Citations

Abstract Context SDHB mutations are found in an increasing number of neoplasms, most notably in paragangliomas and pheochromocytomas (PPGLs). SDHB-PPGLs are slow-growing tumors, but ∼50% of them may develop metastasis. The molecular basis of metastasis in these tumors is a long-standing and unresolved problem. Thus, a better understanding of the biology of metastasis is needed. Objective This study aimed to identify gene methylation changes relevant for metastatic SDHB-PPGLs. Design We performed genome-wide profiling of DNA methylation in diverse clinical and genetic PPGL subtypes, and validated protocadherin γ-C3 (PCDHGC3) gene promoter methylation in metastatic SDHB-PPGLs. Results We define an epigenetic landscape specific for metastatic SDHB-PPGLs. DNA methylation levels were found significantly higher in metastatic SDHB-PPGLs than in SDHB-PPGLs without metastases. One such change included long-range de novo methylation of the PCDHA, PCDHB, and PCDHG gene clusters. High levels of PCDHGC3 promoter methylation were validated in primary metastatic SDHB-PPGLs, it was found amplified in the corresponding metastases, and it was significantly correlated with PCDHGC3 reduced expression. Interestingly, this epigenetic alteration could be detected in primary tumors that developed metastasis several years later. We also show that PCDHGC3 down regulation engages metastasis-initiating capabilities by promoting cell proliferation, migration, and invasion. Conclusions Our data provide a map of the DNA methylome episignature specific to an SDHB-mutated cancer and establish PCDHGC3 as a putative suppressor gene and a potential biomarker to identify patients with SDHB-mutated cancer at high risk of metastasis who might benefit from future targeted therapies.

Abstract Background: Sex is recognized as a significant determinant of outcome among glioblastoma patients, but the relative prognostic importance of glioblastoma features has not been thoroughly explored for sex differences. Methods: Combining multi-modal MR images, biomathematical models, and patient clinical information, this investigation assesses which pretreatment variables have a sex-specific impact on the survival of glioblastoma patients (299 males and 195 females). Results: Among males, tumor (T1Gd) radius was a predictor of overall survival (HR=1.027, p=0.044). Among females, higher tumor cell net invasion rate was a significant detriment to overall survival (HR=1.011, p<0.001). Female extreme survivors had significantly smaller tumors (T1Gd) (p=0.010 t-test), but tumor size was not correlated with female overall survival (p=0.955 CPH). Both male and female extreme survivors had significantly lower tumor cell net proliferation rates than other patients (M p=0.004, F p=0.001, t-test). Additionally, extent of resection, tumor laterality, and IDH1 mutation status were also found to have sex-specific effects on overall survival. Conclusion: Despite similar distributions of the MR imaging parameters between males and females, there was a sex-specific difference in how these parameters related to outcomes.

Background: The management of complex perianal fistulas in Crohn’s disease (CD) represents a challenge for patients, gastroenterologists and colorectal surgeons. There are clear limitations with current medical and surgical options, and healing rates remain far from what is expected. A multidisciplinary approach with optimized medical therapy, usually anti-TNF agents, associated with setons and additional surgical techniques is currently the best strategy to aim fistula healing. Methods: A comprehensive review of the literature was conducted on the use of mesenchymal stem cells (MSCs). Results: The use of mesenchymal stem cells (MSCs) has recently emerged as a promising new therapeutic strategy for complex fistulas in CD patients. This review summarizes the evidence of the use of MSCs in complex CD fistulas, by exploring in detail the types of cells that can be used and their modes of delivery. Additionally, the results of the most recent phase III randomized trial with local MSCs injection are described, and future challenges of this therapeutic option are discussed. Conclusion: The use of MSCs represents hope for better outcomes in patients with CD-related perianal fistulas. More research in the field will help to position this specific therapy in treatment algorithms.

OBJECTIVEConcomitant unruptured intracranial aneurysms (UIAs) are present in patients with carotid artery stenosis not infrequently and result in unique management challenges. Thus, we investigated the risk of rupture of an aneurysm after revascularization of a carotid artery in a contemporary consecutive series of patients seen at our institution.METHODSData from patients who underwent a carotid revascularization in the presence of at least one concomitant UIA at our institution from 1991 to 2018 were retrospectively reviewed. Patients were evaluated for the incidence of aneurysm rupture within 30 days (early period) and after 30 days (late period) of carotid revascularization, as well as for the incidence of periprocedural complications from the treatment of carotid stenosis and/or UIA.RESULTSOur study included 53 patients with 63 concomitant UIAs. There was no rupture within 30 days of carotid revascularization. The overall risk of rupture was 0.87% per patient-year. Treatment (coiling or clipping) of a concomitant UIA, if pursued, could be performed successfully after carotid revascularization.CONCLUSIONSCarotid artery revascularization in the setting of a concomitant UIA can be performed safely without an increased 30-day or late-term risk of rupture. If indicated, treatment of the UIA can take place after the patient recovers from the carotid procedure.

Abstract Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging–Alzheimer's Association describes a biomarker‐based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood‐brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts.

Male and female glioblastomas are biologically distinct, and improving outcomes may require sex-specific approaches to treatment.

Background Automated individualized risk prediction tools linked to electronic health records ( EHR s) are not available for management of patients with peripheral arterial disease. The goal of this study was to create a prognostic tool for patients with peripheral arterial disease using data elements automatically extracted from an EHR to enable real‐time and individualized risk prediction at the point of care. Methods and Results A previously validated phenotyping algorithm was deployed to an EHR linked to the Rochester Epidemiology Project to identify peripheral arterial disease cases from Olmsted County, MN, for the years 1998 to 2011. The study cohort was composed of 1676 patients: 593 patients died over 5‐year follow‐up. The c‐statistic for survival in the overall data set was 0.76 (95% confidence interval [CI], 0.74–0.78), and the c‐statistic across 10 cross‐validation data sets was 0.75 (95% CI, 0.73–0.77). Stratification of cases demonstrated increasing mortality risk by subgroup (low: hazard ratio, 0.35 [95% CI, 0.21–0.58]; intermediate‐high: hazard ratio, 2.98 [95% CI, 2.37–3.74]; high: hazard ratio, 8.44 [95% CI, 6.66–10.70], all P <0.0001 versus the reference subgroup). An equation for risk calculation was derived from Cox model parameters and β estimates. Big data infrastructure enabled deployment of the real‐time risk calculator to the point of care via the EHR . Conclusions This study demonstrates that electronic tools can be deployed to EHR s to create automated real‐time risk calculators to predict survival of patients with peripheral arterial disease. Moreover, the prognostic model developed may be translated to patient care as an automated and individualized real‐time risk calculator deployed at the point of care.