Citations

Introduction Survival prediction in glioblastoma remains challenging, and identification of robust imaging markers could help with this relevant clinical problem. We evaluated multiparametric magnetic resonance imaging–derived radiomics to assess prediction of overall survival (OS) and progression-free survival (PFS). Methodology A retrospective, institutional review board–approved study was performed. There were 93 eligible patients, of which 55 underwent gross tumor resection and chemoradiation (GTR-CR). Overall survival and PFS were assessed in the entire cohort and the GTR-CR cohort using multiple machine learning pipelines. A model based on multiple clinical variables was also developed. Survival prediction was assessed using the radiomics-only, clinical-only, and the radiomics and clinical combined models. Results For all patients combined, the clinical feature–derived model outperformed the best radiomics model for both OS (C-index, 0.706 vs 0.597; P < 0.0001) and PFS prediction (C-index, 0.675 vs 0.588; P < 0.001). Within the GTR-CR cohort, the radiomics model showed nonstatistically improved performance over the clinical model for predicting OS (C-index, 0.638 vs 0.588; P = 0.4). However, the radiomics model outperformed the clinical feature model for predicting PFS in GTR-CR cohort (C-index, 0.641 vs 0.550; P = 0.004). Combined clinical and radiomics model did not yield superior prediction when compared with the best model in each case. Conclusions When considering all patients, regardless of therapy, the radiomics-derived prediction of OS and PFS is inferior to that from a model derived from clinical features alone. However, in patients with GTR-CR, radiomics-only model outperforms clinical feature–derived model for predicting PFS.

Adamantinoma-like Ewing sarcoma (ALES) is a rare malignancy currently considered a variant of Ewing sarcoma with most known cases harboring EWSR1 rearrangements. Herein we present a series of 6 cases of EWSR1-negative ALES. The tumors arose in the sinonasal tract (n=3), major salivary glands (submandibular gland=1; parotid=1), and anterior mediastinum (n=1) in patients ranging from 25 to 79 years of age. Most tumors were basaloid in appearance, growing in large nests separated by interlobular fibrosis without overt squamous pearls. However, 1 case closely resembled a well-differentiated neuroendocrine tumor with uniformly round nuclei, eosinophilic cytoplasm, and trabecular architecture. All cases were diffusely positive for pan-cytokeratin, p40 or p63, and CD99. A subset of cases showed diffuse reactivity for synaptophysin, including 1 sinonasal tumor which also demonstrated sustentacular S100 protein expression. Molecular testing showed FUS rearrangements in all cases. Gene partners included known ETS family members FEV (n=2) and FLI1 (n=1). Our results expand the molecular diagnostic considerations for ALES to include FUS rearrangements. We also show that ALES may harbor FUS::FLI1 fusion, which has not been previously reported in the Ewing family of tumors. Furthermore, ALES may show unusual histologic and immunophenotypic features that can overlap with olfactory carcinoma including S100-positive sustentacular cells. ALES should be considered in the diagnostic differential of small round cell tumors and tumors with neuroendocrine differentiation with immunohistochemical workup to include p40 and CD99/NKX2.2.

Abstract Cardiovascular disease is the leading cause of death in women and men globally, with most due to atherosclerotic cardiovascular disease (ASCVD). Despite progress during the last 30 years, ASCVD mortality is now increasing, with the fastest relative increase in middle-aged women. Missed or delayed diagnosis and undertreatment do not fully explain this burden of disease. Sex-specific factors, such as hypertensive disorders of pregnancy, premature menopause (especially primary ovarian insufficiency), and polycystic ovary syndrome are also relevant, with good evidence that these are associated with greater cardiovascular risk. This position statement from the European Atherosclerosis Society focuses on these factors, as well as sex-specific effects on lipids, including lipoprotein(a), over the life course in women which impact ASCVD risk. Women are also disproportionately impacted (in relative terms) by diabetes, chronic kidney disease, and auto-immune inflammatory disease. All these effects are compounded by sociocultural components related to gender. This panel stresses the need to identify and treat modifiable cardiovascular risk factors earlier in women, especially for those at risk due to sex-specific conditions, to reduce the unacceptably high burden of ASCVD in women.

Importance Endovascular aneurysm repair (EVAR) is the dominant treatment strategy for abdominal aortic aneurysms, encompassing 80% of all repairs in the United States. Endoleaks are ubiquitous and affect 30% of patients treated by EVAR, potentially leading to sac enlargement and increased risk of rupture. The care of EVAR patients requires long-term surveillance by a multidisciplinary team. Accordingly, physicians should be familiar with the fundamentals of endoleak management to achieve optimal outcomes, including timely referral for remediation or providing counseling and reassurance when needed. Observations PubMed and the Cochrane database were searched for articles published between January 2002 and December 2022 in English, addressing epidemiology, diagnosis, and management of endoleaks after EVAR. Endoleaks can be detected intraoperatively or years later, making lifelong surveillance mandatory. Type I and III have the highest risk of rupture (7.5% at 2 years and 8.9% at 1 year, respectively) and should be treated when identified. Intervention should be considered for other types of endoleak when associated with aneurysm sac growth larger than 5 mm based on current guidelines. Type II endoleaks are the most common, accounting for 50% of all endoleaks. Up to 90% of type II endoleaks resolve spontaneously or are not associated with sac enlargement, requiring only observation. Although the risk of rupture is less than 1%, cases that require reintervention are challenging. Recurrence is common despite endovascular treatment, and rupture can occur without evidence of sac growth. Type IV endoleaks and endotension are uncommon, are typically benign, and primarily should be observed. Conclusions and Relevance Endoleak management depends on the type and presence of sac expansion. Type I and III endoleaks require intervention. Type II endoleaks should be observed and treated selectively in patients with significant sac expansion. Since endoleaks can appear any time after EVAR, at least 1 contrast-enhanced computed tomographic angiogram or duplex ultrasound by an experienced laboratory is recommended every 5 years.

Ewing sarcoma is a rare and deadly pediatric bone cancer for which survival rates and treatment options have stagnated for decades. Ewing sarcoma has not benefited from immunotherapy due to poor understanding of how its immune landscape is regulated. We recently reported that ubiquitin-specific protease 6 (USP6) functions as a tumor suppressor in Ewing sarcoma, and identified it as the first cell-intrinsic factor to modulate the Ewing sarcoma immune tumor microenvironment (TME). USP6 induces intratumoral infiltration and activation of multiple innate immune lineages in xenografted nude mice. Here we report that natural killer (NK) cells are essential for its tumor-inhibitory functions, as NK cell depletion reverses USP6-mediated suppression of Ewing sarcoma xenograft growth. USP6 expression in Ewing sarcoma cells directly stimulates NK cell activation and degranulation in vitro, and functions by increasing surface levels of multiple NK cell-activating ligands. USP6 also induces surface upregulation of the receptor for the apoptosis-inducing ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), providing an additional route for enhanced sensitivity to NK cell killing. Furthermore, USP6-expressing Ewing sarcoma and NK cells participate in a paracrine immunostimulatory feedforward loop, wherein IFNγ secreted by activated NK cells feeds back on USP6/Ewing sarcoma cells to induce synergistic expression of chemokines CXCL9 and CXCL10. Remarkably, expression of USP6 in subcutaneous Ewing sarcoma xenografts induces systemic activation and maturation of NK cells, and induces an abscopal response in which growth of distal tumors is inhibited, coincident with increased infiltration and activation of NK cells. This work reveals how USP6 reprograms the Ewing sarcoma TME to enhance antitumor immunity, and may be exploited for future therapeutic benefit. Significance: This study provides novel insights into the immunomodulatory functions of USP6, the only cancer cell–intrinsic factor demonstrated to regulate the immune TME in Ewing sarcoma. We demonstrate that USP6-mediated suppression of Ewing sarcoma tumorigenesis is dependent on NK cells. USP6 directly activates NK cell cytolytic function, inducing both intratumoral and systemic activation of NK cells in an Ewing sarcoma xenograft model.

Purpose: Glioblastoma multiforme (GBM) is a hypoxic tumor resistant to radiotherapy. The purpose of this study was to assess the safety and efficacy of a novel oxygen therapeutic, dodecafluoropentane emulsion (DDFPe), in chemoradiation treatment of GBM. Experimental Design: In this multicenter phase Ib/II dose-escalation study, patients were administered DDFPe via intravenous infusion (0.05, 0.10, or 0.17 mL/kg) while breathing supplemental oxygen prior to each 2 Gy fraction of radiotherapy (30 fractions over 6 weeks). Patients also received standard-of-care chemotherapy [temozolomide (TMZ)]. Serial MRI scans were taken to monitor disease response. Adverse events were recorded and graded. TOLD (tissue oxygenation level–dependent) contrast MRI was obtained to validate modulation of tumor hypoxia. Results: Eleven patients were enrolled. DDFPe combined with radiotherapy and TMZ was well tolerated in most patients. Two patients developed delayed grade 3 radiation necrosis during dose escalation, one each at 0.1 and 0.17 mL/kg of DDFPe. Subsequent patients were treated at the 0.1 mL/kg dose level. Kaplan–Meier analysis showed a median overall survival of 19.4 months and a median progression-free survival of 9.6 months, which compares favorably to historical controls. Among 6 patients evaluable for TOLD MRI, a statistically significant reduction in tumor T1 was observed after DDFPe treatment. Conclusions: This trial, although small, showed that the use of DDFPe as a radiosensitizer in patients with GBM was generally safe and may provide a survival benefit. This is also the first time than TOLD MRI has shown reversal of tumor hypoxia in a clinical trial in patients. The recommended dose for phase II evaluation is 0.1 mL/kg DDFPe. Trial Registration: NCT02189109 Significance: This study shows that DDFPe can be safely administered to patients, and it is the first-in-human study to show reversal of hypoxia in GBM as measured by TOLD MRI. This strategy is being used in a larger phase II/III trial which will hopefully show a survival benefit by adding DDFPe during the course of fractionated radiation and concurrent chemotherapy.

Dual mobility (DM) components are increasingly used to prevent and treat dislocation after total hip arthroplasty (THA). Intraprosthetic dissociation (IPD) is a known rare complication of these implants and has reportedly decreased with modern implants. The purpose of this paper is to report the diagnosis and treatment of modern DM IPD.1453 DM components were implanted between 2010 and 2021. 695 in primary and 758 in revision THA. 49 hips sustained a dislocation of the large head and 5 sustained an IPD at presentation. 6 additional IPD occurred at the time of reduction of large head. The average age was 64, 54% were female and the mean follow-up was three years. Of the 11 IPD, 8 had a history of instability, 5 had abductor insufficiency, 4 had prior lumbar fusion, and 3 were conversions from fracture.The overall IPD incidence was 0.76%. Ten of the 11 DM IPD were missed at initial presentation or at the time of reduction, and all were discharged with presumed reduction. The mean time from IPD to surgical treatment was 3 weeks. One patient died with an IPD at 5 months. A DM head was reimplanted in six, two underwent revision of the acetabular component with exchange of DM head, and four were revised to a constrained liner. The re-revision rate was 55% at a mean 1.8 years. None of the patients who underwent cup revision required subsequent re-revision while half of the constrained liners and exchange of DM heads required re-revision.The overall rate of DM dislocation or IPD is low. It is critical to identify an IPD on radiographs as it was almost universally missed at presentation or when it occurred iatrogenically. For patients presenting with IPD, the surgeon should consider acetabular revision and conversion to a constrained liner or a larger DM, with special attention to removing impinging structures that could increase the risk of re-dislocation.

Abstract Follicular lymphoma (FL) is clinically heterogeneous, with select patients tolerating extended watch-and-wait, whereas others require prompt treatment, suffer progression of disease within 24 months of treatment (POD24), and/or experience aggressive histologic transformation (t-FL). Because our understanding of the relationship between genetic alterations in FL and patient outcomes remains limited, we conducted a clinicogenomic analysis of 370 patients with FL or t-FL (from Cancer and Leukemia Group B/Alliance trials 50402/50701/50803, or real-world cohorts from Washington University School of Medicine, Cleveland Clinic, or University of Miami). FL subsets by grade, stage, watch-and-wait, or POD24 status did not differ by mutation burden, whereas mutation burden was significantly higher in relapsed/refractory (rel/ref) FL and t-FL than in newly diagnosed (dx) FL. Nonetheless, mutation burden in dx FL was not associated with frontline progression-free survival (PFS). CREBBP was the only gene more commonly mutated in FL than in t-FL yet mutated CREBBP was associated with shorter frontline PFS in FL. Mutations in 20 genes were more common in rel/ref FL or t-FL than in dx FL, including 6 significantly mutated genes (SMGs): STAT6, TP53, IGLL5, B2M, SOCS1, and MYD88. We defined a mutations associated with progression (MAP) signature as ≥2 mutations in these 7 genes (6 rel/ref FL or t-FL SMGs plus CREBBP). Patients with dx FL possessing a MAP signature had shorter frontline PFS, revealing a 7-gene set offering insight into FL progression risk potentially more generalizable than the m7–Follicular Lymphoma International Prognostic Index (m7-FLIPI), which had modest prognostic value in our cohort. Future studies are warranted to validate the poor prognosis associated with a MAP signature in dx FL, potentially facilitating novel trials specifically in this high-risk subset of patients.

Abstract Background: With the widespread use of multigene panel genetic testing, population-based studies are necessary to accurately assess penetrance in unselected individuals. We evaluated the prevalence of germline pathogenic or likely pathogenic variants (mutations) in 12 cancer-predisposition genes and associations with ovarian cancer risk in three population-based prospective studies [Nurses’ Health Study (NHS), NHSII, Cancer Prevention Study II]. Methods: We included women with epithelial ovarian or peritoneal cancer (n = 776) and controls who were alive and had at least one intact ovary at the time of the matched case diagnosis (n = 1,509). Germline DNA was sequenced for mutations in 12 genes. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for ovarian cancer risk by mutation status. Results: The mutation frequency across all 12 genes was 11.2% in cases and 3.3% in controls (P &lt; 0.0001). BRCA1 and BRCA2 were the most frequently mutated (3.5% and 3.8% of cases and 0.3% and 0.5% of controls, respectively) and were associated with increased ovarian cancer risk [OR, BRCA1 = 12.38; 95% confidence interval (CI) = 4.72–32.45; OR, BRCA2 = 9.18; 95% CI = 3.98–21.15]. Mutation frequencies for the other genes were ≤1.0% and only PALB2 was significantly associated with risk (OR = 5.79; 95% CI = 1.09–30.83). There was no difference in survival for women with a BRCA germline mutation versus no mutation. Conclusions: Further research is needed to better understand the role of other mutations in ovarian cancer among unselected populations. Impact: Our data support guidelines for germline genetic testing for BRCA1 and BRCA2 among women diagnosed with epithelial ovarian cancer; testing for PALB2 may be warranted.