Citations

Objectives: Traumatic lateral patellar dislocation is frequently associated with cartilage lesions, particularly of the patella and lateral femoral condyle (LFC). Multiple treatment options to address these chondral lesions including debridement, microfracture, cartilage restoration with allo- or autograft, and osteotomies can be utilized at the index patellar stabilization surgery, or in a staged fashion. However, these additional procedures are not without increased morbidity and long-term benefit has not been well elucidated. In patients with traumatic chondral lesions associated with patellofemoral instability (PFI), meniscal coverage of the lesion and intervention to eliminate further patellar instability may be all that is required for a successful outcome. Thus rendering the increased time, morbidity, and cost of chondral procedures unjustified in this setting. The purpose of this study was to assess outcomes of patients with LFC chondral lesions after traumatic patellar dislocations and whether meniscus coverage of the lesion on magnetic resonance imaging (MRI) has an impact on patient outcomes. Methods: A retrospective chart review was performed to compare outcomes for patients with LFC lesions following acute patellar dislocation treated surgically at a single institution. MRI, operative reports, and intraoperative imaging were reviewed to assess for LFC lesions. Size of the LFC lesion and evaluation of meniscus coverage was measured in the coronal plane on T2 MRI sequences (Figure 1). Patient charts were reviewed to follow postoperative rehabilitation and clinical course. Patient reported outcome measures (PROMs) were obtained using the International Knee Documentation Committee (IKDC) score, Lysholm Knee score, Visual Analog Scale (VAS), and Tegner Activity score. Results: A total of 228 patients underwent surgical stabilization for patellar instability from 2001 to 2022, 81 of which had an LFC lesion identified on MRI and confirmed intraoperatively. Seven of these patients underwent a concomitant cartilage restoration procedure (3 internal fixation of osteochondral fragment, 2 microfracture, 1 osteochondral allograft, and 1 MACI) and they were excluded from the study leaving 74 patients. In assessing meniscus coverage of the chondral lesion, 10 of these lesions had no meniscus coverage, 8 had 1-50% coverage, and 56 had 51-100% coverage. The average size of the chondral lesion was 7.1 ± 2.9 mm and the majority were in the anterior one-third of the LFC. Average follow up from the index surgery was 7.6 years (range, 2.2-15.2 years). During this time frame, 12 patients had subsequent knee surgeries, none of which were to address the LFC lesion (Table 2). Postoperatively, nearly all patients reported improvement in their pain with an average VAS pain decrease of 3.7 points. There were no significant differences in PROMs in patients with meniscus coverage versus those without (Table 2). At the time of final follow-up, four patients had radiographic evidence of knee osteoarthritis (OA) within the lateral compartment, and one underwent a total knee arthroplasty (TKA). The patient that underwent a TKA had no meniscal coverage of their chondral lesion at the time of their index procedure. Conclusions: Cartilage lesions secondary to traumatic lateral patellar dislocation are common; however, appropriate management of these lesions remains unclear. The present findings suggest that not surgically addressing chondral lesions in patients with overlying meniscus coverage can allow for high functional outcomes and minimal pain after patellar stabilization procedures. Although only four patients progressed to radiographic evidence of OA, long term data will be valuable to understand whether overlying meniscus coverage is also protective against the development of OA and progression to TKA.

Achieving negative surgical margins is critical for patient outcomes in breast-conserving surgery (BCS), however positive margins require reoperation in 20% to 40% of cases currently. This study explores design criteria and current barriers and facilitators to margin definition and assessment as part of designing an intraoperative tool for margin assessment during BCS. We conducted observations of nine surgeries by four surgeons at a quaternary medical center. We analyzed the data using the Systems Engineering Initiative for Patient Safety (SEIPS) model to identify barriers and facilitators to margin assessment. We identified 38 barriers and 62 facilitators, which we inductively categorized into dimensions. The dimensions included teamwork, information display design, intraoperative tool use, and tissue characteristics. Teamwork was the most frequently observed dimension, followed by information display design and intraoperative tool use. This study provides insights to support the design of workflow-adaptive solutions and improve margin accuracy and surgical performance in breast oncology procedures.

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive and chemo-resistant sarcomas with poor survival rates. Loss of CDKN2A or P53 following NF1 disruption is a key event in MPNST development. Here, we used CRISPR-Cas9 somatic tumorigenesis in mice to identify transcriptomic and metabolomic features distinguishing CDKN2A - versus P53 -deleted MPNSTs. Convergent, multiomic analyses revealed that CDKN2A -deleted MPNSTs are especially dependent on the pentose phosphate pathway (PPP) and NADPH metabolism for growth and viability. Disruption of glucose-6-phosphate dehydrogenase (G6PD), the PPP rate-limiting enzyme, slowed CDKN2A -deleted MPNST growth and sensitized MPNSTs to standard-of-care chemotherapy. Knockdown of the redox-regulated transcription factor NRF2 slowed MPNST growth and decreased G6PD transcription. Analysis of patient MPNSTs identified a NRF2 gene signature correlating with tumor transformation. Furthermore, G6PD and NRF2 expression in PanCancer TCGA samples correlates with patient survival. This work identifies NRF2-PPP dependency as a targetable vulnerability in these difficult-to-treat MPNSTs, particularly in the NF1/CDKN2A -deleted majority.

Abstract Sex differences in cancer outcome, including that of glioblastoma (GBM), are shaped by biological, hormonal, and immunological factors and impact disease progression, treatment responses, survival, and tumor microenvironment (TME) interactions. Platelets regulate the immune responses and tumor progression in many cancers, but it is not clear how they contribute to these sex-based differences by affecting the dynamics of the TME. Here, we show that GBM patients exhibit heightened platelet reactivity driven by PAR4 signaling. In murine GBM models, both pharmacological inhibition of PAR4 using BMS986120 and genetic deletion of PAR4 significantly prolong survival in females but not males. This survival advantage is estrogen dependent: it is preserved in chromosomal male-hormonal female mice within the four-core genotype model and is rescued in ovariectomized mice treated with estrogen. The survival benefit is TME specific and is mediated by platelet-driven enhancement of CD8⁺ T cell infiltration into the tumor. Inhibition of platelet PAR4 signaling increases calcium signaling through an estrogen-dependent interaction between PAR4 and estrogen receptor β (ERβ)—a receptor interaction not previously described. PAR4-activated platelets within the TME suppress CD8⁺ T cell function, and depletion of CD8⁺ T cells abolishes both the tumor-induced platelet reactivity and the survival benefit conferred by PAR4 inhibition. These findings establish platelet-mediated PAR4 signaling as a critical driver of tumor progression and identify sex-specific immune responses as key to therapeutic efficacy.

Abstract Background and Aims Truncating variants in the TTN gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) but also occur as incidental findings in the general population. This study investigated factors associated with the clinical manifestation of TTNtv. Methods An international multicentre retrospective observational study was performed in families with TTNtv-related DCM. Shared frailty models were used to estimate associations of variant characteristics with lifetime risk of DCM, and logistic regression to estimate odds ratios (ORs) for individual-level clinical risk factor profiles (cardiac conditions, cardiovascular comorbidities, lifestyle) and DCM. Results A total of 3158 subjects in 1043 families with TTNtv-related DCM were studied. TTNtv-positive subjects were 21-fold more likely to develop DCM [OR, 21.21; 95% confidence interval (CI), 14.80–30.39]. Disease onset was earlier in males, but was similar for TTNtv of different types and locations. The presence of clinical risk factors was associated with earlier DCM onset (OR, 3.41; 95% CI, 2.06–5.64), with a prior history of atrial fibrillation having a two-fold increased odds of DCM (OR, 2.05; 95% CI, 1.27–3.32). The prevalence of clinical risk factors increased with age; however, the strength of the DCM association was greatest for young-onset (<30 years) disease (OR, 4.75; 95% CI, 2.35–9.60). Administration of beta-adrenergic receptor or renin-angiotensin system-blocking drugs prior to overt DCM was associated with 87% reduced odds of DCM (OR, .13; 95% CI, .08–.23). Conclusions Disease onset in TTNtv-associated familial DCM is dependent on individual patient context and is potentially modifiable by risk factor management and prophylactic therapeutic intervention.

Breast-conserving surgery (BCS) is a standard treatment for breast cancer, but achieving clear negative margins to avoid re-excision remains a challenge. Current intraoperative margin assessment techniques, such as frozen section analysis and imprint cytology, are limited by resource demands and workflow integration challenges. This study explores the physical design considerations for a handheld intraoperative imaging probe to assess tumor cavity margins during BCS. Data were collected through 9 surgical observations, 11 semi-structured interviews with breast surgeons, and interdisciplinary team meetings. Inductive thematic analysis identified key design priorities, including ergonomic handling, flexible probe tips, consistent tissue contact, and compatibility with both direct and tunneled access. Surgeons emphasized the need for quick scanning times and binary margin outputs, with interest in supplementary real-time imaging. These findings offer foundational insights for the iterative development of a clinically viable margin assessment tool aimed at reducing re-excisions and improving surgical outcomes in breast cancer care.

Objectives: To compare thresholds and accuracies of FIB-4, vibration-controlled transient elastography (VCTE), point shear wave elastography (pSWE), 2D shear wave elastography (2D-SWE), and MR elastography (MRE) for detecting hepatic fibrosis in patients with MASLD. Materials and Methods: Systematic searching of MEDLINE, EMBASE, Cochrane Library, Scopus, and the gray literature from inception to March 2024 was performed. Studies evaluating accuracies of FIB-4, VCTE, 2D-SWE, pSWE, and/or MRE for detecting significant (≥F2) and/or advanced (≥F3) hepatic fibrosis in MASLD patients compared to histology were identified. Full-text review and data extraction were performed independently by two reviewers. Multivariate meta-analysis and subgroup analyses were performed using index test and fibrosis grading. Risk of bias was assessed using QUADAS-2. Results: 207 studies with over 80,000 patient investigations were included. FIB-4 1.3 threshold sensitivity was 71% (95% CI 66–75%) for detecting advanced hepatic fibrosis, which improved to 88% (85–91%) using a <0.75 threshold. FIB-4 specificity using a 2.67 threshold was 96% (94–97%). Sensitivities of 88–91% were achieved using thresholds of 3.2 kPa for pSWE, 4.92 kPa for 2D-SWE, 7.18 kPa for VCTE, and 2.32 kPa for MRE. No significant differences were identified for sensitivities in subgroup analysis with thresholds between 7 and 9 kPa. Most imaging-based studies were high risk of bias for the index test. Conclusions: A FIB-4 threshold of <0.75 and modality-dependent thresholds (VCTE < 7 kPa; pSWE <3 kPa; 2D-SWE <5 kPa; and MRE <2.5 kPa) would achieve sensitivities of around 90% when defining low-risk MASLD in population screening. A modified two-tier algorithm aligning with existing Society of Radiologists in Ultrasound guidelines would improve risk stratification accuracies compared to existing guidelines by European and American liver societies.

PURPOSE Tumor treating fields (TTFields) use alternating electric fields to disrupt cancer cell proliferation. Feasibility of TTFields therapy with gemcitabine/nab-paclitaxel was previously demonstrated in patients with advanced pancreatic adenocarcinoma. PANOVA-3 was designed to confirm safety and efficacy of TTFields in patients with unresectable locally advanced pancreatic adenocarcinoma (LA-PAC). METHODS In this global phase III trial, 571 patients with newly diagnosed LA-PAC were randomly assigned to receive gemcitabine 1,000 mg/m 2 and nab-paclitaxel 125 mg/m 2 by intravenous infusion once a day on days 1, 8, and 15 of a 28-day cycle with or without TTFields. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), local PFS, pain-free survival, and overall response rate (ORR). Distant PFS was analyzed post hoc. RESULTS OS was significantly prolonged using TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel (median, 16.2 months [95% CI, 15.0 to 18.0] v 14.2 months [95% CI, 12.8 to 15.4]; hazard ratio [HR], 0.82 [95% CI, 0.68 to 0.99]; P = .039). PFS, local PFS, and ORR were not improved. Pain-free survival was significantly prolonged with TTFields with gemcitabine/nab-paclitaxel (median, 15.2 months [95% CI, 10.3 to 22.8] v 9.1 months [95% CI, 7.4 to 12.7]; HR, 0.74 [95% CI, 0.56 to 0.97]; P = .027), as was distant PFS (median, 13.9 months [95% CI, 12.2 to 16.8] v 11.5 months [95% CI, 10.4 to 12.9]; HR, 0.74 [95% CI, 0.57 to 0.96]; P = .022). Device-related skin adverse events (AEs) were experienced by 76.3% of patients. Most device-related skin AEs were mild to moderate, with 7.7% of patients reporting a grade 3 AE. CONCLUSION This study demonstrated significant OS, pain-free survival, and distant PFS benefits for TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel in patients with unresectable LA-PAC, with no additive systemic toxicity.

3069 Background: Molecular targeted agents have revolutionized cancer diagnosis and treatment. Intraoperative molecular imaging (IMI) is a novel technique that entails performing real-time, in vivo optical imaging during surgery to ensure cancer clearance. A multicenter clinical trial was conducted using abenacianine, a cathepsin targeted near-infrared (NIR) IMI agent to visualize pulmonary nodules during surgery. The primary objective was to assess the efficacy of abenacianine in localizing pulmonary lesions, evaluating surgical margin, and identifying unsuspected disease. Methods: Participants scheduled to undergo surgery for known or suspected cancer in the lung received abenacianine (0.32 mg/kg intravenous) preoperatively 12 to 36 hours before surgery. During a standard-of-care surgery, the lung underwent IMI and additional disease not identified by conventional methods were identified and analyzed. Efficacy was measured by frequency of clinically significant events (CSEs) defined as localization of lesions not found by standard surgical techniques, identification of additional cancers, identification of positive surgical margins confirmed by histology, and detection of cancerous lymph nodes. Results: 89 participants were included in the study. The mean age was 67 years and 57 (64%) were female. Of 89 participants administered abenacianine who underwent standard of care surgical resection for known or suspected cancer in the lung, 40 (45%) had at least one CSE. Abenacianine with NIR imaging identified lesions that were not found by standard surgical methods in 34 (38%) participants, synchronous and occult cancers that were not found by pre-operative imaging in 2 (2%), margins within 10 mm of the closest staple line in 8 (9%), and lymph nodes determined to be cancerous in 1 (1%) participant. Tumors visualized by IMI with abenacianine included non-small cell lung cancers (adenocarcinoma, squamous cell carcinoma, neuroendocrine tumor) and cancers that metastasized to the lung (breast, colorectal, prostate, thymoma, renal cell, sarcoma). Abenacianine was safe and well tolerated in this study; there were no drug-related serious adverse events. Conclusions: This Phase 2 multicenter study demonstrated that using IMI with abenacianine during standard-of-care lung cancer surgery markedly improved clinical outcomes. Abenacianine localized tumors intraoperatively, identified synchronous and occult lesions, helped assess negative margin status, and identified cancerous lymph nodes enabling a more complete oncologic resection. Clinical trial information: NCT06145048 .

Introductory paragraph The extracellular Calcium-sensing receptor (CaSR) regulates cellular responsiveness to physiological changes in ionized calcium (Ca 2+ ) concentrations. The CaSR is expressed in the brain, including in hypothalamic growth hormone stimulating GHRH and anorectic POMC neurons that control growth and energy homeostasis. We embryonically deleted the Casr gene in neurons to create Neuron CaSR -/- mice to delineate the role of this receptor in regulating growth, skeletal development, and energy metabolism. Neuron CaSR -/- mice had reduced size, weight and bone mass compared to littermate controls, with a dysregulated growth hormone axis. They also showed increased adiposity and circulating leptin levels, leptin resistance, and decreased glucose tolerance, along with reduced expression of the anorectic precursor peptide POMC and secondary increases in the expression of the anorectic peptide AgRP in the hypothalamus of Neuron CaSR -/- mice. Knockdown of CaSR in adult mice specifically in the hypothalamic arcuate nucleus, where GHRH, POMC and AgRP neurons reside, also resulted in increased body weight, adiposity, leptin resistance, and glucose intolerance, and reduced bone mass. Together these data suggest that neuronal CaSR critically regulates energy and skeletal metabolism and body growth by modulating hypothalamic function, representing a new paradigm for central integration of calcaemic activities with body function.