Citations

Background: Proper diagnosis in primary care is crucial due to the large number of skin cancer diagnoses each year and its associated growing economic burden. Understanding how primary care providers can be best trained in dermoscopy is instrumental in helping primary care providers differentiate benign and malignant cutaneous lesions so that appropriate action can be taken (eg, biopsy/referral to dermatology or reassurance). Objective: To assess the success of concise dermoscopy training among primary care providers. Design: A cohort study was conducted in primary care at Mayo Clinic, Rochester, including primary care physicians, nurse practitioners, and physician assistants in internal medicine and family medicine. Diagnostic accuracy was measured on standardized testing through image-based recognition and in clinical practice through observation of referral and biopsy patterns both before and after dermoscopy education, focused on the TADA plus method. Results: Forty-three primary care providers completed the image-based recognition tests, with significant improvement in mean score measured after dermoscopy training workshop (20%). Among the thirteen primary care providers who continued to use dermoscopy in clinical practice, a significant improvement (31%) in mean clinical diagnostic accuracy was observed comparing 1 year of practice data before versus after dermoscopy training. Conclusion: Improvement in diagnostic accuracy with utilization of the TADA plus method translates into clinical practice. Therefore, training primary care providers in dermoscopy may improve the dermatologic care patients receive in primary care, especially in rural or medically underserved areas where access to dermatology is limited.

Positive remodeling (PR) is an atherosclerotic plaque feature defined as an increase in arterial caliber at the level of an atheroma, in response to increasing plaque burden. The mechanisms that lead to its formation are incompletely understood, but its role in coronary atherosclerosis has major clinical implications. Indeed, plaques with PR have elevated risk of provoking acute cardiac events. Hence, PR figures among the high-risk plaque features that cardiac imaging studies should report. This review aims to provide an overview of the current literature on coronary PR. It outlines the pathophysiology of PR, the different techniques used to assess its presence, and the imaging findings associated to PR, on both noninvasive and invasive studies. This review also summarizes clinical observations, trials, and studies, focused on the impact of PR on clinical outcome.

PURPOSE This phase II study evaluated the efficacy and tolerability of onvansertib, a polo-like kinase 1 (PLK1) inhibitor, in combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI) + bevacizumab for the second-line treatment of KRAS -mutant metastatic colorectal cancer (mCRC). PATIENTS AND METHODS This multicenter, open-label, single-arm study enrolled patients with KRAS -mutated mCRC previously treated with oxaliplatin and fluorouracil with or without bevacizumab. Patients received onvansertib (15 mg/m 2 once daily on days 1-5 and 15-19 of a 28-day cycle) and FOLFIRI + bevacizumab (days 1 and 15). The primary end point was the objective response rate (ORR), and secondary endpoints included progression-free survival (PFS), duration of response (DOR), and tolerability. Translational and preclinical studies were conducted in KRAS -mutant CRC. RESULTS Among the 53 patients treated, the confirmed ORR was 26.4% (95% CI, 15.3 to 40.3). The median DOR was 11.7 months (95% CI, 9.4 to not reached). Grade 3/4 adverse events were reported in 62% of patients. A post hoc analysis revealed that patients with no prior bevacizumab treatment had a significantly higher ORR and longer PFS compared with patients with prior bevacizumab treatment: ORR of 76.9% versus 10.0% (odds ratio of 30.0, P < .001) and median PFS of 14.9 months versus 6.6 months (hazard ratio of 0.16, P < .001). Our translational findings support that prior bevacizumab exposure contributes to onvansertib resistance. Preclinically, we showed that onvansertib inhibited the hypoxia pathway and exhibited robust antitumor activity in combination with bevacizumab through the inhibition of angiogenesis. CONCLUSION Onvansertib in combination with FOLFIRI + bevacizumab showed significant activity in the second-line treatment of patients with KRAS -mutant mCRC, particularly in patients with no prior bevacizumab treatment. These findings led to the evaluation of the combination in the first-line setting (ClinicalTrails.gov identifier: NCT06106308 ).

Abstract Background Delirium, an acute brain dysfunction, is proposed to be highly prevalent in clinical care and shown to significantly increase the risk of mortality and dementia. Objectives To report on the global prevalence of clinically documented delirium and delirium-related clinical practices in wards caring for paediatric and adult patients in healthcare facilities. Design A prospective, cross-sectional, 39-question survey completed on World Delirium Awareness Day, 15 March 2023. Participants Clinicians or researchers with access to clinical data. Main Outcome and Measure The primary outcome was the prevalence of clinically documented delirium at 8:00 a.m. (4 h) and 8:00 p.m. (±4 h). Secondary outcomes included delirium-related care practices and barriers to use. Descriptive statistics were calculated and multilevel modelling was completed. Results 1664 wards submitted surveys from 44 countries, reporting on delirium assessments at 8:00 a.m. (n = 36 048) and 8:00 p.m. (n = 32 867); 61% reported use of validated delirium assessment tools. At 8:00 a.m., 18% (n = 2788/15 458) and at 8:00 p.m., 17.7% (n = 2454/13 860) were delirium positive. Top prevention measures were pain management (86.7%), mobilisation (81.4%) and adequate fluids (80.4%). Frequently reported pharmacologic interventions were benzodiazepines (52.7%) and haloperidol (46.2%). Top barriers included the shortage of staff (54.3%), lack of time to educate staff (48.6%) and missing knowledge about delirium (38%). Conclusion and Relevance In this study, approximately one out of five patients were reported as delirious. The reported high use of benzodiazepines needs further evaluation as it is not aligned with best-practice recommendations. Findings provide a benchmark for future quality improvement projects and research.

Abstract Protease activated receptor 2 (PAR2) is a G-protein coupled receptor expressed in meningeal neurons, fibroblasts and mast cells that may be targeted to treat migraine. MEDI0618, a fully humanized PAR2 monoclonal antibody, engineered to enhance FcRn-dependent recycling and currently in clinical development, was evaluated in human and rodent in vitro assays, in multiple murine in vivo migraine models and in a model of post-traumatic headache. MEDI0618 bound specifically and with high affinity to cells expressing human PAR2 (hPAR2) and prevented matriptase-induced increase in cytosolic calcium. Similarly, MEDI0618 prevented matriptase-induced calcium in primary fibroblasts and microvascular endothelial cells from human dura mater. MEDI0618 had no effect on hPAR1 receptors. Single-cell calcium imaging of acutely dissociated mouse trigeminal ganglion neurons confirmed expression and functionality of mouse PAR2. Studies in vivo used evoked cutaneous allodynia as a surrogate of headache-like pain and, in some experiments, rearing as a measure of non-evoked headache pain. MEDI0618 was administered subcutaneously to C57BL6/J female mice prior to induction of migraine-like pain with (i) systemic nitroglycerin or compound 48/80 (mast cell degranulator); or (ii) with supradural compound 48/80 or an inflammatory mediator (IM) cocktail. To assess possible efficacy against CGRP receptor (CGRP-R)-independent pain, MEDI0618 was also evaluated in the IM model in animals pretreated with systemic olcegepant (CGRP-R antagonist). Migraine-like pain was also induced by inhalational umbellulone, a TRPA1 agonist, in animals primed with restraint stress in the presence or absence of MEDI0618 as well as in a model of post-traumatic headache pain induced by a mild traumatic brain injury. MEDI0618 prevented cutaneous allodynia elicited by systemic nitroglycerin, compound 48/80 and from supradural compound 48/80 and IM. Systemic olcegepant completely blocked periorbital cutaneous allodynia induced by supradural CGRP but failed to reduce IM-induced cutaneous allodynia. In contrast, MEDI0618 fully prevented IM-induced cutaneous allodynia, regardless of pretreatment with olcegepant. Umbellulone elicited cutaneous allodynia only in restraint stress-primed animals, which was prevented by MEDI0618. MEDI0618 prevented the decrease in rearing behaviour elicited by compound 48/80. However, MEDI0618 did not prevent mild traumatic brain injury-related post-traumatic headache measures. These data indicate that MEDI0618 is a potent and selective inhibitor of PAR2 that is effective in human and rodent in vitro cell systems. Further, blockade of PAR2 with MEDI0618 was effective in all preclinical migraine models studied but not in a model of post-traumatic headache. MEDI0618 may represent a novel therapy for migraine prevention with activity against CGRP-dependent and independent attacks.

BACKGROUND Despite an overall poor prognosis, about 15% of patients with advanced-stage tubo-ovarian high-grade serous carcinoma (HGSC) survive 10 or more years after standard treatment. METHODS We evaluated the tumor microenvironment of this exceptional, understudied group using a large international cohort enriched for long-term survivors (LTS; 10+ years; n = 374) compared with mid-term (MTS; 5–7.99 years; n = 433) and short-term survivors (STS; 2–4.99 years; n = 416). Primary tumor samples were immunostained and scored for intraepithelial and intrastromal densities of 10 immune-cell subsets (including T cells, B cells, plasma cells, myeloid cells, PD-1 + cells, and PD-L1 + cells) and epithelial content. RESULTS Positive associations with LTS compared with STS were seen for 9 of 10 immune-cell subsets. In particular, the combination of intraepithelial CD8 + T cells and intrastromal B cells showed near 5-fold increased odds of LTS compared with STS. All of these associations were stronger in tumors with high epithelial content and/or the C4/Differentiated molecular subtype, despite immune-cell densities generally being higher in tumors with low epithelial content and/or the C2/Immunoreactive molecular subtype. CONCLUSION The tumor microenvironment of HGSC LTS is distinguished by the intersection of T and B cell coinfiltration, high epithelial content, and C4/differentiated molecular subtype, features which may inspire new approaches to immunotherapy. FUNDING Ovarian Cancer Research Program (OCRP) of the Congressionally Directed Medical Research Program (CDMRP), U.S. Department of Defense (DOD); American Cancer Society; BC Cancer Foundation; Canada’s Networks of Centres of Excellence; Canadian Cancer Society; Canadian Institutes of Health Research; Cancer Councils of New South Wales, Victoria, Queensland, South Australia, and Tasmania, Cancer Foundation of Western Australia; Cancer Institute NSW; Cancer Research UK; Deutsche Forschungsgesellschaft; ELAN Funds of the University of Erlangen-Nuremberg; Fred C. and Katherine B. Andersen Foundation; Genome BC; German Cancer Research Center; German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research; Instituto de Salud Carlos III; Mayo Foundation; Minnesota Ovarian Cancer Alliance; Ministerio de Economía y Competitividad; Medical Research Council (MRC); National Center for Advancing Translational Sciences; National Health and Medical Research Council of Australia (NHMRC); Ovarian Cancer Australia; Peter MacCallum Foundation; Sydney West Translational Cancer Research Centre; Terry Fox Research Institute; The Eve Appeal (The Oak Foundation); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; University of Pittsburgh School of Medicine; U.S. National Cancer Institute of the National Institutes of Health; VGH & UBC Hospital Foundation; Victorian Cancer Agency.