Functional monovalency amplifies the pathogenicity of anti-MuSK IgG4 in myasthenia gravis

Human immunoglobulin (Ig) G4 usually displays antiinflammatory activity, and observations of IgG4 autoantibodies causing severe autoimmune disorders are therefore poorly understood. In blood, IgG4 naturally engages in a stochastic process termed "Fab-arm exchange" in which unrelated IgG4s exchange half-molecules continuously. The resulting IgG4 antibodies are composed of two different binding sites, thereby acquiring monovalent binding and inability to cross-link for each antigen recognized. Here, we demonstrate that this process amplifies autoantibody pathogenicity in a classic IgG4-mediated autoimmune disease: muscle-specific kinase (MuSK) myasthenia gravis. In mice, monovalent anti-MuSK IgG4s caused rapid and severemyasthenicmuscleweakness, whereas the same antibodies in their parental bivalent form were less potent or did not induce a phenotype. Mechanistically this could be explained by opposing effects onMuSK signaling. Isotype switching to IgG4 in an autoimmune response thereby may be a critical step in the development of disease. Our study establishes functional monovalency as a pathogenic mechanism in IgG4-mediated autoimmune disease and potentially other disorders.Neurological Motor Disorder

Increased MR-guided high intensity focused ultrasound (MR-HIFU) sonication efficiency of uterine fibroids after carbetocin administration

Purpose: We investigated whether administration of the long-acting uterus stimulant carbetocin increased intra-subject sonication efficiency during Magnetic Resonance image guided High Intensity Focused Ultrasound (MR-HIFU) treatment of uterine fibroids. Method: In this prospective cohort study, thirty women with symptomatic uterine fibroids undergoing MR-HIFU treatment were included between January 2018 and January 2019. Treatment started with three sonications on one side of the uterine fibroid. Subsequently, one ampoule of 1 mL carbetocin (100 µg/mL) was administered intravenously and treatment continued with three sonications on the other side of the uterine fibroid. We compared the intra-subject sonication efficiency, in terms of Energy Efficiency Factor (EEF), thermal dose volume and sonication time to ablate one cm 3 of fibroid tissue, before and after carbetocin administration. Adverse events that occurred within 30 min after carbetocin administration were recorded. Results: Sonication efficiency improved after carbetocin administration as indicated by a significant decrease in EEF and sonication time (p = 0.006 and p = 0.001 respectively), and a significant increase in thermal dose volume reached (p = <0.001). Five women (16.7%) experienced temporary tachycardia, one women in combination with headache, within 30 min after carbetocin administration. Conclusion: Administration of the long-acting uterus stimulant carbetocin improved the MR-HIFU treatment intra-subject sonication efficiency in women with symptomatic uterine fibroids

Prognostic value of total tumor volume in patients with colorectal liver metastases:A secondary analysis of the randomized CAIRO5 trial with external cohort validation

Background:This study aimed to assess the prognostic value of total tumor volume (TTV) for early recurrence (within 6 months) and overall survival (OS) in patients with colorectal liver metastases (CRLM), treated with induction systemic therapy followed by complete local treatment.Methods: Patients with initially unresectable CRLM from the multicenter randomized phase 3 CAIRO5 trial (NCT02162563) who received induction systemic therapy followed by local treatment were included. Baseline TTV and change in TTV as response to systemic therapy were calculated using the CT scan before and the first after systemic treatment, and were assessed for their added prognostic value. The findings were validated in an external cohort of patients treated at a tertiary center. Results:In total, 215 CAIRO5 patients were included. Baseline TTV and absolute change in TTV were significantly associated with early recurrence (P = 0.005 and P = 0.040, respectively) and OS in multivariable analyses (P = 0.024 and P = 0.006, respectively), whereas RECIST1.1 was not prognostic for early recurrence (P = 0.88) and OS (P = 0.35). In the validation cohort (n = 85), baseline TTV and absolute change in TTV remained prognostic for early recurrence (P = 0.041 and P = 0.021, respectively) and OS in multivariable analyses (P &lt; 0.0001 and P = 0.012, respectively), and showed added prognostic value over conventional clinicopathological variables (increase C-statistic, 0.06; 95 % CI, 0.02 to 0.14; P = 0.008). Conclusion: Total tumor volume is strongly prognostic for early recurrence and OS in patients who underwent complete local treatment of initially unresectable CRLM, both in the CAIRO5 trial and the validation cohort. In contrast, RECIST1.1 did not show prognostic value for neither early recurrence nor OS.</p

Combining radiotherapy and focused ultrasound for pain palliation of cancer induced bone pain; a stage I/IIa study according to the IDEAL framework

Background: Cancer induced bone pain (CIBP) strongly interferes with patient's quality of life. Currently, the standard of care includes external beam radiotherapy (EBRT), resulting in pain relief in approximately 60% of patients. Magnetic Resonance guided High Intensity Focused Ultrasound (MR-HIFU) is a promising treatment modality for CIBP. Methods: A single arm, R-IDEAL stage I/IIa study was conducted. Patients presenting at the department of radiation oncology with symptomatic bone metastases in the appendicular skeleton, as well as in the sacrum and sternum were eligible for inclusion. All participants underwent EBRT, followed by MR-HIFU within 4 days. Safety and feasibility were assessed, and pain scores were monitored for 4 weeks after completing the combined treatment. Results: Six patients were enrolled. Median age was 67 years, median lesion diameter was 56,5 mm. In all patients it was logistically possible to plan and perform the MR-HIFU treatment within 4 days after EBRT. All patients tolerated the combined procedure well. Pain response was reported by 5 out of 6 patients at 7 days after completion of the combined treatment, and stabilized on 60% at 4 weeks follow up. No treatment related serious adverse events occurred. Conclusion: This is the first study to combine EBRT with MR-HIFU. Our results show that combined EBRT and MR-HIFU in first-line treatment of CIBP is safe and feasible, and is well tolerated by patients. Superiority over standard EBRT, in terms of (time to) pain relief and quality of life need to be evaluated in comparative (randomized) study

Prognostic value of total tumor volume in patients with colorectal liver metastases: A secondary analysis of the randomized CAIRO5 trial with external cohort validation

Background: This study aimed to assess the prognostic value of total tumor volume (TTV) for early recurrence (within 6 months) and overall survival (OS) in patients with colorectal liver metastases (CRLM), treated with induction systemic therapy followed by complete local treatment. Methods: Patients with initially unresectable CRLM from the multicenter randomized phase 3 CAIRO5 trial (NCT02162563) who received induction systemic therapy followed by local treatment were included. Baseline TTV and change in TTV as response to systemic therapy were calculated using the CT scan before and the first after systemic treatment, and were assessed for their added prognostic value. The findings were validated in an external cohort of patients treated at a tertiary center. Results: In total, 215 CAIRO5 patients were included. Baseline TTV and absolute change in TTV were significantly associated with early recurrence (P = 0.005 and P = 0.040, respectively) and OS in multivariable analyses (P = 0.024 and P = 0.006, respectively), whereas RECIST1.1 was not prognostic for early recurrence (P = 0.88) and OS (P = 0.35). In the validation cohort (n = 85), baseline TTV and absolute change in TTV remained prognostic for early recurrence (P = 0.041 and P = 0.021, respectively) and OS in multivariable analyses (P < 0.0001 and P = 0.012, respectively), and showed added prognostic value over conventional clinicopathological variables (increase C-statistic, 0.06; 95 % CI, 0.02 to 0.14; P = 0.008). Conclusion: Total tumor volume is strongly prognostic for early recurrence and OS in patients who underwent complete local treatment of initially unresectable CRLM, both in the CAIRO5 trial and the validation cohort. In contrast, RECIST1.1 did not show prognostic value for neither early recurrence nor OS

Magnetic resonance-high intensity focused ultrasound (MR-HIFU) therapy of symptomatic uterine fibroids with unrestrictive treatment protocols : A systematic review and meta-analysis

Purpose: Reevaluation of the effectiveness of Magnetic Resonance-High Intensity Focused Ultrasound (MR-HIFU) therapy for uterine fibroids by excluding studies with restrictive treatment protocols that are no longer used. Methods: The National Guideline Clearinghouse, Cochrane Library, TRIP, MEDLINE, EMBASE and WHO International Clinical Trials Registry Platform (ICTRP) databases were searched from inception until the 22nd of June 2018. Keywords included “MR-HIFU”, “MRgFUS”, and “Leiomyoma”. Only studies about MR-HIFU treatment of uterine fibroids with at least three months of clinical follow-up were evaluated for inclusion. Treatments with ultrasound-guided HIFU devices or protocols not aiming for complete ablation were eliminated. The primary outcome was the improvement in fibroid-related symptoms. Technical outcomes included screening and treatment failures, treatment time, application of bowel-interference mitigation strategies and the Non-Perfused Volume (NPV) percentage. Other secondary outcomes were the quality of life, fibroid shrinkage, safety, re-interventions, reproductive outcomes, and costs. Meta-analysis was performed using a random-effects model (DerSimonian and Laird). Results: A total of 18 articles (1323 treated patients) met the inclusion criteria. All selected studies were case series except for one cross-over trial. Overall, the quality of the evidence was poor to moderate. The mean NPV% directly post-treatment was 68.1%. The use of bowel-interference mitigation strategies may lead to increased NPV%. The mean symptom reduction at 12-months was 59.9% and fibroid shrinkage was 37.7%. The number of adverse events was low (8.7%), stratification showed a difference between HIFU systems. The re-intervention percentage at 3–33.6 months follow-up ranged from 0 to 21%. Longer follow-up was associated with a higher risk at re-interventions. Reproductive outcomes and costs couldn't be analyzed. Conclusions: Treatment guidelines aiming for complete ablation enhanced the effectiveness of MR-HIFU therapy. However, controlled trials should define the role of MR-HIFU in the management of uterine fibroids

Comparison of (cost-)effectiveness of magnetic resonance image-guided high-intensity-focused ultrasound with standard (minimally) invasive fibroid treatments: Protocol for a multicenter randomized controlled trial (MYCHOICE)

Background: Magnetic resonance image-guided high-intensity-focused ultrasound (MR-HIFU) is a rather new, noninvasive option for the treatment of uterine fibroids. It is safe, effective, and has a very short recovery time. However, a lack of prospectively collected data on long-term (cost-)effectiveness of the MR-HIFU treatment compared with standard uterine fibroid care prevents the MR-HIFU treatment from being reimbursed for this indication. Therefore, at this point, when conservative treatment for uterine fibroid symptoms has failed or is not accepted by patients, standard care includes the more invasive treatments hysterectomy, myomectomy, and uterine artery embolization (UAE). Primary outcomes of currently available data on MR-HIFU treatment often consist of technical outcomes, instead of patient-centered outcomes such as quality of life (QoL), and do not include the use of the latest equipment or most up-to-date treatment strategies. Moreover, data on cost-effectiveness are rare and seldom include data on a societal level such as productivity loss or use of painkillers. Because of the lack of reimbursement, broad clinical implementation has not taken place, nor is the proper role of MR-HIFU in uterine fibroid care sufficiently clear. Objective: The objective of our study is to determine the long-term (cost-)effectiveness of MR-HIFU compared with standard (minimally) invasive fibroid treatments. Methods: The MYCHOICE study is a national, multicenter, open randomized controlled trial with randomization in a 2:1 ratio to MR-HIFU or standard care including hysterectomy, myomectomy, and UAE. The sample size is 240 patients in total. Women are included when they are 18 years or older, in premenopausal stage, diagnosed with symptomatic uterine fibroids, conservative treatment has failed or is not accepted, and eligible for MR-HIFU. Primary outcomes of the study are QoL 24 months after treatment and costs of treatment including direct health care costs, loss of productivity, and patient costs. Results: Inclusion for the MYCHOICE study started in November 2020 and enrollment will continue until 2024. Data collection is expected to be completed in 2026. Conclusions: By collecting data on the long-term (cost-)effectiveness of the MR-HIFU treatment in comparison to current standard fibroid care, we provide currently unavailable evidence about the proper place of MR-HIFU in the fibroid treatment spectrum. This will also facilitate reimbursement and inclusion of MR-HIFU in (inter)national uterine fibroid care guidelines