The Impact of HLA-DQαß Heterodimer Mismatch on Living Donor Kidney Allograft Outcomes.

BACKGROUND: HLA-DQ mismatch has been identified as a predictor of de novo donor-specific HLA antibody formation and antibody-mediated rejection. There are insufficient data to guide the incorporation of DQ mismatch into organ allocation decisions. METHODS: We used a retrospective longitudinal cohort of adult living donor kidney transplant recipients from 11 centers across the United States for whom high-resolution class II typing was available. HLA-DQαß heterodimer allele mismatch was quantified for all donor-recipient pairs, and outcome data were obtained through linkage with the Scientific Registry of Transplant Recipients. RESULTS: We studied 3916 donor-recipient pairs. Recipient characteristics were notable for a median age of 51 (38-61) y, primarily unsensitized, with 74.5% of the cohort having 0% calculated panel-reactive antibody, and 60.4% with private insurance, for a median follow-up time of 5.86 y. We found that the HLA-DQαß allele and HLA-DR antigen mismatch were each individually associated with an increased hazard of all-cause graft failure (adjusted hazard ratio [aHR] DQ = 1.03 1.14 1.28; aHR DR = 1.03 1.15 1.328), death-censored graft failure (aHR DQ =1.01 1.19 1.40; aHR DR = 0.099 1.18 1.39), and rejection. Having 2 HLA-DQαß allele mismatches further increased the hazard of rejection even when controlling for HLA-DR mismatch (aHR 1.03 1.68 2.74). CONCLUSIONS: HLA-DQαß allele mismatch predicted allograft rejection even when controlling for HLA-DR antigen mismatch and were both independently associated with increased risk of graft failure or rejection in adult living kidney transplant recipients. Given the strong burden of disease arising from the HLA-DQ antibody formation, we suggest that HLA-DQαß should be prioritized over HLA-DR in donor selection.

Exploring Radiofrequency Ablation for T1 Papillary Thyroid Cancer in the United States: Mayo Clinic Experience.

OBJECTIVE: To report the efficacy, safety, and feasibility of radiofrequency ablation (RFA) for T1 papillary thyroid carcinoma (PTC) in a large referral center in the United States. PATIENTS AND METHODS: We conducted a retrospective study of 8 patients who underwent RFA for T1 PTC at Mayo Clinic in Rochester Minnesota, between July 1, 2020, and February 28, 2023. The RFA technique and the type of anesthesia are described. Thyroid function, changes in ablated zone, and adverse events were analyzed for up to 24 months after the procedure. RESULTS: Of the 8 patients included in the study, 7 were female and 1 was male with a mean ± SD age of 53±16.4 years. Thyroid status was unaffected in 7 of the 8 patients. The median duration of RFA was 6 minutes (range, 2 to 14.5 minutes) with energy delivered at between 25 and 45 W. The mean ± SD volume of small PTCs was 0.3±0.2 mL, and the mean largest diameter was 9.5±3.3 mm (range, 6 to 15 mm). The mean ± SD ablated volume at 3 to 6 months was larger than the target lesion (0.8±0.7 mL), with a reduction in mean ± SD ablated volume of 0.4±0.4 mL at 7 to 12 months and 0.1±0.06 mL at 13 to 18 months. The ablated zone almost disappeared at 19 to 24 months (0.04±0.04 mL). There were no major adverse events during or after the RFA procedure. CONCLUSION: This is the first reported series of T1 PTC treated with RFA in the United States. Early postablation imaging revealed that the ablated region was larger than the target lesions, followed by a serial decrease in size. Therefore, RFA at centers with such expertise appears to be a safe and effective treatment for small PTCs. Further studies are needed to evaluate its long-term efficacy and the risk of recurrence.

Update on Percutaneous Ablation for Sarcoma.

PURPOSE OF REVIEW: To provide an update on the current state of percutaneous thermal ablation in the treatment of sarcoma. RECENT FINDINGS: Data continue to accrue in support of ablation for local control and palliation of specific sarcoma subtypes such as extra-abdominal desmoid fibromatosis and for broader indications such as the treatment of oligometastatic disease. The synergistic possibilities of various combination therapies such as cryoablation and immunotherapy represent intriguing areas of active investigation. Histotripsy is an emerging non-invasive, non-thermal ablative modality that may further expand the therapeutic arsenal for sarcoma treatment. Percutaneous thermal ablation is a valuable tool in the multidisciplinary management of sarcoma, offering a minimally invasive adjunct to surgery and radiation therapy. Although there remains a paucity of high-level evidence specific to sarcomas, ablation techniques are demonstrably safe and effective for achieving local tumor control and providing pain relief in select patients and are of particular benefit in those with metastatic disease or requiring palliative care.

Synthesis and antiproliferative activity of a tetrahydrofuran analog of FR901464.

FR901464 is a natural product that exhibits antiproliferative activity at single-digit nanomolar concentrations in cancer cells. Its tetrahydropyran-spiroepoxide covalently binds the spliceosome. Through our medicinal chemistry campaign, we serendipitously discovered that a bromoetherification formed a tetrahydrofuran. The tetrahydrofuran analog was three orders of magnitude less potent than the corresponding tetrahydropyran analogs. This study shows the significance of the tetrahydropyran ring that presents the epoxide toward the spliceosome.

Patient Access of Their Radiology Reports Before and After Implementation of 21st Century Cures Act Information-Blocking Provisions at a Large Multicampus Health System.

BACKGROUND. To implement provisions of the 21st Century Cures Act that address information blocking, federal regulations mandated that health systems provide patients with immediate access to elements of their electronic health information, including imaging results. OBJECTIVE. The purpose of this study was to compare patient access of radiology reports before and after implementation of the information-blocking provisions of the 21st Century Cures Act. METHODS. This retrospective study included patients who underwent outpatient imaging examinations from January 1, 2021, through December 31, 2022, at three campuses within a large health system. The system implemented policies to comply with the Cures Act information-blocking provisions on January 1, 2022. Imaging results were released in patient portals after a 36-hour embargo period before implementation versus being released immediately after report finalization after implementation. Data regarding patient report access in the portal and report acknowledgment by the ordering provider in the EMR were extracted and compared between periods. RESULTS. The study included reports for 1,188,692 examinations in 388,921 patients (mean age, 58.5 ± 16.6 [SD] years; 209,589 women, 179,290 men, eight nonbinary individuals, and 34 individuals for whom sex information was missing). A total of 77.5% of reports were accessed by the patient before implementation versus 80.4% after implementation. The median time from report finalization to report release in the patient portal was 36.0 hours before implementation versus 0.4 hours after implementation. The median time from report release to first patient access of the report in the portal was 8.7 hours before implementation versus 3.0 hours after implementation. The median time from report finalization to first patient access was 45.0 hours before implementation versus 5.5 hours after implementation. Before implementation, a total of 18.5% of reports were first accessed by the patient before being accessed by the ordering provider versus 44.0% after implementation. After implementation, the median time from report release to first patient access was 1.8 hours for patients with age younger than 60 years old versus 4.3 hours for patients 60 years old or older. CONCLUSION. After implementation of institutional policies to comply with 21st Century Cures Act information-blocking provisions, the length of time until patients accessed imaging results decreased, and the proportion of patients who accessed their reports before the ordering provider increased. CLINICAL IMPACT. Radiologists should consider mechanisms to ensure timely and appropriate communication of important findings to ordering providers.

Does Paging Clinicians about Tick-Borne Disease Serological Results Impact Clinical Care? A Retrospective Analysis of 70 Cases in North Carolina.

Delayed treatment of Rocky Mountain spotted fever is associated with increased morbidity and mortality. Because the diagnosis cannot be established from a single serological test, guidelines recommend empirical antibiotic initiation in suspect patients. We evaluated a policy used by UNC Health of paging clinicians when acute testing for Rickettsia returned with a titer ≥1:256. Our objective was to assess the potential effect of paging on routine treatment practices. Notably, we found that a high proportion of cases (N = 28, 40%) were not prescribed antibiotics until the results were available. The vast majority of these cases did not have evidence of compatible symptoms or disease progression. These findings suggest that paging may have prompted unnecessary treatment. Overall, the policy, which has now been discontinued, appears to have had limited benefit. Efforts are urgently needed to improve adherence to testing and treatment guidelines.

Evaluation of the VioOne HIV profile supplemental assay.

HIV is an ongoing global epidemic with estimates of more than a million new infections occurring annually. To combat viral spread, continuous innovations in areas including testing and treatment are necessary. In the United States, the Centers for Disease Control and Prevention recommend that laboratories follow an HIV testing algorithm that first uses a US Food and Drug Administration approved immunoassay to detect antibodies to HIV-1 or HIV-2 as well as HIV-1 p24 antigen in serum or plasma samples. An initially reactive specimen is tested by a supplemental assay for confirmation and to differentiate antibodies to HIV-1 or HIV-2. There are few Food and Drug Administration (FDA)-approved supplemental differentiation tests currently available. A multicenter investigation was conducted to determine the clinical performance for two independent versions of the Avioq VioOne HIV Profile Supplemental Assay (Avioq, Inc., Research Triangle Park, NC). The performance of both assay versions compared favorably with the performance parameters for the Geenius HIV 1/2 Supplemental Assay as published in that assay package insert (Bio-Rad Laboratories, Hercules, CA), the current gold standard for HIV supplemental testing. When comparing the two VioOne assays, version 2 (lacking HIV-2 p27 antibody detection) demonstrated improved reproducibility, specificity, and sensitivity as compared to its predecessor. IMPORTANCE We evaluated the reproducibility, sensitivity, and specificity data for two versions of the VioOne HIV Profile Supplemental Assay and compared these results back to similar results for the Geenius HIV 1/2 Supplemental Assay that are publicly available. Our study concluded that the VioOne HIV Profile Supplemental Assay compared favorably with the Geenius HIV 1/2 Supplemental Assay, thus providing an additional option for clinical laboratories to improve and expand their HIV testing capabilities.

Ethanol ablation of papillary thyroid carcinoma nodal metastases: Long-term outcomes.

BACKGROUND: Percutaneous ethanol ablation has emerged as a treatment for recurrent papillary thyroid carcinoma in the lateral neck after compartment-oriented therapeutic lymphadenectomy. However, the safety and utility of percutaneous ethanol ablation as a primary treatment modality for lateral neck metastases remains undefined. We aimed to investigate long-term outcomes of percutaneous ethanol ablation of lateral neck papillary thyroid carcinoma recurrence both with and without prior lymphadenectomy. METHODS: We conducted a retrospective study of patients with lateral neck papillary thyroid carcinoma treated with percutaneous ethanol ablation from 2013 to 2018. Patient characteristics, disease volume, morbidity, and recurrence (development of new lymphadenopathy within a percutaneous ethanol ablation-treated nodal compartment) were assessed. RESULTS: We identified 117 patients who underwent percutaneous ethanol ablation for papillary thyroid carcinoma lateral neck metastases-67 (57%) had a prior lateral neck dissection. Median follow-up after percutaneous ethanol ablation was 5.5 years (interquartile range 3.1-7.5). On average, 1.4 lymph nodes (range: 1-6) were treated. Three patients (3%) developed transient nerve-related complications after percutaneous ethanol ablation. Of 15 patients who underwent lateral neck dissection after percutaneous ethanol ablation (including patients undergoing repeat lateral neck dissection), dissection was "difficult" in 8 (53%) (7 of whom had previously undergone lateral neck dissection), and 4 (27%) developed complications (transient nerve dysfunction = 3, lymphatic leak = 1). Thirty-three patients (28%) developed recurrent papillary thyroid carcinoma. No difference in recurrence was seen between patients who did or did not undergo pre-percutaneous ethanol ablation lateral neck dissection (no pre-percutaneous ethanol ablation lateral neck dissection: 24%, pre-percutaneous ethanol ablation lateral neck dissection, 31%; hazard ratio = 1.27, 95% confidence interval 0.62-2.58; P = .514). CONCLUSION: Percutaneous ethanol ablation may be a safe primary treatment modality for papillary thyroid carcinoma lateral neck nodal recurrence in selected patients with low-volume nodal disease.

Acute Adverse Events After Iodinated Contrast Agent Administration of 359,977 Injections: A Single-Center Retrospective Study.

OBJECTIVE: To assess the effects of patient variables, examination variables, and seasonality on allergic-like and physiologic reactions to iodinated contrast material (ICM). PATIENTS AND METHODS: All ICM-enhanced computed tomography (CT) examinations performed from June 1, 2009, to May 9, 2017, at our institution were included. Reactions were identified and categorized as allergic-like or physiologic and mild, moderate, or severe. The effect of patient and examination variables on reactions was evaluated by logistic regression models. RESULTS: A total of 359,977 CT examinations performed on 176,886 unique patients were included. A total of 1150 allergic-like reactions (0.32%; 19 severe [0.005%]) and 679 physiologic reactions (0.19%; 3 severe [0.0008%]) occurred. On multivariable analysis, iopromide had higher rates of reactions compared with iohexol (allergic-like reactions: odds ratio [OR], 3.07 [95% CI, 2.37 to 3.98], P<.0001; physiologic reactions: OR, 2.60 [1.92 to 3.52], P<.0001). Non-White patients had higher rates of reactions compared with White patients (allergic-like reactions: OR, 1.77 [1.36-2.30], P<.0001; physiologic reactions: OR, 1.76 [1.27-2.42], P=.0006). Patient age, sex, prior ICM reaction, ICM dose, CT location, and CT type were also significantly associated with reactions. No significant seasonality trend was observed (P=.07 and .80). CONCLUSION: Non-White patients and patients administered iopromide had higher rates of acute reactions compared with White patients and patients administered iohexol. Younger patients (<50 years vs 51 to 60 years), female sex, history of ICM allergy or other allergies, ICM dose, and contrast-enhanced CT location and type also correlated with higher acute reaction rates.

Synthesis and Conformational Analysis of FR901464-Based RNA Splicing Modulators and Their Synergism in Drug-Resistant Cancers.

FR901464 is a cytotoxic natural product that binds splicing factor 3B subunit 1 (SF3B1) and PHD finger protein 5A (PHF5A), the components of the human spliceosome. The amide-containing tetrahydropyran ring binds SF3B1, and it remains unclear how the substituents on the ring contribute to the binding. Here, we synthesized meayamycin D, an analogue of FR901464, and three additional analogues to probe the conformation through methyl scanning. We discovered that the amide-containing tetrahydropyran ring assumes only one of the two possible chair conformations and that methylation of the nitrogen distorts the chair form, dramatically reducing cytotoxicity. Meayamycin D induced alternative splicing of MCL-1, showed strong synergism with venetoclax in drug-resistant lung cancer cells, and was cancer-specific over normal cells. Meayamycin D incorporates an alkyl ether and shows a long half-life in mouse plasma. The characteristics of meayamycin D may provide an approach to designing other bioactive L-shaped molecules.