Abnormal vascular structure and function within brain metastases is linked to pembrolizumab resistance.

BACKGROUND: We recently conducted a phase 2 trial (NCT028865685) evaluating intracranial efficacy of pembrolizumab for brain metastases (BM) of diverse histologies. Our study met its primary efficacy endpoint and illustrates that pembrolizumab exerts promising activity in a select group of patients with BM. Given the importance of aberrant vasculature in mediating immunosuppression, we explored the relationship between checkpoint inhibitor (ICI) efficacy and vascular architecture in the hopes of identifying potential mechanisms of intracranial ICI response or resistance for BM. METHODS: Using Vessel Architectural Imaging (VAI), a histologically validated quantitative metric for in vivo tumor vascular physiology, we analyzed dual echo DSC/DCE MRI for 44 patients on trial. Tumor and peri-tumor cerebral blood volume/flow, vessel size, arterial- and venous-dominance, and vascular permeability were measured before and after treatment with pembrolizumab. RESULTS: BM that progressed on ICI were characterized by a highly aberrant vasculature dominated by large-caliber vessels. In contrast, ICI-responsive BM possessed a more structurally balanced vasculature consisting of both small and large vessels, and there was a trend towards a decrease in under-perfused tissue, suggesting a reversal of the negative effects of hypoxia. In the peri-tumor region, development of smaller blood vessels, consistent with neo-angiogenesis, was associated with tumor growth before radiographic evidence of contrast enhancement on anatomical MRI. CONCLUSIONS: This study, one of the largest functional imaging studies for BM, suggests that vascular architecture is linked with ICI efficacy. Studies identifying modulators of vascular architecture, and effects on immune activity, are warranted and may inform future combination treatments.

Structural and functional vascular dysfunction within brain metastases is linked to pembrolizumab inefficacy.

Structurally and functionally aberrant vasculature is a hallmark of tumor angiogenesis and treatment resistance. Given the synergistic link between aberrant tumor vasculature and immunosuppression, we analyzed perfusion MRI for 44 patients with brain metastases (BM) undergoing treatment with pembrolizumab. To date, vascular-immune communication, or the relationship between immune checkpoint inhibitor (ICI) efficacy and vascular architecture, has not been well-characterized in human imaging studies. We found that ICI-responsive BM possessed a structurally balanced vascular makeup, which was linked to improved vascular efficiency and an immune-stimulatory microenvironment. In contrast, ICI-resistant BM were characterized by a lack of immune cell infiltration and a highly aberrant vasculature dominated by large-caliber vessels. Peri-tumor region analysis revealed early functional changes predictive of ICI resistance before radiographic evidence on conventional MRI. This study was one of the largest functional imaging studies for BM and establishes a foundation for functional studies that illuminate the mechanisms linking patterns of vascular architecture with immunosuppression, as targeting these aspects of cancer biology may serve as the basis for future combination treatments.

FDU-Net: Deep Learning-Based Three-Dimensional Diffuse Optical Image Reconstruction.

Near-infrared diffuse optical tomography (DOT) is a promising functional modality for breast cancer imaging; however, the clinical translation of DOT is hampered by technical limitations. Specifically, conventional finite element method (FEM)-based optical image reconstruction approaches are time-consuming and ineffective in recovering full lesion contrast. To address this, we developed a deep learning-based reconstruction model (FDU-Net) comprised of a Fully connected subnet, followed by a convolutional encoder-Decoder subnet, and a U-Net for fast, end-to-end 3D DOT image reconstruction. The FDU-Net was trained on digital phantoms that include randomly located singular spherical inclusions of various sizes and contrasts. Reconstruction performance was evaluated in 400 simulated cases with realistic noise profiles for the FDU-Net and conventional FEM approaches. Our results show that the overall quality of images reconstructed by FDU-Net is significantly improved compared to FEM-based methods and a previously proposed deep-learning network. Importantly, once trained, FDU-Net demonstrates substantially better capability to recover true inclusion contrast and location without using any inclusion information during reconstruction. The model was also generalizable to multi-focal and irregularly shaped inclusions unseen during training. Finally, FDU-Net, trained on simulated data, could successfully reconstruct a breast tumor from a real patient measurement. Overall, our deep learning-based approach demonstrates marked superiority over the conventional DOT image reconstruction methods while also offering over four orders of magnitude acceleration in computational time. Once adapted to the clinical breast imaging workflow, FDU-Net has the potential to provide real-time accurate lesion characterization by DOT to assist the clinical diagnosis and management of breast cancer.

Deep learning-based automatic tumor burden assessment of pediatric high-grade gliomas, medulloblastomas, and other leptomeningeal seeding tumors.

BACKGROUND: Longitudinal measurement of tumor burden with magnetic resonance imaging (MRI) is an essential component of response assessment in pediatric brain tumors. We developed a fully automated pipeline for the segmentation of tumors in pediatric high-grade gliomas, medulloblastomas, and leptomeningeal seeding tumors. We further developed an algorithm for automatic 2D and volumetric size measurement of tumors. METHODS: The preoperative and postoperative cohorts were randomly split into training and testing sets in a 4:1 ratio. A 3D U-Net neural network was trained to automatically segment the tumor on T1 contrast-enhanced and T2/FLAIR images. The product of the maximum bidimensional diameters according to the RAPNO (Response Assessment in Pediatric Neuro-Oncology) criteria (AutoRAPNO) was determined. Performance was compared to that of 2 expert human raters who performed assessments independently. Volumetric measurements of predicted and expert segmentations were computationally derived and compared. RESULTS: A total of 794 preoperative MRIs from 794 patients and 1003 postoperative MRIs from 122 patients were included. There was excellent agreement of volumes between preoperative and postoperative predicted and manual segmentations, with intraclass correlation coefficients (ICCs) of 0.912 and 0.960 for the 2 preoperative and 0.947 and 0.896 for the 2 postoperative models. There was high agreement between AutoRAPNO scores on predicted segmentations and manually calculated scores based on manual segmentations (Rater 2 ICC = 0.909; Rater 3 ICC = 0.851). Lastly, the performance of AutoRAPNO was superior in repeatability to that of human raters for MRIs with multiple lesions. CONCLUSIONS: Our automated deep learning pipeline demonstrates potential utility for response assessment in pediatric brain tumors. The tool should be further validated in prospective studies.

Radiomics Repeatability Pitfalls in a Scan-Rescan MRI Study of Glioblastoma.

PURPOSE: To determine the influence of preprocessing on the repeatability and redundancy of radiomics features extracted using a popular open-source radiomics software package in a scan-rescan glioblastoma MRI study. MATERIALS AND METHODS: In this study, a secondary analysis of T2-weighted fluid-attenuated inversion recovery (FLAIR) and T1-weighted postcontrast images from 48 patients (mean age, 56 years [range, 22-77 years]) diagnosed with glioblastoma were included from two prospective studies (ClinicalTrials.gov NCT00662506 [2009-2011] and NCT00756106 [2008-2011]). All patients underwent two baseline scans 2-6 days apart using identical imaging protocols on 3-T MRI systems. No treatment occurred between scan and rescan, and tumors were essentially unchanged visually. Radiomic features were extracted by using PyRadiomics (https://pyradiomics.readthedocs.io/) under varying conditions, including normalization strategies and intensity quantization. Subsequently, intraclass correlation coefficients were determined between feature values of the scan and rescan. RESULTS: Shape features showed a higher repeatability than intensity (adjusted P < .001) and texture features (adjusted P < .001) for both T2-weighted FLAIR and T1-weighted postcontrast images. Normalization improved the overlap between the region of interest intensity histograms of scan and rescan (adjusted P < .001 for both T2-weighted FLAIR and T1-weighted postcontrast images), except in scans where brain extraction fails. As such, normalization significantly improves the repeatability of intensity features from T2-weighted FLAIR scans (adjusted P = .003 [z score normalization] and adjusted P = .002 [histogram matching]). The use of a relative intensity binning strategy as opposed to default absolute intensity binning reduces correlation between gray-level co-occurrence matrix features after normalization. CONCLUSION: Both normalization and intensity quantization have an effect on the level of repeatability and redundancy of features, emphasizing the importance of both accurate reporting of methodology in radiomics articles and understanding the limitations of choices made in pipeline design. Supplemental material is available for this article. © RSNA, 2020See also the commentary by Tiwari and Verma in this issue.

Cerebrovascular Disease Progression in Patients With ACTA2 Arg179 Pathogenic Variants.

OBJECTIVE: To establish progression of imaging biomarkers of stroke, arterial steno-occlusive disease, and white matter injury in patients with smooth muscle dysfunction syndrome caused by mutations in the ACTA2 gene, we analyzed 113 cerebral MRI scans from a retrospective cohort of 27 patients with ACTA2 Arg179 pathogenic variants. METHODS: Systematic quantifications of arterial ischemic strokes and white matter lesions were performed on baseline and follow-up scans using planimetric methods. Critical stenosis and arterial vessel diameters were quantified applying manual and semiautomated methods to cerebral magnetic resonance angiograms. We then assessed correlations between arterial abnormalities and parenchymal injury. RESULTS: We found characteristic patterns of acute white matter ischemic injury and progressive internal carotid artery stenosis during infancy. Longitudinal analysis of patients older than 1.2 years showed stable white matter hyperintensities but increased number of cystic-like lesions over time. Progressive narrowing of the terminal internal carotid artery occurred in 80% of patients and correlated with the number of critical stenoses in cerebral arteries and arterial ischemic infarctions. Arterial ischemic strokes occurred in same territories affected by critical stenosis. CONCLUSIONS: We found characteristic, early, and progressive cerebrovascular abnormalities in patients with ACTA2 Arg179 pathogenic variants. Our longitudinal data suggest that while steno-occlusive disease progresses over time and is associated with arterial ischemic infarctions and cystic-like white matter lesions, white matter hyperintensities can remain stable over long periods. The evaluated metrics will enable diagnosis in early infancy and be used to monitor disease progression, guide timing of stroke preventive interventions, and assess response to current and future therapies.

Multi-Institutional Assessment and Crowdsourcing Evaluation of Deep Learning for Automated Classification of Breast Density.

OBJECTIVE: We developed deep learning algorithms to automatically assess BI-RADS breast density. METHODS: Using a large multi-institution patient cohort of 108,230 digital screening mammograms from the Digital Mammographic Imaging Screening Trial, we investigated the effect of data, model, and training parameters on overall model performance and provided crowdsourcing evaluation from the attendees of the ACR 2019 Annual Meeting. RESULTS: Our best-performing algorithm achieved good agreement with radiologists who were qualified interpreters of mammograms, with a four-class κ of 0.667. When training was performed with randomly sampled images from the data set versus sampling equal number of images from each density category, the model predictions were biased away from the low-prevalence categories such as extremely dense breasts. The net result was an increase in sensitivity and a decrease in specificity for predicting dense breasts for equal class compared with random sampling. We also found that the performance of the model degrades when we evaluate on digital mammography data formats that differ from the one that we trained on, emphasizing the importance of multi-institutional training sets. Lastly, we showed that crowdsourced annotations, including those from attendees who routinely read mammograms, had higher agreement with our algorithm than with the original interpreting radiologists. CONCLUSION: We demonstrated the possible parameters that can influence the performance of the model and how crowdsourcing can be used for evaluation. This study was performed in tandem with the development of the ACR AI-LAB, a platform for democratizing artificial intelligence.

Pediatric tethered cord release: an epidemiological and postoperative complication analysis.

BACKGROUND: Tethered cord release (TCR) is a common procedure in pediatric neurosurgery. Despite a reputation for being relatively safe, the risk factors for postoperative complications are poorly understood. METHODS: In this study, the American College of Surgeons-National Surgical Quality Improvement Program Pediatric Database (ACS-NSQIP-P) was reviewed to identify the demographics, risk factors, and 30-day postoperative complications for tethered cord release using univariate and multivariate analysis. A detailed analysis of reasons for readmission and reoperation was also performed. RESULTS: Three thousand and six hundred eighty-two pediatric patients were studied. Males undergoing TCR were younger (5.6 vs. 6.1 years) and had a higher rate of pre-operative comorbidities but lower 30-day complication rate versus females. Patients who later developed complications were more likely to require a microscope intraoperatively, had longer operative times, and worse preoperative American Society of Anesthesiologists (ASA) class. CONCLUSIONS: Despite being a relatively safe procedure, TCR in the pediatric population carries a finite risk of complications. In this large, international database study, males were found to have a greater number of risk factors prior to TCR, while females exhibit a higher risk of developing postoperative complications. This paper provides a large sample size of multi institutional pediatric patients undergoing TCR and may serve as a contemporary "snapshot" for future studies.

Effect of Ultraviolet Radiation on Organic Photovoltaic Materials and Devices.

Organic photovoltaics are a sustainable and cost-effective power-generation technology that may aid the move to zero-emission buildings, carbon neutral cities, and electric vehicles. While state-of-the-art organic photovoltaic devices can be encapsulated to withstand air and moisture, they are currently still susceptible to light-induced degradation, leading to a decline in the long-term efficiency of the devices. In this study, the role of ultraviolet (UV) radiation on a multilayer organic photovoltaic device is systematically uncovered using spectral filtering. By applying long-pass filters to remove different parts of the UV portion of the AM1.5G spectrum, two main photodegradation processes are shown to occur in the organic photovoltaic devices. A UV-activated process is found to cause a significant decrease in the photocurrent across the whole spectrum and is most likely linked to the deterioration of the charge extraction layers. In addition, a photodegradation process caused by UV-filtered sunlight is found to change the micromorphology of the bulk heterojunction material, leading to a reduction in photocurrent at high photon energies. These findings strongly suggest that the fabrication of inherently photostable organic photovoltaic devices will require the replacement of fullerene-based electron transporter materials with alternative organic semiconductors.

SDF 1-alpha Attenuates Myocardial Injury Without Altering the Direct Contribution of Circulating Cells.

Stromal cell-derived factor 1-alpha (SDF) is a potent bone marrow chemokine capable of recruiting circulating progenitor populations to injured tissue. SDF has known angiogenic capabilities, but bone marrow-derived cellular contributions to tissue regeneration remain controversial. Bone marrow from DsRed-transgenic donors was transplanted into recipients to lineage-trace circulating cells after myocardial infarction (MI). SDF was delivered post-MI, and hearts were evaluated for recruitment and plasticity of bone marrow-derived populations. SDF treatment improved ventricular function, border zone vessel density, and CD31+ cell frequency post-MI. Bone marrow-derived endothelial cells were observed; these cells arose through both cell fusion and transdifferentiation. Circulating cells also adopted cardiomyocyte fates, but such events were exceedingly rare and almost exclusively resulted from cell fusion. SDF did not significantly alter the proportion of circulating cells that adopted non-hematopoietic fates. Mechanistic insight into the governance of circulating cells is essential to realizing the full potential of cytokine therapies.

Layered smooth muscle cell-endothelial progenitor cell sheets derived from the bone marrow augment postinfarction ventricular function.

OBJECTIVE: The angiogenic potential of endothelial progenitor cells (EPCs) may be limited by the absence of their natural biologic foundation, namely smooth muscle pericytes. We hypothesized that joint delivery of EPCs and smooth muscle cells (SMCs) in a novel, totally bone marrow-derived cell sheet will mimic the native architecture of a mature blood vessel and act as an angiogenic construct to limit post infarction ventricular remodeling. METHODS: Primary EPCs and mesenchymal stem cells were isolated from bone marrow of Wistar rats. Mesenchymal stem cells were transdifferentiated into SMCs by culture on fibronectin-coated culture dishes. Confluent SMCs topped with confluent EPCs were detached from an Upcell dish to create a SMC-EPC bi-level cell sheet. A rodent model of ischemic cardiomyopathy was then created by ligating the left anterior descending artery. Rats were randomized into 3 groups: cell sheet transplantation (n = 9), no treatment (n = 12), or sham surgery control (n = 7). RESULTS: Four weeks postinfarction, mature vessel density tended to increase in cell sheet-treated animals compared with controls. Cell sheet therapy significantly attenuated the extent of cardiac fibrosis compared with that of the untreated group (untreated vs cell sheet, 198 degrees [interquartile range (IQR), 151-246 degrees] vs 103 degrees [IQR, 92-113 degrees], P = .04). Furthermore, EPC-SMC cell sheet transplantation attenuated myocardial dysfunction, as evidenced by an increase in left ventricular ejection fraction (untreated vs cell sheet vs sham, 33.5% [IQR, 27.8%-35.7%] vs 45.9% [IQR, 43.6%-48.4%] vs 59.3% [IQR, 58.8%-63.5%], P = .001) and decreases in left ventricular dimensions. CONCLUSIONS: The bone marrow-derived, spatially arranged SMC-EPC bi-level cell sheet is a novel, multilineage cellular therapy obtained from a translationally practical source. Interactions between SMCs and EPCs augment mature neovascularization, limit adverse remodeling, and improve ventricular function after myocardial infarction.

Preclinical evaluation of the engineered stem cell chemokine stromal cell-derived factor 1α analog in a translational ovine myocardial infarction model.

RATIONALE: After myocardial infarction, there is an inadequate blood supply to the myocardium, and the surrounding borderzone becomes hypocontractile. OBJECTIVE: To develop a clinically translatable therapy, we hypothesized that in a preclinical ovine model of myocardial infarction, the modified endothelial progenitor stem cell chemokine, engineered stromal cell-derived factor 1α analog (ESA), would induce endothelial progenitor stem cell chemotaxis, limit adverse ventricular remodeling, and preserve borderzone contractility. METHODS AND RESULTS: Thirty-six adult male Dorset sheep underwent permanent ligation of the left anterior descending coronary artery, inducing an anteroapical infarction, and were randomized to borderzone injection of saline (n=18) or ESA (n=18). Ventricular function, geometry, and regional strain were assessed using cardiac MRI and pressure-volume catheter transduction. Bone marrow was harvested for in vitro analysis, and myocardial biopsies were taken for mRNA, protein, and immunohistochemical analysis. ESA induced greater chemotaxis of endothelial progenitor stem cells compared with saline (P<0.01) and was equivalent to recombinant stromal cell-derived factor 1α (P=0.27). Analysis of mRNA expression and protein levels in ESA-treated animals revealed reduced matrix metalloproteinase 2 in the borderzone (P<0.05), with elevated levels of tissue inhibitor of matrix metalloproteinase 1 and elastin in the infarct (P<0.05), whereas immunohistochemical analysis of borderzone myocardium showed increased capillary and arteriolar density in the ESA group (P<0.01). Animals in the ESA treatment group also had significant reductions in infarct size (P<0.01), increased maximal principle strain in the borderzone (P<0.01), and a steeper slope of the end-systolic pressure-volume relationship (P=0.01). CONCLUSIONS: The novel, biomolecularly designed peptide ESA induces chemotaxis of endothelial progenitor stem cells, stimulates neovasculogenesis, limits infarct expansion, and preserves contractility in an ovine model of myocardial infarction.

The "growing teratoma syndrome" in primary mediastinal nonseminomatous germ cell tumors: criteria based on current practice.

OBJECTIVE: Criteria for the growing teratoma syndrome in patients with primary mediastinal nonseminomatous germ cell tumors have not been well established according to current practice. METHODS: An institutional database identified 188 patients who underwent postchemotherapy surgery for primary mediastinal nonseminomatous germ cell tumors from 1981 to 2009. We reviewed the subset of patients who underwent urgent surgery for tumor growth resulting in cardiopulmonary deterioration secondary to mediastinal compression precluding safe completion of 4 cisplatin-based chemotherapy cycles with rapidly declining serum tumor markers. RESULTS: Five men (2.6%) with an average age of 25.8 years were identified. All patients initially presented with a large symptomatic anterior mediastinal mass and elevated serum tumor markers. Patients received an average of 2.4 chemotherapy cycles of a scheduled 4 courses before cardiopulmonary deterioration. Pathology of the resected specimens demonstrated mature teratoma in all patients; however, it was admixed in 4 patients with foci of immaturity (n=1), malignant transformation of teratoma to sarcoma (n=2), and nonseminomatous germ cell tumor (n=2). There was 1 operative death. Three of the 4 operative survivors subsequently completed a total of 4 cycles of chemotherapy after recovery. Two patients are alive and well after an average of 14 years. Two patients died of metastatic disease. CONCLUSIONS: The growing teratoma syndrome should be defined not only as a growing mediastinal mass but also with secondary cardiopulmonary deterioration precluding safe completion of planned chemotherapy in the presence of declining serum tumor markers. Prompt recognition of this syndrome, discontinuation of chemotherapy, and surgical intervention can result in cure.

Declining morbidity and mortality rates in the surgical management of pancreatic necrosis.

Surgical management of patients with pancreatic necrosis (PN) has evolved over the last two decades to include prophylactic antibiotics, initial medical management, and delayed surgical intervention. The purpose of this study is to identify changes in morbidity and mortality rates as our methods of surgical management have evolved. One hundred two consecutive patients (59 males and 43 females, mean age 53 +/- 16 years) with PN managed surgically were classified as group I (1993-2001), after the routine use of prophylactic antibiotics (N = 55), and group II (2002-2005), after the use of International Association of Pancreatology (IAP) guidelines for intervention (N = 47). Age, sex, etiology of pancreatitis, percent of necrosis, infected necrosis, and acute physiology and chronic health evaluation II scores were similar between groups. Despite a significant worsening of Balthazar computed tomography scoring in group II patients (p < 0.0001), operative morbidity (49 [89%] vs 34 [72%], p = 0.03), mortality (10 [18%] vs 2 [4%], p = 0.03), and hospital length of stay (38 +/- 33 days vs 26 +/- 23 days, p = 0.04) were significantly less in group II patients. Current methods of surgical management utilizing IAP guidelines have resulted in a decreased operative morbidity, mortality, and hospital length of stay in patients with PN.