Citations

The use of multiphasic scaffolds to treat injured tendon-to-bone entheses has shown promising results in vitro. Here, we used two versions of a biphasic silk fibroin scaffold to treat an enthesis defect created in a rat patellar model in vivo. One version presented a mixed transition between the bony and the tendon end of the construct (S-MT) while this transition was abrupt in the second version (S-AT). At 12 weeks after surgery, the S-MT scaffold promoted better healing of the injured enthesis, with minimal undesired ossification of the insertion area. The expression of tenogenic and chondrogenic markers was sustained for longer in the S-MT-treated group and the tangent modulus of the S-MT-treated samples was similar to the native tissue at 12 weeks while that of the S-AT-treated enthesis was lower. Our study highlights the important role of the transition zone of multiphasic scaffolds in the treatment of complex interphase tissues such as the tendon-to-bone enthesis.

Abstract Background Reactive granulomatous dermatitis (RGD) is an umbrella term used to describe interstitial granulomatous dermatitis (IGD), palisaded neutrophilic and granulomatous dermatitis (PNGD), and interstitial granulomatous drug eruption (IGDR). Objective The aim of this study was to describe systemic associations of RGD, explore possible associations between histopathologic findings and systemic RGD associations and determine clinical relevance of RGD subtypes. Methods We retrospectively studied clinical and histopathologic characteristics of patients with RGD from 1990 through 2020. Results Of 65 patients with RGD (41 women, 24 men; median age at diagnosis, 62 years), 37 had IGD, 26 had PNGD, and 2 had IGDR. Fifty patients (76.9%) had an associated systemic condition; rheumatologic conditions were identified for 34 (52.3%) patients. The associated systemic condition occurred before RGD in approximately 75% of patients. Statistical analyses did not show significant associations between specific subtypes of RGD and systemic diseases or treatment response, and specific histopathologic findings were not predictive of an associated systemic disease. Conclusions Although most patients with RGD had an associated systemic condition, subtypes of RGD did not correlate with systemic associations, lending support to the use of the umbrella term RGD .

Introduction: Atrial arrhythmias are common in patients with D-TGA and atrial switch. We sought to analyze the arrhythmia substrate and catheter ablation approaches and outcomes. Methods: We performed a retrospective review of all clinical and procedural data in patients with D-TGA followed at a large tertiary care center. Results: In a cohort of 152 patients (mean age 30±11 years), atrial tachycardia was present in 69(45%) patients. Ablations were performed in 39(26%) patients: macro-reentrant atrial flutter (N=37), atrial fibrillation (N=4), and focal automatic atrial tachycardia (N=3). Detailed electrophysiology study data was available for 34 patients. At first ablation (N=28), cavo-tricuspid isthmus dependent flutter (CTI, 23(82%)) was most common, followed by right atriotomy-related flutter (IART, 16(57%)) and focal atrial tachycardia (FAT, 1(3.5%)). Bidirectional CTI block often required ablation on both sides of the baffle to complete the isthmus line. Access to the pulmonary venous atrium was obtained in 82% of first-time ablations (via retrograde aortic access, 74%, baffle puncture, 6%, or baffle fenestration, 12%) and in 100% of redo procedures. The first ablation was acutely successful in 25 (89%) patients; the other 3 patients had either partial procedural success (1), failed ablation (1), or underwent an empirical ablation (1). Long-term arrhythmia recurrence occurred in 13(46%) after the first ablation and class III antiarrhythmic medications were utilized in 12 patients. At least one long-term recurrence occurred in 11(44%) patients. Importantly, clinical arrhythmia burden was significantly reduced post-ablation, with rare and short-limited episodes amenable to antiarrhythmic drugs or cardioversion. Repeat ablation was required in 3 cases. Long-term arrhythmia recurrence after a previously completed CTI line involved different arrhythmia mechanisms: scar-related reentry (80%) and automatic atrial tachycardia (40%). Conclusions: Atrial arrhythmia in patients with D-TGA often involves the CTI and atriotomy scars. Ablation of the CTI typically requires access to the pulmonary venous atrium to achieve bidirectional block. Despite late recurrence, the clinical arrhythmic burden is substantially improved.

Introduction: Conduction disturbance after transcatheter aortic valve replacement (TAVR) remains a common complication. Predictive tools to identify conduction disturbance requiring pacing are limited. Our main objective was to develop a deep learning model to predict the need for a permanent pacemaker. Hypothesis: An electrocardiogram (ECG) based deep learning algorithm can predict the need for permanent pacemaker post TAVR. Methods: We evaluated patients who had TAVR at Mayo Clinic between June 2010 and May 2021. Digital ECGs done on the TAVR date or within 24 hours post procedure were partitioned into training, validation, and testing datasets. We trained a deep learning algorithm on the training data and optimized hyperparameters against the validation data. All model performance metrics are based on the reserved test data that were estimated once model architecture was optimized. Need for permanent pacemaker, defined as pacemaker placement due to development of conduction disturbance post TAVR and at least 1% ventricular pacing on device interrogation done at least 2 weeks post pacemaker implantation, was the training target. Results: A total of 3021 patients were evaluated for inclusion and 2,407 cases were available for modeling (exclusions: prior pacemaker (n=419), unsuccessful TAVR (n=27) and no ECG within the pre-specified period (n=168)). Overall, the median age was 82 (Q1: 76, Q3: 86) and 41% were female. In the withheld test data, 15% had a permanent pacemaker with at least 1% ventricular pacing. The algorithm detected the need for pacemaker in the test set with an AUC of 0.83 (95% CI: 0.73 to 0.92). Accuracy, sensitivity, specificity, positive and negative predictive were 80%, 72%, 81%, 41% and 94%, respectively. Conclusions: This study demonstrates the ability of a deep learning model based on ECG data to assist in making the decision to implant a pacemaker following TAVR with a high negative predictive value. Larger validation studies are warranted.

Large segmental osseous defects heal poorly. Recombinant, human bone morphogenetic protein-2 (rhBMP-2) is used clinically to promote bone healing, but it is applied at very high doses that cause adverse side effects and raise costs while providing only incremental benefit. We describe a previously unexplored, alternative approach to bone regeneration using chemically modified messenger RNA (cmRNA). An optimized cmRNA encoding BMP-2 was delivered to critical-sized femoral osteotomies in rats. The cmRNA remained orthotopically localized and generated BMP locally for several days. Defects healed at doses ≥25 μg of BMP-2 cmRNA. By 4 weeks, all animals treated with 50 μg of BMP-2 cmRNA had bridged bone defects without forming the massive callus seen with rhBMP-2. Moreover, such defects recovered normal mechanical strength quicker and initiated bone remodeling faster. cmRNA regenerated bone via endochondral ossification, whereas rhBMP-2 drove intramembranous osteogenesis; cmRNA provides an innovative, safe, and highly translatable technology for bone healing.

AbstractThe multicenter, phase Ib CC‐122‐DLBCL‐001 dose‐expansion study (NCT02031419) explored the cereblon E3 ligase modulator (CELMoD) agent avadomide (CC‐122) plus rituximab in patients with relapsed/refractory (R/R) diffuse large B‐cell lymphoma (DLBCL) or follicular lymphoma (FL). Patients received avadomide 3 mg/day 5 days on/2 days off plus rituximab 375 mg/m2 on day 8 of cycle 1, day 1 of cycles 2 through 6, and day 1 of every third subsequent cycle for 2 years. Primary endpoints were safety and tolerability; preliminary efficacy was a secondary endpoint. A total of 68 patients were enrolled (DLBCL [n = 27], FL [n = 41; 31 lenalidomide‐naïve, 10 lenalidomide‐treated]). Median age was 62 years (range, 33–84 years), and patients had received a median of 3 (range, 1–8) prior regimens. Among patients with DLBCL, 66.7% had primary refractory disease (partial response or less to initial therapy). Among patients with FL, 65.9% were rituximab‐refractory at study entry and 10.0% were lenalidomide‐refractory. The most common any‐grade avadomide‐related adverse events (AEs) were neutropenia (63.2%), infections/infestations (23.5%), fatigue (22.1%), and diarrhea (19.1%). The most common grade 3/4 avadomide‐related AEs were neutropenia (55.9%) infections/infestations (8.8%), and febrile neutropenia (7.4%). In patients with DLBCL, overall response rate (ORR) was 40.7% and median duration of response (mDOR) was 8.0 months. In patients with FL, ORR was 80.5% and mDOR was 27.6 months; response rates were similar in lenalidomide‐naïve and ‐treated patients. Avadomide plus rituximab was well tolerated, and preliminary antitumor activity was observed in patients with R/R DLBCL and FL, including subgroups with typically poor outcomes. These results support further investigation of novel CELMoD agents in combination with rituximab in R/R DLBCL and FL.

AbstractBackgroundOral lichen planus confers a 1% risk of transformation to oral squamous cell carcinoma. While prior exome sequencing studies have identified multiple genetic mutations in oral squamous cell carcinoma, mutational analyses of lichen planus‐derived OSCC are lacking. We sought to clarify genomic events associated with oral lichen planus transformation.MethodsUsing rigorous diagnostic criteria, we retrospectively identified patients with non‐transforming oral lichen planus (i.e., known to be non‐transforming with 5 years of clinical follow‐up; n = 17), transforming oral lichen planus (tissue marginal to oral squamous cell carcinoma, n = 9), or oral squamous cell carcinoma arising in lichen planus (n = 17). Gene mutational profiles derived from whole‐exome sequencing on fixed mucosal specimens were compared among the groups.ResultsThe four most frequently mutated genes in transforming oral lichen planus and oral squamous cell carcinoma (TP53, CELSR1, CASP8, and KMT2D) identified 12/17 (71%) of oral squamous cell carcinomas and 5/9 (56%) of transforming oral lichen planus but were absent in non‐transforming oral lichen planus. We identified other known oral squamous cell carcinoma mutations (TRRAP, OBSCN, and LRP2) but also previously unreported mutations (TENM3 and ASH1L) in lichen planus‐associated oral squamous cell carcinomas.ConclusionsThese findings suggest alterations in DNA damage response and apoptosis pathways underlie lichen planus‐related oral squamous cell carcinoma transformation and are supported by mutational signatures indicative of DNA damage. This study characterized patterns of mutational events present in oral lichen planus associated with squamous cell carcinoma and in squamous cell carcinoma associated with oral lichen planus but not in non‐transforming oral lichen planus.