Liver resection surgery compared with thermal ablation in high surgical risk patients with colorectal liver metastases: the LAVA international RCT.

BACKGROUND: Although surgical resection has been considered the only curative option for colorectal liver metastases, thermal ablation has recently been suggested as an alternative curative treatment. There have been no adequately powered trials comparing surgery with thermal ablation. OBJECTIVES: Main objective - to compare the clinical effectiveness and cost-effectiveness of thermal ablation versus liver resection surgery in high surgical risk patients who would be eligible for liver resection. Pilot study objectives - to assess the feasibility of recruitment (through qualitative study), to assess the quality of ablations and liver resection surgery to determine acceptable standards for the main trial and to centrally review the reporting of computed tomography scan findings relating to ablation and outcomes and recurrence rate in both arms. DESIGN: A prospective, international (UK and the Netherlands), multicentre, open, pragmatic, parallel-group, randomised controlled non-inferiority trial with a 1-year internal pilot study. SETTING: Tertiary liver, pancreatic and gallbladder (hepatopancreatobiliary) centres in the UK and the Netherlands. PARTICIPANTS: Adults with a specialist multidisciplinary team diagnosis of colorectal liver metastases who are at high surgical risk because of their age, comorbidities or tumour burden and who would be suitable for liver resection or thermal ablation. INTERVENTIONS: Thermal ablation conducted as per local policy (but centres were encouraged to recruit within Cardiovascular and Interventional Radiological Society of Europe guidelines) versus surgical liver resection performed as per centre protocol. MAIN OUTCOME MEASURES: Pilot study - patients' and clinicians' acceptability of the trial to assist in optimisation of recruitment. Primary outcome - disease-free survival at 2 years post randomisation. Secondary outcomes - overall survival, timing and site of recurrence, additional therapy after treatment failure, quality of life, complications, length of hospital stay, costs, trial acceptability, and disease-free survival measured from end of intervention. It was planned that 5-year survival data would be documented through record linkage. Randomisation was performed by minimisation incorporating a random element, and this was a non-blinded study. RESULTS: In the pilot study over 1 year, a total of 366 patients with colorectal liver metastases were screened and 59 were considered eligible. Only nine participants were randomised. The trial was stopped early and none of the planned statistical analyses was performed. The key issues inhibiting recruitment included fewer than anticipated patients eligible for both treatments, misconceptions about the eligibility criteria for the trial, surgeons' preference for one of the treatments ('lack of clinical equipoise' among some of the surgeons in the centre) with unconscious bias towards surgery, patients' preference for one of the treatments, and lack of dedicated research nurses for the trial. CONCLUSIONS: Recruitment feasibility was not demonstrated during the pilot stage of the trial; therefore, the trial closed early. In future, comparisons involving two very different treatments may benefit from an initial feasibility study or a longer period of internal pilot study to resolve these difficulties. Sufficient time should be allowed to set up arrangements through National Institute for Health Research (NIHR) Research Networks. TRIAL REGISTRATION: Current Controlled Trials ISRCTN52040363. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 21. See the NIHR Journals Library website for further project information.

In about 50% of people with bowel cancer, cancer spreads to the liver (colorectal liver metastases) within 5 years of detection and treatment. Liver resection (i.e. surgical removal of a portion of the liver) is the standard treatment in people below 70 years of age who are otherwise well, provided that the liver cancer is confined to a limited part of the liver. Such patients are considered 'low-risk' patients. Older patients and those with major medical problems or extensive cancers are considered 'high-risk' patients, as they are at a higher risk of developing complications following liver resection. Thermal ablation destroys the liver cancers using a needle that heats the cancer deposits until they are destroyed. There is significant uncertainty as to whether or not ablation can offer equivalent survival compared with surgery for 'high-risk' patients. We planned and conducted a randomised controlled trial comparing ablation with surgery to resolve this uncertainty. In this trial, some patients received ablation and others received surgery. The treatment was allocated at random with neither patients nor the study organisers choosing the treatment. The trial had an internal pilot (i.e. a smaller version of the full trial to resolve any 'teething problems' and ensure that a sufficient number of participants can be included in the full trial). Only nine patients were recruited in the 1-year internal pilot, compared with the anticipated recruitment of 45 patients. Therefore, the trial closed early as a result of poor recruitment, and the uncertainty about the best treatment for high-risk patients with colorectal liver metastases continues. The main reasons for the poor recruitment included fewer than anticipated eligible participants, clinicians' unconscious bias towards surgery, and patients' preference for one treatment or the other. In the future, comparisons involving two very different treatments may benefit from a feasibility study or a longer period of pilot study to resolve any difficulties.

Management of acute and chronic iliofemoral venous outflow obstruction: a multidisciplinary team consensus.

The aim of this manuscript was to establish a consensus for the management of acute and chronic venous obstruction among specialists in the UK. Specialist physicians representing vascular surgery, interventional radiology and hematology were invited to 3 meetings to discuss management of acute and chronic iliofemoral obstruction. The meetings outlined controversial areas, included a topic-by-topic review; and on completion reached a consensus when greater than 80% agreement was reached on each topic. Physicians from 19 UK hospitals agreed on treatment protocols and highlighted areas that need development. Potential standard treatment algorithms were created. It was decided to establish a national registry of venous patients led by representatives from the treating multidisciplinary teams. Technical improvements have facilitated invasive treatment of patients with acute and chronic venous obstruction; however, the evidence guiding treatment is weak. Treatment should be conducted in centers with multi-disciplinary input; robust, coordinated data collection; and regular outcome analysis to ensure safe and effective treatment and a basis for future evolvement.

Prolonged-access to cocaine induces distinct Homer2 DNA methylation, hydroxymethylation, and transcriptional profiles in the dorsomedial prefrontal cortex of Male Sprague-Dawley rats.

Repeated cocaine administration induces many long-term structural and molecular changes in the dorsal medial prefrontal cortex (dmPFC) and are known to underlie aspects of cocaine-seeking behavior. DNA methylation is a key long-lasting epigenetic determinant of gene expression and is implicated in neuroplasticity, however, the extent to which this epigenetic modification is involved in the neuroplasticity associated with drug addiction has received limited attention. Here, we examine the relation between DNA methylation and gene expression within the dorsal medial prefrontal cortex (dmPFC) following limited cocaine self-administration (1 h/day), prolonged cocaine self-administration (6 h/day), and saline self-administration (1 h/day). Rats were fitted with intravenous catheters and allowed to lever press for saline or cocaine (0.25 mg/kg/0.1 mL infusion) in the different access conditions for 20 days. Prolonged-access rats exhibited escalation in cocaine intake over the course of training, while limited-access rats did not escalate cocaine intake. Additionally, limited-access and prolonged-access rats exhibited unique Homer2 epigenetic profiles and mRNA expression. In prolonged-access rats, Homer2 mRNA levels in the dmPFC were increased, which was accompanied by decreased DNA methylation and p300 binding within the Homer2 promoter. Limited-access animals exhibited decreased DNA methylation, decreased DNA hydroxymethylation, and increased p300 binding within the Homer2 promoter. These data indicate that distinct epigenetic profiles are induced by limited-versus prolonged-access self-administration conditions that contribute to transcriptional profiles and lend support to the notion that covalent modification of DNA is implicated in addiction-like changes in cocaine-seeking behavior.

Liver resection surgery versus thermal ablation for colorectal LiVer MetAstases (LAVA): study protocol for a randomised controlled trial.

BACKGROUND: Although surgical resection has been considered the only curative option for colorectal liver metastases (CLM), thermal ablation has recently been suggested as an alternative curative treatment. A prospective randomised trial is required to define the efficacy of resection vs ablation for the treatment of colorectal liver metastases. METHODS: Design and setting: This is a multicentre, open, randomised controlled non-inferiority trial design with internal pilot and will be performed in tertiary liver centres in UK and The Netherlands. PARTICIPANTS: Eligible patients will be those with colorectal liver metastases at high surgical risk because of their age, co-morbidities or tumour burden and who would be suitable for liver resection or thermal ablation. INTERVENTION: Thermal ablation as per local policy. CONTROL: Surgical liver resection performed as per centre protocol. Co-interventions: Further chemotherapy will be offered to patients as per current practice. Outcomes Pilot study: Same as main study and in addition patients and clinicians' acceptability of the trial to assist in optimisation of recruitment. PRIMARY OUTCOME: Disease-free survival (DFS) at two years post randomisation. SECONDARY OUTCOMES: Overall survival, timing and site of recurrence, additional therapy after treatment failure, quality of life, complications, length of hospital stay, costs, trial acceptability, DFS measured from end of intervention. FOLLOW-UP: 24 months from randomisation; five-year follow-up for overall survival. SAMPLE SIZE: 330 patients to demonstrate non-inferiority of thermal ablation. DISCUSSION: This trial will determine the effectiveness and cost-effectiveness of thermal ablation vs surgical resection for high-risk people with colorectal liver metastases, and guide the optimal treatment for these patients. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN52040363 . Registered on 9 March 2016.

Use of transabdominal ultrasound-guided transjugular portal vein puncture on radiation dose in transjugular intrahepatic portosystemic shunt formation.

PURPOSE: Transjugular intrahepatic portosystemic shunt (TIPS) creation is used to treat portal hypertension complications. Often the most challenging and time-consuming step in the procedure is the portal vein (PV) puncture. TIPS procedures are associated with prolonged fluoroscopy time and high patient radiation exposures. We measured the impact of transabdominal ultrasound guidance for PV puncture on duration of fluoroscopy time and dose. METHODS: We retrospectively analyzed the radiation dose for all TIPS performed over a four-year period with transabdominal ultrasound guidance for PV puncture (n=212, with 210 performed successfully and data available for 206); fluoroscopy time, dose area product (DAP) and skin dose were recorded. RESULTS: Mean fluoroscopy time was 12 min 9 s (SD, ±14 min 38 s), mean DAP was 40.3±73.1 Gy·cm2, and mean skin dose was 404.3±464.8 mGy. CONCLUSION: Our results demonstrate that ultrasound-guided PV puncture results in low fluoroscopy times and radiation doses, which are markedly lower than the only published dose reference levels.

Minimizing Air Pollution Exposure: A Practical Policy to Protect Vulnerable Older Adults from Death and Disability.

Air pollution causes an estimated 200,000 deaths per year in the United States alone. Older adults are at greater risk of mortality caused by air pollution. Here we quantify the number of older adult facilities in Los Angeles County that are exposed to high levels of traffic derived air pollution, and propose policy solutions to reduce pollution exposure to this vulnerable subgroup. Distances between 20,362 intersections and 858 elder care facilities were estimated, and roads or highways within 500 of facilities were used to estimate traffic volume exposure. Of the 858 facilities, 54 were located near at least one major roadway, defined as a traffic volume over 100,000 cars/day. These 54 facilities house approximately 6,000 older adults. Following standards established for schools, we recommend legislation mandating the placement of new elder care facilities a minimum of 500 feet from major roadways in order to reduce unnecessary mortality risk from pollution exposure.

Real-time, aptamer-based tracking of circulating therapeutic agents in living animals.

A sensor capable of continuously measuring specific molecules in the bloodstream in vivo would give clinicians a valuable window into patients' health and their response to therapeutics. Such technology would enable truly personalized medicine, wherein therapeutic agents could be tailored with optimal doses for each patient to maximize efficacy and minimize side effects. Unfortunately, continuous, real-time measurement is currently only possible for a handful of targets, such as glucose, lactose, and oxygen, and the few existing platforms for continuous measurement are not generalizable for the monitoring of other analytes, such as small-molecule therapeutics. In response, we have developed a real-time biosensor capable of continuously tracking a wide range of circulating drugs in living subjects. Our microfluidic electrochemical detector for in vivo continuous monitoring (MEDIC) requires no exogenous reagents, operates at room temperature, and can be reconfigured to measure different target molecules by exchanging probes in a modular manner. To demonstrate the system's versatility, we measured therapeutic in vivo concentrations of doxorubicin (a chemotherapeutic) and kanamycin (an antibiotic) in live rats and in human whole blood for several hours with high sensitivity and specificity at subminute temporal resolution. We show that MEDIC can also obtain pharmacokinetic parameters for individual animals in real time. Accordingly, just as continuous glucose monitoring technology is currently revolutionizing diabetes care, we believe that MEDIC could be a powerful enabler for personalized medicine by ensuring delivery of optimal drug doses for individual patients based on direct detection of physiological parameters.

Extended access to cocaine self-administration results in reduced glutamate function within the medial prefrontal cortex.

Previous studies have shown that brief access to cocaine yields an increase in D2 receptor binding in the medial prefrontal cortex (mPFC), but that extended access to cocaine results in normalized binding of D2 receptors (i.e. the D2 binding returned to control levels). Extended-access conditions have also been shown to produce increased expression of the NR2 subunit of the N-Methyl-D-aspartate receptor in the mPFC. These results implicate disrupted glutamate and dopamine function within this area. Therefore, in the present study, we monitored glutamate and dopamine content within the mPFC during, or 24 hours after, cocaine self-administration in animals that experienced various amounts of exposure to the drug. Naïve subjects showed decreased glutamate and increased dopamine levels within the mPFC during cocaine self-administration. Exposure to seven 1-hour daily cocaine self-administration sessions did not alter the response to self-administered cocaine, but resulted in decreased basal dopamine levels. While exposure to 17 1-hour sessions also resulted in reduced basal dopamine levels, these animals showed increased dopaminergic, but completely diminished glutamatergic, response to self-administered cocaine. Finally, exposure to 17 cocaine self-administration sessions, the last 10 of which being 6-hour sessions, resulted in diminished glutamatergic response to self-administered cocaine and reduced basal glutamate levels within the mPFC while normalizing (i.e. causing a return to control levels) both the dopaminergic response to self-administered cocaine as well as basal dopamine levels within this area. These data demonstrate directly that the transition to escalated cocaine use involves progressive changes in dopamine and glutamate function within the mPFC.

EASL and mRECIST responses are independent prognostic factors for survival in hepatocellular cancer patients treated with transarterial embolization.

BACKGROUND & AIMS: Standard RECIST criteria may not be the optimal method to assess response to loco-regional therapy for hepatocellular cancer (HCC). EASL and mRECIST, which measure changes in arterialized tumor, have been proposed. Here we compare the three criteria and their associations with survival. METHODS: Response was determined using RECIST 1.1, EASL, and mRECIST criteria in 83 consecutive patients with HCC undergoing palliative therapy with transarterial (chemo) embolization. Results were compared at the first assessment after therapy. Cox regression and Kaplan-Meier survival analyses were used to explore differences in overall survival between the responders and non-responders defined by each method. RESULTS: There was a good correlation between EASL and mRECIST with overall response rates; 58% and 57%, and target lesion responses; 74% and 73%, respectively. There was a poor correlation with RECIST 1.1 with overall and target response rates of 7%. Overall and target lesion progression rates were similar for all three assessments; 27% and 2% for both EASL and mRECIST and 28% and 6% for RECIST 1.1. There was a significant association between survival and overall EASL and mRECIST responses, which was retained in multivariate analysis. EASL response was associated with a 44% risk reduction and mRECIST with a 42% reduction. There was no significant association between survival for RECIST 1.1 responses or target EASL and mRECIST responses. CONCLUSIONS: When measured at a single, early time point post-therapy, EASL and mRECIST overall response rates are associated with survival and should be used in preference to RECIST 1.1 or target responses.

Acute gastrointestinal bleeding: CT angiography with multi-planar reformatting.

Acute gastrointestinal bleeding is a common medical emergency, which carries a significant mortality. CT Angiography is an important non-invasive diagnostic tool, which can be used to plan subsequent endovascular or surgical management. The cases presented demonstrate that a meticulous and systematic approach to image interpretation is necessary, in particular, to detect focal sites of contrast extravasation and small pseudoaneurysms.