Dosimetric and radiobiological investigation of permanent implant prostate brachytherapy based on Monte Carlo calculations

PurposePermanent implant prostate brachytherapy plays an important role in prostate cancer treatment, but dose evaluations typically follow the water-based TG-43 formalism, ignoring patient anatomy and interseed attenuation. The purpose of this study is to investigate advanced TG-186 model-based dose calculations via retrospective dosimetric and radiobiological analysis for a new patient cohort.Methods and MaterialsA cohort of 155 patients treated with permanent implant prostate brachytherapy from The Ottawa Hospital Cancer Centre is considered. Monte Carlo (MC) dose calculations are performed using tissue-based virtual patient models. Dose–volume histogram (DVH) metrics (target, organs at risk) are extracted from 3D dose distributions and compared with those from calculations under TG-43 assumptions (TG43). Equivalent uniform biologically effective dose and tumor control probability are calculated.ResultsFor the target, D₉₀ (V₁₀₀) is 136.7 ± 20.6 Gy (85.8% ± 7.8%) for TG43 and 132.8 ± 20.1 Gy (84.1% ± 8.2%) for MC; D₉₀ is 3.0% ± 1.1% lower for MC than TG43. For organs at risk, MC D_1cc = 104.4 ± 27.4 Gy (TG43: 106.3 ± 28.3 Gy) for rectum and 80.8 ± 29.7 Gy (TG43: 78.4 ± 28.4 Gy) for bladder; D_1cc = 185.9 ± 30.2 Gy (TG43: 191.1 ± 32.0 Gy) for urethra. Equivalent uniform biologically effective dose and tumor control probability are generally lower when evaluated using MC doses. The largest dosimetric and radiobiological discrepancies between TG43 and MC are for patients with intraprostatic calcifications, for whom there are low doses (cold spots) in the vicinity of calcifications within the target, identified with MC but not TG43.ConclusionsDVH metrics and radiobiological indices evaluated with TG43 are systematically inaccurate by upward of several percent compared with MC patient-specific models. Mean cohort DVH metrics and their MC:TG43 variances are sensitive to patient cohort and clinical practice, underlining the importance of further retrospective MC studies toward widespread clinical adoption of advanced model-based dose calculations.     

Expression of beta-catenin and p53 are prognostic factors in deep aggressive fibromatosis

AIMS: To determine the prognostic significance of beta-catenin in aggressive fibromatosis and to identify potential molecular markers for new targeted therapies. METHODS AND RESULTS: A tissue microarray of 37 cases of deep aggressive fibromatosis was constructed and subjected to immunohistochemical analysis for beta-catenin, p53, smooth muscle actin (SMA), desmin, Ki67, c-erbB2, epidermal growth factor receptor (EGFR), c-kit, CD34 and S100. Complete clinical follow-up was available for 23 patients. Nuclear beta-catenin expression was associated with an increased rate of local tumour recurrence (60.0% 1-year and 0% 5-year event-free survival; P < 0.05). Furthermore, p53 expression was associated with an increased risk of tumour recurrence (50% 1-year event-free survival rate and 0% 5-years event-free survival rate, P < 0.05). The coexpression of p53 and beta-catenin was significantly correlated (P < 0.05). No statistically significant association was seen between MIB1 and p53 or beta-catenin expression, respectively. No expression of EGFR, c-erbB2 or c-kit was seen. CONCLUSIONS: The overexpression of beta-catenin and p53 is associated with a decreased event-free survival in deep aggressive fibromatosis. Further studies are required to establish whether these findings can lead to an improvement in the treatment of this rare neoplasm.     

Youth perceptions of alcohol advertising: are current advertising regulations working?

Objectives : We investigated young people’s exposure to alcohol advertising, their intentions to consume and purchase alcohol products following the viewing of advertisements, and whether they perceived the actors in the advertisements as being under the age of 25 years. Methods : Face‐to‐face interviews were completed with 351 risky drinking 16–19‐year‐old Australians, with a sub‐sample (n=68) responding to a range of alcohol advertisements in an in‐depth interview. Results : Participants were exposed to alcohol advertisements from an average of seven specific contexts in the past 12 months, with younger adolescents more likely to recall TV and outdoor billboards (n=351). Positive perception of advertisements was associated with increased intention to use and to purchase advertised products (n=68). A liqueur advertisement actor was perceived by 94% as being under 25 years‐old, and almost 30% thought the advertisement was marketed at people younger than 18 years of age. Conclusions : Young people’s perceptions of alcohol advertising are not necessarily in line with expert/industry assessment; products are sometimes marketed in a way that is highly appealing to young people. Greater appeal was associated with increased intention to consume and to purchase products. Implications for public health : These results indicate deficiencies in the effectiveness of current advertising codes in regard to protecting the health and wellbeing of adolescents.     

A new risk prediction model for critical care: the Intensive Care National Audit & Research Centre (ICNARC) model

OBJECTIVE: To develop a new model to improve risk prediction for admissions to adult critical care units in the UK. DESIGN: Prospective cohort study. SETTING: The setting was 163 adult, general critical care units in England, Wales, and Northern Ireland, December 1995 to August 2003. PATIENTS: Patients were 216,626 critical care admissions. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The performance of different approaches to modeling physiologic measurements was evaluated, and the best methods were selected to produce a new physiology score. This physiology score was combined with other information relating to the critical care admission-age, diagnostic category, source of admission, and cardiopulmonary resuscitation before admission-to develop a risk prediction model. Modeling interactions between diagnostic category and physiology score enabled the inclusion of groups of admissions that are frequently excluded from risk prediction models. The new model showed good discrimination (mean c index 0.870) and fit (mean Shapiro's R 0.665, mean Brier's score 0.132) in 200 repeated validation samples and performed well when compared with recalibrated versions of existing published risk prediction models in the cohort of patients eligible for all models. The hypothesis of perfect fit was rejected for all models, including the Intensive Care National Audit & Research Centre (ICNARC) model, as is to be expected in such a large cohort. CONCLUSIONS: The ICNARC model demonstrated better discrimination and overall fit than existing risk prediction models, even following recalibration of these models. We recommend it be used to replace previously published models for risk adjustment in the UK.     

Acetaminophen selectively suppresses peripheral prostaglandin E2 release and increases COX-2 gene expression in a clinical model of acute inflammation

For years, physical deconditioning has been thought to be both a cause and a result of back pain. As a consequence physical reconditioning has been proposed as treatment-goal in patients with chronic low back pain (LBP). However, it is still unclear whether a patient’s physical fitness level really decreases after pain-onset. The objectives of the present study were, firstly, to test the assumption that long-term non-specific LBP leads to a decrease of the level of physical activity (disuse), secondly, to evaluate any development of physical deconditioning as a result of disuse in CLBP, and thirdly, to evaluate predictors for disuse in CLBP. A longitudinal cohort study over one year including 124 patients with sub-acute LBP (i.e., 4–7 weeks after pain onset) was performed. Main outcome measures were change in physical activity level (PAL) and physical fitness (measured by changes in body weight, body fat and muscle strength) over one year. Hypothesized predictors for disuse were: pain catastrophizing; fear of movement; depression; physical activity decline; the perceived level of disability and PAL prior to pain. Results showed that only in a subgroup of patients a PAL-decrease had occurred after the onset of pain, whereas no signs of physical deconditioning were found. Negative affect and the patients’ perceived physical activity decline in the subacute phase predicted a decreased level of PAL over one year. Based on these results, we conclude that as to the assumption that patients with CLBP suffer from disuse and physical deconditioning empirical evidence is still lacking.     

Simulation of Three-Dimensional Free-Surface Flows Using Two-Dimensional Multilayer Shallow Water Equations

We present an efficient and conservative Eulerian-Lagrangian method for solving two-dimensional hydrostatic multilayer shallow water flows with mass exchange between the vertical layers. The method consists of a projection finite volume method for the Eulerian stage and a method of characteristics to approximate the numerical fluxes for the Lagrangian stage. The proposed method is simple to implement, satisfies the conservation property and it can be used for multilayer shallow water equations on non-flat bathymetry including eddy viscosity and Coriolis forces. It offers a novel method of calculating stratified vertical velocities without the use of the Navier-Stokes equations. Numerical results are presented for several examples and the obtained results for a free-surface flow problem are in close agreement with the analytical solutions. We also test the performance of the proposed method for a test example of wind-driven flows with recirculation     

Endoscopic endonasal versus transcranial approach to resection of olfactory groove meningiomas: a systematic review

Neurosurgical Review - Despite the increasing utility of the endoscopic endonasal approach (EEA) for management of anterior skull base (ASB) pathologies, the optimal treatment strategy for...     

Autosomal dominant polycystic kidney disease (ADPKD)—mechanisms of cyst formation and renal failure*

None of the hypotheses proposed so far to explain cyst formation in autosomal dominant polycystic kidney disease (ADPKD) is entirely satisfactory, e.g. the theory of tubular obstruction by intraluminal polyps or dilatation of nephron segments as a consequence of abnormal compliance of the basement membrane. Recent in vitro studies show that (i) synthesis of basement membrane material is abnormal and that (ii) the direction of transepithelial resorptive flux into a secretory mode is reversed as a consequence of faulty insertion of Na, K-ATP'ase into the luminal membrane. It remains unclear why cystic transformation of a few percent of nephrons should cause endstage renal failure. Our clinical and experimental studies do not provide evidence to support some hypotheses proposed in the past, i.e. that renal parenchyma is compressed by expanding cysts and that glomeruli are overperfused. Our histological studies show that progression to endstage renal failure is associated with (i) progressive arteriolar lesions (out of proportion to the vascular lesions seen in extrarenal vascular beds; and (ii) progressive interstitial fibrosis. It appears that fibroblasts in ADPKD are particularly sensitive to platelet derived growth factor (PDGF) which is secreted by epithelial cells of the cyst wall in a paracrine fashion. In contrast to previous opinion, which was presumably skewed by ascertainment bias, it appears that not all, and perhaps not even a majority, of ADPKD patients progress to endstage renal failure. Factors related to progression are gender, family history and hypertension. Both abnormal sodium excretion and inappropriate renin secretion play a role in the genesis of hypertension. Elevated blood pressure, albeit within the normotensive range, is demonstrable even in prepubertal children. The involvement of renin in renal vasoconstriction of normotensive ADPKD patients suggests a particular role of ACE inhibitors in the management of these patients.     

SMAD4 mutations in colorectal cancer probably occur before chromosomal instability, but after divergence of the microsatellite instability pathway

Loss of chromosome 18q21 is well documented in colorectal cancer, and it has been suggested that this loss targets the DCC, DPC4/SMAD4, and SMAD2 genes. Recently, the importance of SMAD4, a downstream regulator in the TGF-beta signaling pathway, in colorectal cancer has been highlighted, although the frequency of SMAD4 mutations appears much lower than that of 18q21 loss. We set out to investigate allele loss, mutations, protein expression, and cytogenetics of chromosome 18 copy number in a collection of 44 colorectal cancer cell lines of known status with respect to microsatellite instability (MSI). Fourteen of thirty-two MSI(-) lines showed loss of SMAD4 protein expression; usually, one allele was lost and the other was mutated in one of a number of ways, including deletions of various sizes, splice site changes, and missense and nonsense point mutations (although no frameshifts). Of the 18 MSI(-) cancers with retained SMAD4 expression, four harbored missense mutations in the 3' part of the gene and showed allele loss. The remaining 14 MSI(-) lines had no detectable SMAD4 mutation, but all showed allele loss at SMAD4 and/or DCC. SMAD4 mutations can therefore account for about 50-60% of the 18q21 allele loss in colorectal cancer. No MSI(+) cancer showed loss of SMAD4 protein or SMAD4 mutation, and very few had allelic loss at SMAD4 or DCC, although many of these MSI(+) lines did carry TGFBIIR changes. Although SMAD4 mutations have been associated with late-stage or metastatic disease, our combined molecular and cytogenetic data best fit a model in which SMAD4 mutations occur before colorectal cancers become aneuploid/polyploid, but after the MSI(+) and MSI(-) pathways diverge. Thus, MSI(+) cancers may diverge first, followed by CIN(+) (chromosomal instability) cancers, leaving other cancers to follow a CIN(-)MSI(-) pathway.