Citations

Abstract Tumors of neuroendocrine origin are a heterogenous group of related neoplasms which can arise from anywhere in the body. Neuroendocrine neoplasms (NENs) are categorized by site of origin, differentiation status and grade (Ki‐67 expression and/or mitotic rate), with significant prognostic variability accordingly. Historically, the prevalence of bone metastasis is reported to be 6%–12% based on “first generation” (i.e., 111 Indium pentetreotide [Octreoscan®]) somatostatin receptor imaging (SSRI). We conducted a retrospective cohort study including patients with well‐differentiated NENs to determine the clinical and imaging characteristics of osseous metastases when evaluated with higher‐sensitivity 68 Gallium‐DOTATATE positron emission tomography (PET) scans, as well as determining fracture prevalence in selected sub‐cohorts. We also developed a risk score analysis to assess risk of fracture in this cohort. Four hundred twenty‐four patients were identified for inclusion. The median age was 61 years. Most patients were asymptomatic (64%), had sclerotic lesions (77%), Krenning 4 (71%), and had >3 sites (69%) of osseous disease. A high proportion of patients had osseous metastases at sites with high risk for fracture, including vertebra (82%), pelvis (63%), and peri‐trochanteric femur (34%). Fifty‐seven patients (13%) in the entire cohort suffered a fracture. Fracture prevalence was significantly lower in small bowel neuroendocrine tumors (NETs, 7%) and Grades 1 and 2 disease (8% and 9%, respectively), with higher prevalence in pancreatic NETs, paragangliomas/pheochromocytomas, lung carcinoid, and Grade 3 disease (≥20% for each; p ‐values <.05). Our study showed that the rate of osseous metastatic disease approximates 20% in well‐differentiated NENs. Most bone metastases are asymptomatic and the risk of fracture is variable based on the primary site of disease and tumor grade. Our novel risk score analysis for fracture was designed to assist clinician decision making as to management of bone metastasis in this patient population.

Klippel-Trénaunay syndrome (KTS) is a rare congenital vascular-overgrowth disorder within the broader spectrum of PIK3CA -related overgrowth syndromes. Although clinical, radiologic, and orthopedic manifestations are well described, the histologic spectrum of KTS-associated pathology remains under-characterized. Clinicopathologic findings from 21 patients with clinically established KTS were reviewed, including 18 with longitudinal clinical follow-up and 3 consultation cases of rare malignant mesenchymal neoplasms. Cases were identified from institutional pathology and clinical databases, and available hematoxylin and eosin-stained sections and ancillary studies were reviewed. The cohort included 11 males and 10 females. Among the 18 clinically followed patients, 12 had limb length discrepancy or asymmetric limb overgrowth, 9 had documented deep vascular malformations, 4 had intra-articular/synovial malformations, and 10 underwent initial orthopedic evaluation or intervention before age 18. Orthopedic morbidity clustered into mechanical overgrowth-related, vascular malformation-related, and soft tissue/wound-related complications. Histologic findings included superficial and/or deep slow-flow vascular malformations, ulceration and granulation tissue, hemosiderin-laden reactive synovium, and destructive hemorrhagic arthropathy. Intra-articular disease recapitulated a hemophilic arthropathy-like pattern, with hemosiderotic synovitis, papillary synovial hyperplasia, and progressive joint destruction with loss of articular cartilage, exposed subchondral bone destruction and remodeling, all attributable to long-standing intra-articular hemorrhage. Three consultation cases showed malignant mesenchymal neoplasia, including 2 angiosarcomas. Recognition of these patterns is important for pathologists evaluating specimens from patients with known or suspected KTS, particularly when findings mimic hemophilic arthropathy, diffuse-type tenosynovial giant cell tumor, nonsyndromic vascular malformation, and/or end-stage destructive arthropathy.

Background: The limb symmetry index (LSI) is a measure comparing strength and functional movement between the surgical and nonsurgical limbs, used after anterior cruciate ligament reconstruction (ACLR) to guide rehabilitation and assess return-to-sport readiness. With increasing use of the quadriceps tendon autograft (QT-ACLR), limited data exist on whether the LSI score correlates with patient-reported outcome measures (PROMs). Hypothesis/Purpose: To evaluate the predictive value of postoperative strength and functional LSI tests at 3, 6, and 9 months for short-term PROMs, determine Patient Acceptable Symptom State (PASS) thresholds, and assess differences based on PASS achievement. It was hypothesized that quadriceps strength LSI score would more strongly predict 2-year PROMs than hamstring strength LSI score, and that higher 9-month isokinetic quadriceps LSI scores would be associated with higher International Knee Documentation Committee (IKDC) and Lysholm scores. Study Design: Case series; Level of evidence, 4. Methods: Patients undergoing primary QT-ACLR from 2021 to 2024 with LSI testing during rehabilitation (isometric and isokinetic lower extremity strength, Y-Balance, hop testing) and no revision or additional knee surgery were included. The LSI score was assessed at 3, 6, and 9 months, and PROMs, including Lysholm and IKDC scores, were collected at a mean follow-up of 2.0 ± 0.7 years. Multivariable linear regression was used to evaluate associations between LSI measures and PROMs after adjusting for age, sex, and body mass index (BMI). Receiver operating characteristic analysis was used to determine PASS thresholds. Results: A total of 100 knees in 100 patients (mean age, 25.3 ± 11.2 years; BMI, 25.9 ± 6.5 kg/m 2 ; 52% male) were included. Quadriceps and hamstring strength and functional performance progressively improved from 3 to 9 months, with the LSI score reaching 77% to 81% for quadriceps strength and 98% to 100% for hamstring strength by 9 months postoperatively. At a mean follow-up of 2.0 ± 0.7 years, the mean satisfaction score was 8.4 of 10, the Lysholm score was 90.7, and the IKDC score was 77.8. Linear regression, adjusted for age, sex, and BMI, demonstrated that 3-month isometric quadriceps LSI score had a strong effect on IKDC score, explaining substantial variance (β = 3.9; adjusted R 2 [Adj R 2 ] = 0.36; P < .03); 6-month isokinetic quadriceps and hamstrings showed moderate but significant effects (β = 2.9-3.7; Adj R 2 = 0.13-0.17; P < .05) on IKDC score; and 9-month fast quadriceps had a strong effect explaining substantial variance in Lysholm and IKDC scores (β = 3.9-4.7; Adj R 2 = 0.34-0.35; P ≤ .003). Lysholm and IKDC scores correlated with satisfaction and accurately discriminated PASS thresholds (area under the curve, 0.927-0.937; P < .001). Patients achieving the IKDC PASS demonstrated higher LSI scores across time points and all PROMs. Conclusion: After QT-ACLR, strength-associated LSIs were independently associated with PROMs at a mean 2-year follow-up, after adjusting for age, sex, and BMI. Early isometric quadriceps strength at 3 months predicted higher 2-year IKDC scores, with PASS achievers generally attaining a 60% to 70% LSI score by 3 months. Isokinetic quadriceps strength at 9 months predicted both IKDC and Lysholm scores. These findings highlight the importance of early quadriceps strength recovery and the value of LSI measures in predicting PROMs and informing early rehabilitation.

Abstract Everolimus 10 mg daily is the standard dose for advanced neuroendocrine tumors (NETs), but adverse events frequently necessitate dose reduction. As a result, oncologists often adopt a dose‐escalation strategy starting at 5 mg and increasing the dose as tolerated. In this multicenter study, we evaluated the effect of reduced dose (RD) and standard dose (SD) everolimus on survival, progression, and toxicity in patients with advanced NETs. We conducted a multicenter retrospective cohort study of patients with advanced NETs treated with everolimus at Mayo Clinic and University Hospitals (Cleveland, OH). Patients were grouped by starting dose (5 mg vs. 10 mg). Primary endpoints were overall survival (OS), real‐world progression‐free survival (rwPFS), and adverse events. Multivariable Cox models, inverse probability of treatment weighting (IPTW), and time‐varying dose sensitivity analysis were used to account for confounding and dose crossover. Among 170 patients (48 started on 5 mg; 122 on 10 mg), the 5 mg cohort was older, had worse ECOG PS, and was more heavily pretreated. Median OS was 43.7 months (5 mg) versus 81.5 months (10 mg; log‐rank p = .02). However, after multivariable adjustment ( N = 124 G1–G2 patients; 51 events), the association was no longer statistically significant (adjusted HR, 0.59; 95% CI, 0.31–1.12; p = .11). Median rwPFS was 7.0 versus 12.4 months (log‐rank p = .05); the adjusted rwPFS difference was not statistically significant (HR, 0.95; 95% CI, 0.56–1.61; p = .84). Nearly half (46.7%) of 10 mg starters required dose reduction. Any‐grade toxicity was more common with 10 mg (89% vs. 75%; p = .05). The apparent survival advantage of standard‐dose everolimus was substantially attenuated after adjustment. These findings do not establish dose equivalence and should be interpreted in the context of limited statistical power. Given its more favorable observed tolerability profile, RD everolimus warrants prospective evaluation as a starting strategy for patients at increased risk of treatment‐related toxicity who may not tolerate SD.

Abstract The paradigm in the field of oncolytic virotherapy proposes that tumor cell killing by an oncolytic virus (OV) culminates in the priming of antitumor CD8+ T cells. However, this ignores the impact a highly immunodominant antiviral response against the OV has on the subdominant antitumor response, particularly with regard to the naturally low affinity of tumor antigens to their cognate T-cell receptors. To investigate this experimentally, we first studied the interaction between the two responses in B16 and MC38 tumor models, both expressing ovalbumin (OVA). Contrary to the accepted paradigm, the inflammatory vesicular stomatitis virus (VSV) failed to expand OVA-specific T cells in vivo unless armed with tumor-associated antigen (TAA). In fact, treatment with the control VSV led to the ablation of antitumor T cells and a shift toward dysfunction as determined by the upregulation of markers, including LAG3 and CD39, correlating with lower rates of survival. Combination with anti–PD-1 immune checkpoint blockade therapy significantly improved survival only when VSV expressed TAA. VSV-expressing altered peptide ligand variants of tumor antigens, which evade mechanisms of central tolerance, expanded near self-antigen–specific T cells with the ability to cross-react with tolerized tumor antigens, thus providing an antitumor effector population capable of proliferating in the presence of a potent antiviral response. Taken together, these findings offer a rational approach to OV design which preserves acute antitumor therapy provided by antiviral innate and T-cell responses while promoting the induction of tumor-specific T cells. Significance: Oncolytic viruses can induce an antiviral T-cell response that occludes an antitumor response, challenging the paradigm in the field and elucidating strategies to optimize the efficacy of oncolytic viroimmunotherapy.

BACKGROUND: Ventricular fibrillation (VF) remains a leading cause of sudden cardiac death with an incompletely characterized electrophysiological substrate. Traditional large-animal VF models are limited by hemodynamic collapse and myocardial ischemia. This study establishes a reproducible swine model using dual mechanical circulatory devices to enable high-density electroanatomic mapping under nonischemic conditions. METHODS: Five Yorkshire swine (55–65 kg) underwent sustained VF supported by venoarterial extracorporeal membrane oxygenation (2.5–3.0 L/min) and percutaneous left ventricular unloading (Impella CP, P-2–P-4). High-density electroanatomic mapping using CARTO 7 was performed at baseline and after defibrillation. Bipolar voltage was acquired from 7 predefined ventricular regions (21 measurements per animal per time point; n=210 paired observations). Unipolar voltage mapping and continuous surface ECG monitoring were used to assess acute ischemic injury. Systemic perfusion was maintained at systolic arterial pressure ≥80 mm Hg. Linear mixed-effects modeling was used to analyze voltage changes from pre-VF to post-VF. RESULTS: Sustained VF (10±1 minutes) was reproducibly induced and maintained with consistent hemodynamics (systolic arterial pressure, 90±5 mm Hg; extracorporeal membrane oxygenation flow, 2.5±0.5 L/min). All animals were successfully defibrillated. High-density mapping was feasible in all experiments (1000±300 points per chamber). Bipolar voltage showed no change from pre-VF (5.86±2.56 mV) to post-VF (6.53±2.22 mV; mean difference, 0.67 mV [95% CI, –0.31 to 1.65]; P =0.15). Both left ( P =0.17) and right ventricles ( P =0.08) demonstrated voltage preservation. Regional analysis showed no significant changes (all P >0.05); post-VF voltages remained above viability thresholds (>1.5 mV). Unipolar voltage maps recovered toward baseline, with no ECG injury pattern identified after defibrillation. CONCLUSIONS: Dual mechanical circulatory support with venoarterial extracorporeal membrane oxygenation and Impella CP enables reproducible, high-fidelity electroanatomic mapping and preserves myocardial substrate after sustained VF in a large-animal model. This platform overcomes key technical barriers in VF research, providing a nonischemic foundation for future mechanistic and translational studies.

Purpose To assess the reliability, predictability, and discriminative capacity of 3 anatomic measurements, tibial tubercle‐trochlear groove (TT‐TG), tibial tubercle‐posterior cruciate ligament, and patellar tendon‐lateral trochlear ridge (PT‐LTR), where PT‐LTR may offer a complementary approach to assessing recurrent patellofemoral instability (PFI) risk. Methods Patients diagnosed with PFI before primary patellofemoral stabilization surgery at a single institution between 2022 and 2024 were included. A control group without PFI was propensity matched 1:1 for age, sex, and laterality. Magnetic resonance images were evaluated to measure TT‐TG, tibial tubercle‐posterior cruciate ligament, and PT‐LTR. A priori power analysis determined the cohort size. Statistical analyses compared differences between the PFI and control groups with Student t‐tests, receiver operating characteristic analyses, and area under the curve with resultant sensitivity, specificity, and an optimal cutoff. Results Patients included 50 knees with PFI (28 women, 22 men; mean age 18 ± 5 years). The control group included 50 knees (27 women, 23 men; mean age 18 ± 4 years). Excellent inter‐ and intra‐rater reliability (intraclass correlation coefficient > 0.7) was shown for TT‐TG and PT‐LTR in the PFI and control groups. The distances for TT‐TG, tibial tubercle‐posterior cruciate ligament, and PT‐LTR were significant predictors ( P ≤ .025) of PFI. The average PT‐LTR distance difference for the PFI and control groups was 7.0 mm ( P < .001). PT‐LTR showed an area under the curve of 0.80 and, when ≥4.6 mm, was 66% sensitive and 92% specific for PFI. Conclusions The PT‐LTR distance is a reliable and discriminative metric for identifying PFI in both pediatric and adult populations. A PT‐LTR cutoff value of 4.6 mm showed diagnostic discrimination and substantially high specificity for recurrent PFI, indicating strong ability to identify patients with instability. Level of Evidence Level III, retrospective case control study.

Age-related gastrointestinal dysfunction is common, but the mechanisms of aging-associated smooth muscle failure remain unclear. We show that aging in mice slows whole gut and colonic transit, increases regional stiffness, and reduces smooth muscle contractility. Inducible smooth muscle cell (SMC)– specific deletion of Piezo1 preserved youthful transit and force generation, whereas Piezo1 activation in young mice phenocopied aging-associated transit delay. Single-cell transcriptomics, RNA velocity, stiffness-controlled cell and tissue cultures, and pharmacologic studies revealed that Piezo1 couples increased stiffness to Ca 2+ –calcineurin–NFAT signaling, loss of contractile gene programs, leading to age- related contractile loss and contractile-to-synthetic SMC remodeling and gut wall stiffening. Human intestinal SMCs supported conservation of this pathway, and PIEZO1 gain-of-function carriers showed a trend toward delayed colonic transit. Thus, maladaptive SMC Piezo1 mechanotransduction is a targetable mechanism of aging-associated gut dysmotility. Aging alters organ structure, yet how these changes drive functional decline remains poorly defined. We show that progressive stiffening of the gut with age activates the mechanosensitive ion channel Piezo1 in smooth muscle cells, initiating a maladaptive response that impairs contractility and slows intestinal transit. On the other hand, deletion of smooth muscle Piezo1 prevents age-related gut dysmotility. These findings reveal that age-related physical shifts actively drive functional decline through mechanotransduction pathways. By identifying Piezo1 as a critical link between tissue mechanics and organ aging, this work provides a framework for understanding how mechanical cues contribute to age-related dysfunction in the gut and possibly other smooth muscle organs.