At-risk Tissue Research Articles

Prediction of auditory brain stem responses damage in patients with head-and-neck cancers receiving radiotherapy using the functional assays of normal tissue complication probability models.

The purpose of this study was to set four NTCP models on clinical data and develop a model that calculates the possibility of hearing damage due to irradiation of healthy and at-risk brainstem tissue. ABR tests were performed on 50 head-and-neck cancer patients three years after radiotherapy for evaluation of lesions in a part of the auditory nerve or the auditory pathway in the brainstem. It indicated a significant difference in the latency of the waves assessed by the ABR test between the two groups. The paired sample t-test indicated the latency time of waves I, III, V, I-III, and I-V (P < 0.001) in the right ear, and in the left ear latency time of waves III, V, I-III, I-V, and III-V (P < 0.001) were significantly higher in the case group's ear than those in the control group. The confidence interval of the fitted parameters was 95% for NTCP models. ABR test's binary outcome with differential dose-volume histograms (dDVHs) was calculated and imported as input to the NTCP modeling. The values of the parameters n = 2.3-2.9 and the value s = 1 were obtained, which indicated that the brainstem organ is seriality. The best model ranked for the prediction of brainstem hearing damage was the logit model, which had the lowest Akaike value. The nervousness of the auditory organ of the brainstem (VIII nerve) can be declared as one of the reasons for being independent of the received dose.

Abstract 782: Correlation between collagen peptides and physical features of fibrosis in breast tissue from women at increased risk of cancer

Abstract Breast cancer risk increases significantly in women who maintain higher radiologically dense breast tissue as they age. However, the mechanisms that underlie this association remain poorly understood, especially in postmenopausal women. A predominant contributor to dense breasts and differences between women is the relative amount of fibrillar collagens. Experimental models suggest that changes in collagen properties such as fiber alignment and stiffness promote local stromal fibrosis, which we hypothesize may contribute to the relationship between breast density, aging, and tumorigenesis. Normal breast biopsy samples from the contralateral, healthy breast of 32 postmenopausal breast cancer patients participating in a clinical trial for drug effect on breast density were examined and scored for areas of fibrosis and analyzed using second harmonic generation microscopy (SHG) and mass spectrometry proteomics. Our aim was to identify areas of fibrosis and relate the severity of focal fibrosis to the physical properties and peptide composition of collagen fibers. Using GraphPad Prism, we conducted one-way ANOVA and Kruskal-Wallis tests and post-hoc multiple comparison tests. H&amp;E-stained breast tissue samples were scored according to percent fibrosis. The minimum and maximum percent fibrosis were 5% and 100%, respectively, with a median of 60% (95% CI: 97.06%). Out of 31 people, 16 had a higher fibrosis score than the median. Consistent with pathologic scoring of the presence and extent of fibrosis, fiber counts were significantly lower in tissue with lower fibrosis scores than samples with more highly scored fibrosis (p-value &amp;lt;0.001). Distance to the nearest fiber was greater in samples with &amp;lt; 20% fibrosis, whereas greater alignment to the nearest fiber was observed in higher fibrosis percentages. At the molecular level, 22 peptides demonstrated a strong correlation with percent fibrosis (spearman r ≥ 60), of which 13 peptides were statistically significant (p-value &amp;lt;0.0001). The putatively identified peptides belong to type I, III, IV and VI collagens. Fiber length and straightness, but not fiber width, were higher in tissues with greater percent fibrosis. Significant correlations were identified between collagen physical features and peptides: two distinct peptides correlated with collagen fiber length and straightness while 20 peptides correlated with fiber width. These putative peptides belong to types I, III, IV and V collagens with ~70% of the peptides containing at least one hydroxyproline modification. This study is the first to explore the link between focal fibrosis and collagen-associated peptides in healthy breast tissue of high-risk postmenopausal women. These findings provide novel insights on stromal collagens associated with fibrotic changes in normal at-risk breast tissue that may act in tissue susceptibility to tumor formation. Citation Format: Denys Rujchanarong, Alison T. Stopeck, Christina Preece, Ren Sun, Pavani Chalasani, Sean Brown, Ji D. Bai, Heather Jensen Smith, Sungyong You, Peggi M. Angel, Patricia Thompson. Correlation between collagen peptides and physical features of fibrosis in breast tissue from women at increased risk of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 782.

Abstract WP42: Transition to Tenecteplase: A Regional Experience

Background: Timely recognition and treatment of acute ischemic stroke is well-supported to promote better outcomes. Historically, alteplase has been the drug of choice for thrombolytic treatment, and while it is an excellent drug, there were barriers that would routinely come up during administration. Following the results of several studies that compared alteplase to tenecteplase, our leadership team decided to initiate the transition to tenecteplase within our region, spanning several states with approximately 40 hospitals. Purpose: The purpose of this clinical initiative was to implement tenecteplase as the primary thrombolytic in acute ischemic stroke and evaluate time to treatment (door in door out [DIDO] and door to needle [DTN]). Methods: Following the approval by leadership, the first step was identification of stakeholders at facility, market, service-line, and regional levels and initiation of bi-weekly meetings. The project relied heavily on facility-level structure that facilitates stroke quality improvement. We were able to utilize market specific stroke databases to understand historical data and to monitor ongoing success and complications. Results: Post-implementation, several positive changes were noted, which are visualized in the graphs. Conclusions: Through reduction of DIDO, treatment is initiated sooner to reperfuse at-risk brain tissue. Further evaluation is needed on the correlation between the transition and decreased length of stay, but we recognize tenecteplase has been shown to have a better rate of recanalizing large vessel occlusions, potentially resulting in less disability and shorter hospitalizations.

“Hemorrhagic Transformation Following Thrombolytic Therapy in Acute Ischemic Stroke: A Case Series of 5 Patients”

Stroke stands as a global health menace, causing substantial disability and mortality. Timely intervention, specifically within the critical "Golden Hour" following acute ischemic stroke, is imperative. Thrombolytic agents like tissue plasminogen activators (tPA) are pivotal for clot dissolution and blood flow restoration, yet their use introduces the risk of hemorrhagic transformation (HTF).In a recent case series involving five patients receiving thrombolytic therapy for acute ischemic stroke, we illuminate the occurrence of post-treatment HTF, its clinical ramifications, and the intricate challenges in its management. Early intervention in acute ischemic stroke aims to safeguard at-risk brain tissue, with thrombolytic therapy, notably tPA, serving as a primary treatment avenue. However, the associated risk of HTF hovers around 30%–35%, influenced by factors like age, comorbidities, and infarct size. The vulnerable ischemic penumbra, marked by a compromised blood-brain barrier and free radical generation, is particularly susceptible. Treatment decisions, guided by the National Institutes of Health Stroke Scale (NIHSS), pivot on stroke severity assessment, emphasizing the need for vigilant post-treatment monitoring. In conclusion, navigating the delicate balance between the benefits of early thrombolysis and the risks of HTF remains a persistent challenge in optimizing outcomes for acute ischemic stroke patients.

Developing Topics.

The novel diffusion-based Neurite Orientation and Dispersion Imaging (NODDI) model may provide complementary information to Diffusion Tensor Imaging (DTI) to increase sensitivity in characterizing tissue microarchitecture. We examined if one or a combination of both approaches can improve our understanding of at-risk tissue in and around white matter hyperintensities (WMH). From ADNI3, we identified individuals [n = 54, age = 78 ± 7, 46% F) with concurrent measures of multi-shell DTI, 3D FLAIR, and 3D MPRAGE. We segmented WMH from structural data using Lesion Segmentation Toolbox. We derived DTI (FA, MD) and NODDI parameters (NDI, ODI, Fiso) using QSIprep. We dilated up to 5 mm outside the WMH, applied an FA threshold of ≥ 0.2 to exclude gray matter, calculated DTI and NODDI parameters at 1 mm intervals within this region. We performed Pearson correlations between all parameters. Assuming normal white matter at 5 mm, we normalized these parameters with their respective values at 5 mm and plotted the spatial variation of each parameter in and outside the WMH. Normalized DTI and NODDI parameters representing spatial variations within the 5 mm region are shown in Fig 1A. Table 1 shows p-values comparing DTI and NODDI parameters between WMH the subsequent regions outside it. Compared to WMH, Fiso was significantly different at all distances. FA showed similar spatial characteristics with NDI and was negatively correlated with ODI. Fiso correlated very strongly with MD. In the WMHs and its immediate vicinity, low FA, NDI, ODI suggest lower cell density, while low Fiso and MD suggest low extracellular fluid volume. Together these observations may reflect cytotoxic edema, cell loss, and injury. Normal appearing white matter (3-5 mm) showed high FA, NDI, ODI, and low MD consistent with high cell density and normal extracellular water. In the transition between WMH vicinity and normal white matter, low FA, NDI, ODI, high MD and Fiso suggest cell loss only. This transition region could be at risk of converting to WMH. Future work will include longitudinal evaluation of WMH growth in the at-risk tissue. However, final validation of WMH pathology will need histological confirmation.

Investigation of relayed nuclear Overhauser enhancement effect at -1.6 ppm in an ischemic stroke model.

When an ischemic stroke happens, it triggers a complex signalling cascade that may eventually lead to neuronal cell death if no reperfusion. Recently, the relayed nuclear Overhauser enhancement effect at -1.6 ppm [NOE(-1.6 ppm)] has been postulated may allow for a more in-depth analysis of the ischemic injury. This study assessed the potential utility of NOE(-1.6 ppm) in an ischemic stroke model. Diffusion-weighted imaging, perfusion-weighted imaging, and chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) data were acquired from five rats that underwent scans at 9.4 T after middle cerebral artery occlusion. The apparent diffusion coefficient (ADC), cerebral blood flow (CBF), and apparent exchange-dependent relaxations (AREX) at 3.5 ppm and NOE(-1.6 ppm) were quantified. AREX(3.5 ppm) and NOE(-1.6 ppm) were found to be hypointense and exhibited different signal patterns within the ischemic tissue. The NOE(-1.6 ppm) deficit areas were equal to or larger than the ADC deficit areas, but smaller than the AREX(3.5 ppm) deficit areas. This suggested that NOE(-1.6 ppm) might further delineate the acidotic tissue estimated using AREX(3.5 ppm). Since NOE(-1.6 ppm) is closely related to membrane phospholipids, NOE(-1.6 ppm) potentially highlighted at-risk tissue affected by lipid peroxidation and membrane damage. Altogether, the ADC/NOE(-1.6 ppm)/AREX(3.5 ppm)/CBF mismatches revealed four zones of increasing sizes within the ischemic tissue, potentially reflecting different pathophysiological information. Using CEST coupled with ADC and CBF, the ischemic tissue may thus potentially be separated into four zones to better understand the pathophysiology after stroke and improve ischemic tissue fate definition. Further verification of the potential utility of NOE(-1.6 ppm) may therefore lead to a more precise diagnosis.

RADT-13. A BIOLOGIC EQUIVALENT DOSE COMPARISON BETWEEN RADIOSURGERY AND COLLAGEN TILE BRACHYTHERAPY FOR POST-OPERATIVE TREATMENT OF A BRAIN METASTASIS RESECTION CAVITY

Abstract INTRODUCTION Recurrence of a previously irradiated brain metastasis represents a challenging clinical scenario. Repeat radiosurgery results in sub-optimal local control (LC). Two independently published prospective cohort studies demonstrated durable LC in this setting with collagen tile brachytherapy (CTBT), a novel Cesium-131 carrier. Here we compare biologically equivalent dosimetric parameters of CTBT to radiosurgery to understand dose metrics that may underlie durable LC from CTBT. METHODS A patient was selected from the multi-institutional prospective CTBT registry (NCT04427384) with a brain metastasis resection cavity near brainstem. Planning was performed for radiosurgery (30Gy in 5 fractions, BED of 48Gy) and CTBT (Cs-131, activity of 3.5U). To directly compare dosimetric parameters between radiosurgery and CTBT, biologic equivalent doses (BED) were calculated for brainstem(α/β of 3, BED3) and oncologically at-risk tissue(α/β of 10, BED10). TG101 brainstem dose-constraints were referenced, and respective BED were calculated. RESULTS The resection cavity was 4mm away from brainstem and contained 7 CTBT tiles (28 Cs131 seeds). Gradient index (GI) (24Gy BED10 volume/48Gy BED10 volume) was 3.8 for radiosurgery and 2.2 for CTBT. Conformality index (CI) (48Gy BED10 volume/CTV volume) was 1.2 for radiosurgery and 2.6 for CTBT. BED10 to 90% of the cavity wall (2mm rim around the resection cavity) was 49.6Gy for radiosurgery and 92.6Gy for CTBT. BED3 dose limit goals (max dose 31Gy in 5 fractions, BED3 95.1Gy and threshold dose 23Gy in 5 fractions, BED3 of 58.3Gy to 0.5cc) were met for both radiosurgery and CTBT. CONCLUSION BED comparisons demonstrate that CTBT leads to higher CI, lower GI, and higher dose to the cavity wall than radiosurgery while meeting BED3 dose limit goals to an adjacent organ at risk. These dose characteristics might underlie durable LC seen in the recurrent brain metastasis setting, though larger scale analyses are being performed with with clinical outcomes on NCT04427384.

Continued Infarction Growth and Penumbral Consumption After Reperfusion in Vaccine-Naïve Patients With COVID-19: A Case-Control Study.

Background: Neurologic sequelae of SARS-CoV-2 include potentially malignant cerebrovascular events arising from complex hemodynamic, hematologic, and inflammatory processes occurring in concert. Objective: This study concerns the hypothesis that, despite angiographic reperfusion, COVID-19 promotes continued consumption of at-risk tissue volumes after acute ischemic stroke (AIS) unlike what is seen with COVID-negative individuals, yielding critical insights into prognostication and monitoring paradigms in vaccine-naïve patients experiencing AIS. Methods: This retrospective study compared 100 consecutively presenting patients with COVID-19 and AIS between March 2020 and April 2021 with a contemporaneous cohort of 282 patients with AIS who did not have COVID-19. Reperfusion classes were dichotomized into positive (extended thrombolysis in cerebral ischemia [eTICI] score = 2c-3) and negative (eTICI score < 2c) groups. All patients underwent endovascular therapy following initial CT perfusion imaging (CTP) to document infarction core and total hypoperfusion volumes. Results: Ten COVID-positive (mean age ± SD, 67 ± 6 years; seven men, three women) and 144 COVID-negative patients (mean age, 71 ± 10 years; 76 men, 68 women) undergoing endovascular reperfusion with antecedent CTP and follow-up imaging comprised the final dataset. Initial infarction core and total hypoperfusion volumes were 1.5 ± 18 mL and 85 ± 100 mL in COVID-negative patients and 30.5 ± 34 mL and 117 ± 80.5 mL in COVID-positive patients, respectively. Final infarction volumes were significantly larger in patients with COVID-19, with median volumes of 77.8 mL versus 18.2 mL among control patients (p = .01), as were normalized measures of infarction growth relative to baseline infarction volume (p = .05). In adjusted logistic parametric regression models, COVID positivity emerged as a significant predictor for continued infarct growth (OR, 5.1 [95% CI, 1.0-25.95]; p = .05). Conclusion: These findings support the potentially aggressive clinical course of cerebrovascular events in patients with COVID-19, suggesting greater infarction growth and ongoing consumption of at-risk tissues, even following angiographic reperfusion. Clinical Impact: SARS-CoV-2 infection may promote continued infarction progression, despite angiographic reperfusion, in vaccine-naïve patients with large-vessel occlusion AIS. The findings carry potential implications for prognostication, treatment selection, and surveillance for infarction growth among revascularized patients in future waves of infection by novel viral strains.

Quantitative Evaluation of Oxygen Extraction Fraction Changes in the Monkey Brain during Acute Stroke by Using Quantitative Susceptibility Mapping.

The oxygen extraction fraction (OEF) indicates the brain's oxygen consumption and can be estimated by using the quantitative susceptibility mapping (QSM) MRI technique. Recent studies have suggested that OEF alteration following stroke is associated with the viability of at-risk tissue. In the present study, the temporal evolution of OEF in the monkey brain during acute stroke was investigated using QSM. Ischemic stroke was induced in adult rhesus monkeys (n = 8) with permanent middle cerebral artery occlusion (pMCAO) by using an interventional approach. Diffusion-, T2-, and T2*-weighted images were conducted on day 0, day 2, and day 4 post-stroke using a clinical 3T scanner. Progressive changes in magnetic susceptibility and OEF, along with their correlations with the transverse relaxation rates and diffusion indices, were examined. The magnetic susceptibility and OEF in injured gray matter of the brain significantly increased during the hyperacute phase, and then decreased significantly on day 2 and day 4. Moreover, the temporal changes of OEF in gray matter were moderately correlated with mean diffusivity (MD) (r = 0.52; p = 0.046) from day 0 to day 4. Magnetic susceptibility in white matter progressively increased (from negative values to near zero) during acute stroke, and significant increases were seen on day 2 (p = 0.08) and day 4 (p = 0.003) when white matter was significantly degenerated. However, significant reduction of OEF in white matter was not seen until day 4 post-stroke. The preliminary results demonstrate that QSM-derived OEF is a robust approach to examine the progressive changes of gray matter in the ischemic brain from the hyperacute phase to the subacute phase of stroke. The changes of OEF in gray matter were more prominent than those in white matter following stroke insult. The findings suggest that QSM-derived OEF may provide complementary information for understanding the neuropathology of the brain tissue following stroke and predicting stroke outcomes.

Cerebral microdialysis and glucopenia in traumatic brain injury: A review.

Traditionally, intracranial pressure (ICP) and partial brain tissue oxygenation (PbtO2) have been the primary invasive intracranial measurements used to guide management in patients with severe traumatic brain injury (TBI). After injury however, the brain develops an increased metabolic demand which may require an increment in the oxidative metabolism of glucose. Simultaneously, metabolic, and electrical dysfunction can lead to an inability to meet these demands, even in the absence of ischemia or increased intracranial pressure. Cerebral microdialysis provides the ability to accurately measure local concentrations of various solutes including lactate, pyruvate, glycerol and glucose. Experimental and clinical data demonstrate that such measurements of cellular metabolism can yield critical missing information about a patient's physiologic state and help limit secondary damage. Glucose management in traumatic brain injury is still an unresolved question. As cerebral glucose metabolism may be uncoupled from systemic glucose levels due to the metabolic dysfunction, measurement of cerebral extracellular glucose concentrations could provide more predictive information and prove to be a better biomarker to avoid secondary injury of at-risk brain tissue. Based on data obtained from cerebral microdialysis, specific interventions such as ICP-directed therapy, blood glucose increment, seizure control, and/or brain oxygen optimization can be instituted to minimize or prevent secondary insults. Thus, microdialysis measurements of parenchymal metabolic function provides clinically valuable information that cannot be obtained by other monitoring adjuncts in the standard ICU setting.

Multimodal optical imaging with real-time projection of cancer risk and biopsy guidance maps for early oral cancer diagnosis and treatment.

Despite recent advances in multimodal optical imaging, oral imaging systems often do not provide real-time actionable guidance to the clinician who is making biopsy and treatment decisions. We demonstrate a low-cost, portable active biopsy guidance system (ABGS) that uses multimodal optical imaging with deep learning to directly project cancer risk and biopsy guidance maps onto oral mucosa in real time. Cancer risk maps are generated based on widefield autofluorescence images and projected onto the at-risk tissue using a digital light projector. Microendoscopy images are obtained from at-risk areas, and multimodal image data are used to calculate a biopsy guidance map, which is projected onto tissue. Representative patient examples highlight clinically actionable visualizations provided in real time during an imaging procedure. Results show multimodal imaging with cancer risk and biopsy guidance map projection offers a versatile, quantitative, and precise tool to guide biopsy site selection and improve early detection of oral cancers. The ABGS provides direct visible guidance to identify early lesions and locate appropriate sites to biopsy within those lesions. This represents an opportunity to translate multimodal imaging into real-time clinically actionable visualizations to help improve patient outcomes.

Overexpression of Estrogen Receptor α in Mammary Glands of Aging Mice Is Associated with a Proliferative Risk Signature and Generation of Estrogen Receptor α–Positive Mammary Adenocarcinomas

Age is a risk factor for human estrogen receptor-positive breast cancer, with highest prevalence following menopause. While transcriptome risk profiling is available for human breast cancers, it is not yet developed for prognostication for primary or secondary breast cancer development utilizing at-risk breast tissue. Both estrogen receptor α (ER) and aromatase overexpression have been linked to human breast cancer. Herein, conditional genetically engineered mouse models of estrogen receptor 1 (Esr1) and cytochrome P450 family 19 subfamily A member 1 (CYP19A1) were used to show that induction of Esr1 overexpression just before or with reproductive senescence and maintained through age 30 months resulted in significantly higher prevalence of estrogen receptor-positive adenocarcinomas than CYP19A1 overexpression. All adenocarcinomas tested showed high percentages of ER+cells. Mammary cancer development was preceded by a persistent proliferative transcriptome risk signature initiated within 1 week of transgene induction that showed parallels to the Prosigna/Prediction Analysis of Microarray 50 human prognostic signature for early-stage human ER+breast cancer. CYP19A1 mice also developed ER+mammary cancers, but histology was more divided between adenocarcinoma and adenosquamous, with one ER- adenocarcinoma. Results demonstrate that, like humans, generation of ER+adenocarcinoma in mice was facilitated by aging mice past the age of reproductive senescence. Esr1 overexpression was associated with a proliferative estrogen pathway-linked signature that preceded appearance of ER+mammary adenocarcinomas.

PHSOR03 Presentation Time: 12:40 PM: Radiation Dosimetry of a Dual-Modality Balloon Implant for Simultaneous HDR Brachytherapy and Magnetic Nanoparticle Hyperthermia to Treat Brain Tumor Resection Cavities

<h3>Purpose</h3> Glioblastoma multiforme (GBM) is an aggressive brain tumor that generally recurs locally and has a dismal median survival of less than 18 months<i>. In vivo</i> studies have shown that simultaneous hyperthermia and radiation can enhance the radiation response by a factor of up to 5. Our group developed a novel dual-modality thermobrachytherapy (TBT) balloon device to accomplish this goal. The balloon will combine magnetic fluid hyperthermia and HDR brachytherapy, which will be delivered right after brain tumor resection, so that the at-risk tissue adjacent to the tumor resection cavity will conform to the balloon shape and receive uniform radiation and thermal dose. This abstract focuses on the possible effects of hyperthermia on radiation dosimetry as well as the effects of balloon shape. <h3>Methods</h3> The current version of our TBT balloon device consists of a balloon filled with magnetic nanoparticle solution (nanofluid) and a flexible sheath with three ports to insert the HDR catheter and fiber-optic thermal probe and inject the nanofluid. We tested the balloon in air and activated the nanofluid using an external magnetic field induced by a 133 kHz induction coil. Two balloon designs were tested: a spherical one with 4 cm diameter, and a teardrop-shaped balloon with an axial diameter of 3 cm and measuring 3.7 cm along the shaft. We used Gafchromic film and RIT imaging software to analyze the in-air dose distribution of an HDR source dwell in both types of balloons, filled with distilled water and then nanofluid, as well as without and with simultaneous hyperthermia, where the coil power was escalated until reaching intra-balloon temperatures greater than 55°C. Experimental setup and radiation dose profiles can be found in Figure 1. <h3>Results</h3> The presence of the nanofluid, magnetic field and heat up to 66°C did not affect radiation dose distribution significantly in the spherical balloon (less than 10% difference). However, the teardrop-shaped balloon dose profiles showed a notable difference (about 20%) in dose magnitude with the presence of nanofluid and/or heat. Nonetheless dose distributions looked symmetrical in all cases. <h3>Conclusions</h3> The current device design is still in progress, but this study illustrated that a spherical balloon shape may be preferential for simultaneous hyperthermia and HDR brachytherapy. Furthermore, this radiation dosimetry study demonstrated compatibility and robustness of the prototype balloon components and desirable symmetrical dose distribution.

Ischemia-Selective Cardioprotection by Malonate for Ischemia/Reperfusion Injury.

Background:Inhibiting SDH (succinate dehydrogenase), with the competitive inhibitor malonate, has shown promise in ameliorating ischemia/reperfusion injury. However, key for translation to the clinic is understanding the mechanism of malonate entry into cells to enable inhibition of SDH, its mitochondrial target, as malonate itself poorly permeates cellular membranes. The possibility of malonate selectively entering the at-risk heart tissue on reperfusion, however, remains unexplored.Methods:C57BL/6J mice, C2C12 and H9c2 myoblasts, and HeLa cells were used to elucidate the mechanism of selective malonate uptake into the ischemic heart upon reperfusion. Cells were treated with malonate while varying pH or together with transport inhibitors. Mouse hearts were either perfused ex vivo (Langendorff) or subjected to in vivo left anterior descending coronary artery ligation as models of ischemia/reperfusion injury. Succinate and malonate levels were assessed by liquid chromatography-tandem mass spectrometry LC-MS/MS, in vivo by mass spectrometry imaging, and infarct size by TTC (2,3,5-triphenyl-2H-tetrazolium chloride) staining.Results:Malonate was robustly protective against cardiac ischemia/reperfusion injury, but only if administered at reperfusion and not when infused before ischemia. The extent of malonate uptake into the heart was proportional to the duration of ischemia. Malonate entry into cardiomyocytes in vivo and in vitro was dramatically increased at the low pH (≈6.5) associated with ischemia. This increased uptake of malonate was blocked by selective inhibition of MCT1 (monocarboxylate transporter 1). Reperfusion of the ischemic heart region with malonate led to selective SDH inhibition in the at-risk region. Acid-formulation greatly enhances the cardioprotective potency of malonate.Conclusions:Cardioprotection by malonate is dependent on its entry into cardiomyocytes. This is facilitated by the local decrease in pH that occurs during ischemia, leading to its selective uptake upon reperfusion into the at-risk tissue, via MCT1. Thus, malonate’s preferential uptake in reperfused tissue means it is an at-risk tissue-selective drug that protects against cardiac ischemia/reperfusion injury.

Abstract WP97: Automated Analysis For Detecting Large Vessel Occlusion On Non Contrast Ct In Acute Stroke

Background and Purpose: Rapid detection of large vessel occlusion (LVO) is essential for rapid triage for thrombectomy to salvage at-risk tissue. Early detection of LVO on noncontrast CT head (NCCT) could facilitate triage before advanced imaging is obtained. RAPID hyperdense vessel sign (HVS), a new fully automated software- tool for HVS detection is compared to experienced radiologists, for early LVO detection on NCCT, and validated with CTA. Methods: Scans were selected from a database of 335 scans, of which 166 were selected by stratified random selection. Images were evaluated by the Rapid automated software, and six readers, two radiologists, and four neuroradiologists. The Rapid algorithm returns a score between zero and one, and a threshold of 0.5 was applied of HVS. Radiologists read each scan twice, 30 days apart. A scan rating confidence scale was used, from “very confident of absence,” to “very confident of HVS,” and a separate “technically inadequate” rating, and this was compared to the Rapid HVS score. “Very Confident,” or “Confident” rated scans were considered HVS positive. Results: Demographics: 54% were men. Ages ranged 23 - 94 with a median of 65. GE, Philips, Siemens, and Toshiba scanners are represented. Agreement with RAPID for HVS detection was 75% to 84%. Below a HVS score of 0.4 the proportion of LVO positive scans was 46% (indeterminate), between 0.4 and 0.6 the proportion was 62.5% (probable), and above 0.6 the proportion was 90% (likely). The scan rating confidence grade correlated with the Rapid HVS score. The software identified 53% of the LVOs, comparable to human readers (26-57%) A clinical practice simulation of RAPID followed by a reader identified 61.3% (p=0.02 vs readers alone). Among the 61 patients with no LVO on CTA, readers had a false positive rate of less than 7% as compared to 15% for the software. Median software processing time was 54 seconds. Conclusions: Expert readers, and the Rapid software, detect an HVS in about 50% of CT head images with LVO on CTA. When Rapid software is used in tandem with an experienced reader, HVS can be detected in up to two thirds of patients with LVO on CTA. This high percentage of early LVO detection would facilitate faster triage of patients for more advanced imaging and/or therapeutic interventions.

The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Surgical Management of Ulcerative Colitis.

The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Surgical Management of Ulcerative Colitis.

Role of Indocyanine Green to Mitigate Wound Complications in Component Separation Technique for Ventral Hernia Repair-Our Early Experience.

The ease of the anterior component separation technique (ACST) makes it an attractive surgical option for ventral hernia repairs (VHR). Incorporation of indocyanine green-fluorescence angiography (ICG-FA) to map soft tissue perfusion during open ACST is an effective way to minimize the wound complications. This study aims to evaluate the impact of adoption of ICG-FA on wound-related complications following open ACST in VHR. We performed a retrospective review of patients who underwent VHR with the open ACST at a single centre between March 2018 and July 2020. The study comprised of consecutive cases of open ACST with onlay meshplasty done before (March 2018-April 2019) and after (May 2019 to July 2020) implementation of ICG-FA for intra-operative perfusion mapping of subcutaneous tissue and skin. The pre-ICG group and post-ICG group were similar in terms of baseline patient demographics and peri-operative details. The rate of surgical site occurrence's was higher in the pre-ICG group, but this result was not statistically significant (46% vs. 26%; p value 0.189). Skin necrosis, however, was observed in significantly less patients of the post-ICG cohort (29% vs. 5%; p value 0.045). This study demonstrates the effectiveness of perfusion mapping by the use of ICG angiography to determine potential areas of decreased perfusion and thereby minimize wound complications. Using ICG-FA to guide removal of at-risk tissue to minimize wound complications may substantially improve the patients outcome.

Breast-Specific Molecular Clocks Comprised of ELF5 Expression and Promoter Methylation Identify Individuals Susceptible to Cancer Initiation.

A robust breast cancer prevention strategy requires risk assessment biomarkers for early detection. We show that expression of ELF5, a transcription factor critical for normal mammary development, is downregulated in mammary luminal epithelia with age. DNA methylation of the ELF5 promoter is negatively correlated with expression in an age-dependent manner. Both ELF5 methylation and gene expression were used to build biological clocks to estimate chronological ages of mammary epithelia. ELF5 clock-based estimates of biological age in luminal epithelia from average-risk women were within three years of chronological age. Biological ages of breast epithelia from BRCA1 or BRCA2 mutation carriers, who were high risk for developing breast cancer, suggested they were accelerated by two decades relative to chronological age. The ELF5 DNA methylation clock had better performance at predicting biological age in luminal epithelial cells as compared with two other epigenetic clocks based on whole tissues. We propose that the changes in ELF5 expression or ELF5-proximal DNA methylation in luminal epithelia are emergent properties of at-risk breast tissue and constitute breast-specific biological clocks. PREVENTION RELEVANCE: ELF5 expression or DNA methylation level at the ELF5 promoter region can be used as breast-specific biological clocks to identify women at higher than average risk of breast cancer.

Combined Use of X-ray Angiography and Intraprocedural MRI Enables Tissue-based Decision Making Regarding Revascularization during Acute Ischemic Stroke Intervention.

Background For patients with acute ischemic stroke undergoing endovascular mechanical thrombectomy with x-ray angiography, the use of adjuncts to maintain vessel patency, such as stents or antiplatelet medications, can increase risk of periprocedural complications. Criteria for using these adjuncts are not well defined. Purpose To evaluate use of MRI to guide critical decision making by using a combined biplane x-ray neuroangiography 3.0-T MRI suite during acute ischemic stroke intervention. Materials and Methods This retrospective observational study evaluated consecutive patients undergoing endovascular intervention for acute ischemic stroke between July 2019 and May 2020 who underwent either angiography with MRI or angiography alone. Cerebral tissue viability was assessed by using MRI as the reference standard. For statistical analysis, Fisher exact test and Student t test were used to compare groups. Results Of 47 patients undergoing acute stroke intervention, 12 patients (median age, 69 years; interquartile range, 60-77 years; nine men) underwent x-ray angiography with MRI whereas the remaining 35 patients (median age, 80 years; interquartile range, 68-86 years; 22 men) underwent angiography alone. MRI results influenced clinical decision making in one of three ways: whether or not to perform initial or additional mechanical thrombectomy, whether or not to place an intracranial stent, and administration of antithrombotic or blood pressure medications. In this initial experience, decision making during endovascular acute stroke intervention in the combined angiography-MRI suite was better informed at MRI, such that therapy was guided in real time by the viability of the at-risk cerebral tissue. Conclusion Integrating intraprocedural 3.0-T MRI into acute ischemic stroke treatment was feasible and guided decisions of whether or not to continue thrombectomy, to place stents, or to administer antithrombotic medication or provide blood pressure medications. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Lev and Leslie-Mazwi in this issue.

Mild fever as a catalyst for consumption of the ischaemic penumbra despite endovascular reperfusion.

Cerebrovascular ischaemia is potentiated by hyperthermia, and even mild temperature elevation has proved detrimental to ischaemic brain. Infarction progression following endovascular reperfusion relates to multiple patient-specific and procedural variables; however, the potential influence of mild systemic temperature fluctuations is not fully understood. This study aims to assess the relationship between systemic temperatures in the early aftermath of acute ischaemic stroke and the loss of at-risk penumbral tissues, hypothesizing consumption of the ischaemic penumbra as a function of systemic temperatures, irrespective of reperfusion status. A cross-sectional, retrospective evaluation of a single-institution, prospectively collected endovascular therapy registry was conducted. Patients with anterior circulation, large vessel occlusion acute ischaemic stroke who underwent initial CT perfusion, and in whom at least four-hourly systemic temperatures were recorded beginning from presentation and until the time of final imaging outcome were included. Initial CT perfusion core and penumbra volumes and final MRI infarction volumes were computed. Systemic temperature indices including temperature maxima were recorded, and pre-defined temperature thresholds varying between 37°C and 38°C were examined in unadjusted and adjusted regression models which included glucose, collateral status, reperfusion status, CT perfusion-to-reperfusion delay, general anaesthesia and antipyretic exposure. The primary outcome was the relative consumption of the penumbra, reflecting normalized growth of the at-risk tissue volume ≥10%. The final study population comprised 126 acute ischaemic stroke subjects (mean 63 ± 14.5 years, 63% women). The primary outcome of penumbra consumption ≥10% occurred in 51 (40.1%) subjects. No significant differences in baseline characteristics were present between groups, with the exception of presentation glucose (118 ± 26.6 without versus 143.1 ± 61.6 with penumbra consumption, P = 0.009). Significant differences in the likelihood of penumbra consumption relating to systemic temperature maxima were observed [37°C (interquartile range 36.5 − 37.5°C) without versus 37.5°C (interquartile range 36.8 − 38.2°C) with penumbra consumption, P = 0.001]. An increased likelihood of penumbra consumption was observed for temperature maxima in unadjusted (odds ratio 3.57, 95% confidence interval 1.65 − 7.75; P = 0.001) and adjusted (odds ratio 3.06, 95% confidence interval 1.33 − 7.06; P = 0.009) regression models. Significant differences in median penumbra consumption were present at a pre-defined temperature maxima threshold of 37.5°C [4.8 ml (interquartile range 0 − 11.5 ml) versus 21.1 ml (0 − 44.7 ml) for subjects not reaching or reaching the threshold, respectively, P = 0.007]. Mild fever may promote loss of the ischaemic penumbra irrespective of reperfusion, potentially influencing successful salvage of at-risk tissue volumes following acute ischaemic stroke.