Magnetic Resonance Imaging-Guided Biopsy in Active Surveillance of Prostate Cancer.

PURPOSE: The underlying premise of prostate cancer active surveillance (AS) is that cancers likely to metastasize will be recognized and eliminated before cancer-related disease can ensue. Our study was designed to determine the prostate cancer upgrading rate when biopsy guided by magnetic resonance imaging (MRGBx) is used before entry and during AS. MATERIALS AND METHODS: The cohort included 519 men with low- or intermediate-risk prostate cancer who enrolled in prospective studies (NCT00949819 and NCT00102544) between February 2008 and February 2020. Subjects were preliminarily diagnosed with Gleason Grade Group (GG) 1 cancer; AS began when subsequent MRGBx confirmed GG1 or GG2. Participants underwent confirmatory MRGBx (targeted and systematic) followed by surveillance MRGBx approximately every 12 to 24 months. The primary outcome was tumor upgrading to ≥GG3. RESULTS: Upgrading to ≥GG3 was found in 92 men after a median followup of 4.8 years (IQR 3.1-6.5) after confirmatory MRGBx. Upgrade-free probability after 5 years was 0.85 (95% CI 0.81-0.88). Cancer detected in a magnetic resonance imaging lesion at confirmatory MRGBx increased risk of subsequent upgrading during AS (HR 2.8; 95% CI 1.3-6.0), as did presence of GG2 (HR 2.9; 95% CI 1.1-8.2) In men who upgraded ≥GG3 during AS, upgrading was detected by targeted cores only in 27%, systematic cores only in 25% and both in 47%. In 63 men undergoing prostatectomy, upgrading from MRGBx was found in only 5 (8%). CONCLUSIONS: When AS begins and follows with MRGBx (targeted and systematic), upgrading rate (≥GG3) is greater when tumor is initially present within a magnetic resonance imaging lesion or when pathology is GG2 than when these features are absent.

Hemigland Cryoablation of Clinically Significant Prostate Cancer: Intermediate-Term Followup via Magnetic Resonance Imaging Guided Biopsy.

PURPOSE: Contemporary biopsy methods were used to determine the success rate of hemigland cryoablation as a primary treatment for prostate cancer. Previous studies, often including men at low risk, have used magnetic resonance imaging guided biopsy to a variable extent. Here, we uniformly used the new diagnostic modality to study all men, each with clinically significant cancer, at baseline and at short and intermediate-term followup. MATERIALS AND METHODS: In an open label trial (NCT03503643) 61 men with unilateral cancer (all clinically significant, ie Grade Group 2 or greater) underwent primary hemigland cryoablation. Subjects were 80% Caucasian, average age 69 years, prostate specific antigen 6.6 ng/ml and prostate volume 38 cc. Biopsy was performed using magnetic resonance imaging/ultrasound fusion prior to treatment and at the followup intervals of near-term (6 months, in 61) and intermediate-term (18 months, in 27). All utilities of fusion biopsy, ie targeting of magnetic resonance imaging visible lesions, template systematic sampling, and in followup, tracking of prior positive sites, were used throughout the study to detect clinically significant cancer, the primary end point. RESULTS: Following treatment 82% of men (50 of 61) had no biopsy detectable clinically significant prostate cancer at 6-month near-term followup and 82% of men (22 of 27) reaching the 18-month intermediate-term remained biopsy negative. Combination of the 3 sampling methods provided maximal cancer detection. During followup a new focus of cancer was found in the contralateral prostate in only 1 of 27 men. No adverse events above Clavien-Dindo grade 2 were encountered. CONCLUSIONS: Hemigland cryoablation, when rigorously evaluated by all utilities of magnetic resonance imaging guided biopsy, appears to eliminate clinically significant cancer in 82% of men, a success rate that endures for at least 18 months.

Risk of Prostate Cancer after a Negative Magnetic Resonance Imaging Guided Biopsy.

PURPOSE: Magnetic resonance imaging guided biopsy which reveals no cancer may impart reassurance beyond that offered by ultrasound guided biopsy. However, followup of men after a negative magnetic resonance imaging guided biopsy has been mostly by prostate specific antigen testing and reports of followup tissue confirmation are few. We investigated the incidence of clinically significant prostate cancer in such men who, because of persistent cancer suspicion, subsequently underwent a repeat magnetic resonance imaging guided biopsy. MATERIALS AND METHODS: Subjects were all men with a negative initial magnetic resonance imaging guided biopsy who underwent at least 1 further magnetic resonance imaging guided biopsy due to continued clinical suspicion of clinically significant prostate cancer (September 2009 to July 2019). Biopsies were magnetic resonance imaging-ultrasound fusion with targeted and systematic cores. Regions of interest from initial magnetic resonance imaging and any new regions of interest at followup magnetic resonance imaging guided biopsy were targeted. The primary end point was detection of clinically significant prostate cancer (Gleason Grade Group 2 or greater). RESULTS: Of 2,716 men 733 had a negative initial magnetic resonance imaging guided biopsy. Study subjects were 73/733 who underwent followup magnetic resonance imaging guided biopsy. Median (IQR) age and prostate specific antigen density were 64 years (59-67) and 0.12 ng/ml/cc (0.08-0.17), respectively. Baseline PI-RADS® scores were 3 or greater in 74%. At followup magnetic resonance imaging guided biopsy (median 2.4 years, IQR 1.3-3.6), 17/73 (23%) were diagnosed with clinically significant prostate cancer. When followup magnetic resonance imaging revealed a lesion (PI-RADS 3 or greater), clinically significant prostate cancer was found in 17/53 (32%). When followup magnetic resonance imaging was negative (PI-RADS less than 3), cancer was not found (0/20) (p <0.01). Overall 54% of men with PI-RADS 5 at followup magnetic resonance imaging guided biopsy were found to have clinically significant prostate cancer. CONCLUSIONS: Men with negative magnetic resonance imaging following an initial negative magnetic resonance imaging guided biopsy are unlikely to harbor clinically significant prostate cancer and may avoid repeat biopsy. However, when lesions are seen on followup magnetic resonance imaging, repeat magnetic resonance imaging guided biopsy is warranted.

Outcomes After Recurrent Intentional Methanol Exposures Not Treated With Alcohol Dehydrogenase Inhibitors Or Hemodialysis.

BACKGROUND: Relying on a treatment threshold for methanol poisoning of 20 mg/dL (6.2 mmol/L) as a stand-alone criterion may lead to unnecessary and invasive treatment because it is likely too conservative, especially for patients with repeated, intentional methanol exposures. OBJECTIVE: We investigated how often patients with recurrent intentional methanol exposures above this threshold developed biochemical or overt clinical toxicity despite not being treated with either an alcohol dehydrogenase inhibitor (ADHi) or hemodialysis. METHODS: We identified patients with ≥3 methanol-related emergency visits from 2002 to 2015 and selected every visit in which neither ADHi nor hemodialysis were administered despite serum methanol >20 mg/dL but neither metabolic acidosis nor end organ toxicity at presentation. The primary outcome was the incidence of visual deterioration or death. RESULTS: Four patients accounted for the 17 visits that met inclusion criteria. All exposures were intentional substance misuse, and 7 of 17 were via inhalation (i.e., huffing). Initial methanol concentrations ranged from 22 mg/dL to 35 mg/dL (7-11 mmol/L). Four of these 17 visits had undetectable initial ethanol concentrations at presentation, including 1 with an initial methanol concentration of 35 mg/dL. No patients developed visual deterioration, and all were known to have survived the exposure. CONCLUSION: Following recurrent, intentional methanol exposure, isolated serum methanol concentrations as high as 35 mg/dL (11 mmol/L) appear to be well-tolerated without treatment in the absence of metabolic acidosis or end-organ toxicity. To better define the methanol treatment threshold, prospective studies are warranted in which patients are followed closely while fomepizole is withheld.

Coevolution within a transcriptional network by compensatory trans and cis mutations.

Transcriptional networks have been shown to evolve very rapidly, prompting questions as to how such changes arise and are tolerated. Recent comparisons of transcriptional networks across species have implicated variations in the cis-acting DNA sequences near genes as the main cause of divergence. What is less clear is how these changes interact with trans-acting changes occurring elsewhere in the genetic circuit. Here, we report the discovery of a system of compensatory trans and cis mutations in the yeast AP-1 transcriptional network that allows for conserved transcriptional regulation despite continued genetic change. We pinpoint a single species, the fungal pathogen Candida glabrata, in which a trans mutation has occurred very recently in a single AP-1 family member, distinguishing it from its Saccharomyces ortholog. Comparison of chromatin immunoprecipitation profiles between Candida and Saccharomyces shows that, despite their different DNA-binding domains, the AP-1 orthologs regulate a conserved block of genes. This conservation is enabled by concomitant changes in the cis-regulatory motifs upstream of each gene. Thus, both trans and cis mutations have perturbed the yeast AP-1 regulatory system in such a way as to compensate for one another. This demonstrates an example of "coevolution" between a DNA-binding transcription factor and its cis-regulatory site, reminiscent of the coevolution of protein binding partners.

A prostate cancer risk calculator: Use of clinical and magnetic resonance imaging data to predict biopsy outcome in North American men.

INTRODUCTION: A functional tool to optimize patient selection for magnetic resonance imaging (MRI)-guided prostate biopsy (MRGB) is an unmet clinical need. We sought to develop a prostate cancer risk calculator (PCRC-MRI) that combines MRI and clinical characteristics to aid decision-making for MRGB in North American men. METHODS: Two prospective registries containing 2354 consecutive men undergoing MRGB (September 2009 to April 2019) were analyzed. Patients were randomized into five groups, with one group randomly assigned to be the validation cohort against the other four groups as the discovery cohort. The primary outcome was detection of clinically significant prostate cancer (csPCa) defined as Gleason grade group ≥2. Variables included age, ethnicity, digital rectal exam (DRE), prior biopsy, prostate-specific antigen (PSA), prostate volume, PSA density, and MRI score. Odds ratios (OR) were calculated from multivariate logistic regression comparing two models: one with clinical variables only (clinical) against a second combining clinical variables with MRI data (clinical+MRI). RESULTS: csPCa was present in 942 (40%) of the 2354 men available for study. The positive and negative predictive values for csPCa in the clinical+MRI model were 57% and 89%, respectively. The area under the curve of the clinical+MRI model was superior to the clinical model in discovery (0.843 vs. 0.707, p<0.0001) and validation (0.888 vs. 0.757, p<0.0001) cohorts. Use of PCRC-MRI would have avoided approximately 16 unnecessary biopsies in every 100 men. Of all variables examined, Asian ethnicity was the most protective factor (OR 0.46, 0.29-0.75) while MRI score 5 indicated greatest risk (OR15.8, 10.5-23.9). CONCLUSIONS: A risk calculator (PCRC-MRI), based on a large North American cohort, is shown to improve patient selection for MRGB, especially in preventing unnecessary biopsies. This tool is available at https://www.uclahealth.org/urology/prostate-cancer-riskcalculator and may help rationalize biopsy decision-making.

Dextromethorphan, chlorphenamine and serotonin toxicity: case report and systematic literature review.

The aim of this review was to describe a patient with serotonin toxicity after an overdose of dextromethorphan and chlorphenamine and to perform a systematic literature review exploring whether dextromethorphan and chlorphenamine may be equally contributory in the development of serotonin toxicity in overdose. A Medline literature review was undertaken to identify cases of serotonin toxicity due to dextromethorphan and/or chlorphenamine. Case reports were included if they included information on the ingested dose or plasma concentrations of dextromethorphan and/or chlorphenamine, information about co-ingestions and detailed clinical information to evaluate for serotonin toxicity. Cases were reviewed by two toxicologists and serotonin toxicity, defined by the Hunter criteria, was diagnosed when appropriate. The literature was then reviewed to evaluate whether chlorphenamine may be a serotonergic agent. One hundred and fifty-five articles of dextromethorphan or chlorphenamine poisoning were identified. There were 23 case reports of dextromethorphan, of which 18 were excluded for lack of serotonin toxicity. No cases were identified in which serotonin toxicity could be solely attributed to chlorphenamine. This left six cases of dextrometorphane and/or chlorphenamine overdose, including our own, in which serotonin toxicity could be diagnosed based on the presented clinical information. In three of the six eligible cases dextromethorphan and chlorphenamine were the only overdosed drugs. There is substantial evidence from the literature that chlorphenamine is a similarly potent serotonin re-uptake inhibitor when compared with dextrometorphan. Chlorphenamine is a serotonergic medication and combinations of chlorphenamine and dextromethorphan may be dangerous in overdose due to an increased risk of serotonin toxicity.

A Case of Status Epilepticus and Transient Stress Cardiomyopathy Associated with Smoking the Synthetic Psychoactive Cannabinoid, UR-144.

BACKGROUND Synthetic cannabinoids have a higher affinity for the cannabinoid receptors CB1 and CB2 than natural cannabinoids. Their use can be associated with cardiovascular disease and neurological complications. A case is reported of status epilepticus and stress cardiomyopathy following the recreational use of the synthetic cannabinoid, UR-144. CASE REPORT A 19-year-old woman presented to the emergency department in status epilepticus after smoking the synthetic cannabinoid known as 'space'. Recurring seizure activity was controlled after three hours. On hospital day 3, the patient developed severe biventricular failure. Cardiac magnetic resonance imaging (MRI) confirmed the diagnosis of stress cardiomyopathy. A comprehensive urine drug screen was performed using gas chromatography-mass spectrometry (GC-MS), which was positive for UR-144, or (1-pentyl-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)-methanone, and negative for all other illicit recreational drugs. The patient improved at one week following admission, with a left ventricular ejection fraction (LVEF) of 40%. She was discharged home on hospital day 10. CONCLUSIONS The use of the synthetic cannabinoid, UR-144, may be associated with prolonged status epilepticus and stress cardiomyopathy. Physicians should be aware of these potentially lethal complications associated with the recreational use of this and other illicit synthetic cannabinoids.

A Case of an Invisible Ureteral Stent.

A 35-year-old female presented to the emergency department with fevers and flank pain and was found on computed tomography to have a retained ureteral stent that was placed during emergent ureteral repair eight years prior. The stent was only faintly visible on computed tomography and was completely radiolucent on fluoroscopy. We believe that the stent's radiopaque coating degraded and was lost after years of exposure to urine. This case suggests that a stent may become undetectable on standard imaging if left in place for a long enough period of time.

A cohort study of unstable overdose patients treated with intravenous lipid emulsion therapy.

OBJECTIVES: Intravenous lipid emulsion (ILE) has been used increasingly over the last decade for a range of drug overdoses. Although the use of ILE in local anesthetic toxicity (LAST) is well established, the hemodynamic effectiveness of ILE in non-LAST poisonings is still unclear. Thus, the primary objective of this study was to examine a cohort of poisoned patients in whom ILE was administered. METHODS: Consecutive patients were identified by calls to a regional poison center from May 1, 2012 to May 30, 2014. Patients were enrolled if they ingested a drug, developed hemodynamic instability, failed conventional treatment, and received ILE therapy. Data were collected by medical record review. The primary outcome was the change in mean arterial pressure (MAP) in the first hour after ILE administration. Secondary outcomes included survival, length of stay, and the effect of drug class on patient outcome. RESULTS: Thirty-six patients were enrolled. Agents ingested included calcium channel blockers and beta blockers (10/36, 27.8%), tricyclic antidepressants (5/36, 13.9%), bupropion (3/36, 8.3%), and antiepileptic agents (1/36, 2.8%). Seventeen patients (47.2%) ingested multiple agents. Twenty-five patients survived (69.0%). Overall, MAP increased by 13.79 mm Hg (95% CI 1.43-26.15); this did not meet our a priori definition of clinical significance. CONCLUSIONS: Our study did not find a clinically important improvement in MAP after ILE administration. Until future research is done to more definitively study its efficacy, ILE should remain a potential treatment option for hemodynamically unstable overdose patients only after conventional therapy has failed.

The Cost Burden of Complications after Major Surgery for Urological Cancer: Opportunities for Value Creation in Urology.

INTRODUCTION: While improving patient outcomes and controlling costs have become primary pursuits in health care, priority areas for value creation remain unclear. In urology operative morbidity serves as a major barrier to high value care. To guide improvement efforts we assessed the prevalence and cost of inpatient complications among patients undergoing major surgery for urological cancer. METHODS: Using the Nationwide Inpatient Sample from 2009 to 2011 we identified hospital admissions for cancer related prostatectomy, nephrectomy and cystectomy among adults age 18 years or older. We then measured the occurrence of inpatient complications, medical and surgical, and used multivariable, mixed effect models to estimate the associated marginal cost. RESULTS: Among weighted samples of 229,743 prostatectomies, 111,683 nephrectomies and 31,213 cystectomies, inpatient complications occurred in 9.4% (95% CI 8.6-10.2), 32.0% (95% CI 30.7-33.4) and 57.7% (95% CI 54.7-60.6) of hospital admissions, respectively. For these respective samples an adverse event added $4,947 (95% CI 4,523-5,454), $6,782 (95% CI 6,336-7,293) and $10,756 (95% CI 9,999-11,759) to the cost of inpatient care. While surgical events occurred most frequently, medical complications generated $1,699 (95% CI 994-2,423), $2,052 (95% CI 1,545-2,662) and $4,852 (95% CI 3,519-6,531) more in expense per episode for prostate, kidney and bladder cancer cases, respectively. CONCLUSIONS: Many patients undergoing major surgery for urological cancer experience a complication, adding substantially to health care costs. As urologists seek to generate value in urological cancer care, the prevention and management of complications, especially medically driven events, represent an immediate opportunity for quality improvement and cost savings.

Health Insurance Status and Disparities in Kidney Cancer Care.

INTRODUCTION: Through PPACA (Patient Protection and Affordable Care Act) many adults have or will gain health insurance via Medicaid expansion. To understand how this policy change may potentially impact patients with kidney cancer we examined the relationship between insurance status and cancer related outcomes. METHODS: Using SEER (Surveillance, Epidemiology and End Results) data we identified 18,632 patients 26 to 64 years old with kidney cancer from 2007 to 2009. For each patient we classified insurance status as no insurance, Medicaid or private insurance. After adjusting for patient and county characteristics we measured the association of insurance status with cancer stage, treatment and 1-year mortality using multinomial logistic regression with clustering or generalized estimating equations as appropriate. RESULTS: In our study cohort 937 (5.0%) and 2,027 patients (10.9%) had no insurance and Medicaid, respectively. These patients were more likely to be younger, nonwhite, unmarried and residing in areas with lower income, education or employment (p <0.001). On adjusted analyses uninsured and Medicaid patients more often presented with advanced disease (21.3% vs 19.6% vs 11.0%) but less frequently received treatment (86.2% vs 87.9% vs 93.4%, each p <0.001) compared with privately insured patients. These adults also died of kidney cancer more often (13.6% vs 12.5% vs 6.4%, p <0.001) likely due to differences in stage and receipt of cancer directed therapy. CONCLUSIONS: Uninsured and Medicaid patients suffer disproportionately from kidney cancer with equal magnitude. Given the reliance on Medicaid, even as insurance coverage expands differences in outcomes will likely persist, underscoring the need for additional efforts that address disparities in kidney cancer care.

Systematic review of the effect of intravenous lipid emulsion therapy for non-local anesthetics toxicity.

BACKGROUND: The use of intravenous lipid emulsion (ILE) therapy for the treatment of lipophilic drug toxicity is increasing. Despite this, the evidence for its effect in non-local anesthetic toxicity remains sparse. Furthermore, many case reports describe ILE use for substances in which no clear efficacy data exists. The American Academy of Clinical Toxicology established a lipid emulsion workgroup. The aim of this group is to review the available evidence regarding the effect of ILE in non-LA drug poisoning and develop consensus-based recommendations on the use of this therapy. METHODS: A systematic review of the literature was performed to capture articles through 15 December 2014. Relevant articles were determined based upon a predefined methodology. Articles involving pre-treatment experiments, pharmacokinetic studies not involving toxicity, and studies not addressing antidotal use of ILE met pre-defined exclusion criteria. Agreement of at least two members of the subgroup was required before an article could be excluded. RESULTS: The final analysis included 203 articles: 141 for humans and 62 for animals. These include 40 animal experiments and 22 case reports involving animal toxicity. There were three human randomized control trials (RCT): one RCT examined ILE in TCA overdose, one RCT examined ILE in various overdoses, and one study examined ILE in reversal of sedation after therapeutic administration of inhaled anesthesia. One observational study examined ILE in glyphosate overdose. In addition, 137 human case reports or case series were identified. Intravenous lipid emulsion therapy was used in the management of overdose with 65 unique substances. CONCLUSIONS: Despite the use of ILE for multiple substances in the treatment of patients with poisoning and overdose, the effect of ILE in various non-local anesthetic poisonings is heterogenous, and the quality of evidence remains low to very low.

Technique and outcomes of bladder neck intussusception during robot-assisted laparoscopic prostatectomy: A parallel comparative trial.

INTRODUCTION: Postprostatectomy incontinence significantly impairs quality of life. Although bladder neck intussusception has been reported to accelerate urinary recovery after open radical retropubic prostatectomy, its adaption to robotic surgery has not been assessed. Accordingly, we describe our technique and compare outcomes between men treated with and without bladder neck intussusception during robot-assisted laparoscopic prostatectomy. MATERIALS AND METHODS: We performed a comparative trial of 48 men undergoing robot-assisted laparoscopic prostatectomy alternating between bladder neck intussusception (n = 24) and nonintussusception (n = 24). Intussusception was completed using 3-0 polyglycolic acid horizontal mattress sutures anterior and posterior to the bladder neck. We assessed baseline characteristics and clinicopathologic outcomes. Adjusting for age, body mass index, race, and D׳Amico risk classification, we prospectively compared urinary function at 2 days, 2 weeks, 2 months, and last follow-up using the urinary domain of the Expanded Prostate Cancer Index-Short Form. RESULTS: Baseline patient characteristics and clinicopathologic outcomes were similar between treatment groups (P>0.05). Median catheter duration (8 vs. 8d, P = 0.125) and rates of major postoperative complications (4.2% vs. 4.2%, P = 1.000) did not differ. In adjusted analyses, Expanded Prostate Cancer Index-Short Form urinary scores were significantly higher for the intussusception arm at 2 weeks (65.4 vs. 46.6, P = 0.019) before converging at 2 months (69.1 vs. 68.3, P = 0.929) after catheter removal and at last follow-up (median = 7mo, 80.5 vs. 77.0; P = 0.665). CONCLUSIONS: Bladder neck intussusception during robot-assisted laparoscopic prostatectomy is feasible and safe. Although the long-term effects appear limited, intussusception may improve urinary function during the early recovery period.

Evidence-based recommendations on the use of intravenous lipid emulsion therapy in poisoning.

BACKGROUND: Although intravenous lipid emulsion (ILE) was first used to treat life-threatening local anesthetic (LA) toxicity, its use has expanded to include both non-local anesthetic (non-LA) poisoning and less severe manifestations of toxicity. A collaborative workgroup appraised the literature and provides evidence-based recommendations for the use of ILE in poisoning. METHODS: Following a systematic review of the literature, data were summarized in four publications: LA and non-LA poisoning efficacy, adverse effects, and analytical interferences. Twenty-two toxins or toxin categories and three clinical situations were selected for voting. Voting statements were proposed using a predetermined format. A two-round modified Delphi method was used to reach consensus on the voting statements. Disagreement was quantified using RAND/UCLA Appropriateness Method. RESULTS: For the management of cardiac arrest, we recommend using ILE with bupivacaine toxicity, while our recommendations are neutral regarding its use for all other toxins. For the management of life-threatening toxicity, (1) as first line therapy, we suggest not to use ILE with toxicity from amitriptyline, non-lipid soluble beta receptor antagonists, bupropion, calcium channel blockers, cocaine, diphenhydramine, lamotrigine, malathion but are neutral for other toxins, (2) as part of treatment modalities, we suggest using ILE in bupivacaine toxicity if other therapies fail, but are neutral for other toxins, (3) if other therapies fail, we recommend ILE for bupivacaine toxicity and we suggest using ILE for toxicity due to other LAs, amitriptyline, and bupropion, but our recommendations are neutral for all other toxins. In the treatment of non-life-threatening toxicity, recommendations are variable according to the balance of expected risks and benefits for each toxin. For LA-toxicity we suggest the use of Intralipid® 20% as it is the formulation the most often reported. There is no evidence to support a recommendation for the best formulation of ILE for non-LAs. The voting panel is neutral regarding ILE dosing and infusion duration due to insufficient data for non-LAs. All recommendations were based on very low quality of evidence. CONCLUSION: Clinical recommendations regarding the use of ILE in poisoning were only possible in a small number of scenarios and were based mainly on very low quality of evidence, balance of expected risks and benefits, adverse effects, laboratory interferences as well as related costs and resources. The workgroup emphasizes that dose-finding and controlled studies reflecting human poisoning scenarios are required to advance knowledge of limitations, indications, adverse effects, effectiveness, and best regimen for ILE treatment.

Evolution of laparoscopic donor nephrectomy technique and outcomes: a single-center experience with more than 1300 cases.

OBJECTIVE: To describe and illustrate the evolution of surgical technique, emphasizing technical modifications of laparoscopic donor nephrectomy (LDN) and the impact on complication outcome. METHODS: This is a retrospective observational study of prospectively collected data on all consecutive purely LDN surgeries performed at a tertiary academic medical center (n = 1325), performed between March 2000 and October 2013. RESULTS: Over time, LDN was performed on older patients, changing from a mean of 35.7 years in 2000 to 41.2 years in 2013 (P <.001). Additionally, mean blood loss decreased from 75 mL in 2000 to 21.6 mL in 2013 (P <.001). However, body mass index, operative time, and length of stay remained similar. Overall, there were 105 (7.9%) complications: Clavien grade 1 (n = 81, 6.1%) and grade 2 or higher (n = 23, 1.8%). Procedure duration, blood loss, surgeon, year of procedure, laterality, body mass index, age, and gender did not significantly predict complications. There was no significant difference for Clavien complication rates between the early learning period (first 150 cases) and the rest of the series. CONCLUSION: With continual refinement with LDN techniques based on intraoperative observations and technological advances, complication rates remain consistently low, despite increasing donor age.

Drug target optimization in chronic myeloid leukemia using innovative computational platform.

Chronic Myeloid Leukemia (CML) represents a paradigm for the wider cancer field. Despite the fact that tyrosine kinase inhibitors have established targeted molecular therapy in CML, patients often face the risk of developing drug resistance, caused by mutations and/or activation of alternative cellular pathways. To optimize drug development, one needs to systematically test all possible combinations of drug targets within the genetic network that regulates the disease. The BioModelAnalyzer (BMA) is a user-friendly computational tool that allows us to do exactly that. We used BMA to build a CML network-model composed of 54 nodes linked by 104 interactions that encapsulates experimental data collected from 160 publications. While previous studies were limited by their focus on a single pathway or cellular process, our executable model allowed us to probe dynamic interactions between multiple pathways and cellular outcomes, suggest new combinatorial therapeutic targets, and highlight previously unexplored sensitivities to Interleukin-3.

Methodology for AACT evidence-based recommendations on the use of intravenous lipid emulsion therapy in poisoning.

Intravenous lipid emulsion (ILE) therapy is a novel treatment that was discovered in the last decade. Despite unclear understanding of its mechanisms of action, numerous and diverse publications attested to its clinical use. However, current evidence supporting its use is unclear and recommendations are inconsistent. To assist clinicians in decision-making, the American Academy of Clinical Toxicology created a workgroup composed of international experts from various clinical specialties, which includes representatives of major clinical toxicology associations. Rigorous methodology using the Appraisal of Guidelines for Research and Evaluation or AGREE II instrument was developed to provide a framework for the systematic reviews for this project and to formulate evidence-based recommendations on the use of ILE in poisoning. Systematic reviews on the efficacy of ILE in local anesthetic toxicity and non-local anesthetic poisonings as well as adverse effects of ILE are planned. A comprehensive review of lipid analytical interferences and a survey of ILE costs will be developed. The evidence will be appraised using the GRADE system. A thorough and transparent process for consensus statements will be performed to provide recommendations, using a modified Delphi method with two rounds of voting. This process will allow for the production of useful practice recommendations for this therapy.