Mode and site of action of therapies targeting CGRP signaling

Calcitonin; Headache; MigraineCalcitonina; Dolor de cabeza; MigrañaCalcitonina; Mal de cap; MigranyaTargeting CGRP has proved to be efficacious, tolerable, and safe to treat migraine; however, many patients with migraine do not benefit from drugs that antagonize the CGRPergic system. Therefore, this review focuses on summarizing the general pharmacology of the different types of treatments currently available, which target directly or indirectly the CGRP receptor or its ligand. Moreover, the latest evidence regarding the selectivity and site of action of CGRP small molecule antagonists (gepants) and monoclonal antibodies is critically discussed. Finally, the reasons behind non-responders to anti-CGRP drugs and rationale for combining and/or switching between these therapies are addressed.The article-processing charges for the article has been sponsored by the European Headache Federation

Anti-CGRP monoclonal antibodies in chronic migraine with medication overuse: real-life effectiveness and predictors of response at 6 months

Erenumab; Migranya; Anticossos monoclonalsErenumab; Migraña; Anticuerpos monoclonicosErenumab; Migraine; Monoclonal antibodiesBackground In daily practice, anti-CGRP monoclonal antibodies (MAbs) may be useful in chronic migraine (CM) with medication overuse (MO), but data is limited. We evaluated their effectiveness in a real-life clinical cohort. Methods This is a prospective study conducted in CM patients with and without medication overuse treated with monthly MAbs during 6 months (erenumab/galcanezumab). We collected headache characteristics, including acute medication intake, through an electronic diary. We compared patients (1) with and without MO at baseline, (2) with and without ongoing MO after treatment, defining MO resolution as < 10 or 15 days/month of acute medication intake, according to analgesic type, during the 6-month treatment. Results Of 139 CM patients completing 6-month treatment with anti-CGRP MAbs, 71.2% (99/139) had MO at baseline. After 6 months, patients with and without MO at baseline had significant and similar proportions of ≥50% reduction in migraine days/month (MO: 63.6% vs. non-MO: 57.5%, p = 0.500). 60.6% (60/99) no longer satisfied MO definition. Reduction in headache frequency compared to baseline occurred in both MO-ongoing and MO-resolution group, although those who stopped overusing had a greater improvement (headache days/month: − 13.4 ± 7.6 vs. -7.8 ± 7.2, p < 0.0001). No differences in MO resolution were observed according to the MAbs used. Baseline lower pain severity was associated with MO resolution (OR [95%]:0.236[0.054–0.975]; p = 0.049). Conclusions In real-life anti-CGRP MAbs are as effective in CM patients with MO as in patients without it and facilitate MO cessation. Reduction in headache frequency and acute medication days/month occurs regardless of whether patients stop overusing or not.No funding was received for this study

In search of a gold standard patient-reported outcome measure to use in the evaluation and treatment-decision making in migraine prevention: A real-world evidence study

Efficacy; Headache; Health-related quality of lifeEficàcia; Mal de cap; Qualitat de vida relacionada amb la salutEficacia; Dolor de cabeza; Calidad de vida relacionada con la saludBackground Patient-Reported Outcomes (PROs) have been developed to numerically quantify disability, impact and quality of life. They have been widely used in migraine clinical trials. However, we still do not know which PRO more accurately reflects preventive treatment response from a patient’s perspective or which one may help us with treatment decisions in clinical practice. They have been used to enforce the efficacy results in clinical trials and real-world evidence so far. The aim of this study was to analyze which PROM is (1) better correlated with all primary efficacy endpoints and (2) which one is better associated with treatment continuation with CGRP-mAbs at week-12, which is usually the moment when this decision is made. Methods Patients with migraine who had received 3 administrations of CGRP-mAbs were evaluated in this prospective cohort study. Primary efficacy outcomes considered: a change in migraine days (MMD), headache days (MHD), pain intensity (INT), acute medication days (AMD) and 50% responder rate. The Spearman coefficient (rs) was the measure used for quantify the strength of the correlation between PROMs and treatment efficacy outcomes changes. A stepwise logistic regression identified which PROM was independently associated with treatment continuation at week-12. Results 263 patients completed 12 weeks of treatment. The efficacy outcomes and PROMs scores were statistically significantly reduced at week-12 for all patients. The role function-restrictive (RFR) domain of the Migraine-Specific Quality of Life (MSQ) questionnaire was statistically significantly correlated with all primary efficacy outcomes. Relative changes in MSQ total score (OR[95%]: 0.840[0.619-0.973]; p=0.037) and Patient Global Impression of Change (PGIC) scale (OR[95%]: 15.569[6.254-31.533]; p<0.001) were the PROMs associated with treatment continuation as independent factors at week-12. Conclusions Changes in MSQ questionnaire and PGIC scale at week-12 were the PROMs with higher association with CGRP-mAbs response from a patient’s perspective and medical decision-taking.The authors received no financial support for the research, authorship, and/or publication

Impact of anti-CGRP monoclonal antibodies on migraine attack accompanying symptoms: A real-world evidence study

Migraine; Anti-CGRP monoclonal antibodies; PhonophobiaMigraña; Anticuerpos monoclonales anti-CGRP; FonofobiaMigranya; Anticossos monoclonals anti-CGRP; FonofòbiaBackground Clinical trials on anti-calcitonin gene-related peptide monoclonal antibodies poorly investigated their impact on migraine accompanying symptoms. Objective To evaluate the impact of basal accompanying symptoms on anti-CGRP monoclonal antibodies treatment response and their evolution after six months of treatment in migraine patients. Methods Patients with migraine diagnosis seen in the Headache Clinic and treated with erenumab, galcanezumab or fremanezumab were prospectively recruited. They completed a daily eDiary which provided data on headache frequency and the following accompanying symptoms of each day: photophobia, phonophobia, nausea, dizziness, and aura. Patients were classified as responders or non-responders based on 50% or greater reduction in headache days per month at month 6 (≥50% response rate). Accompanying symptoms ratios based on headache days per month were assessed per patient at baseline and after three and six months. Comparisons for basal characteristics, basal accompanying symptoms ratios and their evolution after six months between responders and non-responders were performed. Results One hundred and fifty-eight patients were included, 44% (69/158) showed ≥50% response rate after six months. A significant reduction in headache days per month in both groups was found at month 6 (−9.4 days/month in ≥50% response rate group; p < 0.001, −2.2 days/month in <50% response rate group; p = 0.004). Additionally, significant decreases in photophobia (−19.5%, p < 0.001), phonophobia (−12.1%, p = 0.010) and aura ratios (−25.1%, p = 0.008) were found in ≥50% response rate group. No statistically significant reductions were found in nausea and dizziness in any group since their reduction was correlated with the decrease in headache days per month. Higher photophobia ratios at baseline were predictive of an increased response between months 3 and 6 (Incidence Risk Ratio = 0.928, p = 0.040). Conclusions The days per month with photophobia, phonophobia and aura decreased at a higher rate than headache days per month after six months in the ≥50% response group. Higher photophobia ratios were associated with higher response rates between three and six months. It could indicate an involvement of peripheral CGRP in photophobia as well as a central modulation of migraine through these treatments which mainly act on the periphery

Headache attributed to SARS-CoV-2 infection, vaccination and the impact on primary headache disorders of the COVID-19 pandemic: A comprehensive review

COVID-19; Telemedicine; VaccineCOVID-19; Telemedicina; VacunaCOVID-19; Telemedicina; VacunaObjective The objective is to summarize the knowledge on the epidemiology, pathophysiology and management of secondary headache attributed to SARS-CoV-2 infection and vaccination; as well as to delineate their impact on primary headache disorders. Methods This is a narrative review of the literature regarding primary and secondary headache disorders in the setting of COVID-19 pandemic. We conducted a literature search in 2022 on PubMed, with the keywords “COVID 19” or “vaccine” and “headache” to assess the appropriateness of all published articles for their inclusion in the review. Results Headache is a common and sometimes difficult-to-treat symptom of both the acute and post-acute phase of SARS-CoV-2 infection. Different pathophysiological mechanisms may be involved, with the trigeminovascular system as a plausible target. Specific evidence-based effective therapeutic options are lacking at present. Headache attributed to SARS-CoV-2 vaccinations is also common, its pathophysiology being unclear. People with primary headache disorders experience headache in the acute phase of COVID-19 and after vaccination more commonly than the general population. Pandemic measures, forcing lifestyle changes, seemed to have had a positive impact on migraine, and changes in headache care (telemedicine) have been effectively introduced. Conclusions The ongoing COVID-19 pandemic is a global challenge, having an impact on the development of secondary headaches, both in people with or without primary headaches. This has created opportunities to better understand and treat headache and to potentiate strategies to manage patients and ensure care

A study of differential microRNA expression profile in migraine: the microMIG exploratory study

Epigenetics; Migraine; MicroRNAEpigenética; Migraña; MicroARNEpigenètica; Migranya; MicroARNBackground Several studies have described potential microRNA (miRNA) biomarkers associated with migraine, but studies are scarcely reproducible primarily due to the heterogeneous variability of participants. Increasing evidence shows that disease-related intrinsic factors together with lifestyle (environmental factors), influence epigenetic mechanisms and in turn, diseases. Hence, the main objective of this exploratory study was to find differentially expressed miRNAs (DE miRNA) in peripheral blood mononuclear cells (PBMC) of patients with migraine compared to healthy controls in a well-controlled homogeneous cohort of non-menopausal women. Methods Patients diagnosed with migraine according to the International Classification of Headache Disorders (ICHD-3) and healthy controls without familial history of headache disorders were recruited. All participants completed a very thorough questionnaire and structured-interview in order to control for environmental factors. RNA was extracted from PBMC and a microarray system (GeneChip miRNA 4.1 Array chip, Affymetrix) was used to determine the miRNA profiles between study groups. Principal components analysis and hierarchical clustering analysis were performed to study samples distribution and random forest (RF) algorithms were computed for the classification task. To evaluate the stability of the results and the prediction error rate, a bootstrap (.632 + rule) was run through all the procedure. Finally, a functional enrichment analysis of selected targets was computed through protein–protein interaction networks. Results After RF classification, three DE miRNA distinguished study groups in a very homogeneous female cohort, controlled by factors such as demographics (age and BMI), life-habits (physical activity, caffeine and alcohol consumptions), comorbidities and clinical features associated to the disease: miR-342-3p, miR-532-3p and miR-758-5p. Sixty-eight target genes were predicted which were linked mainly to enriched ion channels and signaling pathways, neurotransmitter and hormone homeostasis, infectious diseases and circadian entrainment. Conclusions A 3-miRNA (miR-342-3p, miR-532-3p and miR-758-5p) novel signature has been found differentially expressed between controls and patients with migraine. Enrichment analysis showed that these pathways are closely associated with known migraine pathophysiology, which could lead to the first reliable epigenetic biomarker set. Further studies should be performed to validate these findings in a larger and more heterogeneous sample.This study was solely funded by the Migraine Research Foundation

Early and annual projected savings from anti-CGRP monoclonal antibodies in migraine prevention: a cost-benefit analysis in the working-age population

Anti-CGRP monoclonal antibodies; Migraine prevention; Cost-benefitAnticuerpos monoclonales anti-CGRP; Prevención de la migraña; Costo-beneficioAnticossos monoclonals anti-CGRP; Prevenció de la migranya; Cost-beneficiBackground Migraine is one of the main causes of disability worldwide. Anti-CGRP monoclonal antibodies (MAbs) have proven to be safe and efficacious as preventive migraine treatments. However, their use is restricted in many countries due to their apparently high cost. Cost-benefit studies are needed. Objective To study the cost-benefit of anti-CGRP MAbs in working-age patients with migraine. Methods This is a prospective cohort study of consecutive migraine patients treated with anti-CGRP MAbs (erenumab, fremanezumab and galcanezumab) following National reimbursement policy in a specialized headache clinic. Migraine characteristics and the work impact scale (WPAI) were compared between baseline (M0) and after 3 (M3) and 6 months (M6) of treatment. Using WPAI and the municipal average hourly wage, we calculated indirect costs (absenteeism and presenteeism) at each time point. Direct costs (emergency visits, acute medication use) were also analysed. A cost-benefit study was performed considering the different costs and savings of treating with MAbs. Based on these data an annual projection was conducted. Results From 256 treated working-age patients, 148 were employed (89.2% women; mean age 48.0 ± 8.5 years), of which 41.2% (61/148) were responders (> 50% reduction in monthly headache days (MHD)). Statistically significant reductions between M0 and M3/M6 were found in absenteeism (p < 0.001) and presenteeism (p < 0.001). Average savings in indirect costs per patient at M3 were absenteeism 105.4 euros/month and presenteeism 394.3 euros/month, similar for M6. Considering the monthly cost of anti-CGRP MAbs, the cost-benefit analysis showed savings of 159.8 euros per patient at M3, with an annual projected savings of 639.2 euros/patient. Both responders and partial responders (30–50% reduction in MHD) presented a positive cost-benefit balance. The overall savings of the cohort at M3/M6 compensated the negative cost-benefit balance for non-responders (< 30% reduction in MHD). Conclusion Anti-CGRP MAbs have a positive impact in the workforce significantly reducing absenteeism and presenteeism. In Spain, this benefit overcomes the expenses derived from their use already at 3 months and is potentially sustainable at longer term; also in patients who are only partial responders, prompting reconsideration of current reimbursement criteria and motivating the extension of similar cost-benefit studies in other countries

A prognostic score for predicting survival in patients with pancreatic head adenocarcinoma and distal cholangiocarcinoma

Background/aim: Survival of patients with pancreatic cancer remains poor despite improvements in therapeutic strategies. This study aims to create a novel preoperative score to predict prognosis in patients with tumors of the pancreaticobiliary head. Patients and methods: Data on 190 patients who underwent to pancreaticoduodenectomy at Sapienza University of Rome from January 2010 to December 2018 were retrospectively analyzed. After exclusion criteria, 101 patients were considered eligible for retrospective study. Preoperative biological, clinical and radiological parameters were considered. Results: Pancreatic ductal adenocarcinoma [hazard ratio (HR)=1.995, 95% confidence intervaI (CI)=1.1-3.3; p=0.01], carbohydrate antigen 19.9 (CA 19.9) &gt;230 U/ml (HR=2.414, 95% CI=2.4-1.5, p&lt;0.0001) and Wirsung duct diameter &gt;3 mm (HR=1.592, 95% CI=1.5-0.9; p=0.08) were the only parameters associated with poor prognosis. Through these parameters, a prognostic score (PHT score) was developed which predicted worst survival when exceeding 2 and better survival when ≤2. Conclusion: The PHT score may have a potential impact on predicting overall survival and consequently modulate the timing and type of treatment (up-front surgery vs. neoadjuvant therapy) patients are offered

Metastatic renal cell carcinoma invading liver, duodenum and ivc, surgical treatment and literature review. A case report

Renal Cell Carcinoma has a biologic predisposition for direct vascular invasion: intravascular tumor thrombus is found in 5% to 20% of the cases inside the renal vein or the inferior vena cava. Despite new and effective conservative therapy such as targeted therapy and immunotherapy, cytoreductive nephrectomy and palliative nephrectomy continues to have an important role in T4 patient. The patient selection for cytoreductive nephrectomy should be done carefully. This report present an unique case of metastatic RCC with invasion of the duodenum, liver and retrohepatic IVC, the adopted surgical approach and a review of the literature. Complete surgical extirpation is possible in cases of RCC invading other organs such as pancreas, duodenum, liver, retroperitoneum and IVC. In this scenario, to narrow the possible intraoperative complication, a multidisciplinary approach and equipe is recommended

Pancreatic ductal adenocarcinoma and distal cholangiocarcinoma: a proposal of preoperative diagnostic score for differential diagnosis

Purpose:The differential diagnosis between primary adenocarcinoma of the pancreas head and distalcholangiocarcinoma remains a clinical challenge. Recent studies have shown important differences in terms ofsurvival between these tumors. Therefore, different treatments should be considered, but the preoperativehistological diagnosis is still difficult. Aim of this study is to create a preoperative diagnostic score for differentialdiagnosis between primary pancreatic adenocarcinoma and primary distal cholangiocarcinoma.Methods:One hundred eighty consecutive patients who underwent pancreaticoduodenectomy at SapienzaUniversity of Rome from January 2010 to December 2019 were retrospectively analyzed. Inclusion criteria werepancreatic or biliary histologic origin obtained by definitive postoperative histological examination. Exclusion criteriawere diagnosis of ampullary carcinoma, non-ampullary duodenal adenocarcinoma, pancreatic metastasis, andbenign disease. One hundred one patients were considered eligible for the retrospective study. Preoperativebiological, clinical, and radiological parameters were considered.Results:CRP &gt; 10 mg/dL (p= 0.001), modified Glasgow Prognostic Score 2 (p= 0.002), albumin &lt; 35 g/L (p= 0.05),CA 19-9 &gt; 230 U/mL (p= 0.001), and Wirsung diameter &gt; 3 mm (p&lt; 0.001) were significant at univariate logisticanalysis. Multivariate logistic analysis has shown that parameters independently associated with primary pancreaticadenocarcinoma were CRP &gt; 10 mg/dL (p= 0.012), CA 19-9 &gt; 230 U/mL (p= 0.043), and diameter of the Wirsung&gt; 3 mm (p= 0.005). Through these parameters, a diagnostic score has been developed to predict a primarypancreatic adenocarcinoma when &gt; 1 and a primary distal cholangiocarcinoma when &lt; 1.Conclusion:This feasible and low-cost diagnostic score could have a potential impact to differentiate pancreaticcancer histologic origin and to improve target therapeutic strategy