Golgi screen identifies the RhoGEF Solo as a novel regulator of RhoB and endocytic transport.

The control of intracellular membrane trafficking by Rho GTPases is central to cellular homeostasis. How specific guanine nucleotide exchange factors and GTPase-activating proteins locally balance GTPase activation in this process is nevertheless largely unclear. By performing a microscopy-based RNAi screen, we here identify the RhoGEF protein Solo as a functional counterplayer of DLC3, a RhoGAP protein with established roles in membrane trafficking. Biochemical, imaging and optogenetics assays further uncover Solo as a novel regulator of endosomal RhoB. Remarkably, we find that Solo and DLC3 control not only the activity, but also total protein levels of RhoB in an antagonistic manner. Together, the results of our study uncover the first functionally connected RhoGAP-RhoGEF pair at endomembranes, placing Solo and DLC3 at the core of endocytic trafficking.

Machine Learning Predicts Unplanned Care Escalations for Post-Anesthesia Care Unit Patients during the Perioperative Period: A Single-Center Retrospective Study.

BACKGROUND:  Despite low mortality for elective procedures in the United States and developed countries, some patients have unexpected care escalations (UCE) following post-anesthesia care unit (PACU) discharge. Studies indicate patient risk factors for UCE, but determining which factors are most important is unclear. Machine learning (ML) can predict clinical events. We hypothesized that ML could predict patient UCE after PACU discharge in surgical patients and identify specific risk factors. METHODS: We conducted a single center, retrospective analysis of all patients undergoing non-cardiac surgery (elective and emergent). We collected data from pre-operative visits, intra-operative records, PACU admissions, and the rate of UCE. We trained a ML model with this data and tested the model on an independent data set to determine its efficacy. Finally, we evaluated the individual patient and clinical factors most likely to predict UCE risk. RESULTS: Our study revealed that ML could predict UCE risk which was approximately 5% in both the training and testing groups. We were able to identify patient risk factors such as patient vital signs, emergent procedure, ASA Status, and non-surgical anesthesia time as significant variable. We plotted Shapley values for significant variables for each patient to help determine which of these variables had the greatest effect on UCE risk. Of note, the UCE risk factors identified frequently by ML were in alignment with anesthesiologist clinical practice and the current literature. CONCLUSIONS: We used ML to analyze data from a single-center, retrospective cohort of non-cardiac surgical patients, some of whom had an UCE. ML assigned risk prediction for patients to have UCE and determined perioperative factors associated with increased risk. We advocate to use ML to augment anesthesiologist clinical decision-making, help decide proper disposition from the PACU, and ensure the safest possible care of our patients.

Sociodemographic Disparities in Postoperative Nausea and Vomiting.

BACKGROUND: Postoperative nausea and vomiting (PONV) prophylaxis is consistently considered a key indicator of anesthesia care quality. PONV may disproportionately impact disadvantaged patients. The primary objectives of this study were to examine the associations between sociodemographic factors and the incidence of PONV and clinician adherence to a PONV prophylaxis protocol. METHODS: We conducted a retrospective analysis of all patients eligible for an institution-specific PONV prophylaxis protocol (2015-2017). Sociodemographic and PONV risk data were collected. Primary outcomes were PONV incidence and clinician adherence to PONV prophylaxis protocol. We used descriptive statistics to compare sociodemographics, procedural characteristics, and protocol adherence for patients with and without PONV. Multivariable logistic regression analysis followed by Tukey-Kramer correction for multiple comparisons was used to test for associations between patient sociodemographics, procedural characteristics, PONV risk, and (1) PONV incidence and (2) adherence to PONV prophylaxis protocol. RESULTS: Within the 8384 patient sample, Black patients had a 17% lower risk of PONV than White patients (adjusted odds ratio [aOR], 0.83; 95% confidence interval [CI], 0.73-0.95; P = .006). When there was adherence to the PONV prophylaxis protocol, Black patients were less likely to experience PONV compared to White patients (aOR, 0.81; 95% CI, 0.70-0.93; P = .003). When there was adherence to the protocol, patients with Medicaid were less likely to experience PONV compared to privately insured patients (aOR, 0.72; 95% CI, 0.64-1.04; P = .017). When the protocol was followed for high-risk patients, Hispanic patients were more likely to experience PONV than White patients (aOR, 2.96; 95% CI, 1.18-7.42; adjusted P = .022). Compared to White patients, protocol adherence was lower for Black patients with moderate (aOR, 0.76; 95% CI, 0.64-0.91; P = .003) and high risk (aOR, 0.57; 95% CI, 0.42-0.78; P = .0004). CONCLUSIONS: Racial and sociodemographic disparities exist in the incidence of PONV and clinician adherence to a PONV prophylaxis protocol. Awareness of such disparities in PONV prophylaxis could improve the quality of perioperative care.

Sensitivity of global terrestrial ecosystems to climate variability.

The identification of properties that contribute to the persistence and resilience of ecosystems despite climate change constitutes a research priority of global relevance. Here we present a novel, empirical approach to assess the relative sensitivity of ecosystems to climate variability, one property of resilience that builds on theoretical modelling work recognizing that systems closer to critical thresholds respond more sensitively to external perturbations. We develop a new metric, the vegetation sensitivity index, that identifies areas sensitive to climate variability over the past 14 years. The metric uses time series data derived from the moderate-resolution imaging spectroradiometer (MODIS) enhanced vegetation index, and three climatic variables that drive vegetation productivity (air temperature, water availability and cloud cover). Underlying the analysis is an autoregressive modelling approach used to identify climate drivers of vegetation productivity on monthly timescales, in addition to regions with memory effects and reduced response rates to external forcing. We find ecologically sensitive regions with amplified responses to climate variability in the Arctic tundra, parts of the boreal forest belt, the tropical rainforest, alpine regions worldwide, steppe and prairie regions of central Asia and North and South America, the Caatinga deciduous forest in eastern South America, and eastern areas of Australia. Our study provides a quantitative methodology for assessing the relative response rate of ecosystems--be they natural or with a strong anthropogenic signature--to environmental variability, which is the first step towards addressing why some regions appear to be more sensitive than others, and what impact this has on the resilience of ecosystem service provision and human well-being.

DLC3 suppresses MT1-MMP-dependent matrix degradation by controlling RhoB and actin remodeling at endosomal membranes.

Cancer cells degrade the extracellular matrix through actin-rich protrusions termed invadopodia. The formation of functional invadopodia requires polarized membrane trafficking driven by Rho GTPase-mediated cytoskeletal remodeling. We identify the Rho GTPase-activating protein deleted in liver cancer 3 (DLC3; also known as STARD8) as an integral component of the endosomal transport and sorting machinery. We provide evidence for the direct regulation of RhoB by DLC3 at endosomal membranes to which DLC3 is recruited by interacting with the sorting nexin SNX27. In TGF-ß-treated MCF10A breast epithelial cells, DLC3 knockdown enhanced metalloproteinase-dependent matrix degradation, which was partially rescued by RhoB co-depletion. This was recapitulated in MDA-MB-231 breast cancer cells in which early endosomes demonstrated aberrantly enriched F-actin and accumulated the metalloproteinase MT1-MMP (also known as MMP14) upon DLC3 knockdown. Remarkably, Rab4 (herein referring to Rab4A) downregulation fully rescued the enhanced matrix degradation of TGF-ß-treated MCF10A and MDA-MB-231 cells. In summary, our findings establish a novel role for DLC3 in the suppression of MT1-MMP-dependent matrix degradation by inactivating RhoB signaling at endosomal membranes. We propose that DLC3 function is required to limit endosomal actin polymerization, Rab4-dependent recycling of MT1-MMP and, consequently, matrix degradation mediated by invadopodial activity.

Chest pain CT in the Emergency Department: evaluating the coronary arteries even when not specifically asked for?

Background Computed tomography (CT) for excluding acute aortic syndrome (AAS) and pulmonary embolism (PE) simultaneously in patients with chest pain could be used to exclude coronary artery disease (CAD). Purpose To evaluate the frequency of further testing for CAD in patients receiving a CT in the emergency department (ED) for simultaneous evaluation for AAS and PE. Material and Methods This retrospective study was conducted over a three-year period including all patients with acute chest pain visiting our ED. All patients were included that received an electrocardiography (ECG)-gated CT of the entire chest enquiring simultaneously for AAS and PE. Those patients were followed up for 30 days after their initial ED visit whether they received further testing for CAD. Results Within the study period, a total of 157 patients with acute chest pain received a chest pain CT for simultaneous evaluation of both AAS and PE. Image quality was deemed sufficient to evaluate the coronary arteries in 80% of the patients. Thirty-seven patients (24%) underwent additional testing for CAD within 30 days of their ED visit, including catheter coronary angiography (n = 25), cardiac-stress single-photon emission-CT (n = 6), and cardiac magnetic resonance imaging (MRI) (n = 6). Conclusion Of patients presenting to the ED with acute chest pain who received a chest pain CT for simultaneous evaluation of AAS and PE, 24% had further imaging for CAD within 30 days of the initial ED visit. Immediate evaluation of the coronary arteries as part of a chest pain CT should be considered here for not delaying diagnosis.

A pilot study to explore patterns and predictors of delayed kidney decline after cardiopulmonary bypass.

There is no current consensus on the follow up of kidney function in patients undergoing cardiopulmonary bypass (CPB). The main objectives of this pilot study is to collect preliminary data on kidney function decline encountered on the first postoperative visit of patients who have had CPB and to identify predictors of kidney function decline post hospital discharge. Design: Retrospective chart review. Adult patients undergoing open heart procedures utilizing CPB. Patient demographics, type of procedure, pre-, intra-, and postoperative clinical, hemodynamic echocardiographic, and laboratory data were abstracted from electronic medical records. Acute kidney disease (AKD), and chronic kidney disease (CKD) were diagnosed based on standardized criteria. Interval change in medications, hospital admissions, and exposure to contrast, from hospital discharge till first postoperative visit were collected. AKD, and CKD as defined by standardized criteria on first postoperative visit. 83 patients were available for analysis. AKD occurred in 27 (54%) of 50 patients and CKD developed in 12 (42%) out of 28 patients. Older age was associated with the development of both AKD and CKD. Reduction in right ventricular cardiac output at baseline was associated with AKD (OR: 0.5, 95% CI: 0.3, 0.79, P = 0.01). Prolongation of transmitral early diastolic filling wave deceleration time was associated with CKD (OR: 1.02, 95% CI: 1.01, 1.05, P = 0.03). In-hospital acute kidney injury (AKI) was a predictor of neither AKD nor CKD. AKD and CKD occur after CPB and may not be predicted by in-hospital AKI. Older age, right ventricular dysfunction and diastolic dysfunction are important disease predictors. An adequately powered longitudinal study is underway to study more sensitive predictors of delayed forms of kidney decline after CPB.

Bluetongue Risk Map for Vaccination and Surveillance Strategies in India.

Bluetongue virus (BTV, Sedoreoviridae: Orbivirus) causes an economically important disease, namely, bluetongue (BT), in domestic and wild ruminants worldwide. BTV is endemic to South India and has occurred with varying severity every year since the virus was first reported in 1963. BT can cause high morbidity and mortality to sheep flocks in this region, resulting in serious economic losses to subsistence farmers, with impacts on food security. The epidemiology of BTV in South India is complex, characterized by an unusually wide diversity of susceptible ruminant hosts, multiple vector species biting midges (Culicoides spp., Diptera: Ceratopogonidae), which have been implicated in the transmission of BTV and numerous co-circulating virus serotypes and strains. BT presence data (1997-2011) for South India were obtained from multiple sources to develop a presence/absence model for the disease. A non-linear discriminant analysis (NLDA) was carried out using temporal Fourier transformed variables that were remotely sensed as potential predictors of BT distribution. Predictive performance was then characterized using a range of different accuracy statistics (sensitivity, specificity, and Kappa). The top ten variables selected to explain BT distribution were primarily thermal metrics (land surface temperature, i.e., LST, and middle infrared, i.e., MIR) and a measure of plant photosynthetic activity (the Normalized Difference Vegetation Index, i.e., NDVI). A model that used pseudo-absence points, with three presence and absence clusters each, outperformed the model that used only the recorded absence points and showed high correspondence with past BTV outbreaks. The resulting risk maps may be suitable for informing disease managers concerned with vaccination, prevention, and control of BT in high-risk areas and for planning future state-wide vector and virus surveillance activities.

Renal angiomyolipoma: Beyond size criteria for predicting rupture.

INTRODUCTION: Renal angiomyolipomas (AMLs) are vascular tumours that while histologically benign, carry a risk of rupture and potentially life-threatening haemorrhage. Selective arterial embolisation (SAE) has been demonstrated as effective treatment; however, given most tumours are asymptomatic, the challenge facing the radiologist is selection of which AML should undergo treatment. This study considers presence and size of intratumoural aneurysm, to advance the readers treatment decision-making beyond historical size criteria. METHODS: Retrospective cohort analysis of all SAE-treated AML at a quaternary-level institution in the last 10 years was completed independently by two radiologists. Computerised tomography (CT) and angiographic imaging were reviewed to evaluate tumour size, presence of intratumoural aneurysm and aneurysm size. Univariant and multivariant statistical analyses were used to identify predictors of spontaneous rupture and haemorrhage. RESULTS: Twenty-seven renal AML underwent SAE. Five tumours had presented with haemorrhage. Twenty-two were asymptomatic or without CT/angiographic detectable haemorrhage. There was no statistically significant size difference between ruptured (mean 7.8 cm, range 6.1-12.0 cm) and unruptured AML (7.5 cm, 3.3-21.7 cm) in the study population. Eighty percent of ruptured AML and 27% of unruptured AML contained at least one intratumoural aneurysm (P-value < 0.05). Mean aneurysm size in ruptured AMLs was 5.4 mm, versus 4.6 mm among unruptured AML (P-value > 0.05). CONCLUSION: The presence of intratumoural aneurysm is a useful predictor for AMLs that are at risk of spontaneous rupture and haemorrhage. Intratumoural aneurysm should therefore be considered when selecting patients to undergo SAE.

Is Size All That Matters? New Predictors of Complications and Bleeding in Renal Angiomyolipoma.

Purpose: Renal angiomyolipoma (AML) is the most common benign renal tumor. Whilst generally asymptomatic, they can cause life-threatening bleeding. Selective angioembolization (SAE) may be used to treat large symptomatic and asymptomatic AMLs. We aimed to evaluate the efficacy of SAE for symptomatic and asymptomatic renal AMLs and determine characteristics that predict spontaneous bleeding. Patients and Methods: Data were retrospectively collected from a prospectively maintained database from July 2011 to April 2022. Patients were included if AML was >4cm and they underwent subsequent SAE. Follow-up imaging was analyzed to calculate mean reduction in AML size. Clinical notes were reviewed to analyze lesion characteristics including vascularity, fat content and presence of aneurysm as well as post-procedural complications. Results: 26 patients with 30 AMLs were identified. Interval of follow-up imaging ranged from 1 to 60 months. 25 AMLs were embolized electively with 5 emergency embolizations performed for bleeding. Mean reduction in AML volume was 41% at 3 months (p=0.013) and 63% at 12 months (p=0.007). All 5 bleeding AMLs had a rich vascularity with 60% also having either aneurysms or a low fat content. Complications included post-embolic syndrome (n=9), segmental renal parenchyma devascularization (n=3), acute bleeding requiring re-embolization (n=2), nephrectomy for ongoing bleeding (n=1) and delayed bleeding managed conservatively (n=1). No deterioration in renal function was observed. Conclusion: SAE is an effective procedure for managing symptomatic and asymptomatic renal AML, with minimal significant complications. AML vascularity, fat content and aneurysms may be useful characteristics to assess future risk of bleeding in patients with renal AML.

Economic Evaluation of Anesthesiology-Led Cardiac Implantable Electronic Device Service.

BACKGROUND: Implementation of an anesthesiology-led cardiac implantable electronic device (CIED) service can be viewed to have economic and efficiency challenges. This study evaluates the cost savings of an anesthesiology-led CIED service. METHODS: A total of 830 patients presented in the pre-implementation period from 1 March 2016 to 31 December 2017, and 1981 patients presented in the post-implementation period from 1 January 2018 to 31 October 2021. Interrupted time-series analysis for single-group comparisons was used to evaluate the cost savings resulting from reduction in operating room (OR) start delays for patients with CIEDs. RESULTS: OR start-time delay was reduced by 10.6 min (95%CI: -20.5 to -0.83), comparing pre- to post-implementation. For an OR cost of USD 45/min, we estimated the direct cost to the department to be USD 1.68/min. The intervention translated into a total cost reduction during the intervention period of USD 250,000 (USD 18,000 to USD 470,000) per year for the institution and USD 9800 (USD 730 to USD 17,000) per year for the department. The yearly cost of employing a full-time team of CIED specialists would have been USD 135,456. The service triggered electrophysiology consultation on 13 device malfunctions. CONCLUSIONS: An anesthesiology-led CIED service resulted in substantial cost savings, increased OR efficiency and patient safety.

Percutaneous transhepatic biliary puncture simulator: a cord network prototype.

BACKGROUND: The aim of this study was to present a percutaneous transhepatic biliary puncture simulator that can be used without radiation exposure and that reflects the conventional anatomy of the biliary ducts and its vicinity structures. METHODS: An anatomically based model of the biliary tree was developed using a cord network fixed to a wooden frame. The skin, ribs, intercostal muscles, and right lower lobe pleura were simulated using foam sponge, plastic tubes, a polystyrene foam panel, and an air pad, respectively. For the puncture, we used a 20-G Chiba needle and a wire with distal double arches; these were used to troll a cord, simulating the successful puncture of a bile duct. A camera was also placed above the model to allow the trainees to train eye-hand coordination while viewing the image on a monitor in real time. The simulator was tested with 60 radiology residents to evaluate the confidence and skills transferability of the training model. RESULTS: After receiving an introduction of the system and 5 min of training under tutor surveillance, all participants were able to troll a cord of the biliary simulator by themselves in less than 4 min. Only one participant punctured the simulated pleura. The participants' evaluations showed positive results, with increased user confidence and skills transferability after the training session. CONCLUSIONS: This proposed simulator can be an effective tool to improve a trainee's confidence and competence while achieving procedural and non-procedural interventional radiology skills related to the liver. TRIAL REGISTRATION: Retrospectively registered.

Effect of Neuraxial Analgesic Procedures on Intraoperative Hemodynamics During Routine Clinical Care of Gynecological and General Surgeries: A Case-Control Query of Electronic Data.

BACKGROUND: The purpose of this study was to determine whether neuraxial analgesic procedures affect intraoperative hemodynamics and/or postoperative outcomes. Previous studies have examined effects in small samples of patients in highly controlled research environments. This study examined "real-world" data from a large sample of subjects receiving routine clinical cares. METHODS: A matched case-control analysis of electronic medical records from a large, academic hospital was performed. Patients who underwent neuraxial procedures preoperatively for postoperative analgesia for abdominal surgery (n=1570) were compared with control patients matched according to age, sex, ASA class and type of surgical procedure. Intraoperative hemodynamic measures, fluids and pressor utilization were quantified. Postoperative outcomes were determined based on the changes in laboratory values, the ordering of imaging studies and admission to an intensive care unit during the seven days following surgery as well as 30-day mortality. RESULTS: Medical records of 1082 patients who received an epidural catheter placement and 488 patients who received a lumbar intrathecal morphine injection were compared with an equal number of matched control patients. Preoperative placement of an epidural catheter for the management of postoperative pain was demonstrated to be associated with significant reductions in mean arterial pressure intraoperatively and poorer postoperative outcomes (more intensive care unit [ICU] admissions, more myocardial injuries) when compared with controls. A similar analysis of preoperatively administered intrathecal morphine injections was not associated with intraoperative alterations in blood pressure and had improved outcomes (less ICU admissions) in comparison with controls. CONCLUSION: In a "real-world" sample, intrathecal morphine administration proved to be highly beneficial as a neuraxial analgesic procedure as it was not associated with intraoperative hypotension and was associated with improved clinical outcomes, in contrast to opposite findings associated with epidural catheter placement. There should be a careful consideration of elective neuraxial method utilized for postoperative pain control, with the present study raising significant concerns related to the use of epidural analgesia and its potential effect on clinical outcomes.

Coil embolization of a thoracic aorta hematoma with branch artery pseudoaneurysm - case report.

BACKGROUND: A thoracic aorta hematoma with branch artery pseudonaneurysm is a very rare complication of thoraric blunt trauma. The standard treatment of this type of injury is aortic endograft placement. CASE PRESENTATION: We present a case in which a thoracic aorta hematoma with branch artery pseudoaneurysm was treated with coil embolization instead of endografting. CONCLUSIONS: Coil embolization of aortic injuries may be a safe and definitive treatment alternative in selected cases. This technique has the potential to reduce the risk of procedure-related complications.

Effects of Intraoperative Ketamine on Post-Operative Recovery in Obstructive Sleep Apnea Patients: A Case-Control Study.

Objective To evaluate the post-operative outcomes of patients with obstructive sleep apnea (OSA) given intraoperative ketamine. Design: case-control study A total of 574 patients (287 received ketamine and 287 were matched controls) diagnosed with OSA and body mass index (BMI) > 30 who received general anesthesia were included in this study. Patients given intraoperative ketamine were matched (1:1) with those who did not receive ketamine for age, gender, BMI, ethnicity, anesthesia time, intraoperative fentanyl dose, ketamine dose, and surgery type. A sub-analysis was performed based on the dose of ketamine administered and also on the surgery type. Measured outcomes include post-operative pain scores, post-operative opioid requirements, respiratory status, oxygen use, and duration post-operatively. Results Intraoperative ketamine use did not decrease pain scores or post-operative opioid use when compared with the control (no intraoperative ketamine) group. Patients who received high-dose ketamine had significantly higher post-operative pain scores (p=0.048) while in the post-anesthesia care unit (PACU) and required supplemental oxygen for a longer period of time (p = 0.030), pain scores were not significant for patients who underwent orthopedic/spine procedures (p = 0.074), and high-dose ketamine group patients who underwent orthopedic/spine surgery required significantly more opioids in the PACU (p = 0.031). Among patients who received low-dose ketamine, those who underwent head, ear, nose, and throat surgery required significantly more opioids in PACU (p = 0.022). Conclusions Low-dose intraoperative ketamine did not decrease pain scores or post-operative opioid use significantly and did not improve standard respiratory recovery parameters for OSA patients after surgery. Neither low- nor high-dose ketamine demonstrated the anticipated benefits of low pain scores and reduced post-operative opioid use. These outcomes will differ depending on the surgery type and dose of ketamine used.

Chest pain CT in the emergency department: Watch out for the myocardium.

RATIONALE AND OBJECTIVES: To evaluate the frequency and relevance of hypodense myocardium (HM) encountered in patients undergoing chest-pain CT in the emergency department (ED). MATERIAL AND METHODS: In this IRB-approved retrospective study, ECG-gated chest-pain CT examinations of 300 consecutive patients (mean age 60 ± 17 years) presenting with acute chest-pain to our ED were evaluated. Once ST-segment elevation infarction was excluded, chest-pain CT including the coronary arteries (rule-out acute coronary syndrome (ACS), pulmonary embolism (PE) and acute aortic syndrome (AAS): chest-pain CTcoronary, n = 121) or not including the coronary arteries was performed (rule-out PE and AAS: chest-pain CTw/o coronary, n = 179). Each myocardial segment was assessed for the presence of HM; attenuation was measured and compared to normal myocardium. RESULTS: HM was identified in 27/300 patients (9%): 12/179 in chest-pain CTw/o coronary (7%) and 15/121 in chest-pain CTcoronary (12%). Mean attenuation of HM (40 ± 17 HU) was significantly lower than that of healthy myocardium (103 ± 18 HU, p < 0.001), with a mean difference of 61 ± 19 HU. In 15/27 patients (55.6%) with HM, the final diagnosis was acute MI, and in the remaining 12/27 patients (44.4%) previous MI was found in the patients' history. Chest-pain CTw/o coronary identified HM in 10/15 patients (66.6%) with a final diagnosis of acute MI. CONCLUSION: HM indicating acute MI are often encountered in chest pain CT in the ED, also in chest-pain CTw/o coronary when MI is not suspected. This indicates that the myocardium should always be analyzed for hypodense regions even when MI not suspected.

New Interventional Treatment Model for Pancreatic Neoplasms Using Gemcitabine-Eluting Hydrogel Devices: In Vitro and In Vivo Results.

OBJECTIVES: In vitro and in vivo evaluation of fast- and slow-release gemcitabine-eluting hydrogel (GEH) devices. METHODS: For in vitro elution, the GEH devices were placed in phosphate-buffered saline at 37 °C. Periodically, the solution was analyzed for gemcitabine. The devices consisting of fast release (n = 8), slow release (n = 6), or bland (n = 4) were delivered through a 5-Fr catheter into the gastroduodenal artery of a pig. Additionally, four pigs were treated with intravenous (IV) injection of gemcitabine. Pigs were killed at day 1 (n = 9), day 7 (n = 11), or day 21 (n = 2). Gemcitabine concentrations in the plasma and tissues were determined. RESULTS: In vitro, gemcitabine was completely eluted within 6 h or 30 days for the fast- and slow-release devices, respectively. All 22 pigs were treated without morbidity or mortality. Gemcitabine plasma concentrations peaked at about 105,000 ± 30,000, 252 ± 101, 22 ± 29, and 0 ± 0 ppb for the IV, fast-release, slow-release, and bland treatments, respectively. At days 1 and 7, gemcitabine concentrations were higher in the pancreas for the GEH devices than IV. Gemcitabine delivery to the pancreas was sustained over 21 days in the slow-release group. CONCLUSIONS: Treatment with GEH devices resulted in at least equivalent gemcitabine concentration in the pancreas and reduced concentration in the plasma, heart, liver, and duodenum, at least equivalent to IV injection and reduced concentrations elsewhere. These results show the potential of sustained local delivery of gemcitabine to treat pancreatic neoplasms with reduced side effects.

HMGA1 Expression in Human Hepatocellular Carcinoma Correlates with Poor Prognosis and Promotes Tumor Growth and Migration in in vitro Models.

BACKGROUND: HMGA1 is a non-histone nuclear protein that regulates cellular proliferation, invasion and apoptosis and is overexpressed in many carcinomas. In this study we sought to explore the expression of HMGA1 in HCCs and cirrhotic tissues, and its effect in in vitro models. METHODS: We evaluated HMGA1 expression using gene expression microarrays (59 HCCs, of which 37 were matched with their corresponding cirrhotic tissue and 5 normal liver donors) and tissue microarray (192 HCCs, 108 cirrhotic tissues and 79 normal liver samples). HMGA1 expression was correlated with clinicopathologic features and patient outcome. Four liver cancer cell lines with stable induced or knockdown expression of HMGA1 were characterized using in vitro assays, including proliferation, migration and anchorage-independent growth. RESULTS: HMGA1 expression increased monotonically from normal liver tissues to cirrhotic tissue to HCC (P<.01) and was associated with Edmondson grade (P<.01). Overall, 51% and 42% of HCCs and cirrhotic tissues expressed HMGA1, respectively. Patients with HMGA1-positive HCCs had earlier disease progression and worse overall survival. Forced expression of HMGA1 in liver cancer models resulted in increased cell growth and migration, and vice versa. Soft agar assay showed that forced expression of HMGA1 led to increased foci formation, suggesting an oncogenic role of HMGA1 in hepatocarcinogenesis. CONCLUSIONS: HMGA1 is frequently expressed in cirrhotic tissues and HCCs and its expression is associated with high Edmondson grade and worse prognosis in HCC. Our results suggest that HMGA1 may act as oncogenic driver of progression, implicating it in tumor growth and migration potential in liver carcinogenesis.