Factor VIII trafficking to CD4+ T cells shapes its immunogenicity and requires several types of antigen-presenting cells.

Despite >80 years of clinical experience with coagulation factor VIII (FVIII) inhibitors, surprisingly little is known about the in vivo mechanism of this most serious complication of replacement therapy for hemophilia A. These neutralizing antidrug alloantibodies arise in ∼30% of patients. Inhibitor formation is T-cell dependent, but events leading up to helper T-cell activation have been elusive because of, in part, the complex anatomy and cellular makeup of the spleen. Here, we show that FVIII antigen presentation to CD4+ T cells critically depends on a select set of several anatomically distinct antigen-presenting cells, whereby marginal zone B cells and marginal zone and marginal metallophilic macrophages but not red pulp macrophages (RPMFs) participate in shuttling FVIII to the white pulp in which conventional dendritic cells (DCs) prime helper T cells, which then differentiate into follicular helper T (Tfh) cells. Toll-like receptor 9 stimulation accelerated Tfh cell responses and germinal center and inhibitor formation, whereas systemic administration of FVIII alone in hemophilia A mice increased frequencies of monocyte-derived and plasmacytoid DCs. Moreover, FVIII enhanced T-cell proliferation to another protein antigen (ovalbumin), and inflammatory signaling-deficient mice were less likely to develop inhibitors, indicating that FVIII may have intrinsic immunostimulatory properties. Ovalbumin, which, unlike FVIII, is absorbed into the RPMF compartment, fails to elicit T-cell proliferative and antibody responses when administered at the same dose as FVIII. Altogether, we propose that an antigen trafficking pattern that results in efficient in vivo delivery to DCs and inflammatory signaling, shape the immunogenicity of FVIII.

Percutaneous Cryoablation of Plasmacytomas: Oncologic Effectiveness and Adverse Events.

PURPOSE: To evaluate the oncologic outcomes and adverse events associated with cryoablation of plasmacytomas. MATERIALS AND METHODS: Retrospective review of an institutional percutaneous ablation database showed that 43 patients underwent 46 percutaneous cryoablation procedures for treatment of 44 plasmacytomas between May 2004 and March 2021. The treatment of 25 (25 of 44, 56.8%) tumors was augmented with bone consolidation/cementoplasty. The median patient age was 64 years (interquartile range [IQR], 54-69), and 30 of 43 (69.8%) patients were men. The median maximum plasmacytoma diameter was 5.0 cm (IQR, 3.1-7.0). Thirty of 44 (68.2%) tumors were periacetabular, vertebral, or located in the iliac wing. Twenty-nine of 44 (65.9%) cryoablated plasmacytomas were recurrent tumors after prior external beam radiation therapy (EBRT). Survival analyses were performed using the Kaplan-Meier method. Adverse events were graded using Society of Interventional Radiology criteria. RESULTS: The 5-year estimated local tumor recurrence-free survival was 85.3% (95% CI, 74.1%-98.1%), the 5-year estimated new plasmacytoma-free survival was 49.9% (95% CI, 33.9%-73.4%), and the 5-year estimated overall survival was 70.4% (95% CI, 56.9%-87.1%). Nine of 46 (19.6%) major adverse events occurred in 8 patients, including 3 of 46 (6.5%) new or progressive pathologic fractures at the ablation site requiring surgical intervention, 3 of 46 (6.5%) nerve injuries, 1 of 46 (2.2%) avascular necrosis and femoral head collapse, 1 of 46 (2.2%) septic arthritis, and 1 of 46 (2.2%) acute renal failure caused by rhabdomyolysis. CONCLUSIONS: Percutaneous cryoablation is a viable treatment option for patients with plasmacytomas, including those with recurrent plasmacytomas after EBRT. Postcryoablation adverse events are relatively common.

Chemical Exposure-Induced Developmental Neurotoxicity in Head-Regenerating Schmidtea mediterranea.

The growing number of commercially used chemicals that are under-evaluated for developmental neurotoxicity (DNT) combined with the difficulty in describing the etiology of exposure-related neurodevelopmental toxicity has created a reticent threat to human health. Current means of screening chemicals for DNT are limited to expensive, time-consuming, and labor-intensive traditional laboratory animal models. In this study, we hypothesize that exposed head-regenerating planarian flatworms can effectively and efficiently categorize DNT in known developmental neurotoxins (ethanol and bisphenol A [BPA]). Planarian flatworms are an established alternative animal model for neurodevelopmental studies and have remarkable regenerative abilities allowing neurodevelopment to be induced via head resection. Here, we observed changes in photophobic behavior and central nervous system (CNS) morphology to evaluate the impact of exposure to low concentrations of ethanol, BPA, and BPA industry alternatives bisphenol F, and bisguaiacol on neurodevelopment. Our studies show that exposure to 1% v/v ethanol during regeneration induces a recoverable 48-h delay in the development of proper CNS integrity, which aligns with behavioral assessments of cognitive ability. Exposure to BPA and its alternatives induced deviations to neurodevelopment in a range of severities, distinguished by suppressions, delays, or a combination of the 2. These results suggest that quick and inexpensive behavioral assessments are a viable surrogate for tedious and costly immunostaining studies, equipping more utility and resolution to the planarian model for neurodevelopmental toxicity in the future of mass chemical screening. These studies demonstrate that behavioral phenotypes observed following chemical exposure are classifiable and also temporally correlated to the anatomical development of the CNS in planaria. This will facilitate and accelerate toxicological screening assays with this alternative animal model.

Association of Virtual Surgical Planning With External Incisions in Complex Maxillectomy Reconstruction.

Importance: Maxillectomy can commonly be performed through a transoral approach, but maxillectomy defect reconstruction can be difficult to precisely design, contour, and inset through this approach. Objective: To evaluate whether the use of virtual surgical planning (VSP) and 3-dimensional (3-D) modeling is associated with a decrease in the requirement of lateral rhinotomy (LR) for patients undergoing total and partial maxillectomy reconstruction. Design, Setting, and Participants: This retrospective cohort study was conducted among patients undergoing subtotal or total maxillectomy with microvascular free flap reconstruction with or without VSP and 3-D modeling at a single tertiary care academic medical center between January 1, 2008, and October 3, 2019. Interventions: Maxillectomy and free flap reconstruction with or without VSP. Main Outcomes and Measures: Necessity of LR or other external incision for contouring, placement, and fixation of reconstruction as well as surgical complications. Results: Fifteen patients (12 men [80%]; mean age, 64 years) underwent maxillectomy with free flap reconstruction without VSP. Eight patients (53%) in this group underwent total maxillectomy, and 4 patients in this group (27%) underwent partial maxillectomy. Twenty-three patients (18 men [78%]; mean age, 58 years) underwent maxillectomy with free flap reconstruction and VSP and 3-D modeling. Twelve of these patients (52%) underwent total maxillectomy, and 11 (48%) underwent partial maxillectomy. Lateral rhinotomy was necessary for 1 patient (4%) in the VSP group vs 12 patients (80%; 95% CI, 54%-98%) in the pre-VSP group. There were no LR complications in the VSP group vs 6 in the pre-VSP group. Among both groups, 14 patients underwent fibula free flap, 22 patients underwent subscapular system free flap, and 2 patients underwent cutaneous or osteocutaneous radial forearm free flap. There were no flap failures in the LR group and 1 flap failure in the group without LR. Conclusions and Relevance: This cohort study suggests that the use of VSP and 3-D modeling for maxillectomy reconstruction is associated the a decrease in the need for external incisions without compromising reconstructive flap utility.

The role of imaging in the management of progressive glioblastoma : a systematic review and evidence-based clinical practice guideline.

QUESTION: Which imaging techniques most accurately differentiate true tumor progression from pseudo-progression or treatment related changes in patients with previously diagnosed glioblastoma? TARGET POPULATION: These recommendations apply to adults with previously diagnosed glioblastoma who are suspected of experiencing progression of the neoplastic process. RECOMMENDATIONS LEVEL II: Magnetic resonance imaging with and without gadolinium enhancement is recommended as the imaging surveillance method to detect the progression of previously diagnosed glioblastoma. LEVEL II: Magnetic resonance spectroscopy is recommended as a diagnostic method to differentiate true tumor progression from treatment-related imaging changes or pseudo-progression in patients with suspected progressive glioblastoma. LEVEL III: The routine use of positron emission tomography to identify progression of glioblastoma is not recommended. LEVEL III: Single-photon emission computed tomography imaging is recommended as a diagnostic method to differentiate true tumor progression from treatment-related imaging changes or pseudo-progression in patients with suspected progressive glioblastoma.