The choice of which ASM to administer and for how long is not based on solid RCT evidence. Management of post-stroke PSE should be done according to an evidence-based framework, considering the individuality of the patient and the pharmacological properties of the drugs.

Effects of a True Prophylactic Treatment on Hippocampal and Amygdala Synaptic Plasticity and Gene Expression in a Rodent Chronic Stress Model of Social Defeat.

Post-traumatic stress disorder (PTSD) is a complex stress-related disorder induced by exposure to traumatic stress that is characterized by symptoms of re-experiencing, avoidance, and hyper-arousal. While it is widely accepted that brain regions involved in emotional regulation and memory-e.g., the amygdala and hippocampus-are dysregulated in PTSD, the pathophysiology of the disorder is not well defined and therefore, pharmacological interventions are extremely limited. Because stress hormones norepinephrine and cortisol (corticosterone in rats) are heavily implicated in the disorder, we explored whether preemptively and systemically antagonizing ß-adrenergic and glucocorticoid receptors with propranolol and mifepristone are sufficient to mitigate pathological changes in synaptic plasticity, gene expression, and anxiety induced by a modified social defeat (SD) stress protocol. Young adult, male Sprague Dawley rats were initially pre-screened for anxiety. The rats were then exposed to SD and chronic light stress to induce anxiety-like symptoms. Drug-treated rats were administered propranolol and mifepristone injections prior to and continuing throughout SD stress. Using competitive ELISAs on plasma, field electrophysiology at CA1 of the ventral hippocampus (VH) and the basolateral amygdala (BLA), quantitative RT-PCR, and behavior assays, we demonstrate that our SD stress increased anxiety-like behavior, elevated long-term potentiation (LTP) in the VH and BLA, and altered the expression of mineralocorticoid, glucocorticoid, and glutamate receptors. These measures largely reverted to control levels with the administration of propranolol and mifepristone. Our findings indicate that SD stress increases LTP in the VH and BLA and that prophylactic treatment with propranolol and mifepristone may have the potential in mitigating these and other stress-induced effects.

European Headache Federation (EHF) critical re-appraisal and meta-analysis of oral drugs in migraine prevention-part 1: amitriptyline.

OBJECTIVE: The aim of this paper is to critically re-appraise the published trials assessing amitriptyline for migraine prophylaxis. METHODS: We report our methods and results following the Preferred Reporting Items for Systematic Reviews (PRISMA), by searching MEDLINE, EMBASE, Cochrane CENTRAL, and ClinicalTrials.gov for randomized trials of pharmacologic treatments for migraine prophylaxis. We included randomized trials that compared amitriptyline with placebo for migraine prophylaxis in adults. Our outcomes of interest were informed by the Outcome Set for preventive intervention trials in chronic and episodic migraine (COSMIG) and include the proportion of patients who experience a 50% or more reduction in migraine days per month, migraine days per month, and adverse events leading to discontinuation. We assessed risk of bias by using a modified Cochrane RoB 2.0 tool and the certainty of evidence by using the GRADE approach. RESULTS: Our search yielded 10.826 unique records, of which three trials (n = 622) were eligible for data synthesis and analysis. We found moderate certainty evidence that amitriptyline increases the proportion of patients who experience a 50% or more reduction in monthly migraine days, compared to placebo (relative risk: 1.60 (95% CI 1.17 to 2.19); absolute risk difference: 165 more per 1,000 (95% CI 47 more to 327 more). We found moderate certainty evidence that amitriptyline increases the proportion of patients who discontinue due to adverse events compared to placebo (risk difference: 0.05 (95% CI 0.01 to 0.10); absolute risk difference: 50 more per 1,000 (95% CI 10 more to 100 more). CONCLUSIONS: Our meta-analysis showed that amitriptyline may have a prophylactic role in migraine patients, however these results are far from robust. This warrants further large-scale research to evaluate the role of amitriptyline in migraine prevention.

European Headache Federation (EHF) critical re-appraisal and meta-analysis of oral drugs in migraine prevention-part 2: flunarizine.

OBJECTIVE: Novel disease-specific and mechanism-based treatments sharing good evidence of efficacy for migraine have been recently marketed. However, reimbursement by insurers depends on treatment failure with classic anti-migraine drugs. In this systematic review and meta-analysis, we aimed to identify and rate the evidence for efficacy of flunarizine, a repurposed, first- or second-line treatment for migraine prophylaxis. METHODS: A systematic search in MEDLINE, Cochrane CENTRAL, and ClinicalTrials.gov was performed for trials of pharmacological treatment in migraine prophylaxis, following the Preferred Reporting Items for Systematic Reviews (PRISMA). Eligible trials for meta-analysis were randomized, placebo-controlled studies comparing flunarizine with placebo. Outcomes of interest according to the Outcome Set for preventive intervention trials in chronic and episodic migraine (COSMIG) were the proportion of patients reaching a 50% or more reduction in monthly migraine days, the change in monthly migraine days (MMDs), and Adverse Events (AEs) leading to discontinuation. RESULTS: Five trials were eligible for narrative description and three for data synthesis and analysis. No studies reported the predefined outcomes, but one study assessed the 50% reduction in monthly migraine attacks with flunarizine as compared to placebo showing a benefit from flunarizine with a low or probably low risk of bias. We found that flunarizine may increase the proportion of patients who discontinue due to adverse events compared to placebo (risk difference: 0.02; 95% CI -0.03 to 0.06). CONCLUSIONS: Published flunarizine trials predate the recommended endpoints for evaluating migraine prophylaxis drugs, hence the lack of an adequate assessment for these endpoints. Further, modern-day, large-scale studies would be valuable in re-evaluating the efficacy of flunarizine for the treatment of migraines, offering additional insights into its potential benefits.

Migraine symptoms, healthcare resources utilization and disease burden in a large Polish migraine cohort : Results from 'Migraine in Poland'-a nationwide cross-sectional survey.

BACKGROUND: The Migraine in Poland study is the first large scale nationwide cross-sectional online survey of symptoms, approaches to management, treatment patterns, quality of life, and sociodemographic characteristics of the Polish migraine patients' cohort, conducted from August 2021 to June 2022. METHODS: A cross-sectional online survey was designed based on the American Migraine Prevalence and Prevention (AMPP) Study. Participants were recruited through broad advertisement through various channels. The survey included questions allowing for the diagnosis of migraine without aura (MwoA) based on the third edition of the International Classification of Headache Disorders (ICHD-3). Moreover, the questionnaire assessed sociodemographic and headache features, comorbidities, consultation rates with medical professionals, as well as the use of abortive or preventive treatment, including non-pharmacological methods, psychological symptoms and the burden of migraine. RESULTS: A structured online questionnaire was submitted by 3225 respondents aged 13 to 80 (mean age 38.9, 87.1% women). In this group 1679 (52.7%) of participants fulfilled ICHD-3 diagnostic criteria for MwoA, which was in most cases (88.3%) confirmed by a medical professional in the past. In this group the average number of monthly headache days was 4.7, while 47.8% of participants had at least 4 migraine days per month. Mean Migraine Disability Assessment score was 42.65 (median 32). Among MwoA respondents, 1571 (93.6%) had consulted their headache with a medical professional in the past - mostly neurologists (n = 1450 (83.4%) and primary care physicians (n = 1393 (82.9%). In the MwoA cohort, 1553 (92.5%) of participants declared the current use of some form of treatment, although only 193 (11.5%) respondents were currently on preventive medications. The most prevalent comorbidities included: chronic rhinitis (37.1%), allergies (35.9%) and low blood pressure (26.9%). Anxiety (20.4%) and depression (21.3%) were highly prevalent among participants. CONCLUSIONS: People with migraine in Poland face similar difficulties as their peers in other countries. Despite relatively high access to neurologist consultations and good diagnosis accuracy, migraine still poses diagnostic and therapeutic difficulties. In this context, migraine undertreatment in Polish population must be underlined, especially in context of high disease burden.

Repeated greater occipital nerve injections with corticosteroids in medically intractable chronic cluster headache: a retrospective study.

INTRODUCTION: Current prophylactic drugs for cluster headache are associated with limited efficacy, serious side effects and poor tolerability. Greater occipital nerve injection (GON-injection) has been proven effective and safe as a single, one-time injection in episodic (ECH), and to a lesser extent, chronic cluster headache (CCH). We aim to analyse the effectiveness and safety of repeated GON-injections in medically intractable chronic cluster headache (MICCH). METHODS: Clinical data of all cluster headache patients who had received at least one GON-injection between 2014 and 2018 in our tertiary headache centre were retrieved from patients' medical records. Clinical history was taken as part of routine care shortly before and 6 weeks after GON-injection. RESULTS: We identified 47 MICCH patients (79 injections), and compared results with 22 non-MI CCH patients (30 injections) and 50 ECH patients (63 injections). Nineteen MICCH patients received repeated injections (32 in total, range 2-8). Rates of clinical relevant improvement to a first injection were similar in all groups (MICCH: 60%, non-MICCH 73%, ECH 76%; attack freedom: MICCH: 30%, non-MICCH 32%, ECH 43%). Furthermore, no difference in response to the first and second injection was shown between groups (all p > 0.29). Median effect duration in MICCH was 6 weeks (IQR 2.8-12 weeks). Side effects were only mild and local. CONCLUSION: In this retrospective analysis, first and repeated GON-injections were well-tolerated and equally effective in MICCH as in non-MICCH, and ECH.

The disease burden of migraine patients receiving prophylactic treatments in Korea: a population-based claims database analysis.

BACKGROUND: Despite guideline recommendations, the limited benefits and failure of prophylactic treatment in patients with migraine have been reported. This study aimed to estimate the incremental burden (i.e., healthcare resource use and cost) of disease in patients who received at least one prophylactic treatment compared to those who did not. METHODS: This study analyzed the Health Insurance Review and Assessment Service database, which covers the entire population of Korea from December 2014 to November 2019. We included adult patients with migraine (≥18 years) who had ≥1 claim with migraine diagnosis (G43) or received ≥1 prescription of triptan or ergotamine between December 2015 and November 2018. We defined two groups: (1) migraine patients who received at least one prophylactic treatment (prophylaxis group) and (2) migraine patients who never received prophylactic treatments (non-prophylaxis group). We performed propensity score matching to balance the baseline covariates between the two groups. In a matched cohort, we estimated healthcare resource use and costs in terms of outpatient visits, outpatient visits to neurologists, emergency department (ED) visits, and hospitalizations. RESULTS: After matching, 633,709 and 633,709 patients were identified in the prophylaxis and non-prophylaxis groups, respectively. The healthcare resource utilization was significantly higher in the prophylaxis group than in the non-prophylaxis group in terms of the number of outpatient visits (2.34 vs 1.70), outpatient visits to neurologists (2.23 vs 1.61), ED visits (1.07 vs 1.05), and hospitalizations (1.12 vs 1.09) (all P <  0.05). The estimated annual costs per patient were significantly higher in the prophylaxis group than in the non-prophylaxis group for outpatient (102.37 USD vs. 62.46 USD), neurology outpatient (141.80 USD vs. 120.30 USD), and ED visits (550.51 USD vs. 234.14 USD) and hospitalization (817.01 USD vs. 645.97 USD) (all P <  0.001). CONCLUSIONS: Migraine patients who received ≥1 prophylactic treatment had a higher burden of disease than migraine patients who received no prophylaxis. This indicates that despite migraine prophylaxis, the migraine-related disease burden remains high, and more efficient migraine prophylaxis strategies are needed.

Applications of transcranial magnetic stimulation in migraine: evidence from a scoping review.

Transcranial magnetic stimulation (TMS), a non-invasive brain stimulation method, is trying to emerge as a migraine management strategy for both attack treatment and prevention. This scoping review presents 16 among single-pulse (to manage episodic and chronic migraine) and repetitive TMS randomized clinical trials (to manage chronic migraine). The works we reviewed suggest that TMS may be adopted as add-on therapy in those patients who are refractory to pharmacological therapy only with special arrangements for individualized treatment strategies or research. There are still limited clinical research programs and metaanalysis to promote routinely TMS employment, as TMS has been shown either to have no significant effects for any outcome or to be effective for migraine. These diverging conclusions depend on several biasing factors, including the lack of reliable, large, sham-controlled clinical trials, the dyshomogeneity in study designs (including the area of stimulation, the frequency of stimulation, the number of pulses, pulse intensity, and the number of sessions), patient selection criteria (migraine w/o aura, episodic and chronic migraine; TMS contraindication), and the lack of outcomes homogeneity and long-term real-world efficacy data. Therefore, in the future, it will be important to conduct larger randomized trials to confirm TMS usefulness in migraine management (acute attack and prophylactic treatment), identify those patients who may benefit from TMS, maybe independently of pharmacological treatments (i.e., using TMS as an alternative and not only as an add-on treatment). Otherwise, TMS will play a role in treating migraine only with special arrangements for individualized management strategies or research.

A Novel Prophylaxis Strategy Using Liposomal Vaccine Adjuvant CAF09b Protects against Influenza Virus Disease.

The SARS-CoV-2 pandemic caused a massive health and societal crisis, although the fast development of effective vaccines reduced some of the impact. To prepare for future respiratory virus pandemics, a pan-viral prophylaxis could be used to control the initial virus outbreak in the period prior to vaccine approval. The liposomal vaccine adjuvant CAF®09b contains the TLR3 agonist polyinosinic:polycytidylic acid, which induces a type I interferon (IFN-I) response and an antiviral state in the affected tissues. When testing CAF09b liposomes as a potential pan-viral prophylaxis, we observed that intranasal administration of CAF09b liposomes to mice resulted in an influx of innate immune cells into the nose and lungs and upregulation of IFN-I-related gene expression. When CAF09b liposomes were administered prior to challenge with mouse-adapted influenza A/Puerto Rico/8/1934 virus, it protected from severe disease, although the virus was still detectable in the lungs. However, when CAF09b liposomes were administered after influenza challenge, the mice had a similar disease course to controls. In conclusion, CAF09b may be a suitable candidate as a pan-viral prophylactic treatment for epidemic viruses, but must be administered prior to virus exposure to be effective.

Onabotulinumtoxin A (ONA-BoNT/A) in the treatment of chronic migraine.

Migraine is a common primary headache disease, which reduces quality of life. About 8% of migraineurs suffer from chronic migraine (CM), which is the most severe and troublesome type. It has been proven that onabotulinumtoxinA (ONA-BoNT/A) significantly improves CM, presumably inhibiting the release of calcitonin gene-related peptide (CGRP) and other neurotransmitters from c-fibres endings, and thus decreasing activation of nociceptive pathways and transmission of pain. The aim of this position paper was to assess the place of ONA-BoNT/A for the prophylaxis of CM in adults. The authors have compared the efficacy, safety and tolerance of the toxin to those of classical oral preventive therapies as well as to recently introduced anti-CGRP-pathway monoclonal antibodies. The results of randomised controlled studies of ONA-BoNT/A have been compared to open label (real world practice) trials.

Personalized neoantigen vaccine prevents postoperative recurrence in hepatocellular carcinoma patients with vascular invasion.

BACKGROUND: Clinically, prophylactic anti-recurrence treatments for hepatocellular carcinoma (HCC) patients after radical surgery are extremely limited. Neoantigen based vaccine can generate robust anti-tumor immune response in several solid tumors but whether it could induce anti-tumor immune response in HCC and serve as a safe and effective prophylactic strategy for preventing postoperative HCC recurrence still remain largely unclear. METHODS: Personalized neoantigen vaccine was designed and immunized for 10 HCC patients with high risk of postoperative recurrence in a prime-boost schedule. The safety and immune response were assessed through adverse events, tissue sequencing, ELISpot, TCR sequencing. The clinical response was evaluated by recurrence-free survival (RFS) and personalized circulating tumor DNA (ctDNA) sequencing. RESULTS: In the 10 enrolled patients, no obvious adverse events were observed during neoantigen vaccinations. Until the deadline of clinical trial, 8 of 10 patients were confirmed with clinical relapse by imaging, the other 2 patients remained relapse-free. From receiving first neoantigen vaccination, the median RFS of 10 patients were 7.4 months. Among 7 patients received all planned neoantigen vaccinations, 5 of them demonstrated neoantigen-induced T cell responses and have significantly longer RFS after radical surgery than other 5 patients without responsive neoantigens or only with prime vaccination and propensity scores matching control patients (p = 0.035). Moreover, tracking personalized neoantigen mutations in ctDNA could provide real-time evaluation of clinical response in HCC patients during neoantigen vaccination and follow up. CONCLUSION: Personalized neoantigen vaccine is proved as a safe, feasible and effective strategy for HCC anti-recurrence, and its progression could be sensitively monitored by corresponding neoantigen mutations in ctDNA, and thus provided solid information for individualized medicine in HCC. TRIAL REGISTRATION: This study was registered at Chinese Clinical Trial Registry; Registration number: ChiCTR1900020990 .

The potential role of emicizumab prophylaxis in severe von Willebrand disease.

BACKGROUND: Severe von Willebrand disease (VWD) may be associated with chronic joint damage and may require prophylactic therapy. Emicizumab is a humanized bispecific antibody, which mimics the function of coagulation factor VIII (FVIII), and it has been approved for prophylaxis in hemophilia A. METHODS: This is the first study assessing the potential future role of emicizumab as an alternative prophylactic treatment in patients with severe VWD, based upon a thrombin generation (TG) ex vivo analysis. We report 51 weeks of successful off label emicizumab prophylaxis in a child with severe VWD and recurrent hemarthroses and progressive arthropathy despite adherence to previous prophylaxis with replacement therapy. RESULTS AND CONCLUSIONS: Our work demonstrated that ex vivo spiking with emicizumab increased TG in plasma from patients with type 3 VWD. Similar TG results were observed in our treated patient, whose therapy was well tolerated without any adverse events. Both in vitro and ex vivo TG data support sufficient hemostasis without exceeding the range seen in healthy volunteers. Further collaborative studies on the efficacy and safety of emicizumab prophylaxis in severe VWD is warranted.

Few X-ray and PUVA treatments accelerate photocarcinogenesis in hairless mice.

PUVA is a treatment that combines oral methoxypsoralen (8-MOP) with ultraviolet radiation A (UVA). It is used for severe psoriasis and the early stages of T-cell lymphoma. X-rays are an effective treatment for skin cancers. Both treatments are in higher doses used to treat skin malignancies and simultaneously increase the risk of keratinocyte cancer. The main objective of this study was to test whether a few PUVA or X-ray treatments could delay the development of ultraviolet radiation (UVR)-induced skin tumors in a well-established hairless mouse model. Three groups of immunocompetent mice (total, N = 75) were included in the study. All groups were UVR-exposed during the study period. In addition, one group was treated with PUVA and another group was treated with X-rays at days 45, 52, 90 and 97. A control group was treated with UVR only. We recorded when the first, second and third skin tumors were induced in each mouse. Skin tumors developed significantly earlier in both the PUVA and X-ray groups (median, 188 days) than in the control mice (median, 215 days; p < 0.001). Therefore, a few X-ray and PUVA treatments both significantly accelerated the development of skin tumors in hairless mice, compared to UVR controls. Neither treatment showed a delay of UVR-induced skin tumors and caution should be exercised before applying these treatments to sun-damaged skin.

A retrospective observation on 105 patients with chronic cluster headache receiving indomethacin.

BACKGROUND: Indomethacin (IMC) as a prophylactic treatment is considered to be ineffective in cluster headache (CH). However, small series suggested the interest of IMC in CH. Some authors support that an IMC test is useful in all trigeminal autonomic cephalalgias. We described clinical features of IMC responders in a retrospective cohort of chronic cluster headache (CCH). METHODS: This single-center and retrospective study was conducted in a tertiary care specialist headache center in France. Patients were selected between January 2007 and December 2008. We included all patients fulfilling CCH criteria (ICHD-3-beta). Data were collected from medical records. We recorded all the prescriptions of IMC as a prophylactic treatment. Responders were defined by 50% reduction in attack frequency; complete response was defined by disappearance of the attacks. The non-responders must have received at least 100 mg daily during 7 days. RESULTS: The study consisted of 324 CCH, 121 female (37%) and 203 males (63%) with an average age at onset of 33.93 (± 14.71) years. Of the patients, 105 were treated with IMC. Thirty patients (29%) were responders. Thirty-four patients (32%) were non-responders. Responding status was undefined for 41 patients (39%). Twelve patients (11%) had a complete response. Responders were composed by 18 women (60%) and 12 men (40%) and had on average 44.89 (± 12.88) years. The minimal effective dose was 86.11 mg daily (± 48.72). DISCUSSION: This study shows the interest of IMC in CCH patients. We recommend an IMC test as a third-line treatment in CCH.