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

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

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

Use of multiparametric MRI to characterize uterine fibroid tissue types

Background Although the biological characteristics of uterine fibroids (UF) have implications for therapy choice and effectiveness, there is limited MRI data about these characteristics. Currently, the Funaki classification and Scaled Signal Intensity (SSI) are used to predict treatment outcome but both screening-tools appear to be suboptimal. Therefore, multiparametric and quantitative MRI was studied to evaluate various biological characteristics of UF. Methods 87 patients with UF underwent an MRI-examination. Differences between UF tissues and myometrium were investigated using T2-mapping, Apparent Diffusion Coefficient (ADC) maps with different b-value combinations, contrast-enhanced T1-weighted and T2-weighted imaging. Additionally, the Funaki classification and SSI were calculated. Results Significant differences between myometrium and UF tissue in T2-mapping (p = 0.001), long-TE ADC low b-values (p = 0.002), ADC all b-values (p < 0.001) and high b-values (p < 0.001) were found. Significant differences between Funaki type 3 versus type 1 and 2 were observed in SSI (p < 0.001) and T2-values (p < 0.001). Significant correlations were found between SSI and T2-mapping (p < 0.001; rho(s) = 0.82), ADC all b-values (p = 0.004; rho(s) = 0.31), ADC high b-values (p < 0.001; rho(s) = 0.44) and long-TE ADC low b-values (p = 0.004; rho(s) = 0.31). Conclusions Quantitative MR-data allowed us to distinguish UF tissue from myometrium and to discriminate different UF tissue types and may, therefore, be a useful tool to predict treatment outcome/determine optimal treatment modality

Lessons learned during implementation of MR-guided High-Intensity Focused Ultrasound treatment of uterine fibroids

Background: Although promising results have been reported for Magnetic Resonance image-guided High-Intensity Focused Ultrasound (MR-HIFU) treatment of uterine fibroids, this treatment is not yet widely implemented in clinical practice. During the implementation of a new technology, lessons are learned and an institutional learning-curve often has to be completed. The primary aim of our prospective cohort study was to characterize our learning-curve based on our clinical outcomes. Secondary aims included identifying our lessons learned during implementation of MR-HIFU on a technical, patient selection, patient counseling, medical specialists and organizational level. Results: Our first seventy patients showed significant symptom reduction and improvement of quality of life at 3, 6 and 12 months after MR-HIFU treatment compared to baseline. After the first 25 cases, a clear plateau phase was reached in terms of failed treatments. The median non-perfused volume percentage of these first 25 treatments was 44.6% (range: 0-99.7), compared to a median of 74.7% (range: 0-120.6) for the subsequent treatments. Conclusions: Our findings describe the learning-curve during the implementation of MR-HIFU and include straight-forward suggestions to shorten learning-curves for future users. Moreover, the lessons we learned on technique, patient selection, patient counseling, medical specialists and organization, together with the provided supplements, may be of benefit to other institutions aiming to implement MR-HIFU treatment of uterine fibroids

Artificial intelligence for assessment of vascular involvement and tumor resectability on CT in patients with pancreatic cancer

Abstract Objective This study aimed to develop and evaluate an automatic model using artificial intelligence (AI) for quantifying vascular involvement and classifying tumor resectability stage in patients with pancreatic ductal adenocarcinoma (PDAC), primarily to support radiologists in referral centers. Resectability of PDAC is determined by the degree of vascular involvement on computed tomography scans (CTs), which is associated with considerable inter-observer variability. Methods We developed a semisupervised machine learning segmentation model to segment the PDAC and surrounding vasculature using 613 CTs of 467 patients with pancreatic tumors and 50 control patients. After segmenting the relevant structures, our model quantifies vascular involvement by measuring the degree of the vessel wall that is in contact with the tumor using AI-segmented CTs. Based on these measurements, the model classifies the resectability stage using the Dutch Pancreatic Cancer Group criteria as either resectable, borderline resectable, or locally advanced (LA). Results We evaluated the performance of the model using a test set containing 60 CTs from 60 patients, consisting of 20 resectable, 20 borderline resectable, and 20 locally advanced cases, by comparing the automated analysis obtained from the model to expert visual vascular involvement assessments. The model concurred with the radiologists on 227/300 (76%) vessels for determining vascular involvement. The model’s resectability classification agreed with the radiologists on 17/20 (85%) resectable, 16/20 (80%) for borderline resectable, and 15/20 (75%) for locally advanced cases. Conclusions This study demonstrates that an AI model may allow automatic quantification of vascular involvement and classification of resectability for PDAC. Relevance statement This AI model enables automated vascular involvement quantification and resectability classification for pancreatic cancer, aiding radiologists in treatment decisions, and potentially improving patient outcomes. Key points • High inter-observer variability exists in determining vascular involvement and resectability for PDAC. • Artificial intelligence accurately quantifies vascular involvement and classifies resectability for PDAC. • Artificial intelligence can aid radiologists by automating vascular involvement and resectability assessments. Graphical Abstrac