Transcriptomic characterization of cancer-testis antigens identifies MAGEA3 as a driver of tumor progression in hepatocellular carcinoma.

Cancer testis antigens (CTAs) are an extensive gene family with a unique expression pattern restricted to germ cells, but aberrantly reactivated in cancer tissues. Studies indicate that the expression (or re-expression) of CTAs within the MAGE-A family is common in hepatocellular carcinoma (HCC). However, no systematic characterization has yet been reported. The aim of this study is to perform a comprehensive profile of CTA de-regulation in HCC and experimentally evaluate the role of MAGEA3 as a driver of HCC progression. The transcriptomic analysis of 44 multi-regionally sampled HCCs from 12 patients identified high intra-tumor heterogeneity of CTAs. In addition, a subset of CTAs was significantly overexpressed in histologically poorly differentiated regions. Further analysis of CTAs in larger patient cohorts revealed high CTA expression related to worse overall survival and several other markers of poor prognosis. Functional analysis of MAGEA3 was performed in human HCC cell lines by gene silencing and in a genetic mouse model by overexpression of MAGEA3 in the liver. Knockdown of MAGEA3 decreased cell proliferation, colony formation and increased apoptosis. MAGEA3 overexpression was associated with more aggressive tumors in vivo. In conclusion MAGEA3 enhances tumor progression and should be considered as a novel therapeutic target in HCC.

DNA Methylation Profiling of Human Hepatocarcinogenesis.

BACKGROUND AND AIMS: Mutations in TERT (telomerase reverse transcriptase) promoter are established gatekeepers in early hepatocarcinogenesis, but little is known about other molecular alterations driving this process. Epigenetic deregulation is a critical event in early malignancies. Thus, we aimed to (1) analyze DNA methylation changes during the transition from preneoplastic lesions to early HCC (eHCC) and identify candidate epigenetic gatekeepers, and to (2) assess the prognostic potential of methylation changes in cirrhotic tissue. APPROACH AND RESULTS: Methylome profiling was performed using Illumina HumanMethylation450 (485,000 cytosine-phosphateguanine, 96% of known cytosine-phosphateguanine islands), with data available for a total of 390 samples: 16 healthy liver, 139 cirrhotic tissue, 8 dysplastic nodules, and 227 HCC samples, including 40 eHCC below 2cm. A phylo-epigenetic tree derived from the Euclidean distances between differentially DNA-methylated sites (n = 421,997) revealed a gradient of methylation changes spanning healthy liver, cirrhotic tissue, dysplastic nodules, and HCC with closest proximity of dysplasia to HCC. Focusing on promoter regions, we identified epigenetic gatekeeper candidates with an increasing proportion of hypermethylated samples (beta value > 0.5) from cirrhotic tissue (<1%), to dysplastic nodules (≥25%), to eHCC (≥50%), and confirmed inverse correlation between DNA methylation and gene expression for TSPYL5 (testis-specific Y-encoded-like protein 5), KCNA3 (potassium voltage-gated channel, shaker-related subfamily, member 3), LDHB (lactate dehydrogenase B), and SPINT2 (serine peptidase inhibitor, Kunitz type 2) (all P < 0.001). Unsupervised clustering of genome-wide methylation profiles of cirrhotic tissue identified two clusters, M1 and M2, with 42% and 58% of patients, respectively, which correlates with survival (P < 0.05), independent of etiology. CONCLUSIONS: Genome-wide DNA-methylation profiles accurately discriminate the different histological stages of human hepatocarcinogenesis. We report on epigenetic gatekeepers in the transition between dysplastic nodules and eHCC. DNA-methylation changes in cirrhotic tissue correlate with clinical outcomes.

Unannotated small RNA clusters associated with circulating extracellular vesicles detect early stage liver cancer.

OBJECTIVE: Surveillance tools for early cancer detection are suboptimal, including hepatocellular carcinoma (HCC), and biomarkers are urgently needed. Extracellular vesicles (EVs) have gained increasing scientific interest due to their involvement in tumour initiation and metastasis; however, most extracellular RNA (exRNA) blood-based biomarker studies are limited to annotated genomic regions. DESIGN: EVs were isolated with differential ultracentrifugation and integrated nanoscale deterministic lateral displacement arrays (nanoDLD) and quality assessed by electron microscopy, immunoblotting, nanoparticle tracking and deconvolution analysis. Genome-wide sequencing of the largely unexplored small exRNA landscape, including unannotated transcripts, identified and reproducibly quantified small RNA clusters (smRCs). Their key genomic features were delineated across biospecimens and EV isolation techniques in prostate cancer and HCC. Three independent exRNA cancer datasets with a total of 479 samples from 375 patients, including longitudinal samples, were used for this study. RESULTS: ExRNA smRCs were dominated by uncharacterised, unannotated small RNA with a consensus sequence of 20 nt. An unannotated 3-smRC signature was significantly overexpressed in plasma exRNA of patients with HCC (p<0.01, n=157). An independent validation in a phase 2 biomarker case-control study revealed 86% sensitivity and 91% specificity for the detection of early HCC from controls at risk (n=209) (area under the receiver operating curve (AUC): 0.87). The 3-smRC signature was independent of alpha-fetoprotein (p<0.0001) and a composite model yielded an increased AUC of 0.93. CONCLUSION: These findings directly lead to the prospect of a minimally invasive, blood-only, operator-independent clinical tool for HCC surveillance, thus highlighting the potential of unannotated smRCs for biomarker research in cancer.

Gadoxetate-enhanced abbreviated MRI is highly accurate for hepatocellular carcinoma screening.

OBJECTIVES: The primary objective was to compare the performance of 3 different abbreviated MRI (AMRI) sets extracted from a complete gadoxetate-enhanced MRI obtained for hepatocellular carcinoma (HCC) screening. Secondary objective was to perform a preliminary cost-effectiveness analysis, comparing each AMRI set to published ultrasound performance for HCC screening in the USA. METHODS: This retrospective study included 237 consecutive patients (M/F, 146/91; mean age, 58 years) with chronic liver disease who underwent a complete gadoxetate-enhanced MRI for HCC screening in 2017 in a single institution. Two radiologists independently reviewed 3 AMRI sets extracted from the complete exam: non-contrast (NC-AMRI: T2-weighted imaging (T2wi)+diffusion-weighted imaging (DWI)), dynamic-AMRI (Dyn-AMRI: T2wi+DWI+dynamic T1wi), and hepatobiliary phase AMRI (HBP-AMRI: T2wi+DWI+T1wi during the HBP). Each patient was classified as HCC-positive/HCC-negative based on the reference standard, which consisted in all available patient data. Diagnostic performance for HCC detection was compared between sets. Estimated set characteristics, including historical ultrasound data, were incorporated into a microsimulation model for cost-effectiveness analysis. RESULTS: The reference standard identified 13/237 patients with HCC (prevalence, 5.5%; mean size, 33.7 ± 30 mm). Pooled sensitivities were 61.5% for NC-AMRI (95% confidence intervals, 34.4-83%), 84.6% for Dyn-AMRI (60.8-95.1%), and 80.8% for HBP-AMRI (53.6-93.9%), without difference between sets (p range, 0.06-0.16). Pooled specificities were 95.5% (92.4-97.4%), 99.8% (98.4-100%), and 94.9% (91.6-96.9%), respectively, with a significant difference between Dyn-AMRI and the other sets (p < 0.01). All AMRI methods were effective compared with ultrasound, with life-year gain of 3-12 months against incremental costs of US$ < 12,000. CONCLUSIONS: NC-AMRI has limited sensitivity for HCC detection, while HBP-AMRI and Dyn-AMRI showed excellent sensitivity and specificity, the latter being slightly higher for Dyn-AMRI. Cost-effectiveness estimates showed that AMRI is effective compared with ultrasound. KEY POINTS: • Comparison of different abbreviated MRI (AMRI) sets reconstructed from a complete gadoxetate MRI demonstrated that non-contrast AMRI has low sensitivity (61.5%) compared with contrast-enhanced AMRI (80.8% for hepatobiliary phase AMRI and 84.6% for dynamic AMRI), with all sets having high specificity. • Non-contrast and hepatobiliary phase AMRI can be performed in less than 14 min (including set-up time), while dynamic AMRI can be performed in less than 17 min. • All AMRI sets were cost-effective for HCC screening in at-risk population in comparison with ultrasound.

Lung base CT findings in COVID-19 adult patients presenting with acute abdominal complaints: case series from a major New York City health system.

OBJECTIVE: To describe demographic, clinical, and lung base CT findings in COVID-19 patients presenting with abdominal complaints. METHODS: In this retrospective study, 76 COVID-19 patients who underwent abdominal CT for abdominal complaints from March 1 to April 15, 2020, in a large urban multihospital Health System were included. Those with positive abdominal CT findings (n = 14) were then excluded, with 62 patients undergoing final analysis (30M/32F; median age 63 years, interquartile range (IQR) 52-75 years, range 30-90 years). Demographic and clinical data were extracted. CT lung base assessment was performed by a cardiothoracic radiologist. Data were compared between discharged and hospitalised patients using Wilcoxon or Fisher's exact tests. RESULTS: The majority of the population was non-elderly (56.4%, < 65 years) and most (81%) had underlying health conditions. Nineteen percent were discharged and 81% were hospitalised. The most frequent abdominal symptoms were pain (83.9%) and nausea/vomiting/anorexia (46.8%). Lung base CT findings included ground-glass opacities (95.2%) in a multifocal (95.2%) and peripheral (66.1%) distribution. Elevated laboratory values (when available) included C-reactive protein (CRP) (97.3%), D-dimer (79.4%), and ferritin (68.8% of males and 81.8% of females). Older age (p = 0.045), hypertension (p = 0.019), and lower haemoglobin in women (p = 0.042) were more frequent in hospitalised patients. There was no difference in lung base CT findings between discharged and hospitalised patients (p > 0.165). CONCLUSIONS: COVID-19 patients can present with abdominal symptoms, especially in non-elderly patients with underlying health conditions. Lung base findings on abdominal CT are consistent with published reports. Radiologists should be aware of atypical presentations of COVID-19. KEY POINTS: • COVID-19 infected patients can present with acute abdominal symptoms, especially in non-elderly patients with underlying health conditions, and may frequently require hospitalisation (81%). • There was no difference in lung base CT findings between patients who were discharged and those who were hospitalised. • Lung base CT findings included multifocal and peripheral ground-glass opacities, consistent with published reports.

Investigation of optical neuro-monitoring technique for detection of maintenance and emergence states during general anesthesia.

The American Society of Anesthesiologist recommends peripheral physiological monitoring during general anesthesia, which offers no information regarding the effects of anesthetics on the brain. Since no "gold standard" method exists for this evaluation, such a technique is needed to ensure patient comfort, procedure quality and safety. In this study we investigated functional near infrared spectroscopy (fNIRS) as possible monitor of anesthetic effects on the prefrontal cortex. Anesthetic drugs, such as sevoflurane, suppress the cerebral metabolism and alter the cerebral blood flow. We hypothesize that fNIRS derived features carry information on the effects of anesthetics on the prefrontal cortex (PFC) that can be used for the classification of the anesthetized state. In this study, patients were continuously monitored using fNIRS, BIS and standard monitoring during surgical procedures under sevoflurane general anesthesia. Maintenance and emergence states were identified and fNIRS features were identified and compared between states. Linear and non-linear machine learning algorithms were investigated as methods for the classification of maintenance/emergence. The results show that changes in oxygenated (HbO2) and deoxygenated hemoglobin (HHb) concentration and blood volume measured by fNIRS were associated with the transition between maintenance and emergence that occurs as a result of sevoflurane washout. We observed that during maintenance the signal is relatively more stable than during emergence. Maintenance and emergence states were classified with 94.7% accuracy with a non-linear model using the locally derived mean total hemoglobin, standard deviation of HbO2, minimum and range of HbO2 and HHb as features. These features were found to be correlated with the effects of sevoflurane and to carry information that allows real time and automatic classification of the anesthetized state with high accuracy.

Anesthetic concerns for robotic-assisted laparoscopic radical prostatectomy: an update.

The anesthetic concerns of patients undergoing robotic-assisted laparoscopic radical prostatectomy (RALP) are primarily related to the use of pneumoperitoneum in the steep Trendelenburg position. This combination will affect cerebrovascular, ocular, respiratory, and hemodynamic homeostasis. Possible non-surgical complications range from mild subcutaneous emphysema to devastating ischemic optic neuropathy. The anesthetic management of RALP patients involves a thorough preoperative evaluation, careful positioning on the operative table, managing ventilation issues, and appropriate fluid management. Close coordination between the anesthesia and surgical teams is required for a successful surgery. This updated review will discuss the anesthetic concerns and perioperative management of patients presenting for RALP.

MRI is the most commonly used imaging modality for HCC screening at a tertiary care transplant center.

PURPOSE: In this study, we describe the patterns of hepatocellular carcinoma (HCC) screening with imaging and factors associated with imaging modality selection in a tertiary care transplant center. METHODS: This was a retrospective study where all adult patients with cirrhosis and/or chronic hepatitis B virus infection referred for HCC screening with ultrasound (US), CT or MRI were identified during 2017. The association between imaging methods, demographic/clinical data were analyzed by uni- and multivariate analysis. RESULTS: A total of 1437 patients were included (median age 61y, 59% male, median BMI 27.5 kg/m2, median AFP 3.4 ng/mL, 37% with HCV and 87% with cirrhosis). Index screening imaging method utilization included MRI (51%), US (33%) and CT (16%). Use of US as the index imaging modality for screening was significantly associated with race/ethnicity [Odds Ratio (OR) 1.71-2.01, all p < 0.05] in multivariate analysis. Presence of cirrhosis (OR 0.29, p < 0.001) and referral by a hepatologist (OR 0.23, p < 0.001) were associated with screening with MRI in the multivariate analysis; while gender, age, BMI, etiology and income at ZIP code of residence were not significantly associated with imaging modality selection. HCC was observed in 62 patients (prevalence 4.3%). Rate of HCC detection was significantly higher with MRI vs US (5.9% vs. 1.5%, p = 0.001). CONCLUSION: MRI was the most frequently used modality (> 50%) for HCC screening in our tertiary care center, in contrast with the current practice guidelines. Race/ethnicity, cirrhosis and referral by a hepatologist were associated with the imaging method used for HCC screening.

A Multifaceted, Student-Led Approach to Improving the Opioid Prescribing Practices of Hospital Medicine Clinicians.

BACKGROUND: The development of guidelines for opioid prescribing, including those from the Society of Hospital Medicine and the Centers for Disease Control and Prevention, has been associated with changes in prescription patterns. However, many providers remain unaware of best practices surrounding appropriate opioid prescribing. METHODS: The research team implemented a multimodal quality improvement intervention, led by first-year medical students, designed to increase clinician adherence to current prescribing guidelines for patients discharged on opioids. This intervention included an awareness campaign, educational sessions for providers, and weekly performance feedback. RESULTS: A total of 4,993 discharges were identified in the baseline period and 4,811 discharges in the intervention period. During the baseline period, 12.3% of all patients discharged were discharged with opioid prescriptions vs. 11.4% during the intervention period (p = 0.165). Of these, approximately 60% were new opioid prescriptions during both periods (p = 0.991). The study's efforts were associated with a decrease in the percentage of patients discharged with opioid prescriptions longer than seven days (45.2% preintervention to 39.5% postintervention, p < 0.042); an increase in the percentage of patients with follow-up appointments within seven days of discharge (38.6% to 65.9%, p = 0.001); and an increase in documentation of prescription history obtained from the state Prescription Monitoring Program registry (32.5% to 39.7%, p = 0.042). CONCLUSION: This intervention provided a successful framework to engage learners in improving opioid prescribing practices. The results are promising, but the experiences highlight the significant effort and resources needed to change prescriber practices, potentially limiting sustainability.

Gadoxetate disodium-enhanced MRI: Assessment of arterial phase artifacts and hepatobiliary uptake in a large series.

PURPOSE: To report the quality of gadoxetate disodium MRI in a large series by assessing the prevalence of: 1) arterial phase (AP) artifacts and its predictive factors, 2) decreased hepatic contrast uptake during the hepatobiliary phase (HBP). METHODS: This retrospective single center study included 851 patients (M/F:537/314, mean age: 63y) with gadoxetate disodium MRI. The MRI protocol included unenhanced, dual arterial [early and late arterial phases (AP)], portal venous, transitional and hepatobiliary phases. Three radiologists graded dynamic images using a 5-scale score (1: no motion, 5: severe, nondiagnostic) for assessment of transient severe motion (TSM, defined as a score ≥4 during at least one AP with a score ≤3 during other phases). HBP uptake was assessed using a 3-scale score (based on portal vein/hepatic signal). The association between demographic, clinical and acquisition parameters with TSM was tested in uni- and multivariate logistic regression. RESULTS: TSM was observed in 103/851 patients (12.1 %): 83 (9.8 %) in one AP and 20 (2.3 %) in both APs. A score of 5 (nondiagnostic) was assigned in 7 patients in one AP (0.8 %) and none in both. Presence of TSM was significantly associated with age (p = 0.002) and liver disease (p = 0.033) in univariate but not in multivariate analysis (p > 0.05). No association was found between acquisition parameters and TSM occurrence. Limited or severely limited HBP contrast uptake was observed in 87 patients (10.2 %), and TSM was never associated with severely limited HBP contrast uptake. CONCLUSION: TSM was present in approximately 12 % of gadoxetate disodium MRIs, rarely on both APs (2.3 %), and was poorly predicted. TSM was never associated with severely limited HBP contrast uptake.

Association of Surgical and Hospital Volume and Patient Characteristics With 30-Day Readmission Rates.

Importance: Thirty-day readmission rates have been suggested as a marker for quality of care. By investigating the factors associated with readmissions in all otolaryngology subspecialties we provide data relevant for the development of risk stratification systems to improve outcomes. Objective: To establish the association of surgical and hospital volume and patient characteristics with 30-day readmission rates to guide the development of otolaryngology-specific risk stratification models. Design, Setting, and Participants: A retrospective cohort study including adult patients who underwent inpatient otolaryngology surgery in New York State between 1995 and 2015 was conducted using the Statewide Planning and Research Cooperative System (SPARCS). Regression techniques were used to describe relationships of patient-level factors, hospital, and surgeon volume to 30-day readmission rates in New York State. Main Outcomes and Measures: The main outcome measures were patient-, surgeon-, and hospital-level risk factors for readmission. Secondary outcome measures were rate of readmissions by subspecialty procedure and by diagnosis on readmission. Results: We identified 254 257 cases of otolaryngology surgery (147 065 women [58%], mean [SD] age 50 [17] years). The 30-day readmission rate was 6%. In a multivariable model, odds ratios (ORs) identified Medicaid insurance (OR, 1.46; 99% CI, 1.36-1.57), Medicare insurance (OR, 1.32; 99% CI, 1.24-1.42), bottom quartile income (OR, 1.08; 99% CI, 1.01-1.15), patient comorbidities measured by the Charlson Comorbidity Index (CCI) (CCI >1; OR, 2.31; 99% CI, 2.16-2.47), length of stay (LOS) (LOS >10 days; OR, 2.29; 99% CI, 2.00-2.45), rhinology (OR, 1.37; 99% CI, 1.24-1.51), laryngology (OR, 1.98; 99% CI, 1.62-2.43), and head and neck cancer (OR, 1.27; 99% CI, 1.17-1.37) procedures as readmission predictors. High-volume surgeons were protective of 30-day readmission (OR, 0.67; 99% CI, 0.635-0.708) relative to low volume. Hospital volume was not significantly associated to readmissions. The most common causes of readmission included wound- (2682 patients, 18%), respiratory- (1776 patients, 12%), cardiovascular- (1210 patients, 8%), and volume- (1089 patients, 7%) related disorders. Conclusions and Relevance: This study evaluated the combined effects of patient-, surgeon-, and hospital-level factors on 30-day readmission after otolaryngology surgery. Socioeconomic factors, patient comorbidities, surgeon volumes, and procedure were significantly associated with 30-day readmission. Though the cause of 30-day readmission is multifactorial, a large portion is driven by socioeconomic factors. Addressing these disparities at the system level is necessary to address the described readmission disparities. The development of risk-stratification models based on patient-, procedure-, and surgeon-level factors may help facilitate resource distribution.

Time on Therapy for at Least Three Months Correlates with Overall Survival in Metastatic Renal Cell Carcinoma.

With 15 drugs currently approved for the treatment of metastatic renal cell carcinoma (mRCC) and even more combination regimens with immunotherapy on the horizon, there remains a distinct lack of molecular biomarkers for therapeutic efficacy. Our study reports on real-world clinical outcomes of mRCC patients from a tertiary academic medical center treated with empirically selected standard-of-care therapy. We utilized the Stanford Renal Cell Carcinoma Database (RCCD) to report on various outcome measures, including overall survival (OS) and the median number of lines of targeted therapies received from the time of metastatic diagnosis. We found that most metastatic patients did not survive long enough to attempt even half of the available targeted therapies. We also noted that patients who failed to receive a clinical benefit within the first two lines of therapy could still go on to experience clinical benefit in later lines of therapy. The term, "clinical benefit" was assigned to a line of therapy if a patient remained on drug treatment for three months or longer. Moreover, patients with clinical benefit in at least one line of therapy experienced significantly longer OS compared to those who did not have clinical benefit in at least one line of therapy. Developing biomarkers that identify patients who will receive clinical benefit in individual lines of therapy is one potential strategy for achieving rational drug sequencing in mRCC.

Investigation of data-driven optical neuromonitoring approach during general anesthesia with sevoflurane.

Anesthesia monitoring currently needs a reliable method to evaluate the effects of the anesthetics on its primary target, the brain. This study focuses on investigating the clinical usability of a functional near-infrared spectroscopy (fNIRS)-derived machine learning classifier to perform automated and real-time classification of maintenance and emergence states during sevoflurane anesthesia. For 19 surgical procedures, we examine the entire continuum of the maintenance-transition-emergence phases and evaluate the predictive capability of a support vector machine (SVM) classifier during these phases. We demonstrate the robustness of the predictions made by the SVM classifier and compare its performance with that of minimum alveolar concentration (MAC) and bispectral (BIS) index-based predictions. The fNIRS-SVM investigated in this study provides evidence to the usability of the fNIRS signal for anesthesia monitoring. The method presented enables classification of the signal as maintenance or emergence automatically as well as in real-time with high accuracy, sensitivity, and specificity. The features local mean HbTotal, std [Formula: see text], local min Hb and [Formula: see text], and range Hb and [Formula: see text] were found to be robust biomarkers of this binary classification task. Furthermore, fNIRS-SVM was capable of identifying emergence before movement in a larger number of patients than BIS and MAC.

Near-infrared spectroscopy for the evaluation of anesthetic depth.

The standard-of-care guidelines published by the American Society of Anesthesiologists (ASA) recommend monitoring of pulse oximetry, blood pressure, heart rate, and end tidal CO2 during the use of anesthesia and sedation. This information can help to identify adverse events that may occur during procedures. However, these parameters are not specific to the effects of anesthetics or sedatives, and therefore they offer little, to no, real time information regarding the effects of those agents and do not give the clinician the lead-time necessary to prevent patient "awareness." Since no "gold-standard" method is available to continuously, reliably, and effectively monitor the effects of sedatives and anesthetics, such a method is greatly needed. Investigation of the use of functional near-infrared spectroscopy (fNIRS) as a method for anesthesia or sedation monitoring and for the assessment of the effects of various anesthetic drugs on cerebral oxygenation has started to be conducted. The objective of this paper is to provide a thorough review of the currently available published scientific studies regarding the use of fNIRS in the fields of anesthesia and sedation monitoring, comment on their findings, and discuss the future work required for the translation of this technology to the clinical setting.