Multiscale quantification of morphological heterogeneity with creation of a predictor of longer survival in glioblastoma

Intratumor heterogeneity is a main cause of the dismal prognosis of glioblastoma (GBM). Yet, there remains a lack of a uniform assessment of the degree of heterogeneity. With a multiscale approach, we addressed the hypothesis that intratumor heterogeneity exists on different levels comprising traditional regional analyses, but also innovative methods including computer-assisted analysis of tumor morphology combined with epigenomic data. With this aim, 157 biopsies of 37 patients with therapy-naive IDH-wildtype GBM were analyzed regarding the intratumor variance of protein expression of glial marker GFAP, microglia marker Iba1 and proliferation marker Mib1. Hematoxylin and eosin stained slides were evaluated for tumor vascularization. For the estimation of pixel intensity and nuclear profiling, automated analysis was used. Additionally, DNA methylation profiling was conducted separately for the single biopsies. Scoring systems were established to integrate several parameters into one score for the four examined modalities of heterogeneity (regional, cellular, pixel-level and epigenomic). As a result, we could show that heterogeneity was detected in all four modalities. Furthermore, for the regional, cellular and epigenomic level, we confirmed the results of earlier studies stating that a higher degree of heterogeneity is associated with poorer overall survival. To integrate all modalities into one score, we designed a predictor of longer survival, which showed a highly significant separation regarding the OS. In conclusion, multiscale intratumor heterogeneity exists in glioblastoma and its degree has an impact on overall survival. In future studies, the implementation of a broadly feasible heterogeneity index should be considered.     

Attenuation Coefficient Estimation of Normal Placentas

Attenuation coefficient estimation has the potential to be a useful tool for placental tissue characterization. A current challenge is the presence of inhomogeneities in biological tissue that result in a large variance in the attenuation coefficient estimate (ACE), restricting its clinical utility. In this work, we propose a new Attenuation Estimation Region Of Interest (AEROI) selection method for computing the ACE based on the (i) envelope signal-to-noise ratio deviation and (ii) coefficient of variation of the transmit pulse bandwidth. The method was first validated on a tissue-mimicking phantom, for which an 18%–21% reduction in the standard deviation of ACE and a 14%–24% reduction in the ACE error, expressed as a percentage of reported ACE, were obtained. A study on 59 post-delivery clinically normal placentas was then performed. The proposed AEROI selection method reduced the intra-subject standard deviation of ACE from 0.72 to 0.39 dB/cm/MHz. The measured ACE of 59 placentas was 0.77 ± 0.37 dB/cm/MHz, which establishes a baseline for future studies on placental tissue characterization.     

Kenneth Gergen’s concept of multi-being: an application to the nurse–patient relationship

The nurse–patient relationship is of great significance for both nurses and patients. The purpose of this article is to gain an understanding of how the individual is constituted through a focus on the execution of the patient’s and nurse’s role in the joint relationship. The article represents a social-constructionist consideration using Kenneth Gergen’s concept of multi-being. Gergen’s notions of the self as a multi-being focuses on the individual’s relational character through former relationships and social interactions. Gergen’s concept is applied onto nurses and patients as individuals to gain an understanding of the broader institutional and social context of each role and their interactions within the nurse–patient relationship. The article focuses on the nurse–patient relationship in general with regard to specific challenges in the home care setting. Various demands and experiences from a myriad of past relationships merge as potential actions for nurses and patients during the forming of a relationship. Nurses as multi-beings see themselves confronted with guidelines and legal conditions, their own as well as the patients’ expectations and the actual possible forming of a relationship in the light of daily nursing care. Patients as multi-beings experience an extended social environment that comprises the nurse–patient relationship while simultaneously having to cope with illness and increasing care dependency within their own homes. Discrepancies can be observed in the relationship with regard to the inherent human qualities, the demands of forming a relationship, and the actual relationship arising due to framework conditions.

     

Combination drug regimens for metastatic clear cell renal cell carcinoma

Renal cell carcinomas (RCC) make up about 90% of kidney cancers, of which 80% are of the clear cell subtype. About 20% of patients are already metastatic at the time of diagnosis. Initial treatment is often cytoreductive nephrectomy, but systemic therapy is required for advanced RCC. Single agent targeted therapies are moderately toxic and only somewhat effective, leading to development of immunotherapies and combination therapies. This review identifies limitations of monotherapies for metastatic renal cell carcinoma, discusses recent advances in combination therapies, and highlights therapeutic options under development. The goal behind combining various modalities of systemic therapy is to potentiate a synergistic antitumor effect. However, combining targeted therapies may cause increased toxicity. The initial attempts to create therapeutic combinations based on inhibition of the vascular endothelial growth factor or mammalian target of rapamycin pathways were largely unsuccessful in achieving a profile of increased synergy without increased toxicity. To date, five combination therapies have been approved by the U.S. Food and Drug Administration, with the most recently approved therapies being a combination of checkpoint inhibition plus targeted therapy. Several other combination therapies are under development, including some in the phase 3 stage. The new wave of combination therapies for metastatic RCC has the potential to increase response rates and improve survival outcomes while maintaining tolerable side effect profiles.     

Middle Meningeal Artery Embolization Using Combined Particle Embolization and n-BCA with the Dextrose 5% in Water Push Technique for Chronic Subdural Hematomas: A Prospective Safety and Feasibility Study

BACKGROUND AND PURPOSE:Embolization of the middle meningeal artery for treatment of refractory or recurrent chronic subdural hematomas has gained momentum during the past few years. Little has been reported on the use of the n-BCA liquid embolic system for middle meningeal artery embolization. We present the technical feasibility of using diluted n-BCA for middle meningeal artery embolization.MATERIALS AND METHODS:We sought to examine the safety and technical feasibility of the diluted n-BCA liquid embolic system for middle meningeal artery embolization. Patients with chronic refractory or recurrent subdural hematomas were prospectively enrolled from September 2019 to June 2020. The primary outcome was the safety and technical feasibility of the use of diluted n-BCA for embolization of the middle meningeal artery. The secondary end point was the efficacy in reducing hematoma volume.RESULTS:A total of 16 patients were prospectively enrolled. Concomitant burr-hole craniotomies were performed in 12 of the 16 patients. Two patients required an operation following middle meningeal artery embolization for persistent symptoms. The primary end point was met in 100% of cases in which there were no intra- or postprocedural complications. Distal penetration of the middle meningeal artery branches was achieved in all the enrolled cases. A 7-day post–middle meningeal artery embolization follow-up head CT demonstrated improvement (>50% reduction in subdural hematoma volume) in 9/15 (60%) patients, with 6/15 (40%) showing an unchanged or stable subdural hematoma. At day 21, available CT scans demonstrated substantial further improvement (>75% reduction in subdural hematoma volume).CONCLUSIONS:Embolization of the middle meningeal artery using diluted n-BCA and ethiodized oil (1:6) is safe and feasible from a technical standpoint. The use of a dextrose 5% bolus improves distal penetration of the glue.

Despite traditional treatment with surgical evacuation, chronic subdural hematomas (cSDHs) tend to have an indolent course with frequent recurrences.¹ In recent years, embolization of the middle meningeal artery (MMA) for treatment of refractory or recurrent cSDH has gained momentum, with recent literature showing a significant reduction in the size of the cSDH as well as lower rates of recurrence.² The primary endovascular techniques used to date have involved the use of polyvinyl alcohol particles (PVA) and Onyx liquid embolic (ethylene-vinyl alcohol dissolved in dimethyl-sulfoxide; Medtronic). Another commonly used liquid embolic agent in the neurointerventional area is n-BCA, which is a liquid adhesive that polymerizes rapidly on contact with ionic substances and can be injected to achieve permanent vessel occlusion. The rates of polymerization and flow and the penetration depth can be modified using varying amounts of ethiodized oil as well as concurrent infusion of dextrose 5% in water (D5W) during n-BCA (Trufill, Cordis Neurovascular) injection (D5W-push technique).³ Data on the use of n-BCA as an embolic agent in cases of cSDH are extremely limited. Herein, we sought to study the safety and technical feasibility of using diluted n-BCA for embolization of the MMA for cSDHs.