Citations

Abstract Purpose: DICER1-related tumor predisposition increases risk for a spectrum of benign and malignant tumors. In 2018, the International Pleuropulmonary Blastoma (PPB)/DICER1 Registry published guidelines for testing- and imaging-based surveillance of individuals with a known or suspected germline DICER1 pathogenic or likely pathogenic (P/LP) variant. One of the goals of the Registry is to continue to refine these guidelines as additional data become available. Experimental Design: Individuals were enrolled in the International PPB/DICER1 Registry, the International Ovarian and Testicular Stromal Tumor Registry, and/or the NCI Natural History of DICER1 Syndrome study. Results: Review of participant records identified 713 participants with a germline DICER1 P/LP variant from 38 countries. To date, 5 cases of type I and 29 cases of type Ir PPB have been diagnosed by surveillance in enrolled individuals. One hundred and three individuals with a germline P/LP variant developed a primary ovarian Sertoli–Leydig cell tumor at a median age of 14 years (range: 11 months–66 years); 13% were diagnosed before 8 years of age, the current age of onset of pelvic surveillance. Additionally, 4% of Sertoli–Leydig cell tumors were diagnosed before 4 years of age. Conclusions: Ongoing data collection highlights the role of lung surveillance in the early detection of PPB and suggests that imaging-based detection and early resection may decrease the risk of advanced PPB. DICER1-related ovarian tumors were detected before 8 years of age, prompting the Registry to recommend earlier initiation of ovarian surveillance with pelvic ultrasound beginning at the time of detection of a germline DICER1 P/LP variant.

Background: Surgical repair of full thickness biceps tears has demonstrated adequate outcomes in short and mid-term studies. However, data on the long-term outcomes of full thickness distal biceps injuries and their treatment are currently lacking. Purpose/Hypothesis: The purpose of this study was to report on patient demographics, injury characteristics, and long-term outcomes for patients with full-thickness distal biceps tears. It was hypothesized that complete distal biceps tears managed operatively would demonstrate robust clinical success at long-term follow-up. Study Design: Case series; Level of evidence, 4. Methods: Patients with magnetic resonance imaging–confirmed, complete distal biceps tendon rupture sustained between 1996 and 2016 were identified. Patients were cross-referenced with a regional geographic database. Results: A total of 66 patients (3 female, 63 male) with a median age of 50.8 years (IQR, 41.5-60.4) and a median clinical follow-up of 14.7 years (IQR, 9.6-17.9 years) were included. Patients who sustained a full-thickness distal biceps tendon tear were likely to be in their early 50s, male, right-hand dominant, current/former smokers, and laborers with a history of traumatic injury during an intentional movement. Most of these patients had pain and supination weakness but no loss of range of motion. All included tears were treated operatively. At final follow-up, patients maintained a majority of near-normal range of motion (median total arc of flexion/extension 140° and supination/pronation 80°), excellent elbow flexion strength (91% of patients had full strength), and adequate elbow supination strength (76% of patients had full strength). The overall complication rate was 24%, with 16 out of 66 patients experiencing some type of complication between infection, rerupture, heterotopic ossification, reoperation, and nerve complications. Overall return to work was 98%, and 85% of those who returned to work did so without restrictions. Conclusion: Complete tears of the distal biceps were most common in patients 50 years of age, male sex, right-hand dominant, and current/former smokers. The most common profession was laborer, and injuries were primarily traumatic in nature during intentional activity. Patients managed operatively demonstrated high rates of success at long-term follow-up with respect to elbow function and clinical outcomes.

OBJECTIVE The Woven EndoBridge (WEB) device was approved to treat wide-necked bifurcation aneurysms. The device is designed as an intrasaccular flow disruptor covering aneurysm widths up to 10 mm. Although prior studies combined all aneurysm sizes, it is known that aneurysms behave differently in response to endovascular treatment based on their size. Therefore, the authors’ objective was to identify ideal middle cerebral artery (MCA) aneurysm width and neck sizes most suitable for WEB treatment. METHODS The WorldWideWEB consortium is a large multicenter retrospective database that analyzes intracranial aneurysms treated with the WEB device. In this study, all unruptured MCA bifurcation aneurysms with available measurements were included. Cutoff values based on aneurysm width and neck in relation to aneurysm occlusion status were measured using the receiver operating characteristic (ROC) curve. Propensity score matching (PSM) was then used to compare treatment outcomes between aneurysms smaller and larger than the cutoff value for both width and neck size. RESULTS The ideal cutoff values for MCA bifurcation aneurysm width and neck were 6.1 mm and 4.6 mm, respectively. On PSM, 87 matched pairs were compared based on width size (≤ 6.1 mm and > 6.1 mm), and 77 matched pairs were compared based on neck size (≤ 4.6 mm and > 4.6 mm). There was a significant difference in adequate aneurysm occlusion between aneurysms smaller and larger than those cutoff values for both widths (93% vs 76%, p = 0.0017) and neck sizes (90% vs 70%, p = 0.0026). The retreatment rate was also significantly higher for larger aneurysms in both parameters. CONCLUSIONS This study shows that MCA bifurcation aneurysms ≤ 6.1 mm in width and ≤ 4.6 mm in neck size are significantly better candidates for WEB treatment, leading to improved occlusion status and reduced retreatment rate, which are important considerations when using WEB devices.

AbstractWithin the past decade, there have been multiple innovations in the field of nerve surgery. In this review, we highlight critical changes and innovations that have helped advance the field and present opportunities for further study. This includes the modification and clarification of the classification schema for nerve injuries which informs prognosis and treatment, and a refined understanding and application of electrodiagnostic studies to guide patient selection. We provide indications for operative intervention based on this nerve injury classification and propose strategies best contoured for varying injury presentations at differing time points. Lastly, we discuss new developments in surgical techniques and approaches based on these advancements.

Importance Historically, women with aortic stenosis have experienced worse outcomes and inadequate recognition compared to men, being both underdiagnosed and undertreated, while also facing underrepresentation in clinical trials. Objective To determine whether women with small aortic annuli undergoing transcatheter aortic valve replacement have better clinical and hemodynamic outcomes with a self-expanding valve (SEV) or balloon-expandable valve (BEV). Design, Setting, Participants The Small Annuli Randomized to Evolut or SAPIEN Trial (SMART) was a large-scale randomized clinical trial focusing on patients with small aortic annuli undergoing transcatheter aortic valve replacement, randomized to receive SEVs or BEVs and included 716 patients treated at 83 centers in Canada, Europe, Israel, and the US from April 2021 to October 2022. This prespecified secondary analysis reports clinical and hemodynamic findings for all 621 women enrolled in SMART. Data for this report were analyzed from February to April 2024. Interventions Transcatheter aortic valve replacement with an SEV or a BEV. Main Outcomes and Measures The composite coprimary clinical end point comprised death, disabling stroke, or heart failure–related rehospitalization. The coprimary valve function end point was the incidence of bioprosthetic valve dysfunction, both assessed through 12 months. Secondary end points included the incidence of moderate or severe prosthesis-patient mismatch. Results A total of 621 women (mean [SD] age, 80.2 [6.2] years; 312 randomized to the SEV group and 309 to the BEV group) were included in the present analysis. At 12 months, there were no significant differences in the coprimary clinical end point between the SEV and BEV groups (9.4% vs 11.8%, absolute risk difference −2.3%; 95% CI −7.2 to 2.5, P = .35). However, SEV implantation was associated with less bioprosthetic valve dysfunction (8.4% vs 41.8%; absolute risk difference, −33.4%; 95% CI, −40.4 to −26.4; P < .001). SEV implantation resulted in lower aortic valve gradients and larger effective orifice areas at 30 days and 12 months and less mild or greater aortic regurgitation at 12 months compared to BEV implantation. Prosthesis-patient mismatch was significantly lower with SEVs, regardless of the definition used and adjustment for body mass index. Use of SEVs was associated with better quality of life outcomes as assessed by the Valve Academic Research Consortium-3 ordinal quality of life measure. Conclusions and Relevance Among women with severe symptomatic aortic stenosis and small aortic annuli undergoing transcatheter aortic valve replacement, the use of SEVs, compared to BEVs, resulted in similar clinical outcomes and a markedly reduced incidence of bioprosthetic valve dysfunction through 12 months, including a lower risk of prosthesis-patient mismatch and better 12-month quality of life. Trial Registration ClinicalTrials.gov Identifier: NCT04722250

Abstract Disclosure: D. Ferone: Consulting Fee; Self; Camurus AB, Ipsen, Novartis-AAA, Recordati. Grant Recipient; Self; Camurus AB, Ipsen, Novartis-AAA, Recordati. Research Investigator; Self; Camurus AB. J.L. Spencer-Segal: Advisory Board Member; Self; Camurus AB. Research Investigator; Self; Camurus AB. G. Fidan Yaylali: None. M. Doknic: Speaker; Self; Pfizer, Inc., Novo Nordisk, Merck, Sandoz. E. Isaeva: None. A. Dreval: None. A. Gilis-Januszewska: None. E. Gezer: None. I. Bancos: Advisory Board Member; Self; Diurnal, Spruce, Neurocrine, Adrenas, Sparrow, Corcept, HRA Pharmaceuticals, Recordati, Xeris, AstraZeneca, Novo Nordisk. Grant Recipient; Self; Recordati, HRA Pharmaceuticals. L. Katznelson: Advisory Board Member; Self; Camurus AB, Recordati. M. Harrie: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. A. Svedberg: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. A.M. Pedroncelli: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. F. Tiberg: Employee; Self; Camurus AB. Stock Owner; Self; Camurus AB. Background: Acromegaly is a rare, serious disorder characterized by overproduction of growth hormone (GH) and insulin-like growth factor 1 (IGF-1). There is a need for new, convenient therapies that provide effective disease control. CAM2029 is a novel subcutaneous octreotide depot designed for convenient once-monthly self-administration (ready-to-use syringe or injection pen). In a 24-week, Phase 3 trial (ACROINNOVA 1), CAM2029 was superior to placebo at attaining IGF-1 response (≤upper limit of normal [ULN] at week 22/24: 72.2% vs 37.5%; P=0.0018) in patients with acromegaly previously controlled under standard of care (SoC; octreotide long-acting repeatable [LAR]/lanreotide Autogel). Here, we report interim data from another Phase 3 trial of CAM2029 (ACROINNOVA 2; NCT04125836), focusing on the “New to CAM2029” subgroup of patients whose acromegaly was either controlled or uncontrolled under SoC. Methods: This 52-week, Phase 3, open-label trial (with a 52-week extension) enrolled patients who had received CAM2029 or placebo in ACROINNOVA 1 (reported separately) and “New to CAM2029” patients who were adequately or inadequately controlled (IGF-1 ≤2x ULN) on a stable dose of octreotide LAR/lanreotide Autogel for ≥3 months (data reported here). In the main part of the trial, new patients received once-monthly CAM2029 20 mg for up to 52 weeks. The primary endpoint was adverse events (AEs). Secondary endpoints included (i) the proportion of patients with IGF-1 ≤1x ULN (weeks 50/52 mean), (ii) the change from baseline in IGF-1, and (iii) the combined IGF-1 and GH response. Baseline values reflected SoC treatment. Data cutoff: May 23, 2023. Results: Eighty-one new patients were enrolled (mean age 51.8 years; 59.3% female). No new or unexpected safety signals were observed. The most common treatment-emergent AEs were injection site erythema (n=22) or swelling (n=13), and headache (n=12). AEs were mostly mild (grade 1/2); there were no serious or Grade 3 treatment-related AEs attributed to CAM2029. IGF-I response increased from 14.8% at baseline SoC (12/81) to 33.3% (20/60 patients with available data) at weeks 50/52. The estimated increase in IGF-1 response (linear probability model) from baseline at week 52 was 21.9% (95% CI: 9.6, 34.1). Biochemical control for both IGF-1 and GH improved over time: 30.0% of patients (18/60) had a combined IGF-1 and GH response at the end of the main part of trial, vs 11.7% (7/60) at baseline. Conclusion: CAM2029 was well tolerated with a safety profile consistent with that of SoC. Biochemical control rates improved from SoC baseline over 52 weeks of CAM2029 treatment in the “New to CAM2029” patients. These findings reinforce the efficacy and safety of CAM2029 in patients with acromegaly, including patients with uncontrolled disease with current SoC treatment (octreotide LAR/lanreotide Autogel). Presentation: 6/1/2024

Post-hepatectomy liver failure (PHLF) remains a significant risk for patients undergoing partial hepatectomy (PHx). Reliable prognostic markers and treatments to enhance liver regeneration are lacking. Plasma nanoparticles, including lipoproteins, exosomes, and extracellular vesicles (EVs), can reflect systemic and tissue-wide proteostasis and stress, potentially aiding liver regeneration. However, their role in PHLF is still unknown. Methods: Our study included nine patients with hepatocellular carcinoma (HCC) undergoing PHx: three patients with PHLF, three patients undergoing the associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) procedure, and three matched controls without complications after PHx. Patient plasma was collected before PHx as well as 1 and 5 days after. EVs were isolated by ultracentrifugation, and extracted proteins were subjected to quantitative mass spectrometry using a super-SILAC mix prepared from primary and cancer cell lines. Results: We identified 2625 and quantified 2570 proteins in the EVs of PHx patients. Among these, 53 proteins were significantly upregulated and 32 were downregulated in patients with PHLF compared to those without PHLF. Furthermore, 110 proteins were upregulated and 78 were downregulated in PHLF patients compared to those undergoing ALPPS. The EV proteomic signature in PHLF indicates significant disruptions in protein translation, proteostasis, and intracellular vesicle biogenesis, as well as alterations in proteins involved in extracellular matrix (ECM) remodelling and the metabolic and cell cycle pathways, already present before PHx. Conclusions: Longitudinal proteomic analysis of the EVs circulating in the plasma of human patients undergoing PHx uncovers proteomic signatures associated with PHLF, which reflect dying hepatocytes and endothelial cells and were already present before PHx.

Abstract Accumulating evidence suggests dysregulated immune checkpoint (IC) signaling can exacerbate COVID-19 severity, but the role of these molecules in the pathogenesis of fatal COVID-19-related diffuse alveolar damage (DAD) remains elusive. Understanding how IC proteins influence acute lung injury due to COVID-19 can provide insights into potential therapeutic strategies to modulate immune responses and improve patient outcomes. Here, in a single-center autopsy cohort, we determined the cellular localization of ICs in lung tissue from cases of fatal COVID-19, DAD-comparators, and non-fibrotic controls by using immunohistochemistry, and investigated their association with clinical outcomes. We expanded our findings by performing analyses of publicly available single-cell RNA sequencing datasets from patients with fatal COVID-19 and non-fibrotic controls. We demonstrated the presence of protein-protein interaction networks of ICs in the lung cellular niche by performing transcriptomic profiling of lung tissue-derived RNA counts from patients with fatal COVID-19. Further, we leveraged data from the largest international, multi-center COVID-19 autopsy cohort and validated that, among patients with fatal COVID-19, those with higher PD-L1/CD274 expression in lung endothelial cells had more rapid clinical deterioration. Lastly, in a cohort of individuals with early COVID-19, IC plasma protein levels were elevated in those with persistent SARS-CoV-2 RNAemia and adverse clinical outcomes. Collectively, our data provide unique pathological insights into the role of IC dysregulation and differential disease severity in COVID-19.