Advancing Health Equity in Lung Cancer Screening and the Role of Humanomics.

Identifying and managing lung cancer, the leading cause of cancer-specific mortality, depend on multiple medical and sociodemographic factors. Humanomics is a model that acknowledges that negative societal stressors from systemic inequity affect individual health by altering pro-inflammatory gene expression. The same factors which may predispose individuals to lung cancer may also obstruct equitably prompt diagnosis and treatment. Increasing lung cancer screening access can lessen disparities in outcomes among disproportionately affected communities. Here, the authors describe several individual, provider, and health system-level obstacles to lung cancer screening and offer actionable solutions to increase access.

A Common Path: Magnetic Resonance Imaging of Müllerian and Wolffian Duct Anomalies.

PURPOSE OF REVIEW: This review summarizes the pathway of Mullerian and Wolffian duct development, anomalies that result from disruptions to this pathway, and the characteristics on advanced imaging that identify them. RECENT FINDINGS: In-office evaluation for reproductive anomalies is usually inadequate for the diagnosis of congenital reproductive anomalies. Magnetic resonance imaging (MRI) has usurped invasive diagnostic methods including laparoscopy, hysteroscopy, and vasography as the new gold standard. Because of its superior soft-tissue delineation and the availability of advanced functional sequences, MRI offers a sophisticated method of distinguishing reproductive anomalies from one another, characterizing the degree of defect severity, and evaluating for concomitant urogenital anomalies non-invasively and without radiation exposure to the patient. Congenital anomalies of the Mullerian and Wolffian duct can be incredibly nuanced, requiring prompt and accurate diagnosis for management of infertility. Definitive diagnosis should be made early with MRI.

Acing the Fundamentals of Radiology: An Online Series for Medical Students and Interns.

PURPOSE: The current undergraduate radiology education predominantly integrates radiology with other disciplines during preclerkship years and is often taught by nonradiologists. Early exposure to radiology and profound understanding of scientific fundamentals of imaging modalities and techniques are essential for a better understanding and interest in the specialty. Furthermore, the COVID-19 pandemic-related impact on in-person medical education aggravated the need for alternative virtual teaching initiatives to provide essential knowledge to medical students. METHODS: The authors designed an online 7-session course on the principles of imaging modalities for medical students and fresh graduates in the United States and abroad. The course was delivered online and taught by radiologists from different US institutions. Pretests and posttests were delivered before and after each session, respectively, to assess change in knowledge. At the end of the course, a survey was distributed among students to collect their assessment and feedback. RESULTS: A total of 162 students and interns initially enrolled in the program by completing a sign-up interest form. An average of 65 participants attended each live session, with the highest attendance being 93 live attendees. An average of 44 attendees completed both the pretest and posttest for each session. There was a statistically significant increase in posttest scores compared with pretest scores ( P < 0.01) for each session; on average, the posttest scores were 48% higher than the pretest scores. A total of 84 participants answered the end-of-course survey. A total of 11% of the respondents described themselves as first year, 17% as second year, 18% as third year, 21% as fourth year, and 33% as "other." Attendees were enrolled in medical schools across 21 different countries with 35% of the respondents studying medicine in the United States. More than 76% of the respondents stated that they "strongly agree" that the program increased their understanding of radiology, increased their interest in radiology, and would be useful in their clinical practice in the future. Eighty-three percent of the respondents stated that they "strongly agree" that "this course was a worthwhile experience." Particularly, more than 84% of the respondents stated that among the most important components in enhancing their understanding of radiology were "the interpretation of normal imaging" and "interpretation of clinical cases." Ninety-two percent of the respondents stated that "the amount of effort to complete the requirements for this program was just right." Participants were also asked to rate each of the 8 sessions using the following scale: poor = 1 point, fair = 2, good = 3, and excellent = 4. The average rating for all 8 sessions was 3.61 points (SD = 0.55), which translates to 96% of the sessions being rated good or excellent. Eighty percent of the participants reported that the topics presented in the program were "excellent and clinically important to learn," and 20% of the participants reported that the topics presented were "good and somewhat important to learn." The participants were asked to evaluate their confidence regarding basic radiology skills before and after the program using the following scale: not confident at all = 1 point, somewhat confident = 2, moderately confident = 3, and very confident = 4. Figure 2 summarizes the responses of the participants. CONCLUSIONS: An online course to teach the fundamentals of imaging modalities could be delivered through a webinar format to medical students and interns in several countries to address the potential gaps in radiology education, therefore increasing their understanding of the different imaging modalities and their proper use in medicine.

Stress and the Gut-Brain Axis: Implications for Cancer, Inflammation and Sepsis.

BACKGROUND: The gut-brain axis has been discussed, directly or indirectly, for centuries, with the ideas of the gut affecting anything from moods to overall physiology being discussed across the centuries. With a recent explosion in research that looks to the microbiota as a mechanistic link between the gut and the brain, one sees that the gut-brain axis has various means of communication, such as through the vagus nerve and the enteric nervous system and can use the metabolites in the gut to communicate to the brain. METHODS: The purpose of this review is to view the gut-brain axis through the lens of stress and how stress, from the prenatal period all the way through adulthood can impact the physiology of a human being. Studies have shown multiple mechanisms of measurable change with disruption in the microbiota that lead to behavioral changes. There are also effects of gut inflammation on the brain and the corresponding systemic response observed. CONCLUSION: The overall literature is encouraging that the more understanding of the gut-brain axis, the greater ability to wield that understanding for therapeutic benefits.

Predicting Schwannoma Growth in a Tumor Model Using Targeted Imaging.

INTRODUCTION: Vestibular schwannoma (VS) is a common pathology encountered in neurotology clinics. Many patients are observed with a "wait and scan" approach. Previous efforts to determine radiographic indicators of future growth have been unsuccessful. Using a mouse subcutaneous tumor model, we seek to determine if fluorescent imaging with directed immunotargets could be used to predict schwannoma growth rate. METHODS: Anti-VEGFR2 and anti-Her2/Neu monoclonal antibodies were covalently linked to a near-infrared probe (IRDye800). Immunodeficient mice underwent subcutaneous injections with a rat-derived schwann (R3) cell line. When tumor growth was evident, either Anti-VEGFR2-IRDye800, anti-Her2/Neu-IRDye800, or Immunoglobulin G (IgG) Isotype-IRDye800 (control) were injected via tail vein. The mice were serially imaged in a closed field near-IR device. Fluorescent data were analyzed for tumor signal and correlated with tumor sie and growth rate. Heterogeneity of fluorescent tumor signal was also assessed. RESULTS: In both anti-VEGFR2 and anti-Her2/Neu groups, there were strong correlations between day 1 mean tumor fluorescence and eventual maximum tumor volume (p = 0.002, 0.001; r2 = 0.92, 0.86). There was also strong correlation with maximum tumor signal on day 1 and maximum tumor volume (p = 0.003, 0.008; r2 = 0.90, 0.91). There was no such correlation in the control group (p = 0.99, 0.75; r2 = 0.0002, 0.028). CONCLUSION: Given the potential morbidity in VS intervention, observation is an appropriate approach for patients with slow-growing or stagnant tumors. We seek to identify immunotargets in a murine model that show promise in predicting schwannoma growth with advanced imaging techniques. Both Her2/Neu and VEGFR2 correlated strongly wth tumor size and growth rates and are promising targets that merit further investigation.

How Fast Can We Go: Abbreviated Prostate MR Protocols.

PURPOSE OF REVIEW: Multiparametric MRI (mpMRI), composed of T2WI, DWI, and DCE sequences, is effective in identifying prostate cancer (PCa), but length and cost preclude its application as a PCa screening tool. Here we review abbreviated MRI protocols that shorten or omit conventional mpMRI components to reduce scan time and expense without forgoing diagnostic accuracy. RECENT FINDINGS: The DCE sequence, which plays a limited diagnostic role in PI-RADS, is eliminated in variations of the biparametric MRI (bpMRI). T2WI, the lengthiest sequence, is truncated by only acquiring the axial plane or utilizing 3D acquisition with subsequent 2D reconstruction. DW-EPISMS further accelerates DWI acquisition. The fastest protocol described to date consists of just DW-EPISMS and axial-only 2D T2WI and runs less than 5 min. Abbreviated protocols can mitigate scan expense and increase scan access, allowing prostate MRI to become an efficient PCa screening tool.

Comparison of Panitumumab-IRDye800CW and 5-Aminolevulinic Acid to Provide Optical Contrast in a Model of Glioblastoma Multiforme.

Maximal safe resection of malignant tissue is associated with improved progression-free survival and better response to radiation and chemotherapy for patients with glioblastoma (GBM). 5-Aminolevulinic acid (5-ALA) is the current FDA-approved standard for intraoperative brain tumor visualization. Unfortunately, autofluorescence in diffuse areas and high fluorescence in dense tissues significantly limit discrimination at tumor margins. This study is the first to compare 5-ALA to an investigational new drug, panitumumab-IRDye800CW, in the same animal model. A patient-derived GBM xenograft model was established in 16 nude mice, which later received injections of 5-ALA, panitumumab-IRDye800CW, IRDye800CW, 5-ALA and IRDye800CW, or 5-ALA and panitumumab-IRDye800CW. Brains were prepared for multi-instrument fluorescence imaging, IHC, and quantitative analysis of tumor-to-background ratio (TBR) and tumor margin accuracy. Statistical analysis was compared with Wilcoxon rank-sum or paired t test. Panitumumab-IRDye800CW had a 30% higher comprehensive TBR compared with 5-ALA (P = 0.0079). SDs for core and margin regions of interest in 5-ALA-treated tissues were significantly higher than those found in panitumumab-IRDye800CW-treated tissues (P = 0.0240 and P = 0.0284, respectively). Panitumumab-IRDye800CW specificities for tumor core and margin were more than 10% higher than those of 5-ALA. Higher AUC for panitumumab-IRDye800CW indicated strong capability to discriminate between normal and malignant brain tissue when compared with 5-ALA. This work demonstrates that panitumumab-IRDye800CW shows potential as a targeting agent for fluorescence intraoperative detection of GBM. Improved margin definition and surgical resection using panitumumab-IRDye800 has the potential to improve surgical outcomes and survival in patients with GBM compared with 5-ALA.

Surgical margins in oral cavity squamous cell carcinoma: Current practices and future directions.

OBJECTIVE: To discuss the current available techniques for intraoperative margin assessment in the surgical treatment of oral squamous cell carcinoma (OSCC) through a review of the available literature. METHODS: A systematic review was undertaken of the available English literature between 2008 through 2018 regarding surgical margins in OCSS. A total of 893 relevant articles were returned; 144 met criteria for review; and 64 articles were included. RESULTS: In this review, we discuss the data surrounding the use of frozen section in OCSS. Additionally, alternative techniques for margin assessment are discussed, including Mohs, molecular analysis, nonfluorescent dyes, fluorescent dyes, autofluorescent imaging, narrow-band imaging, optical coherence tomography, confocal microscopy, high-resolution microendoscopy, and spectroscopy. For each technique, particular emphasis is placed on the local recurrence, disease-free survival, and overall survival rates when available. CONCLUSION: This review provides support for the practice of specimen-driven margin assessment when using frozen section analysis to improve the utility of the results. Finally, several alternatives for intraoperative margin assessment currently under investigation, including pathologic, wide-field imaging and narrow-field imaging techniques, are presented. We aim to fuel further investigation into methods for margin assessment that will improve survival for patients with OSCC through a critical analysis of the available techniques. LEVEL OF EVIDENCE: NA Laryngoscope, 130:128-138, 2020.

Targeting MMP-14 for dual PET and fluorescence imaging of glioma in preclinical models.

PURPOSE: There is a clinical need for agents that target glioma cells for non-invasive and intraoperative imaging to guide therapeutic intervention and improve the prognosis of glioma. Matrix metalloproteinase (MMP)-14 is overexpressed in glioma with negligible expression in normal brain, presenting MMP-14 as an attractive biomarker for imaging glioma. In this study, we designed a peptide probe containing a near-infrared fluorescence (NIRF) dye/quencher pair, a positron emission tomography (PET) radionuclide, and a moiety with high affinity to MMP-14. This novel substrate-binding peptide allows dual modality imaging of glioma only after cleavage by MMP-14 to activate the quenched NIRF signal, enhancing probe specificity and imaging contrast. METHODS: MMP-14 expression and activity in human glioma tissues and cells were measured in vitro by immunofluorescence and gel zymography. Cleavage of the novel substrate and substrate-binding peptides by glioma cells in vitro and glioma xenograft tumors in vivo was determined by NIRF imaging. Biodistribution of the radiolabeled MMP-14-binding peptide or substrate-binding peptide was determined in mice bearing orthotopic patient-derived xenograft (PDX) glioma tumors by PET imaging. RESULTS: Glioma cells with MMP-14 activity showed activation and retention of NIRF signal from the cleaved peptides. Resected mouse brains with PDX glioma tumors showed tumor-to-background NIRF ratios of 7.6-11.1 at 4 h after i.v. injection of the peptides. PET/CT images showed localization of activity in orthotopic PDX tumors after i.v. injection of 68Ga-binding peptide or 64Cu-substrate-binding peptide; uptake of the radiolabeled peptides in tumors was significantly reduced (p < 0.05) by blocking with the non-labeled-binding peptide. PET and NIRF signals correlated linearly in the orthotopic PDX tumors. Immunohistochemistry showed co-localization of MMP-14 expression and NIRF signal in the resected tumors. CONCLUSIONS: The novel MMP-14 substrate-binding peptide enabled PET/NIRF imaging of glioma models in mice, warranting future image-guided resection studies with the probe in preclinical glioma models.

Current and Future Imaging Methods for Evaluating Response to Immunotherapy in Neuro-Oncology.

Imaging plays a central role in evaluating responses to therapy in neuro-oncology patients. The advancing clinical use of immunotherapies has demonstrated that treatment-related inflammatory responses mimic tumor growth via conventional imaging, thus spurring the development of new imaging approaches to adequately distinguish between pseudoprogression and progressive disease. To this end, an increasing number of advanced imaging techniques are being evaluated in preclinical and clinical studies. These novel molecular imaging approaches will serve to complement conventional response assessments during immunotherapy. The goal of these techniques is to provide definitive metrics of tumor response at earlier time points to inform treatment decisions, which has the potential to improve patient outcomes. This review summarizes the available immunotherapy regimens, clinical response criteria, current state-of-the-art imaging approaches, and groundbreaking strategies for future implementation to evaluate the anti-tumor and immune responses to immunotherapy in neuro-oncology applications.

Fluorescence Imaging of Nerves During Surgery.

OBJECTIVE: This review details the agents for fluorescence-guided nerve imaging in both preclinical and clinical use to identify factors important in selecting nerve-specific fluorescent agents for surgical procedures. BACKGROUND: Iatrogenic nerve injury remains a significant cause of morbidity in patients undergoing surgical procedures. Current real-time identification of nerves during surgery involves neurophysiologic nerve stimulation, which has practical limitations. Intraoperative fluorescence-guided imaging provides a complimentary means of differentiating tissue types and pathology. Recent advances in fluorescence-guided nerve imaging have shown promise, but the ideal agent remains elusive. METHODS: In February 2018, PubMed was searched for articles investigating peripheral nerve fluorescence. Key terms used in this search include: "intraoperative, nerve, fluorescence, peripheral nerve, visualization, near infrared, and myelin." Limits were set to exclude articles exclusively dealing with central nervous system targets or written in languages other than English. References were cross-checked for articles not otherwise identified. RESULTS: Of the nonspecific agents, tracers that rely on axonal transport showed the greatest tissue specificity; however, neurovascular dyes already enjoy wide clinical use. Fluorophores specific to nerve moieties result in excellent nerve to background ratios. Although noteworthy findings on tissue specificity, toxicity, and route of administration specific to each fluorescent agent were reported, significant data objectively quantifying nerve-specific fluorescence and toxicity are lacking. CONCLUSIONS: Fluorescence-based nerve enhancement has advanced rapidly over the past 10 years with potential for continued utilization and progression in translational research. An ideal agent would be easily administered perioperatively, would not cross the blood-brain barrier, and would fluoresce in the near-infrared spectrum. Agents administered systemically that target nerve-specific moieties have shown the greatest promise. Based on the heterogeneity of published studies and methods for reporting outcomes, it appears that the development of an optimal nerve imaging agent remains challenging.

A Novel Combination of Withaferin A and Sulforaphane Inhibits Epigenetic Machinery, Cellular Viability and Induces Apoptosis of Breast Cancer Cells.

With cancer often classified as a disease that has an important epigenetic component, natural compounds that have the ability to regulate the epigenome become ideal candidates for study. Humans have a complex diet, which illustrates the need to elucidate the mechanisms of interaction between these bioactive compounds in combination. The natural compounds withaferin A (WA), from the Indian winter cherry, and sulforaphane (SFN), from cruciferous vegetables, have numerous anti-cancer effects and some report their ability to regulate epigenetic processes. Our study is the first to investigate the combinatorial effects of low physiologically achievable concentrations of WA and SFN on breast cancer cell proliferation, histone deacetylase1 (HDAC1) and DNA methyltransferases (DNMTs). No adverse effects were observed on control cells at optimal concentrations. There was synergistic inhibition of cellular viability in MCF-7 cells and a greater induction of apoptosis with the combinatorial approach than with either compound administered alone in both MDA-MB-231 and MCF-7 cells. HDAC expression was down-regulated at multiple levels. Lastly, we determined the combined effects of these bioactive compounds on the pro-apoptotic BAX and anti-apoptotic BCL-2 and found decreases in BCL-2 and increases in BAX. Taken together, our findings demonstrate the ability of low concentrations of combinatorial WA and SFN to promote cancer cell death and regulate key epigenetic modifiers in human breast cancer cells.

Epigenetic Regulation of Epidermal Stem Cell Biomarkers and Their Role in Wound Healing.

As an actively renewable tissue, changes in skin architecture are subjected to the regulation of stem cells that maintain the population of cells responsible for the formation of epidermal layers. Stems cells retain their self-renewal property and express biomarkers that are unique to this population. However, differential regulation of the biomarkers can initiate the pathway of terminal cell differentiation. Although, pockets of non-clarity in stem cell maintenance and differentiation in skin still exist, the influence of epigenetics in epidermal stem cell functions and differentiation in skin homeostasis and wound healing is clearly evident. The focus of this review is to discuss the epigenetic regulation of confirmed and probable epidermal stem cell biomarkers in epidermal stratification of normal skin and in diseased states. The role of epigenetics in wound healing, especially in diseased states of diabetes and cancer, will also be conveyed.