Predictors of perioperative complications in paediatric cranial vault reconstruction surgery: a multicentre observational study from the Pediatric Craniofacial Collaborative Group.

BACKGROUND: The current incidence of major complications in paediatric craniofacial surgery in North America has not been accurately defined. In this report, the Pediatric Craniofacial Collaborative Group evaluates the incidence and determines the independent predictors of major perioperative complications using a multicentre database. METHODS: The Pediatric Craniofacial Surgery Perioperative Registry was queried for subjects undergoing complex cranial vault reconstruction surgery over a 5-year period. Major perioperative complications were identified through a structured a priori consensus process. Logistic regression was applied to identify predictors of a major perioperative complication with bootstrapping to evaluate discrimination accuracy and provide internal validity of the multivariable model. RESULTS: A total of 1814 patients from 33 institutions in the US and Canada were analysed; 15% were reported to have a major perioperative complication. Multivariable predictors included ASA physical status 3 or 4 (P=0.005), craniofacial syndrome (P=0.008), antifibrinolytic administered (P=0.003), blood product transfusion >50 ml kg-1 (P<0.001), and surgery duration over 5 h (P<0.001). Bootstrapping indicated that the predictive algorithm had good internal validity and excellent discrimination and model performance. A perioperative complication was estimated to increase the hospital length of stay by an average of 3 days (P<0.001). CONCLUSIONS: The predictive algorithm can be used as a prognostic tool to risk stratify patients and thereby potentially reduce morbidity and mortality. Craniofacial teams can utilise these predictors of complications to identify high-risk patients. Based on this information, further prospective quality improvement initiatives may decrease complications, and reduce morbidity and mortality.

A prospective multicentre phase III validation study of AZGP1 as a biomarker in localized prostate cancer.

BACKGROUND: Prostate cancers (PCs) with similar characteristics at the time of diagnosis can have very different disease outcomes. Conventional biomarkers of PC still lack precision in identifying individuals at high risk of PC recurrence. While many candidate biomarkers are proposed in the literature, few are in clinical practice as they lack rigorous validation. This study prospectively enrolled an independent phase III cohort to evaluate the clinical utility of zinc-alpha 2-glycoprotein (AZGP1) as a prognostic biomarker in localized PC. PATIENTS AND METHODS: In our multicentre, prospective phase III study, AZGP1 status in 347 radical prostatectomy specimens was assayed by immunohistochemistry in a NATA-accredited laboratory. The AZGP1 score was assessed in a multivariable model incorporating established prognostic factors. We also report extended outcomes from our previous phase II study. The primary endpoint was biochemical relapse-free survival (BRFS). Secondary endpoints were metastasis-free survival (MFS) and PC-specific survival (PCSS). RESULTS: In the phase II cohort, with a median follow-up of 15.8 years, low/absent AZGP1 expression was an independent predictor of poor BRFS (HR, 1.4; 95% CI, 1.1-1.9; P = 0.03), MFS (HR, 2.8; 95% CI, 1.2-6.6; P = 0.02) and PCSS (HR, 3.8; 95% CI, 1.5-9.5; P = 0.005). These results were validated in our prospective phase III cohort. Low/absent AZGP1 expression independently predicted for BRFS (HR, 1.9; 95% CI, 1.1-3.3; P = 0.02), with shorter MFS (HR, 2.0; 95% CI, 1.1-3.4; P = 0.02). AZGP1 improved the discriminatory value when incorporated into existing prognostic risk models. CONCLUSION: Our study provides prospective phase III validation that absent/low AZGP1 expression provides independent prognostic value in PC. This study provides robust evidence for the incorporation of this biomarker into clinical practice.

Focal irreversible electroporation for prostate cancer: functional outcomes and short-term oncological control.

BACKGROUND: Current data on the use of irreversible electroporation (IRE) in the treatment of prostate cancer (PCa) is limited. We aim to evaluate the safety, short-term functional and oncological outcomes of focal IRE in low-intermediate risk PCa. METHODS: Between February 2013 and May 2014, 32 consecutive men underwent IRE at a single centre. Patients with low-intermediate risk PCa who had not received previous PCa treatment were included for analysis. The tumour was ablated using 3-6 electrodes, ensuring a minimum 5-mm safety margin around the visible magnetic resonance imaging (MRI) lesion. Follow-up included recording Clavien complications, Expanded Prostate Cancer Index Composite (EPIC) questionnaires (baseline, 1.5, 3, 6 months), 6-month multi-parametric MRI (mp-MRI) and 7-month biopsy. Findings on mp-MRI and biopsy were sub-divided into infield, adjacent or outfield of the treatment zone. RESULTS: Twenty-five men were included for final analysis. Safety follow-up revealed one Clavien Grade 3 complication and five Grade 1 complications. Functional follow-up confirmed no significant change in American Urological Association urinary symptom score, sexual or bowel function. Infield, there were no suspicious findings on mp-MRI (n=24) or biopsy (n=21) in all patients. Adjacent to the treatment zone, five (21%) had suspicious findings on mp-MRI with four (19%) proving to be significant on biopsy. Outfield, there were two (8%) with suspicious findings on mp-MRI and one (5%) significant finding on biopsy. For the five patients with significant findings on follow-up biopsy, one is awaiting repeat IRE, one had radical prostatectomy and three remained on active surveillance. CONCLUSIONS: In selected patients with low-intermediate risk PCa, focal IRE appears to be safe with minimal morbidity. There were no infield recurrences and 76% of patients were histologically free of significant cancer at 8 months. Almost all recurrences were adjacent to the treatment zone, and this was addressed by widening the treatment margins.

The Diagnostic Performance of Multiparametric Magnetic Resonance Imaging to Detect Significant Prostate Cancer.

PURPOSE: We assess the accuracy of multiparametric magnetic resonance imaging for significant prostate cancer detection before diagnostic biopsy in men with an abnormal prostate specific antigen/digital rectal examination. MATERIALS AND METHODS: A total of 388 men underwent multiparametric magnetic resonance imaging, including T2-weighted, diffusion weighted and dynamic contrast enhanced imaging before biopsy. Two radiologists used PI-RADS to allocate a score of 1 to 5 for suspicion of significant prostate cancer (Gleason 7 with more than 5% grade 4). PI-RADS 3 to 5 was considered positive. Transperineal template guided mapping biopsy of 18 regions (median 30 cores) was performed with additional manually directed cores from magnetic resonance imaging positive regions. The anatomical location, size and grade of individual cancer areas in the biopsy regions (18) as the primary outcome and in prostatectomy specimens (117) as the secondary outcome were correlated to the magnetic resonance imaging positive regions. RESULTS: Of the 388 men who were enrolled in the study 344 were analyzed. Multiparametric magnetic resonance imaging was positive in 77.0% of patients, 62.5% had prostate cancer and 41.6% had significant prostate cancer. The detection of significant prostate cancer by multiparametric magnetic resonance imaging had a sensitivity of 96%, specificity of 36%, negative predictive value of 92% and positive predictive value of 52%. Adding PI-RADS to the multivariate model, including prostate specific antigen, digital rectal examination, prostate volume and age, improved the AUC from 0.776 to 0.879 (p <0.001). Anatomical concordance analysis showed a low mismatch between the magnetic resonance imaging positive regions and biopsy positive regions (4 [2.9%]), and the significant prostate cancer area in the radical prostatectomy specimen (3 [3.3%]). CONCLUSIONS: In men with an abnormal prostate specific antigen/digital rectal examination, multiparametric magnetic resonance imaging detected significant prostate cancer with an excellent negative predictive value and moderate positive predictive value. The use of multiparametric magnetic resonance imaging to diagnose significant prostate cancer may result in a substantial number of unnecessary biopsies while missing a minimum of significant prostate cancers.

Aminocaproic acid administration is associated with reduced perioperative blood loss and transfusion in pediatric craniofacial surgery.

BACKGROUND: Severe blood loss is a common complication of craniofacial reconstruction surgery. The antifibrinolytic ε-aminocaproic acid (EACA) reduces transfusion requirements in children undergoing cardiac surgery and in older children undergoing spine surgery. Tranexamic acid (TXA), another antifibrinolytic with a similar mechanism of action, has been shown to reduce blood loss and transfusion requirements in children undergoing craniofacial surgery. However, TXA has been associated with an increase in post-operative seizures and is more expensive than EACA. There is currently little published data evaluating the efficacy of EACA in children undergoing craniofacial surgery. METHODS: This is a retrospective study of prospectively collected data from our craniofacial perioperative registries for children under 6 years of age who underwent anterior or posterior cranial vault reconstruction. We compared calculated blood loss, blood donor exposures, and post-operative drain output between subjects who received EACA and those who did not. RESULTS: The registry queries returned data from 152 subjects. Eighty-six did not receive EACA and 66 received EACA. The EACA group had significantly lower calculated blood loss (82 ± 43 vs. 106 ± 63 ml/kg, P = 0.01), fewer intraoperative blood donor exposures (median 2, interquartile range 1-2 vs. median 2, interquartile range 1-3; P = 0.02) and lower surgical drain output in the first post-operative 24 h (28 ml/kg vs. 37 ml/kg, P = 0.001) than the non-EACA group. CONCLUSION: In this analysis of prospectively captured observational data, EACA administration was associated with less calculated blood loss, intraoperative blood donor exposures, and post-operative surgical drain output.

Population pharmacokinetics of ϵ-aminocaproic acid in adolescents undergoing posterior spinal fusion surgery.

BACKGROUND: Despite demonstrated efficacy of ϵ-aminocaproic acid (EACA) in reducing blood loss in adolescents undergoing spinal fusion, there are no population-specific pharmacokinetic data to guide dosing. The aim of this study was to determine the pharmacokinetics of EACA in adolescents undergoing spinal fusion surgery and make dosing recommendations. METHODS: Twenty children ages 12-17 years were enrolled, with 10 children in each of two groups based on diagnosis (idiopathic scoliosis or non-idiopathic scoliosis). Previously reported data from infants undergoing craniofacial surgery were included in the model to enable dosing recommendations over a wide range of weights, ages, and diagnoses. A population non-linear mixed effects modelling approach was used to characterize EACA pharmacokinetics. RESULTS: Population pharmacokinetic parameters were estimated using a two-compartment disposition model with allometrically scaled weight and an age effect on clearance. Pharmacokinetic parameters for the typical patient were a plasma clearance of 153 ml min(-1) 70 kg(-1) (6.32 ml min(-1) kg(-0.75)), intercompartmental clearance of 200 ml min(-1) 70 kg(-1) (8.26 ml min(-1) kg(-0.75)), central volume of distribution of 8.78 litre 70 kg(-1) (0.13 litre kg(-1)), and peripheral volume of distribution of 15.8 litre 70 kg(-1) (0.23 litre kg(-1)). Scoliosis aetiology did not have a clinically significant effect on drug pharmacokinetics. CONCLUSIONS: The following dosing schemes are recommended according to patient weight: weight <25 kg, 100 mg kg(-1) loading dose and 40 mg kg(-1) h(-1) infusion; weight ≤25 kg-<50 kg, 100 mg kg(-1) loading dose and 35 mg kg(-1) h(-1) infusion; and weight ≥50 kg, 100 mg kg(-1) loading dose and 30 mg kg(-1) h(-1) infusion. An efficacy trial employing this dosing strategy is warranted. CLINICAL TRIAL REGISTRATION: NCT01408823.

Expression of E6AP and PML predicts for prostate cancer progression and cancer-specific death.

BACKGROUND: The promyelocytic leukemia (PML) tumor suppressor plays an important role in the response to a variety of cellular stressors and its expression is downregulated or lost in a range of human tumors. We have previously shown that the E3 ligase E6-associated protein (E6AP) is an important regulator of PML protein stability but the relationship and clinical impact of PML and E6AP expression in prostatic carcinoma is unknown. METHODS: E6AP and PML expression was assessed in tissue microarrays from a phase I discovery cohort of 170 patients treated by radical prostatectomy for localized prostate cancer (PC). Correlation analysis was carried out between PML and E6AP expression and clinicopathological variates including PSA as a surrogate of disease recurrence. The results were confirmed in a phase II validation cohort of 318 patients with associated clinical recurrence and survival data. RESULTS: Survival analysis of the phase I cohort revealed that patients whose tumors showed reduced PML and high E6AP expression had reduced time to PSA relapse (P = 0.012). This was confirmed in the phase II validation cohort where the expression profile of high E6AP/low PML was significantly associated with reduced time to PSA relapse (P < 0.001), clinical relapse (P = 0.016) and PC-specific death (P = 0.014). In multivariate analysis, this expression profile was an independent prognostic indicator of PSA relapse and clinical relapse independent of clinicopathologic factors predicting recurrence. CONCLUSION: This study identifies E6AP and PML as potential prognostic markers in localized prostate carcinoma and supports a role for E6AP in driving the downregulation or loss of PML expression in prostate carcinomas.

Initial assessment of safety and clinical feasibility of irreversible electroporation in the focal treatment of prostate cancer.

BACKGROUND: To evaluate the safety and clinical feasibility of focal irreversible electroporation (IRE) of the prostate. METHODS: We assessed the toxicity profile and functional outcomes of consecutive patients undergoing focal IRE for localised prostate cancer in two centres. Eligibility was assessed by multi-parametric magnetic resonance imaging (mpMRI) and targeted and/or template biopsy. IRE was delivered under transrectal ultrasound guidance with two to six electrodes positioned transperineally within the cancer lesion. Complications were recorded and scored accordingly to the NCI Common Terminology Criteria for Adverse Events; the functional outcome was physician reported in all patients with at least 6 months follow-up. A contrast-enhanced MRI 1 week after the procedure was carried out to assess treatment effect with a further mpMRI at 6 months to rule out evidence of residual visible cancer. RESULTS: Overall, 34 patients with a mean age of 65 years (s.d. = ± 6) and a median PSA of 6.1 ng ml(-1) (interquartile range (IQR) = 4.3-7.7) were included. Nine (26%), 24 (71%) and 1 (3%) men had low, intermediate and high risk disease, respectively (D'Amico criteria). After a median follow-up of 6 months (range 1-24), 12 grade 1 and 10 grade 2 complications occurred. No patient had grade >/= 3 complication. From a functional point of view, 100% (24/24) patients were continent and potency was preserved in 95% (19/20) men potent before treatment. The volume of ablation was a median 12 ml (IQR = 5.6-14.5 ml) with the median PSA after 6 months of 3.4 ng ml(-1) (IQR = 1.9-4.8 ng ml(-1)). MpMRI showed suspicious residual disease in six patients, of whom four (17%) underwent another form of local treatment. CONCLUSIONS: Focal IRE has a low toxicity profile with encouraging genito-urinary functional outcomes. Further prospective development studies are needed to confirm the functional outcomes and to explore the oncological potential.

Circulating microRNAs predict biochemical recurrence in prostate cancer patients.

BACKGROUND: Circulating microRNAs (miRNAs) are emerging as promising biomarkers for prostate cancer. Here, we investigated the potential of these molecules to assist in prognosis and treatment decision-making. METHODS: MicroRNAs in the serum of patients who had experienced rapid biochemical recurrence (BCR) (n=8) or no recurrence (n=8) following radical prostatectomy (RP) were profiled using high-throughput qRT-PCR. Recurrence-associated miRNAs were subsequently quantitated by qRT-PCR in a validation cohort comprised of 70 patients with Gleason 7 cancers treated by RP, 31 of whom had undergone disease progression following surgery. The expression of recurrence-associated miRNAs was also examined in tumour tissue cohorts. RESULTS: Three miRNAs - miR-141, miR-146b-3p and miR-194 - were elevated in patients who subsequently experienced BCR in the screening study. MiR-146b-3p and miR-194 were also associated with disease progression in the validation cohort, as determined by log-rank tests and Cox proportional hazards regression. Multivariate analysis revealed that miR-146b-3p possessed prognostic information beyond standard clinicopathological parameters. Analysis of tissue cohorts revealed that miR-194 was robustly expressed in the prostate, elevated in metastases, and its expression in primary tumours was associated with a poor prognosis. CONCLUSION: Our study suggests that circulating miRNAs, measured at the time of RP, could be combined with current prognostic tools to predict future disease progression in men with intermediate risk prostate cancers.

Population pharmacokinetics of epsilon-aminocaproic acid in infants undergoing craniofacial reconstruction surgery.

BACKGROUND: Understanding the clinical pharmacology of the antifibrinolytic epsilon-aminocaproic acid (EACA) is necessary for rational drug administration in children. The aim of this study is to determine the pharmacokinetics (PKs) of EACA in infants aged 6-24 months undergoing craniofacial reconstruction surgery. METHODS: Cohorts of six infants were enrolled sequentially to one of the three escalating loading dose-continuous i.v. infusion (CIVI) regimens: 25 mg kg(-1), 10 mg kg(-1) h(-1); 50 mg kg(-1), 20 mg kg(-1) h(-1); 100 mg kg(-1), 40 mg kg(-1) h(-1). Plasma EACA concentrations were determined using a validated high-performance liquid chromatography-tandem mass spectrometry assay. A population non-linear mixed effects modelling approach was used to characterize EACA PKs. RESULTS: Population PK parameters of EACA were estimated using a two-compartment disposition model with weight expressed as an allometric covariate and an age effect. The typical patient in this study had an age of 38.71 weeks and a weight of 8.82 kg. PK parameters for this typical patient were: pre-/postoperative plasma drug clearance of 32 ml min(-1) (3.6 ml kg(-1) min(-1)), inter-compartmental clearance of 42.4 ml min(-1) (4.8 ml min(-1) kg(-1)), central volume of distribution of 1.27 litre (0.14 litre kg(-1)), and peripheral volume of distribution of 2.53 litre (0.29 litre kg(-1)). Intra-operative clearance and central volume of distribution were 89% and 80% of the pre-/postoperative value, respectively. CONCLUSIONS: EACA clearance increased with weight and age. The dependence of clearance on body weight supports weight-based dosing. Based on this study, a loading dose of 100 mg kg(-1) followed by a CIVI of 40 mg kg(-1) h(-1) is appropriate to maintain target plasma EACA concentrations in children aged 6-24 months undergoing these procedures.

A novel method of bladder neck imbrication to improve early urinary continence following robotic-assisted radical prostatectomy.

Early return of continence forms an important component of quality of life for patients after robotic-assisted radical prostatectomy (RALP). Here we describe the steps of bladder neck imbrication and vesico-urethral anastomosis improving early continence after RALP. Between April 2008 and July 2009, 202 consecutive patients underwent RALP for clinically localised prostate cancer in a tertiary referral centre by a single surgeon. One hundred and thirty-two (65 %) of these patients agreed to participate in the study. Prior to November 2008, 51 patients underwent standard RALP as described by Patel et al. From November 2008, 81 patients underwent a novel method of bladder neck imbrication. The robotic urethro-vesical anastomosis commences on the posterior wall of the urethra and proceeds anteriorly. In our technique the anastomosis is halted with the suture arms fixed to the anterior abdominal wall. A new suture is used to perform a two-layer repair, anchoring proximally then continuing anteriorly to the level of the urethral stump, where it returns upon itself. The aim is to narrow the urethra to 16 Fr and tighten the second layer to create an imbrication effect. Posterior reconstruction was performed in all patients. Outcome measures were recorded prospectively using the Expanded Prostate Cancer Index Composite tool. Our technique shows significant improvement at all stages of follow-up in urinary summary and incontinence scores. Absolute continence rates increased from 8.2 to 20.5 %, 26.7 to 44.3 %, and 47.7 to 62.3 % at 1.5, 3 and 6 months, respectively. These results support the use of our technique in patients undergoing RALP.

Survival gains needed to offset persistent adverse treatment effects in localised prostate cancer.

BACKGROUND: Men diagnosed with localised prostate cancer (LPC) face difficult choices between treatment options that can cause persistent problems with sexual, urinary and bowel function. Controlled trial evidence about the survival benefits of the full range of treatment alternatives is limited, and patients' views on the survival gains that might justify these problems have not been quantified. METHODS: A discrete choice experiment (DCE) was administered in a random subsample (n=357, stratified by treatment) of a population-based sample (n=1381) of men, recurrence-free 3 years after diagnosis of LPC, and 65 age-matched controls (without prostate cancer). Survival gains needed to justify persistent problems were estimated by substituting side effect and survival parameters from the DCE into an equation for compensating variation (adapted from welfare economics). RESULTS: Median (2.5, 97.5 centiles) survival benefits needed to justify severe erectile dysfunction and severe loss of libido were 4.0 (3.4, 4.6) and 5.0 (4.9, 5.2) months. These problems were common, particularly after androgen deprivation therapy (ADT): 40 and 41% overall (n=1381) and 88 and 78% in the ADT group (n=33). Urinary leakage (most prevalent after radical prostatectomy (n=839, mild 41%, severe 18%)) needed 4.2 (4.1, 4.3) and 27.7 (26.9, 28.5) months survival benefit, respectively. Mild bowel problems (most prevalent (30%) after external beam radiotherapy (n=106)) needed 6.2 (6.1, 6.4) months survival benefit. CONCLUSION: Emerging evidence about survival benefits can be assessed against these patient-based benchmarks. Considerable variation in trade-offs among individuals underlines the need to inform patients of long-term consequences and incorporate patient preferences into treatment decisions.

Quantification of dissolved organic carbon at very low levels in natural ice samples by a UV-induced oxidation method.

The study of chemical impurities trapped in solid precipitation and accumulated in polar ice sheets and high-elevation, midlatitude cold glaciers over the last several hundreds of years provides a unique way to reconstruct our changing atmosphere from the preindustrial era to the present day. Numerous ice core studies of inorganic species have already evaluated the effects of growing anthropogenic emissions of SO(2) or NO(x) on the chemical composition of the atmosphere in various regions of the world. While it was recently shown that organic species dominate the atmospheric aerosol mass, the contribution of anthropogenic emissions to their budget remains poorly understood. The study of organics in ice is at the infancy stage, and it still is difficult to draw a consistent picture of the organic content of polar ice from sparse available data. A UV oxidation method and IR quantification of CO(2) was optimized to obtain measurements of dissolved organic carbon content as low as a few ppbC. Stringent working conditions were defined to prevent contamination during the cleaning of ice. Measurements in various ice cores corresponding to preindustrial times revealed dissolved organic carbon content of less than 10 ppbC in Antarctica and up to 75 ppbC in alpine ice.