Association of Cannabis Use with Complications Among Patients with Gastroesophageal Reflux Disease: Insights from National Inpatient Sample.

Background/Objective: Cannabis, one of the most widely used recreational drug in the United States, has had a significant surge in usage following its legalization in 1996. In recent years, there has been research into the physiological effects of cannabis on the gastrointestinal (GI) system. Our study aims to systematically examine the association between cannabis use and complications of gastroesophageal reflux disease (GERD). Materials and Methods: We queried the 2016-2020 National Inpatient Sample database to identify patient encounters with GERD. Patients with eosinophilic esophagitis or missing demographics were excluded. We compared patient demographics, comorbidities, and complications among cannabis users and nonusers. Multivariate logistic regression analysis was used to investigate the relationship between cannabis use and complications of GERD. Results: A total of 27.2 million patient encounters were included in the analysis, out of which 507,190 were cannabis users. Majority of the cannabis users were aged between 45-64 years (46.6%), males (57.4%), White (63.84%), and belonged to the lowest income quartile (40.6%). Cannabis users demonstrated a higher prevalence of esophagitis compared to nonusers (6.11% vs. 3.23%, p<0.001). However, they exhibited a lower rates of esophageal stricture (0.6% vs. 0.8%, p<0.001) and esophageal cancer (0.2% vs. 0.24%, p<0.001). After adjusting for confounding factors, cannabis users were noted to have higher odds of esophagitis (adjusted odds ratio [aOR]: 1.34, 95% confidence interval [CI]: 1.30-1.39, p<0.001). A lower odds of esophageal stricture (aOR: 0.88, 95% CI: 0.81-0.96, p=0.02) and esophageal cancer (aOR: 0.48,95% CI: 0.42-0.57, p<0.001) were noted. Conclusion: Our cross-sectional study using the nationally available database indicates an association between cannabis use and higher odds of esophagitis, along with lower odds of esophageal stricture and cancer. While these findings suggest a potential relationship between cannabis use and esophageal complications, it is limited in establishing causality. Therefore, further long-term studies are warranted to understand the mechanism behind this association and to determine if cannabis use has an impact on esophagus.

Considering the cellular landscape in marrow stimulation techniques for cartilage repair.

BACKGROUND: Marrow stimulation is a common reparative approach to treat injuries to cartilage and other soft tissues (e.g., rotator cuff). It involves the recruitment of bone marrow elements and mesenchymal stem cells (MSCs) into the defect, theoretically initiating a regenerative process. However, the resulting repair tissue is often weak and susceptible to deterioration with time. The populations of cells at the marrow stimulation site (beyond MSCs), and their contribution to inflammation, vascularity, and fibrosis, may play a role in quality of the repair tissue. SUMMARY: In this review, we accomplish three goals: 1) systematically review clinical trials on the augmentation of marrow stimulation and evaluate their assumptions on the biological elements recruited; 2) detail the cellular populations in bone marrow and their impact on healing; and 3) highlight emerging technologies and approaches that could better guide these specific cell populations towards enhanced cartilage or soft tissue formation. KEY MESSAGES: We found that most clinical trials do not account for cell heterogeneity, nor do they specify the regenerative element recruited, and those that do typically utilize descriptions such as "clots", "elements", and "blood". Furthermore, our review of bone marrow cell populations demonstrates a dramatically heterogenous cell population, including hematopoietic cells, immune cells, fibroblasts, macrophages, and only a small population of MSCs. Finally, the field has developed numerous innovative techniques to enhance the chondrogenic potential (and reduce the anti-regenerative impacts) of these various cell types. We hope this review will guide approaches that account for cellular heterogeneity and improve marrow stimulation techniques to treat chondral defects.

Suprasternal approach for insertion of Impella 5.5 into the proximal right subclavian artery.

The Impella 5.5 (Abiomed) is a percutaneous, temporary left ventricular assist device (LVAD) that serves as an important method of treatment of acute cardiogenic shock refractory to medical management. The Impella 5.5 and 5.0 are commonly inserted through the right axillary artery; however, this may be limited by inadequate vessel diameter to accommodate the Impella and inadequate vessel quality. A central approach to Impella 5.5 incision has been described in the pediatric population, particularly via the innominate artery through a suprasternal and/or neck incision, with success. As an alternative to axillary Impella placement, we propose the usage of a limited suprasternal incision for Impella 5.5 insertion in the adult population, either through the proximal right subclavian artery or the distal innominate artery. This may offer multiple advantages, such as increased vessel diameter and quality of more proximal vessels, avoidance of partial sternotomy, avoidance of a second infraclavicular wound site if the patient progresses to require LVAD or transplant, avoidance of lymphatic and nerve injury through the axillary exposure, ease of manipulation for repositioning, and patient rehabilitation. Potential limitations include difficulty due to body habitus, potential risk of stroke with the innominate approach, and wound complications. A central approach is a reasonable alternative to axillary Impella placement in patients with inadequate axillary artery caliber, defined as less than 6-7 mm diameter, poor artery quality to accommodate anastomosis, and small body habitus, allowing for ease of exposure.

Targeting of lysosomal-bound protein mEAK-7 for cancer therapy.

mEAK-7 (mammalian EAK-7 or MTOR-associated protein, eak-7 homolog), is an evolutionarily conserved lysosomal membrane protein that is highly expressed in several cancer cells. Multiple recent studies have identified mEAK-7 as a positive activator of mTOR (mammalian/mechanistic target of rapamycin) signaling via an alternative mTOR complex, implying that mEAK-7 plays an important role in the promotion of cancer proliferation and migration. In addition, structural analyses investigating interactions between mEAK-7 and V-ATPase, a protein complex responsible for regulating pH homeostasis in cellular compartments, have suggested that mEAK-7 may contribute to V-ATPase-mediated mTORC1 activation. The C-terminal α-helix of mEAK-7 binds to the D and B subunits of the V-ATPase, creating a pincer-like grip around its B subunit. This binding undergoes partial disruption during ATP hydrolysis, potentially enabling other proteins such as mTOR to bind to the α-helix of mEAK-7. mEAK-7 also promotes chemoresistance and radiation resistance by sustaining DNA damage-mediated mTOR signaling through interactions with DNA-PKcs (DNA-dependent protein kinase catalytic subunit). Taken together, these findings indicate that mEAK-7 may be a promising therapeutic target against tumors. However, the precise molecular mechanisms and signal transduction pathways of mEAK-7 in cancer remain largely unknown, motivating the need for further investigation. Here, we summarize the current known roles of mEAK-7 in normal physiology and cancer development by reviewing the latest studies and discuss potential future developments of mEAK-7 in targeted cancer therapy.

The Curious Case of a Painful Leg Ulcer.

Sickle cell disease is a condition that can involve numerous organ systems secondary to vascular occlusion. Herein, we present a case of a 21-year-old male with sickle cell disease requiring long-term hydroxyurea therapy. Upon migrating to the United States from Yemen, the patient developed a rapidly progressive, exquisitely painful ulcer on his right lower extremity. Given his country of origin, a broad differential, including select infectious diseases, was essential. Moreover, establishing the unequivocally correct diagnosis was crucial to determine proper and safe therapy. Ultimately, a lesional biopsy demonstrated numerous sickled red blood cells occluding blood vessels, leading to the diagnosis of sickle cell disease-related leg ulceration.

Impact of aspirin use on rates of metastasis in patients with esophageal cancer: insights from the National Inpatient Sample.

Despite advancing treatment methods, esophageal cancer (EC) maintains a high mortality rate and poor prognosis. Through various mechanisms, aspirin has been suggested to have a chemopreventive effect on EC. However, the long-term impact, particularly regarding the rate of metastasis, needs to be further elucidated. NIS 2016-2020 was used to identify adult patients (age > 18 years) with EC using ICD-10 codes. Patients with missing demographics and mortality were excluded. Patients were stratified into two groups based on aspirin use. Data were collected on patient demographics, Elixhauser Comorbidity Index (ECI), and comorbidities (hypertension, chronic pulmonary disease, coronary artery disease (CAD), chronic kidney disease (CKD), congestive heart failure (CHF), coagulopathy, alcohol use, smoking, and obesity). The outcomes studied were rates of total metastasis, gastrointestinal (GI) metastasis, non-GI metastasis, and lymphoid metastasis. Multivariate logistic regression analysis was performed to evaluate the impact of aspirin use on various metastases after adjusting for patient demographics, comorbidities, and ECI. Out of 190,655 patients, 20,650 (10.8%) patients were aspirin users. Majority of the patients in the aspirin group were aged > 65 years (74.7%), males (82.1%), White race (84%), and had medicare insurance (71%). There was a higher incidence of diabetes, hypertension, chronic pulmonary disease, CAD, CKD, CHF, and smoking in aspirin users than non-aspirin users. Patients with aspirin users had a lower incidence of metastasis (28.9% vs. 38.7%, P < 0.001), GI metastasis (14.2% vs. 20.6%, P < 0.001), non-GI metastasis (15.1% vs. 22%, P < 0.001), and lymphoid metastasis (8.9% vs. 11.3%, P < 0.001) than non-aspirin users. After adjusting for confounding factors, patients with aspirin use had lower odds of having metastasis (aOR-0.73, 95% CI-0.70-0.77, P < 0.001). Our study noted that aspirin use is associated with a reduction in the rate of metastasis in patients with EC. These studies support the use of aspirin in patients with EC and suggest the need for further studies to understand the mechanism by which aspirin use reduces metastasis in patients with EC.

Hydroxyapatite deposition disease, an overlooked differential diagnosis in the emergency department: a case series and review of literature.

Hydroxyapatite crystal deposition disease (HADD) poses diagnostic challenges in the emergency department (ED) as it may clinically present similarly to infection and other musculoskeletal conditions. Misdiagnosis often leads to unnecessary treatments and resource over-utilization. This review article provides an overview of HADD in seven patients who presented to the ED secondary to an acute presentation of this disease process. HADD is a prevalent pathology, which commonly involves the shoulder, followed by the hip, elbow, wrist, and knee. Predisposing risk factors, such as diabetes and certain genetic factors, have also been identified. Clinical history and imaging, particularly radiographs, play a vital role in diagnosing HADD, with characteristic calcification patterns observed in different stages of the disease. Conservative nonsurgical therapy is the mainstay of treatment, providing effective symptom relief in over 90% of cases. By recognizing HADD as a crucial differential diagnosis for patients with acute or chronic pain, healthcare resource utilization can be optimized, leading to improved patient care in the ED.

Kaposi's Sarcoma Cases Manifesting as Non-Specific "Edema".

Kaposi sarcoma can have a myriad cutaneous presentation, but an underrecognized one is an initial manifestation of simply edema. Herein, we highlight a series of cases where edema was the presenting feature of Kaposi Sarcoma and emphasize the importance of recognizing this finding as a possible sign of KS. Keywords: Kaposi Sarcoma, HIV, edema.

Recent technological development of penile prosthesis: a literature review.

Background and Objective: In contemporary Urology, the gold standard for treatment of erectile dysfunction refractory to medical therapy has been implantation with a penile prosthesis. The past 40 years has witnessed evolutions in technology and surgical techniques, which have led to increased patient satisfaction rates and decreased complication and infection rates. This review is an update to a prior review article that evaluates these advancements in the context of patient satisfaction and different rates of complications following surgeries. In addition, the review compares malleable and inflatable prostheses with regard to infection rate, mechanical failure rate, and erosion rate. Methods: A literature search was conducted using Medline and Google Scholar to examine papers from 1973 to the present day. Keywords, such as, "penile prosthesis surgery", "malleable penile prosthesis", "inflatable penile prosthesis", "two-piece Inflatable Penile Prosthesis (IPP)", and "three-piece IPP" were utilized during the search. A total of 76 papers were included, and all were in English. Key Content and Findings: Studies on the latest models of each of the three prostheses (malleable, two-piece IPP, three-piece IPP) revealed patient satisfaction ratings at or above 75%. Both types of IPPs were associated with greater satisfaction and lower erosion rates while malleable prostheses were associated with lower mechanical failure rates. Although no significant differences in infection rates were noted between the prosthesis types, a history of diabetes, obesity, and smoking were predictive of infection events. Conclusions: The three-piece IPP, if indicated for a suitable patient, is generally accepted as the best type of prosthesis given its biological mimicry to an erect human penis.

Single-Cell RNA Sequencing Reveals Dysregulated POSTN+WNT5A+ Fibroblast Subclusters in Prurigo Nodularis.

Prurigo nodularis (PN) is an intensely pruritic, inflammatory skin disease with a poorly understood pathogenesis. We performed single-cell transcriptomic profiling of 28,695 lesional and nonlesional PN cells. Lesional PN has increased dysregulated fibroblasts (FBs) and myofibroblasts. FBs in lesional PN were shifted toward a cancer-associated FB-like phenotype, with POSTN+WNT5A+ cancer-associated FBs increased in PN and similarly so in squamous cell carcinoma. A multicenter cohort study revealed an increased risk of squamous cell carcinoma and cancer-associated FB-associated malignancies (breast and colorectal) in patients with PN. Systemic fibroproliferative diseases (renal sclerosis and idiopathic pulmonary fibrosis) were upregulated in patients with PN. Ligand-receptor analyses demonstrated an FB neuronal axis with FB-derived WNT5A and periostin interactions with neuronal receptors melanoma cell adhesion molecule and ITGAV. These findings identify a pathogenic and targetable POSTN+WNT5A+ FB subpopulation that may predispose cancer-associated FB-associated malignancies in patients with PN.

Expert-centered Evaluation of Deep Learning Algorithms for Brain Tumor Segmentation.

Purpose To present results from a literature survey on practices in deep learning segmentation algorithm evaluation and perform a study on expert quality perception of brain tumor segmentation. Materials and Methods A total of 180 articles reporting on brain tumor segmentation algorithms were surveyed for the reported quality evaluation. Additionally, ratings of segmentation quality on a four-point scale were collected from medical professionals for 60 brain tumor segmentation cases. Results Of the surveyed articles, Dice score, sensitivity, and Hausdorff distance were the most popular metrics to report segmentation performance. Notably, only 2.8% of the articles included clinical experts' evaluation of segmentation quality. The experimental results revealed a low interrater agreement (Krippendorff α, 0.34) in experts' segmentation quality perception. Furthermore, the correlations between the ratings and commonly used quantitative quality metrics were low (Kendall tau between Dice score and mean rating, 0.23; Kendall tau between Hausdorff distance and mean rating, 0.51), with large variability among the experts. Conclusion The results demonstrate that quality ratings are prone to variability due to the ambiguity of tumor boundaries and individual perceptual differences, and existing metrics do not capture the clinical perception of segmentation quality. Keywords: Brain Tumor Segmentation, Deep Learning Algorithms, Glioblastoma, Cancer, Machine Learning Clinical trial registration nos. NCT00756106 and NCT00662506 Supplemental material is available for this article. © RSNA, 2023.

Predictors and impact of aspiration pneumonia in patients undergoing esophagogastroduodenoscopy: national inpatient sample 2016-2020.

OBJECTIVES: Aspiration pneumonia is a rare but feared complication among patients undergoing esophagogastroduodenoscopy (EGD). Our study aims to assess the incidence as well as risk factors for aspiration pneumonia in patients undergoing EGD. METHODS: National Inpatient Sample 2016-2020 was used to identify adult patients undergoing EGD. Patients were stratified into two groups based on the presence of aspiration pneumonia. Multivariate logistic regression analysis was performed to identify the risk factors associated with aspiration pneumonia. We adjusted for patient demographics, Elixhauser comorbidities and hospital characteristics. RESULTS: Of the 1.8 million patients undergoing EGD, 1.9% of the patients developed aspiration pneumonia. Patients with aspiration pneumonia were mostly males (59.54%), aged >65 years old (66.19%), White (72.2%), had Medicare insurance (70.5%) and were in the lowest income quartile (28.7%). On multivariate analysis, the age >65 group, White race, congestive heart failure (CHF), neurological disorders and chronic obstructive pulmonary disease were associated with higher odds of aspiration pneumonia. This complication was associated with higher in-hospital mortality (9% vs. 0.8%; P  < 0.001) and longer length of stay (10.54 days vs. 4.85 days; P  < 0.001). CONCLUSION: Our study found that rates of post-EGD aspiration pneumonia are increasing. We found a significant association between various comorbidities and aspiration pneumonia. Our data suggests that we need to optimize these patients before EGD, as the development of aspiration is associated with worsened outcomes. Further prospective studies are needed to clarify these associations.

Clinical and Genomic Predictors of Adverse Events in Newly Diagnosed Glioblastoma.

PURPOSE: Adverse clinical events cause significant morbidity in patients with GBM (GBM). We examined whether genomic alterations were associated with AE (AE) in patients with GBM. EXPERIMENTAL DESIGN: We identified adults with histologically confirmed IDH-wild-type GBM with targeted next-generation sequencing (OncoPanel) at Dana Farber Cancer Institute from 2013 to 2019. Seizure at presentation, lymphopenia, thromboembolic events, pseudoprogression, and early progression (within 6 months of diagnosis) were identified as AE. The biologic function of genetic variants was categorized as loss-of-function (LoF), no change in function, or gain-of-function (GoF) using a somatic tumor mutation knowledge base (OncoKB) and consensus protein function predictions. Associations between functional genomic alterations and AE were examined using univariate logistic regressions and multivariable regressions adjusted for additional clinical predictors. RESULTS: Our study included 470 patients diagnosed with GBM who met the study criteria. We focused on 105 genes that had sequencing data available for ≥ 90% of the patients and were altered in ≥10% of the cohort. Following false-discovery rate (FDR) correction and multivariable adjustment, the TP53, RB1, IGF1R, and DIS3 LoF alterations were associated with lower odds of seizures, while EGFR, SMARCA4, GNA11, BRD4, and TCF3 GoF and SETD2 LoF alterations were associated with higher odds of seizures. For all other AE of interest, no significant associations were found with genomic alterations following FDR correction. CONCLUSIONS: Genomic biomarkers based on functional variant analysis of a routine clinical panel may help identify AE in GBM, particularly seizures. Identifying these risk factors could improve the management of patients through better supportive care and consideration of prophylactic therapies.

Interference Screw versus Cement Fixation in Anterior Cruciate Ligament Soft Tissue Grafts: A Biomechanical Study.

Shortcomings of fixation have been reported as a source of graft failure in anterior cruciate ligament (ACL) reconstruction. While interference screws have long been used as fixation devices for ACL reconstruction, they are not without complications. Previous studies have highlighted the use of bone void filler as a fixation method; however, no biomechanical comparisons using soft tissue grafts with interference screws exist to our knowledge. The purpose of this study is to evaluate the fixation strength of a calcium phosphate cement bone void filler compared with screw fixation in an ACL reconstruction bone replica model with human soft tissue grafts. In total, 10 ACL grafts were constructed using semitendinosus and gracilis tendons harvested from 10 donors. Grafts were affixed with either an 8-10 mm × 23 mm polyether ether ketone interference screw (n = 5) or with approximately 8 mL of calcium phosphate cement (n = 5) into open cell polyurethane blocks. Graft constructs were tested to failure in cyclic loading under displacement control at a rate of 1 mm per second. When compared with screw construct, the cement construct showed a 978% higher load at yield, 228% higher load at failure, 181% higher displacement at yield, 233% higher work at failure, and a 545% higher stiffness. Normalized data for the screw constructs relative to the cement constructs from the same donor showed 14 ± 11% load at yield, 54 ± 38% load at failure, and 172 ± 14% graft elongation. The results of this study indicate that cement fixation of ACL grafts may result in a stronger construct compared with the current standard of fixation with interference screws. This method could potentially reduce the incidence of complications associated with interface screw placement such as bone tunnel widening, screw migration, and screw breakage.

Oral and oropharyngeal cancer screening and tobacco cessation discussions, NHANES 2011-2018.

OBJECTIVE: Oral cavity and oropharyngeal cancer (OOPC) is a devastating disease often caught in late stages. People who use tobacco are at higher risk of OOPC. Tobacco cessation discussions and OOPC screenings are important factors in decreasing the risk of OOPC or its late stage diagnosis. As research on sex differences has been increasing-from research on biomedical to psychological and sociological determinants-there is a potential difference, by sex, as to whom is more likely to have a tobacco cessation discussion and OOPC screening. The objective of this study is to determine if there is an association of sex with tobacco cessation discussions and OOPC screenings conducted by dental healthcare professionals among participants who currently use tobacco. METHOD: Data from 8 years of the National Health and Nutrition Examination Survey (2011-2018) were merged. Data from participants, ages 30 years and above, who self-reported current use of tobacco, a dental visit within the previous year and responsed to questions about oral cancer screening were analysed for frequency determination and logistic regression analysis. Having the combination of neither OOPC screening nor discussion about the benefits of not using tobacco was the outcome in the analysis. RESULTS: There were 22.1% who had an OOPC screening by a dental professional within the previous year. Of the 41% who reported having had a conversation with a dental professional within the previous year about the benefits of tobacco cessation, 9.8% reported having both the conversation and OOPC screening. Males were less likely than females to have the combination of neither OOPC screening nor advice about tobacco cessation than females (adjusted odds ratio: 0.74; 95%CI: 0.57, 0.96). CONCLUSION: There is an increased need for OOPC screening and the discussion of tobacco use by dental professionals among their patients who use tobacco, particularly for female patients.

A semi-automatic segmentation method for meningioma developed using a variational approach model.

BACKGROUND: Meningioma is the commonest primary brain tumour. Volumetric post-contrast magnetic resonance imaging (MRI) is recognised as gold standard for delineation of meningioma volume but is hindered by manual processing times. We aimed to investigate the utility of a model-based variational approach in segmenting meningioma. METHODS: A database of patients with a meningioma (2007-2015) was queried for patients with a contrast-enhanced volumetric MRI, who had consented to a research tissue biobank. Manual segmentation by a neuroradiologist was performed and results were compared to the mathematical model, using a battery of tests including the Sørensen-Dice coefficient (DICE) and JACCARD index. A publicly available meningioma dataset (708 segmented T1 contrast-enhanced slices) was also used to test the reliability of the model. RESULTS: 49 meningioma cases were included. The most common meningioma location was convexity (n = 15, 30.6%). The mathematical model segmented all but one incidental meningioma, which failed due to the lack of contrast uptake. The median meningioma volume by manual segmentation was 19.0 cm3 (IQR 4.9-31.2). The median meningioma volume using the mathematical model was 16.9 cm3 (IQR 4.6-28.34). The mean DICE score was 0.90 (SD = 0.04). The mean JACCARD index was 0.82 (SD = 0.07). For the publicly available dataset, the mean DICE and JACCARD scores were 0.90 (SD = 0.06) and 0.82 (SD = 0.10), respectively. CONCLUSIONS: Segmentation of meningioma volume using the proposed mathematical model was possible with accurate results. Application of this model on contrast-enhanced volumetric imaging may help reduce work burden on neuroradiologists with the increasing number in meningioma diagnoses.

Multiple embryo manipulations in PGT-A cycles may result in inferior clinical outcomes.

RESEARCH QUESTION: Do embryos that undergo a thaw, biopsy and re-vitrification (TBR) for pre-implantation genetic testing for aneuploidy (PGT-A) have different ploidy and transfer outcomes compared with fresh biopsied embryos? DESIGN: Retrospective cohort study of all embryos that underwent the following procedures: fresh biopsy for PGT-A (fresh biopsy); embryos that were warmed, biopsied for PGT-A and re-vitrified (single biopsy TBR); embryos with a no signal result after initial biopsy that were subsequently warmed, biopsied and re-vitrified (double biopsy TBR). The patients who underwent transfers of those embryos at a single academic institution between March 2013 and December 2021 were also studied. RESULTS: About 30% of embryos planned for TBR underwent attrition. Euploidy rates were similar after biopsy: fresh biopsy (42.7%); single biopsy TBR (47.5%) (adjusted RR: 0.99, 0.88 to 1.12); and double biopsy TBR 50.3% (adjusted RR: 0.99, 0.80 to 1.21). Ongoing pregnancy over 8 weeks was not statistically significant (double biopsy TBR: 6/19 [31.6%] versus fresh biopsy: 650/1062 [61.2%]) (adjusted RR 0.52, 95% CI 0.26 to 1.03). The miscarriage rate increased (double biopsy TBR: 4/19 [21.1%] versus fresh biopsy: 66/1062 [6.2%])(RR 3.39, 95% CI 1.38 to 8.31). Live birth rate was also lower per transfer for the double biopsy TBR group (double biopsy TBR [18.75%] versus fresh biopsy [53.75%]) (RR 0.35, 95% CI 0.12 to 0.98), though not after adjustment (adjusted RR 0.37, 95% CI 0.13 to 1.09). These differences were not seen when single biopsy TBR embryos were transferred. CONCLUSIONS: Embryos that undergo TBR have an equivalent euploidy rate to fresh biopsied embryos. Despite that, double biopsy TBR embryos may have impaired transfer outcomes.

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.

Plasmacytoid Dendritic Cells Are Not Major Producers of Type 1 IFN in Cutaneous Lupus: An In-Depth Immunoprofile of Subacute and Discoid Lupus.

The immunologic drivers of cutaneous lupus erythematosus (CLE) and its clinical subtypes remain poorly understood. We sought to characterize the immune landscape of discoid lupus erythematosus and subacute CLE using multiplexed immunophenotyping. We found no significant differences in immune cell percentages between discoid lupus erythematosus and subacute CLE (P > .05) with the exception of an increase in TBK1 in discoid lupus erythematosus (P < .05). Unbiased clustering grouped subjects into 2 major clusters without respect to clinical subtype. Subjects with a history of smoking had increased percentages of neutrophils, disease activity, and endothelial granzyme B compared with nonsmokers. Despite previous assumptions, plasmacytoid dendritic cells (pDCs) did not stain for IFN-1. Skin-eluted and circulating pDCs from subjects with CLE expressed significantly less IFNα than healthy control pDCs upon toll-like receptor 7 stimulation ex vivo (P < .0001). These data suggest that discoid lupus erythematosus and subacute CLE have similar immune microenvironments in a multiplexed investigation. Our aggregated analysis of CLE revealed that smoking may modulate disease activity in CLE through neutrophils and endothelial granzyme B. Notably, our data suggest that pDCs are not the major producers of IFN-1 in CLE. Future in vitro studies to investigate the role of pDCs in CLE are needed.