Citations

Background: The aim of this study was to evaluate the prevalence and perceived efficacy of cannabidiol (CBD) products in patients presenting to an orthopedic hand and upper extremity clinic. Materials and Methods: New patients seen for an initial surgical consultation between July and December 2022 were surveyed regarding CBD use, pain, and function. Pain was measured with the Numeric Pain Rating Scale (NPRS, 0–10) and function with the Single Assessment Numeric Evaluation (SANE, 0–100). Demographic and clinical factors were collected via chart review. Results: A total of 918 patients completed the survey (53% female; mean age 63 years, range 18–97). Joints involved included elbows (106), wrists (335), and hands/fingers (667). Common diagnoses included arthritis (199), tendinopathy (273), and nerve-related conditions (160). Overall, 15% (135/918) reported prior CBD use, and 39% (53/135) perceived pain relief. CBD users were more likely to be female (65% vs 51%; P =0.003), to present with wrist pathology (44% vs 35%; P =0.038), and to have arthritis (36% vs 19%; P <0.001). Compared to non-users, CBD users reported higher pain scores (mean NPRS 6.2 vs 5.1; P <0.001) and lower contralateral function (mean SANE 77.3 vs 87.4; P <0.001). Conclusions In this cohort, CBD use was uncommon, and only a minority of users reported subjective benefit. CBD users tended to report higher pain and worse function, particularly in the setting of wrist arthritis. CBD products did not appear to provide measurable objective improvement in pain or function. Further studies are needed to clarify optimal dosing, administration, and potential role in upper extremity care.

Summary: Peripheral Artery Disease (PAD) is a significant global health concern, leading to morbidity through progressive stenosis and eventually occlusion of the lower extremity arterial vasculature. Advanced imaging modalities play a major role in diagnosing PAD, in planning endovascular as well as surgical interventions, and in monitoring post-treatment outcomes. This review highlights the current major imaging techniques, including duplex ultrasound, computed tomography angiography (CTA) and magnetic resonance angiography (MRA). It provides insights into their applications, advantages, limitations and the importance of individualized imaging strategies for optimizing patient outcomes.

Abstract Background Cyclin-dependent kinase 12 (CDK12) regulates general gene transcription elongation and plays multiple roles in RNA splicing, DNA damage-response, cell cycle, and genomic stability. However, transcriptional partners that guide CDK12-specific gene programs have not been identified. Genomic alterations in CDK12 have been observed in multiple cancers, exhibiting both pro-tumorigenic and tumor-suppressive functions, suggesting a context-dependent mechanism of action. Methods CDK12 copy number alterations and gene expression levels were analyzed in matched primary and brain metastatic patient tumors. Clinical significance was assessed by immunohistochemistry in a large cohort of primary breast cancer patient tumors. RNA sequencing, ChIP sequencing, and molecular studies were conducted to explore CDK12’s mechanism of action, and pharmacological studies were performed both in vitro and in vivo using models of advanced (endocrine-resistant and metastatic) estrogen receptor positive (ER+) disease. Results CDK12 amplifications and gene overexpression were observed in brain metastatic tumors. In ER+ primary patient tumors, high CDK12 protein expression was significantly associated with poor overall survival, particularly within the ER+/HER2-negative group. In ER+ endocrine resistant models, CDK12 regulated estrogen signaling pathways, with ER/MED1 identified as the master transcriptional complex directing CDK12-specific pro-tumorigenic gene programs. Pharmacological inhibition of CDK12 significantly reduced viability in endocrine resistant and metastatic cell and organoid models in vitro, and decreased metastatic spread in vivo. Conclusion This work describes a novel mechanism for CDK12, suggesting a potential vulnerability in ER+ breast cancer. These findings provide a basis for further investigation into the role of CDK12 inhibition as a therapeutic approach, particularly in advanced disease settings.

BACKGROUND The use of Mohs micrographic surgery as a treatment for melanoma is rising, but the reliability of Mohs surgeons in assessing MART-1 melanoma en-face margins has not been evaluated. OBJECTIVE To evaluate interrater and intrarater reliability of Mohs surgeons in interpreting margins of early-stage melanoma. METHODS Twenty Mohs surgeons were asked to independently review images of frozen section MART-1 en-face peripheral margins of in situ or early-stage melanoma. Surgeons determined margins as positive or negative at initial evaluation and 6 weeks later. Primary outcomes were interrater and intrarater reliability. RESULTS Interrater agreement was 84.1% (95% confidence interval [CI]: 75.5%–92.8%) for assessment 1 and 87.5% (95% CI: 78.4%–96.4%) for assessment 2, with kappa values 0.68 (95% CI: 0.50–0.82) and 0.75 (95% CI: 0.57–0.88). Average intrarater percent agreement was 95.0% (95% CI: 70.6%–100.0%) with average kappa 0.90 (95% CI: 0.50–1.00). CONCLUSION Substantial interrater and nearly perfect intrarater agreement was identified among surgeons assessing melanoma margins utilizing MART-1 immunostaining, demonstrating consistent and reproducible assessment of melanoma margins during Mohs cases.

Abstract Chimeric antigen receptor (CAR) T-cell (CAR-T) treatment for B-cell acute lymphoblastic leukemia (ALL) induces high initial response rates, but most patients relapse. Low disease burden (often defined as &lt;5% blasts in the bone marrow) is associated with better outcomes. CAR HEMATOTOX (HT) is a score using prelymphodepletion hematologic and inflammatory parameters to predict outcomes in lymphoma. Here, we assess its prognostic utility in a large multicenter adult B-cell ALL cohort. Patients who received brexucabtagene autoleucel across 33 centers in North America were included as part of the Real-World Outcomes Collaborative of CAR-T in Adult ALL (ROCCA) consortium. An independent cohort of 61 patients with ALL treated with an investigational CD19 CAR-T therapy at 1 center was also described. Among 199 ROCCA consortium patients, 43 (22%) patients with HTlow scores had lower rates of delayed neutrophil recovery than those with HThigh scores (26% vs 52%, P = .002) and fewer severe infections (2.5% vs 18.8%, P = .011). They also had higher response rates, overall survival (OS), and event-free survival (EFS), as well as lower nonrelapse mortality and cumulative incidence of relapse. The survival differences remained significant after multivariable adjustment for disease burden and other covariates. In the investigational cohort of 61 patients, patients with HTlow scores had improved OS and EFS, as well as higher peak CAR-T expansion. In summary, CAR HT score is a prognostic factor independent of disease burden in adult ALL. HTlow score is associated with superior outcomes after CD19 CAR-Ts and higher CAR-T expansion in a single-center cohort. These trials were registered at www.clinicaltrials.gov as #NCT01044069 and #NCT01860937.

Abstract Objectives γ‐Aminobutyric acid B receptor (GABA B R)‐IgG (immunoglobulin G) is an intermediate‐risk paraneoplastic autoantibody often associated with seizures. We aimed to assess the clinical and oncological features of GABA B R‐IgG autoimmune encephalitis (AE) and evaluate the performance of antibody testing. Methods Patients testing positive for GABA B R‐IgG in serum/cerebrospinal fluid (CSF) at Mayo Clinic Neuroimmunology Laboratory were identified. Archived sera were retested by cell‐based assay (CBA) at 1:100 and 1:200 dilutions. A live‐cell flow cytometry–based assay (LCFBA) was developed and validated using archived sera and CSF. True positivity included patients with classic presentations of GABA B R‐IgG AE or oncological explanations for antibody presence. Results Eighty‐six patients (median age 63 years; 43 female) presented with classic presentations of GABA B R‐IgG AE: encephalopathy with prominent seizures ( n = 55), status epilepticus ( n = 23), and rapidly progressive dementia ( n = 8). In addition, 44 patients (33%) had a false‐positive result for GABA B R‐IgG characterized by non‐specific symptoms/alternate diagnoses. Malignancy was identified in 78% of true‐positive patients, predominantly small cell lung carcinoma (SCLC). Testing serum at 1:100 dilution on CBA and using tissue immunofluorescence assay (IFA) in serum and CSF improved the identification of true‐positive patients ( p < 0.001). CBA at 1:100 dilution performed better than conventional CBA (at 1:10 dilution, p < 0.001) and tissue IFA ( p = 0.031). An in‐house LCFBA showed 100% sensitivity and specificity in CSF, performing similarly to conventional CBA ( p = 0.125) in CSF, but better than tissue IFA ( p = 0.031). Furthermore, serum LCFBA performed better than conventional CBA ( p = 0.022) and tissue IFA ( p = 0.006). LCFBA had the highest diagnostic accuracy and was closely followed by CBA at 1:100 dilution. Significance GABA B R‐IgG AE often presents as encephalopathy with seizures or status epilepticus in the context of an underlying SCLC. Multimodal evaluation using tissue IFA and fixed CBA at higher dilutions improves detection of true cases. LCFBA performs very well as a diagnostic test with very high sensitivity and specificity.

Abstract Background Spatially fractionated radiation therapy (SFRT) is a technique that delivers heterogenous dose distributions consisting of alternating regions of high dose “peaks” and low dose “valleys”. Current delivery methods for SFRT using megavoltage x‐rays usually treat large and bulky tumors with brass grid or volumetric modulated arc therapy (VMAT) lattice techniques. The size and spacing of high dose regions in these approaches are typically on the order of centimeters. However, multiple studies have suggested that decreasing these dimensions may improve the therapeutic ratio. Furthermore, a more compact approach to SFRT would allow for a greater number of high dose regions within the tumor, as well as application to smaller and more irregularly shaped targets thereby increasing the number of patients that could benefit from SFRT. Purpose This study describes the commissioning and first patient treatment using mini‐lattice radiation therapy (MLRT). MLRT uses a clinical linear accelerator and decreases the size and spacing of standard lattice SFRT by using individual multileaf collimator (MLC) leaves to deliver 5 mm wide high dose regions. Methods MLRT plans were created in the Varian Eclipse treatment planning system for a Varian Truebeam equipped with Millennium 120 MLCs. MLRT uses 6 MV Flattening Filter Free high dose rate and the width of individual MLCs to define 5 mm by 5 mm openings separated by closed MLCs to deliver alternating opened and blocked regions. Dynamic conformal arcs were used to conform MLCs to 4 mm spherical mini‐lattice structures in the gross tumor volume (GTV). A MLRT‐specific beam model was commissioned to accurately model the small MLRT fields. Film measurements were performed to assess the accuracy of MLRT plans calculations. Plans for seven treatment sites in different parts of the body for retrospective patient candidates were created with varying numbers of mini‐lattices and separation distances to assess the impact of varying these parameters on treatment dose metrics. MLRT was used for the first time to treat a patient with two fractions of MLRT. Results The AcurosXB calculation algorithm with modified x and y spot sizes, dosimetric leaf gap, transmission factor, and output factor table was used to generate a beam model for accurate MLRT calculations. The MLRT‐specific beam model resulted in gamma passing rates (1%/0.5 mm criteria) of 90%–99% for retrospective patient MLRT film measurements. Dose volume histogram statistics, equivalent uniform dose, and mean dose showed a higher number of mini‐lattices with smaller separation increased the dose to the GTV and surrounding tissue. Separation distances between mini‐lattices did not impact plan heterogeneity as measured by D10%/D90%. The first patient treated with the MLRT technique reported pain relief, had stable disease, and no acute toxicities following both fractions. Conclusions MLRT is feasible using clinical linear accelerators and existing radiation oncology infrastructure. It enables targeting smaller tumors with SFRT, allows for a greater number of high dose regions within the target compared to standard VMAT lattice techniques, and may be a useful technique for challenging treatment scenarios.

Abstract Hepatocellular carcinoma (HCC) mortality is increasing globally, partly due to the growing prevalence of nonviral liver diseases. Genome‐wide association studies (GWAS) have identified genetic variants associated with HCC development. Leveraging GWAS summary statistics and linkage disequilibrium score regression (LDSR), we investigated disease co‐development with hepatitis C virus‐negative (HCV‐negative) HCC to provide unique insights into HCC etiology and prioritize relationships for further causal inquiry. We utilized the LDSR statistical framework to estimate the genetic correlation and heritability between HCV‐negative HCC with 901 epidemiologic, behavioral, and clinical traits from the United Kingdom Biobank (UKBB). First, we set the threshold for observed scale heritability of each trait at 0.02 to ensure reliable inferences with adequate study power. Next, we observed significant positive genetic correlations between HCV‐negative HCC and blood‐based biomarkers of liver injury (ALT, GGT) and allostatic load (including glycated hemoglobin, blood pressure, and total albumin). We also identified a positive genetic correlation between HCV‐negative HCC and diseases associated with metabolic dysfunction‐associated steatotic liver disease (MASLD), including diabetes, hypertension, chronic ischemic heart disease, and others. Taken together, our results help to identify polygenic and pleiotropic signals related to different phenotypic traits associated with HCC and support further exploration of the predictive power of blood‐based biomarkers identified in this study for inferring HCC development among HCV‐negative individuals.

Objectives: To compare ACL reconstruction with quadriceps autograft with or without LET for primary ACL reconstruction Methods: A retrospective study was performed from 2013- 2021 including patient undergoing quadriceps autograft (QA) or QA plus lateral extra-articular tenodesis (LET) for primary ACLR. Exclusion criteria included patients undergoing multi-ligamentous reconstruction, concomitant procedures outside of meniscal work, revision cases, and patients with less than 2 years of follow up. The surgeon favored LET in young (less than 18 years old) females participating in cutting and twisting sports. An additional relative indication was a high-grade pivot shift (2 or 3+). Clincal outcomes incldued IKDC and Lysholm scores, retrun to sport/return to sport at same level and time to return to sport in athletes along with complication rates. Failure rate was determined by rate of graft re-tearing and presence of a residual pivot shift (2+ or higher) at final follow up. Results: A total of 142 patients underwent QA+LET with 18 excluded, leaving 124 patients in this group. The QA group had 371 patients with 57 excluded, leaving 314 for analysis. The QA+LET group had a significantly higher percentage of females, ligamentous laxity, and athletes. IKDC scores were significantly higher in the QA+LET group at final follow up. Lysholm scores were significantly higher in the QA group at 6 months, with no difference at other time points. Graft re-tear rates were similar between the 2 groups. Residual pivot shift at final follow up was significantly higher in the QA group (21% vs. 11%, p = 0.012) as was overall failure rate (24% vs. 14.5%. p = 0.026). Return to sport was similar between the 2 groups, but time to return to sport and return at the same or higher level was significantly higher in the QA+LET group. Hematomas were more common (12.9% vs. 0%) in the QA+LET group. Conclusions: Addition of an LET to QA leads to lower residual pivot shift when compared to QA alone. The addition of a LET to QA may lead to a higher return to sport at same or higher level compared to QA alone. This provides preliminary data that will be built upon with results from the Stability 2 trial.