CT Surveillance for Local Recurrence After Pancreatic Cancer Resection: Evaluation of Imaging Findings From the SAR Disease-Focused Panel Consensus Statement.

Background: A Society of Abdominal Radiology (SAR) Pancreatic Ductal Adenocarcinoma (PDAC) Disease-Focused Panel (DFP) consensus statement described findings suspicious for local recurrence (LR) on surveillance imaging after PDAC resection. Objective: To evaluate the interreader agreement and predictive utility of potential imaging findings of LR on serial surveillance CT examinations after Whipple procedure for PDAC, using the SAR PDAC DFP consensus statement. Methods: This retrospective study included 126 patients (mean age, 68.5±10.3 years; 72 men, 54 women) who underwent Whipple surgery for PDAC between January 2009 and December 2014. Three radiologists independently reviewed baseline and subsequent postoperative contrast-enhanced abdominopelvic CT examinations performed within 2 years postoperatively, evaluating features in the SAR PDAC DFP consensus statement relating to surgical bed stranding, surgical bed soft tissue, vessel encasement, main pancreatic duct dilatation, and ascites. Interreader agreement was calculated. The reference standard for LR development within 2 years postoperatively incorporated all available information. Imaging features' frequencies were calculated for recurrence examinations (i.e., first surveillance examinations indicating LR). For baseline postoperative examinations, features associations' with eventual LR development were assessed by multivariable logistic regression analysis. Results: LR developed within 2 years postoperatively in 81/126 patients. For both baseline and subsequent examinations, agreement for stranding and soft tissue morphology were poor, for vessel encasement was fair, for soft tissue and ascites were moderate, and for main pancreatic duct dilatation was substantial. On recurrence examinations, across readers, new or increased stranding was present in 27-77%; new or increased soft tissue, 80-86%; soft tissue with vessel encasement and luminal narrowing, 36-59%; new or increased main pancreatic duct dilatation, 25-26%; and new or increased ascites, 20-23%. On baseline postoperative examinations, independent predictors of eventual LR were soft tissue for all three readers (OR=2.78-6.85) and stranding for reader 1 (OR=3.59); main pancreatic duct dilatation and ascites were not independent predictors of LR for any reader. Conclusion: This study highlights the role of soft tissue, particularly when associated with vessel encasement and luminal narrowing, in raising suspicion for LR after PDAC resection. Clinical Impact: This study supports the SAR PDAC DFP consensus statement, while highlighting opportunities for continued optimization.

A preoperative nomogram incorporating CT to predict the probability of ovarian clear cell carcinoma.

OBJECTIVES: To evaluate clinical, laboratory, and radiological variables from preoperative contrast-enhanced computed tomography (CECT) for their ability to distinguish ovarian clear cell carcinoma (OCCC) from non-OCCC and to develop a nomogram to preoperatively predict the probability of OCCC. METHODS: This IRB-approved, retrospective study included consecutive patients who underwent surgery for an ovarian tumor from 1/1/2000 to 12/31/2016 and CECT of the abdomen and pelvis ≤90 days before primary debulking surgery. Using a standardized form, two experienced oncologic radiologists independently analyzed imaging features and provided a subjective 5-point impression of the probability of the histological diagnosis. Nomogram models incorporating clinical, laboratory, and radiological features were created to predict histological diagnosis of OCCC over non-OCCC. RESULTS: The final analysis included 533 patients with surgically confirmed OCCC (n = 61) and non-OCCC (n = 472); history of endometriosis was more often found in patients with OCCC (20% versus 3.6%; p < 0.001), while CA-125 was significantly higher in patients with non-OCCC (351 ng/mL versus 70 ng/mL; p < 0.001). A nomogram model incorporating clinical (age, history of endometriosis and adenomyosis), laboratory (CA-125) and imaging findings (peritoneal implant distribution, morphology, laterality, and diameter of ovarian lesion and of the largest solid component) had an AUC of 0.9 (95% CI: 0.847, 0.949), which was comparable to the AUCs of the experienced radiologists' subjective impressions [0.8 (95% CI: 0.822, 0.891) and 0.9 (95% CI: 0.865, 0.936)]. CONCLUSIONS: A presurgical nomogram model incorporating readily accessible clinical, laboratory, and CECT variables was a powerful predictor of OCCC, a subtype often requiring a distinctive treatment approach.

Phase Ib Study of Enzalutamide with or Without Sorafenib in Patients with Advanced Hepatocellular Carcinoma.

LESSONS LEARNED: Androgen receptor as assessed by immunohistochemistry is expressed in a high proportion of patients with hepatocellular carcinoma (HCC). Enzalutamide at 160 mg orally daily is safe and tolerable in patients with advanced HCC but has no single-agent antitumor activity. Enzalutamide, a CYP3A4 inducer, at a standard dose of 160 mg reduces the exposure of sorafenib, a CYP3A4 substrate. Enzalutamide and sorafenib is safe and tolerable in patients with advanced HCC, but the addition of enzalutamide to sorafenib did not enhance the antitumor activity of sorafenib. BACKGROUND: Androgen receptor (AR) interference is deleterious to hepatocellular carcinoma (HCC) in preclinical models. METHODS: This is a multicenter, phase Ib study of enzalutamide ± sorafenib in patients with advanced HCC. In part 1, a 3 + 3 dose de-escalation design with expansion established the recommended phase II dose (RP2D) of enzalutamide in patients in whom sorafenib treatment had failed. In part 2, a 3 + 3 dose escalation with expansion established the safety of enzalutamide with sorafenib in treatment-naive patients with HCC. Secondary objectives included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), pharmacokinetics (PK), and determination of AR expression by immunohistochemistry. A 7-day run-in with sorafenib alone in part 2 allowed assessment of the impact of enzalutamide on sorafenib pharmacokinetics. RESULTS: In part 1, 16 patients received enzalutamide 160 mg daily. No dose-limiting toxicity (DLT) occurred; 1 patient required dose reduction. Responses were not observed; median PFS and OS were 1.8 (95% confidence interval [CI]: 1.6-3.6) and 7 (95% CI: 3.6 to not reached [NR]) months, respectively. In part 2, patients received sorafenib 400 mg daily (4) or twice a day (8) both with enzalutamide at the recommended phase II dose-no DLTs were observed. ORR was 10% (95% CI: 0.3-44.5), and median PFS and OS were 2.9 (95% CI: 1.6 to NR) and 6.7 (95% CI: 4.6 to NR) months, respectively. Enzalutamide reduced sorafenib exposure by 60%. Tumor AR expression did not associate with outcome. CONCLUSION: Enzalutamide is ineffective in HCC; further development is not supported by this study.

Advancing cancer patient care by integrating circulating tumor cell technology to understand the spatial and temporal dynamics of cancer.

Spatial and temporal dynamics of cancer, studied with physical science approaches at critical transition points of the disease can provide insight into the biology of cancer and the evolutionary changes that occur both naturally and in response to therapy. A very promising development in translational cancer medicine has been the emergence of circulating tumor cells (CTC) as minimally invasive "liquid biopsies." We envision that the future utility of CTC will not simply be confined to enumeration, but also include their routine characterization using a high-content approach that investigates morphometrics, protein expression and genomic profiling. This novel approach guided by mathematical models to predict the spread of disease from the primary site to secondary site can bring the bench to the bedside for cancer patients. It is agnostic with reference to drug choice and treatment regimen, which also means that each patient is unique. The approach is Bayesian from a data collection perspective and is patient-centric rather than drug or new chemical entity-centric. The analysis of data comes from an understanding of commonalities and differences that are detected among patients with a given cancer type. Thus, patients are treated over the course of their disease with various drug regimens that reflects our real-time understanding of their evolving tumor genomics and response to treatment. This likely means that smaller cohorts of patients receive any given regimen but we hypothesize that it would lead to better patient outcomes than with the current classic approach to drug testing and development.

Convolutional network denoising for acceleration of multi-shot diffusion MRI.

Multi-shot echo planar imaging is a promising technique to reduce geometric distortions and increase spatial resolution in diffusion-weighted MRI (DWI), at the expense of increased scan time. Moreover, performing DWI in the body requires multiple repetitions to obtain sufficient signal-to-noise ratio, which further increases the scan time. This work proposes to reduce the number of repetitions and perform denoising of high b-value images using a convolutional network denoising trained on single-shot DWI to accelerate the acquisition of multi-shot DWI. Convolutional network denoising is demonstrated to accelerate the acquisition of 2-shot DWI by a factor of 4 compared to the clinical standard on patients with rectal cancer. Image quality was evaluated using qualitative scores from expert body radiologists between accelerated and non-accelerated acquisition. Additionally, the effect of convolutional network denoising on each image quality score was analyzed using a Wilcoxon signed-rank test. Convolutional network denoising would enable to increase the number of shots without increasing scan time for significant geometric artifact reduction and spatial resolution increase.

Non-emergent hemoptysis in patients with primary or metastatic lung tumors: The role of transarterial embolization.

PURPOSE: To evaluate the role of systemic arterial embolization for the management of non-emergent hemoptysis in patients with primary or metastatic lung tumors. MATERIALS AND METHODS: This is a retrospective single center study of consecutive patients who underwent systemic arterial embolization for non-emergent hemoptysis between 2011 and 2023. Study endpoints included technical success, clinical success (partial or complete resolution of hemoptysis) and overall survival. Hemoptysis-free and overall survival were estimated using the Kaplan-Meier method. Predictive factors for hemoptysis-free survival and overall survival were evaluated using univariate analysis (Cox regression). Post-procedural 30-day adverse events were recorded in line with Common Terminology Criteria for Adverse Events (CTCAE) v5.0. RESULTS: A total of 30 patients were identified. Technical success was achieved in 24/30 (80 %) patients. Clinical success following embolization was achieved in 23/30 (76.7 %) patients. Median length of hospitalization was 5 days (Range: 1 to 16 days). Median overall survival was 194 days (95 % CI: 89 to 258). Median hemoptysis-free survival was 286 days (95 % CI: 42 to not reached). No significant clinical or procedural predictors of hemoptysis-free survival or overall survival were identified. Serious adverse events (CTCAE Grade > 3) occurred in 1 patient (3.4 % - fatal respiratory failure). CONCLUSION: Embolization of non-emergent hemoptysis in patients with lung malignancies is safe and effective. Recurrence is however high in this patient population, likely due to the nature of the underlying disease.

Deformable Mapping of Rectal Cancer Whole-Mount Histology with Restaging MRI at Voxel Scale: A Feasibility Study.

Purpose To develop a radiology-pathology coregistration method for 1:1 automated spatial mapping between preoperative rectal MRI and ex vivo rectal whole-mount histology (WMH). Materials and Methods This retrospective study included consecutive patients with rectal adenocarcinoma who underwent total neoadjuvant therapy followed by total mesorectal excision with preoperative rectal MRI and WMH from January 2019 to January 2022. A gastrointestinal pathologist and a radiologist established three corresponding levels for each patient at rectal MRI and WMH, subsequently delineating external and internal rectal wall contours and the tumor bed at each level and defining eight point-based landmarks. An advanced deformable image coregistration model based on the linearized iterative boundary reconstruction (LIBR) approach was compared with rigid point-based registration (PBR) and state-of-the-art deformable intensity-based multiscale spectral embedding registration (MSERg). Dice similarity coefficient (DSC), modified Hausdorff distance (MHD), and target registration error (TRE) across patients were calculated to assess the coregistration accuracy of each method. Results Eighteen patients (mean age, 54 years ± 13 [SD]; nine female) were included. LIBR demonstrated higher DSC versus PBR for external and internal rectal wall contours and tumor bed (external: 0.95 ± 0.03 vs 0.86 ± 0.04, respectively, P < .001; internal: 0.71 ± 0.21 vs 0.61 ± 0.21, P < .001; tumor bed: 0.61 ± 0.17 vs 0.52 ± 0.17, P = .001) and versus MSERg for internal rectal wall contours (0.71 ± 0.21 vs 0.63 ± 0.18, respectively; P < .001). LIBR demonstrated lower MHD versus PBR for external and internal rectal wall contours and tumor bed (external: 0.56 ± 0.25 vs 1.68 ± 0.56, respectively, P < .001; internal: 1.00 ± 0.35 vs 1.62 ± 0.59, P < .001; tumor bed: 2.45 ± 0.99 vs 2.69 ± 1.05, P = .03) and versus MSERg for internal rectal wall contours (1.00 ± 0.35 vs 1.62 ± 0.59, respectively; P < .001). LIBR demonstrated lower TRE (1.54 ± 0.39) versus PBR (2.35 ± 1.19, P = .003) and MSERg (2.36 ± 1.43, P = .03). Computation time per WMH slice for LIBR was 35.1 seconds ± 12.1. Conclusion This study demonstrates feasibility of accurate MRI-WMH coregistration using the advanced LIBR method. Keywords: MR Imaging, Abdomen/GI, Rectum, Oncology Supplemental material is available for this article. © RSNA, 2024.

Accuracy and Clinical Impact of Persistent Disease Diagnosed on Diffusion-Weighted Imaging and Accuracy of Pelvic Nodal Assessment on Magnetic Resonance Imaging for Squamous Cell Carcinoma of the Anus in the 6-Month Interval Post Chemoradiotherapy.

PURPOSE: To evaluate the diagnostic performance of diffusion-weighted imaging (DWI) in the 6-month interval post chemoradiation therapy (CRT) in determining persistent disease and whether persistent diffusion restriction on DWI at 6 months is associated with overall survival; and secondarily, to investigate the accuracy of pelvic lymph node assessment on T2-weighted imaging and DWI in the 6-month interval post CRT, in patients with squamous cell carcinoma of the anus. METHODS AND MATERIALS: This retrospective study included patients with squamous cell carcinoma of the anus who underwent CRT followed by restaging rectal MRI from January 2010 to April 2020, with ≥1 year of follow-up after CRT. DW images were qualitatively evaluated by 2 junior and 2 senior abdominal radiologists to determine anal persistent disease. The reference standard for anal persistent disease was digital rectal examination/endoscopy and histopathology. Diagnostic performance was estimated using sensitivity, specificity, negative predictive value, and positive predictive value. Survival outcomes were evaluated via Kaplan-Meier analysis, and associations between survival outcomes and DWI status were tested for significance using the log-rank test. Additionally, DW and T2-weighted images were evaluated to determine lymph node status. RESULTS: Among 84 patients (mean age, 63 ± 10.2 years; 64/84 [76%] female), 14 of 84 (17%) had confirmed persistent disease. Interreader agreement on DWI between all 4 radiologists was moderate (Light's κ = 0.553). Overall, DWI had a sensitivity of 71.4%, specificity of 72.1%, positive predictive value of 34.5%, and negative predictive value of 92.5%. Patients with a negative DWI showed better survival than patients with a positive DWI (3-year overall survival of 92% vs 79% and 5-year overall survival of 87% vs 74%), although the difference did not reach statistical significance (P = .063). All patients with suspicious lymph nodes (14/14, 100%) showed negative pathology or decreased size during follow-up. CONCLUSIONS: At 6 months post CRT, DWI showed value in excluding anal persistent disease. Persistent diffusion restriction on DWI was not significantly associated with overall survival. Pelvic nodal assessment on DWI and T2-weighted imaging was limited in predicting persistent nodal metastases.

Hepatic Hilar Block as an Adjunct to Transarterial Embolization of Neuroendocrine Tumors: A Retrospective Review of Safety and Efficacy.

PURPOSE: This study investigates whether hepatic hilar nerve blocks (HHNB) provide safe, effective analgesia in patients with neuroendocrine tumors (NET) treated with transarterial embolization (TAE). METHODS: The retrospective study included all NETs treated with TAE or TAE + HHNB from 1/2020 to 8/2022. Eighty-five patients (45 men), mean age 62 years, were treated in 165 sessions (TAE, n = 153; TAE + HHNB, n = 12). For HHNBs, ≤10 mL bupivacaine HCl 0.25% ± 2 mg methylprednisolone were injected under ultrasound guidance. The aims were to assess safety of HHNB and reduction in pain. Groups were compared with Pearson's chi-squared and Wilcoxon rank sum tests. Logistic regression assessed independent risk factors for pain. RESULTS: No immediate complications from HHNBs were reported. No difference in incidence of major complications between TAE and TAE + HHNB one month post-embolization was observed (7.19% vs. 8.33%, p = 0.895). No differences in mean length of hospital stay after treatment were observed (TAE 2.2 days [95%CI: 1.74-2.56] vs. TAE + HHNB 2.8 days [95%CI: 1.43-4.26]; p = 0.174). Post-procedure pain was reported in 88.2% of TAE and 75.0% of TAE + HHNB patients (p = 0.185). HHNB recipients were more likely to use analgesic patches (25.0% vs. 5.88%; p = 0.014). No other differences in analgesic use were observed. CONCLUSIONS: HHNBs can safely be performed in patients with NETs. No difference in hospital stays or analgesic drug use was observed. Managing pain after TAE is an important goal; further study is warranted.

Treatment response and tumor evolution: lessons from an extended series of multianalyte liquid biopsies in a metastatic breast cancer patient.

Currently, clinical characterization of metastatic breast cancer is based on tissue samples taken at time of diagnosis. However, tissue biopsies are invasive and tumors are continuously evolving, which indicates the need for minimally invasive longitudinal assessment of the tumor. Blood-based liquid biopsies provide minimal invasive means for serial sampling over the course of treatment and the opportunity to adjust therapies based on molecular markers. Here, we aim to identify cellular changes that occur in breast cancer over the lifespan of an affected patient through single-cell proteomic and genomic analysis of longitudinally sampled solid and liquid biopsies. Three solid and 17 liquid biopsies from peripheral blood of an ER+/HER2- metastatic breast cancer patient collected over 4 years and eight treatment regimens were analyzed for morphology, protein expression, copy-number alterations, and single-nucleotide variations. Analysis of 563 single morphometrically similar circulating tumor cells (CTCs) and 13 cell-free DNA (cfDNA) samples along with biopsies of the primary and metastatic tumor revealed progressive genomic evolution away from the primary tumor profiles, along with changes in ER expression and the appearance of resistance mutations. Both the abundance and the genomic alterations of CTCs and cfDNA were highly correlated and consistent with genomic alterations in the tissue samples. We demonstrate that genomic evolution and acquisition of drug resistance can be detected in real time and at single-cell resolution through liquid biopsy analytes and highlight the utility of liquid biopsies to guide treatment decisions.

Preanalytical Variables for the Genomic Assessment of the Cellular and Acellular Fractions of the Liquid Biopsy in a Cohort of Breast Cancer Patients.

Liquid biopsy allows assessment of multiple analytes, providing temporal information with potential for improving understanding of cancer evolution and clinical management of patients. Although liquid biopsies are intensely investigated for prediction and response monitoring, preanalytic variables are of primary concern for clinical implementation, including categories of collection method and sample storage. Herein, an integrated high-density single-cell assay workflow for morphometric and genomic analysis of the liquid biopsy is used to characterize the effects of preanalytical variation and reproducibility of data from a breast cancer cohort. Following prior work quantifying performance of commonly used blood collection tubes, this study completes the analysis of four time points to assay (24, 48, 72, and 96 hours), demonstrating precision up to 48 hours after collection for assay sensitivity, highly reproducible rare cell enumeration, morphometric characterization, and high efficiency and capacity for single-cell genomic analysis. For the cell-free analysis, both freezing and use of fresh plasma produced similar quality and quantity of cell-free DNA for sequencing. The genomic analysis (copy number variation and single-nucleotide variation) described herein is broadly applicable to liquid biopsy platforms capable of isolating cell-free and cell-based DNA. Morphometric parameters and genomic signatures of individual circulating tumor cells were evaluated in relation to patient clinical response, providing preliminary evidence of clinical validity as a potential biomarker aiding clinical diagnostics or monitoring progression.

Single cell correlation analysis of liquid and solid biopsies in metastatic colorectal cancer.

As cancer care is transitioning to personalized therapies with necessary complementary or companion biomarkers there is significant interest in determining to what extent non-invasive liquid biopsies reflect the gold standard solid biopsy. We have established an approach for measuring patient-specific circulating and solid cell concordance by introducing tumor touch preparations to the High-Definition Single Cell Analysis workflow for high-resolution cytomorphometric characterization of metastatic colorectal cancer (mCRC). Subgroups of cells based on size, shape and protein expression were identified in both liquid and solid biopsies, which overall displayed high inter- and intra- patient pleomorphism at the single-cell level of analysis. Concordance of liquid and solid biopsies was patient-dependent and between 0.1-0.9. Morphometric variables displayed particularly high correlation, suggesting that circulating cells do not represent distinct subpopulations from the solid tumor. This was further substantiated by significant decrease in concentration of circulating cells after mCRC resection. Combined with the association of circulating cells with tumor burden and necrosis of hepatic lesions, our overall findings demonstrate that liquid biopsy cells can be informative biomarkers in the mCRC setting. Patient-specific level of concordance can readily be measured to establish the utility of circulating cells as biomarkers and define biosignatures for liquid biopsy assays.

Clonal diversity revealed by morphoproteomic and copy number profiles of single prostate cancer cells at diagnosis.

Tumor heterogeneity is prevalent in both treatment-naïve and end-stage metastatic castration-resistant prostate cancer (PCa), and may contribute to the broad range of clinical presentation, treatment response, and disease progression. To characterize molecular heterogeneity associated with de novo metastatic PCa, multiplatform single cell profiling was performed using high definition single cell analysis (HD-SCA). HD-SCA enabled morphoproteomic and morphogenomic profiling of single cells from touch preparations of tissue cores (prostate and bone marrow biopsies) as well as liquid samples (peripheral blood and bone marrow aspirate). Morphology, nuclear features, copy number alterations, and protein expression were analyzed. Tumor cells isolated from prostate tissue touch preparation (PTTP) and bone marrow touch preparation (BMTP) as well as metastatic tumor cells (MTCs) isolated from bone marrow aspirate were characterized by morphology and cytokeratin expression. Although peripheral blood was examined, circulating tumor cells were not definitively observed. Targeted proteomics of PTTP, BMTP, and MTCs revealed cell lineage and luminal prostate epithelial differentiation associated with PCa, including co-expression of EpCAM, PSA, and PSMA. Androgen receptor expression was highest in MTCs. Hallmark PCa copy number alterations, including PTEN and ETV6 deletions and NCOA2 amplification, were observed in cells within the primary tumor and bone marrow biopsy samples. Genomic landscape of MTCs revealed to be a mix of both primary and bone metastatic tissue. This multiplatform analysis of single cells reveals several clonal origins of metastatic PCa in a newly diagnosed, untreated patient with polymetastatic disease. This case demonstrates that real-time molecular profiling of cells collected through prostate and bone marrow biopsies is feasible and has the potential to elucidate the origin and evolution of metastatic tumor cells. Altogether, biological and genomic data obtained through longitudinal biopsies can be used to reveal the properties of PCa and can impact clinical management.

Effect of Blood Collection Tube Type and Time to Processing on the Enumeration and High-Content Characterization of Circulating Tumor Cells Using the High-Definition Single-Cell Assay.

CONTEXT: - As circulating tumor cell (CTC) assays gain clinical relevance, it is essential to address preanalytic variability and to develop standard operating procedures for sample handling in order to successfully implement genomically informed, precision health care. OBJECTIVE: - To evaluate the effects of blood collection tube (BCT) type and time-to-assay (TTA) on the enumeration and high-content characterization of CTCs by using the high-definition single-cell assay (HD-SCA). DESIGN: - Blood samples of patients with early- and advanced-stage breast cancer were collected into cell-free DNA (CfDNA), EDTA, acid-citrate-dextrose solution, and heparin BCTs. Time-to-assay was evaluated at 24 and 72 hours, representing the fastest possible and more routine domestic shipping intervals, respectively. RESULTS: - We detected the highest CTC levels and the lowest levels of negative events in CfDNA BCT at 24 hours. At 72 hours in this BCT, all CTC subpopulations were decreased with the larger effect observed in high-definition CTCs and cytokeratin-positive cells smaller than white blood cells. Overall cell retention was also optimal in CfDNA BCT at 24 hours. Whole-genome copy number variation profiles were generated from single cells isolated from all BCT types and TTAs. Cells from CfDNA BCT at 24-hour TTA exhibited the least noise. CONCLUSIONS: - Circulating tumor cells can be identified and characterized under a variety of collection, handling, and processing conditions, but the highest quality can be achieved with optimized conditions. We quantified performance differences of the HD-SCA for specific preanalytic variables that may be used as a guide to develop best practices for implementation into patient care and/or research biorepository processes.

Fatty acids cause alterations of human arterial smooth muscle cell proteoglycans that increase the affinity for low-density lipoprotein.

OBJECTIVE: The dyslipidemia of insulin resistance, with high levels of albumin-bound fatty acids, is a strong cardiovascular disease risk. Human arterial smooth muscle cell (hASMC) matrix proteoglycans (PGs) contribute to the retention of apoB lipoproteins in the intima, a possible key step in atherogenesis. We investigated the effects of high NEFA levels on the PGs secreted by hASMCs and whether these effects might alter the PG affinity for low-density lipoprotein. METHODS AND RESULTS: hASMC exposed for 72 hours to high concentrations (800 micromol/L) of linoleate (LO) or palmitate upregulated the core protein mRNAs of the major PGs, as measured by quantitative PCR. Insulin (1 nmol/L) and the PPARgamma agonist rosiglitazone (10 micromol/L) blocked these effects. In addition, high LO increased the mRNA levels of enzymes required for glycosaminoglycan (GAG) synthesis. Exposure to NEFA increased the chondroitin sulfate:heparan sulfate ratio and the negative charge of the PGs. Because of these changes, the GAGs secreted by LO-treated cells had a higher affinity for human low-density lipoprotein than GAGs from control cells. Insulin and rosiglitazone inhibited this increase in affinity. CONCLUSIONS: The response of hASMC to NEFA could induce extracellular matrix alterations favoring apoB lipoprotein deposition and atherogenesis.

Secretory phospholipase A2 group V: lesion distribution, activation by arterial proteoglycans, and induction in aorta by a Western diet.

OBJECTIVE: To study the distribution of group V secretory phospholipase A2 (sPLA2) in human and mouse lesions and compare its expression by human vascular cells, its activity toward lipoproteins, and the interaction with arterial proteoglycans (proteoglycans) with those of sPLA2-IIA. In addition, we also investigated the effect of a Western diet and lipopolysaccharide challenge on the aortic expression of these enzymes in mouse models. METHODS AND RESULTS: Immunohistochemistry showed sPLA2-V in human and mouse lesions to be associated with smooth muscle cells and also surrounding foam cells in lipid core areas. mRNA of the enzyme was expressed in human lesions and human vascular cells, supporting the immunohistochemistry data. sPLA2-V but not sPLA2-IIA was active on lipoproteins in human serum. The association with proteoglycans enhanced 2- to 3-fold sPLA2-V activity toward low-density lipoproteins but not that of the group IIA enzyme. Experiments in mouse models showed that treatment with a Western diet induced expression of sPLA2-V but not that of sPLA2-IIA in aorta. On the other hand, lipopolysaccharide-induced acute inflammation augmented the expression of sPLA2-IIA but not that of sPLA2-V. CONCLUSIONS: These results indicate that these phospholipases could have different roles in atherosclerosis.

HNF4α antagonists discovered by a high-throughput screen for modulators of the human insulin promoter.

Hepatocyte nuclear factor (HNF)4α is a central regulator of gene expression in cell types that play a critical role in metabolic homeostasis, including hepatocytes, enterocytes, and pancreatic ß cells. Although fatty acids were found to occupy the HNF4α ligand-binding pocket and were proposed to act as ligands, there is controversy about both the nature of HNF4α ligands as well as the physiological role of the binding. Here, we report the discovery of potent synthetic HNF4α antagonists through a high-throughput screen for effectors of the human insulin promoter. These molecules bound to HNF4α with high affinity and modulated the expression of known HNF4α target genes. Notably, they were found to be selectively cytotoxic to cancer cell lines in vitro and in vivo, although in vivo potency was limited by suboptimal pharmacokinetic properties. The discovery of bioactive modulators for HNF4α raises the possibility that diseases involving HNF4α, such as diabetes and cancer, might be amenable to pharmacologic intervention by modulation of HNF4α activity.

Fatty acid-induced atherogenic changes in extracellular matrix proteoglycans.

PURPOSE OF REVIEW: Nonesterified fatty acids change the expression and properties of the extracellular matrix proteoglycans of arterial and hepatic cells. We review how this may contribute to arterial disease in insulin resistance and type 2 diabetes. RECENT FINDINGS: Elevated nonesterified fatty acids characterize the dyslipidemia of insulin resistance and type 2 diabetes. In hepatocytes high levels of fatty acids cause changes in proteoglycans leading to a matrix with decreased affinity for VLDL remnants. Furthermore, liver proteoglycans from insulin resistant hyperlipidemic Zucker rats showed alterations also associated with decreased remnant affinity. In arterial smooth muscle cells overexposure to fatty acids augmented expression of matrix proteoglycans for which LDL showed increased affinity. Fatty acids appeared to compromise insulin signaling by protein kinase C activation. The observed fatty acid-induced changes in matrix proteoglycans in liver and arteries can be an important component of the atherogenicity of the dyslipidemia of insulin resistance and type 2 diabetes. SUMMARY: Overexposure to fatty acids can contribute to generate a remnant-rich dyslipidemia and to precondition the arterial intima for lipoprotein deposition via changes in expression of matrix proteoglycans. Normalizing fatty acid should be a key target in treatment of the atherogenic dyslipidemia of insulin resistance.

Guía de práctica clínica para la detección temprana, diagnóstico y tratamiento de la fase aguda de intoxicación de pacientes con abuso o dependencia del alcohol: Parte II: Evaluación y manejo de los pacientes con intoxicación aguda por alcohol / Clinical practice guide for early detection, diagnosis and treatment of the acute intoxication phase in patients with alcohol abuse or dependence Part II: evaluation and management of patients with acute alcohol intoxication

Introducción: El alcohol es la segunda sustancia psicotrópica más usada en el mundo y el tercer factor de riesgo para muerte prematura y discapacidad. Su uso nocivo es un problema de salud pública mundial, dado su impacto personal, laboral, familiar, económico y social. Es de suma importancia la identificación de intoxicación aguda por alcohol, el síndrome de abstinencia alcohólica y sus complicaciones, como delirium tremens y encefalopatía de Wernicke, para garantizar de esta manera un tratamiento oportuno para estos pacientes. Este artículo busca presentar la evidencia encontrada para el abordaje y el tratamiento de estas presentaciones clínicas. Método: Revisiones sistemáticas de la evidencia disponible y se evaluaron las guías pertinentes identificadas en la literatura, para decidir, en cada pregunta, si se adopta o se adapta a una recomendación ya existente, o bien, si se desarrollan recomendaciones de novo. Para las recomendaciones de novo y aquellas adaptadas, se realizó una síntesis de la evidencia, se elaboraron tablas de evidencia y se formularon las recomendaciones basadas en evidencia. Resultados: Se encuentra evidencia y se realizan recomendaciones para abordaje y tratamiento pertinente de intoxicación alcohólica aguda, síndrome de abstinencia, delirium tremens y encefalopatía de Wernicke...

Introduction: Worldwide, alcohol is the second most-used psychotropic substance and the third risk factor for early death and disability. Its noxious use is a world public health problem given its personal, labor, family, economic and social impact. The identification of acute alcohol intoxication is extremely important, as well as the alcohol withdrawal syndrome and its complications, such as delirium tremens and Wernicke’s encephalopathy in order to grant a timely treatment for those patients. This article introduces the evidence found so as to face and treat these clinic manifestations. Methodology: Systematic revision of the evi dence available together with an evaluation of pertinent guidelines found in literature so as to decide whether to adopt or adapt the existing recommendation for each question or to develop de novo recommendations. For de novo recommendations as well as those adapted, it was carried out an evidence synthesis, together with evidence tables and formulation of recommendations based on the evidence. Results: Evidence was found and recommendations were made for the diagnosis and treatment of acute alcohol intoxication, withdrawal syndrome, delirium tremens and Wernicke’s encephalopathy...