A critical evaluation of secondary cancer risk models applied to Monte Carlo dose distributions of 2-dimensional, 3-dimensional conformal and hybrid intensity-modulated radiation therapy for breast cancer

The comparison of radiotherapy techniques regarding secondary cancer risk has yielded contradictory results possibly stemming from the many different approaches used to estimate risk. The purpose of this study was to make a comprehensive evaluation of different available risk models applied to detailed whole-body dose distributions computed by Monte Carlo for various breast radiotherapy techniques including conventional open tangents, 3D conformal wedged tangents and hybrid intensity modulated radiation therapy (IMRT). First, organ-specific linear risk models developed by the International Commission on Radiological Protection (ICRP) and the Biological Effects of Ionizing Radiation (BEIR) VII committee were applied to mean doses for remote organs only and all solid organs. Then, different general non-linear risk models were applied to the whole body dose distribution. Finally, organ-specific non-linear risk models for the lung and breast were used to assess the secondary cancer risk for these two specific organs. A total of 32 different calculated absolute risks resulted in a broad range of values (between 0.1% and 48.5%) underlying the large uncertainties in absolute risk calculation. The ratio of risk between two techniques has often been proposed as a more robust assessment of risk than the absolute risk. We found that the ratio of risk between two techniques could also vary substantially considering the different approaches to risk estimation. Sometimes the ratio of risk between two techniques would range between values smaller and larger than one, which then translates into inconsistent results on the potential higher risk of one technique compared to another. We found however that the hybrid IMRT technique resulted in a systematic reduction of risk compared to the other techniques investigated even though the magnitude of this reduction varied substantially with the different approaches investigated. Based on the epidemiological data available, a reasonable approach to risk estimation would be to use organ-specific non-linear risk models applied to the dose distributions of organs within or near the treatment fields (lungs and contralateral breast in the case of breast radiotherapy) as the majority of radiation-induced secondary cancers are found in the beam-bordering regions.

Multimodal treatment for high-risk prostate cancer with high-dose intensity-modulated radiation therapy preceded or not by radical prostatectomy, concurrent intensified-dose docetaxel and long-term androgen deprivation therapy: results of a prospective phase II trial.

BACKGROUND The optimal management of high-risk prostate cancer remains uncertain. In this study we assessed the safety and efficacy of a novel multimodal treatment paradigm for high-risk prostate cancer. METHODS This was a prospective phase II trial including 35 patients with newly diagnosed high-risk localized or locally advanced prostate cancer treated with high-dose intensity-modulated radiation therapy preceded or not by radical prostatectomy, concurrent intensified-dose docetaxel-based chemotherapy and long-term androgen deprivation therapy. Primary endpoint was acute and late toxicity evaluated with the Common Terminology Criteria for Adverse Events version 3.0. Secondary endpoint was biochemical and clinical recurrence-free survival explored with the Kaplan-Meier method. RESULTS Acute gastro-intestinal and genito-urinary toxicity was grade 2 in 23% and 20% of patients, and grade 3 in 9% and 3% of patients, respectively. Acute blood/bone marrow toxicity was grade 2 in 20% of patients. No acute grade ≥ 4 toxicity was observed. Late gastro-intestinal and genito-urinary toxicity was grade 2 in 9% of patients each. No late grade ≥ 3 toxicity was observed. Median follow-up was 63 months (interquartile range 31-79). Actuarial 5-year biochemical and clinical recurrence-free survival rate was 55% (95% confidence interval, 35-75%) and 70% (95% confidence interval, 52-88%), respectively. CONCLUSIONS In our phase II trial testing a novel multimodal treatment paradigm for high-risk prostate cancer, toxicity was acceptably low and mid-term oncological outcome was good. This treatment paradigm, thus, may warrant further evaluation in phase III randomized trials.

Temporal evolution of strut light intensity after implantation of bioresorbable polymeric intracoronary scaffolds in the ABSORB cohort B trial-an application of a new quantitative method based on optical coherence tomography.

BACKGROUND Quantitative light intensity analysis of the strut core by optical coherence tomography (OCT) may enable assessment of changes in the light reflectivity of the bioresorbable polymeric scaffold from polymer to provisional matrix and connective tissues, with full disappearance and integration of the scaffold into the vessel wall. The aim of this report was to describe the methodology and to apply it to serial human OCT images post procedure and at 6, 12, 24 and 36 months in the ABSORB cohort B trial. METHODS AND RESULTS In serial frequency-domain OCT pullbacks, corresponding struts at different time points were identified by 3-dimensional foldout view. The peak and median values of light intensity were measured in the strut core by dedicated software. A total of 303 corresponding struts were serially analyzed at 3 time points. In the sequential analysis, peak light intensity increased gradually in the first 24 months after implantation and reached a plateau (relative difference with respect to baseline [%Dif]: 61.4% at 12 months, 115.0% at 24 months, 110.7% at 36 months), while the median intensity kept increasing at 36 months (%Dif: 14.3% at 12 months, 75.0% at 24 months, 93.1% at 36 months). CONCLUSIONS Quantitative light intensity analysis by OCT was capable of detecting subtle changes in the bioresorbable strut appearance over time, and could be used to monitor the bioresorption and integration process of polylactide struts.

Beta-alanine supplementation improves jumping power and affects severe-intensity performance in professional alpine skiers.

INTRODUCTION Supplementation with beta-alanine may have positive effects on severe-intensity, intermittent, and isometric strength-endurance performance. These could be advantageous for competitive alpine skiers, whose races last 45 to 150 s, require metabolic power above the aerobic maximum, and involve isometric muscle work. Further, beta-alanine supplementation affects the muscle force-frequency relationship, which could influence explosiveness. We explored the effects of beta-alanine on explosive jump performance, severe exercise energy metabolism, and severe-intensity ski-like performance. METHODS Nine male elite alpine skiers consumed 4.8 g/d beta-alanine or placebo for 5 weeks in a double-blind fashion. Before and after, they performed countermovement jumps (CMJ), a 90-s cycling bout at 110% VO2max (CLT), and a maximal 90-s box jump test (BJ90). RESULTS Beta-alanine improved maximal (+7 ± 3%, d = 0.9) and mean CMJ power (+7 ± 2%, d = 0.7), tended to reduce oxygen deficit (-3 ± 8%, p = .06) and lactate accumulation (-12 ± 31%) and enhance aerobic energy contribution (+1.3 ± 2.9%, p = .07) in the CLT, and improved performance in the last third of BJ90 (+7 ± 4%, p = .02). These effects were not observed with placebo. CONCLUSIONS Beta-alanine supplementation improved explosive and repeated jump performance in elite alpine skiers. Enhanced muscle contractility could possibly explain improved explosive and repeated jump performance. Increased aerobic energy production could possibly help explain repeated jump performance as well.

Definitive intensity modulated radiotherapy in locally advanced hypopharygeal and laryngeal squamous cell carcinoma: mature treatment results and patterns of locoregional failure.

PurposeTo assess clinical outcomes and patterns of loco-regional failure (LRF) in relation to clinical target volumes (CTV) in patients with locally advanced hypopharyngeal and laryngeal squamous cell carcinoma (HL-SCC) treated with definitive intensity modulated radiotherapy (IMRT) and concurrent systemic therapy.MethodsData from HL-SCC patients treated from 2007 to 2010 were retrospectively evaluated. Primary endpoint was loco-regional control (LRC). Secondary endpoints included local (LC) and regional (RC) controls, distant metastasis free survival (DMFS), laryngectomy free survival (LFS), overall survival (OS), and acute and late toxicities. Time-to-event endpoints were estimated using Kaplan-Meier method, and univariate and multivariate analyses were performed using Cox proportional hazards models. Recurrent gross tumor volume (RTV) on post-treatment diagnostic imaging was analyzed in relation to corresponding CTV (in-volume, > 95% of RTV inside CTV; marginal, 20¿95% inside CTV; out-volume, < 20% inside CTV).ResultsFifty patients (stage III: 14, IVa: 33, IVb: 3) completed treatment and were included in the analysis (median follow-up of 4.2 years). Three-year LRC, DMFS and overall survival (OS) were 77%, 96% and 63%, respectively. Grade 2 and 3 acute toxicity were 38% and 62%, respectively; grade 2 and 3 late toxicity were 23% and 15%, respectively. We identified 10 patients with LRF (8 local, 1 regional, 1 local¿+¿regional). Six out of 10 RTVs were fully included in both elective and high-dose CTVs, and 4 RTVs were marginal to the high-dose CTVs.ConclusionThe treatment of locally advanced HL-SCC with definitive IMRT and concurrent systemic therapy provides good LRC rates with acceptable toxicity profile. Nevertheless, the analysis of LRFs in relation to CTVs showed in-volume relapses to be the major mode of recurrence indicating that novel strategies to overcome radioresistance are required.

Measuring Intensity of End of Life Care: A Systematic Review.

BACKGROUND Many studies have measured the intensity of end of life care. However, no summary of the measures used in the field is currently available. OBJECTIVES To summarise features, characteristics of use and reported validity of measures used for evaluating intensity of end of life care. METHODS This was a systematic review according to PRISMA guidelines. We performed a comprehensive literature search in Ovid Medline, Embase, The Cochrane Library of Systematic Reviews and reference lists published between 1990-2014. Two reviewers independently screened titles, abstracts, full texts and extracted data. Studies were eligible if they used a measure of end of life care intensity, defined as all quantifiable measures describing the type and intensity of medical care administered during the last year of life. RESULTS A total of 58 of 1590 potentially eligible studies met our inclusion criteria and were included. The most commonly reported measures were hospitalizations (n = 44), intensive care unit admissions (n = 39) and chemotherapy use (n = 27). Studies measured intensity of care in different timeframes ranging from 48 hours to 12 months. The majority of studies were conducted in cancer patients (n = 31). Only 4 studies included information on validation of the measures used. None evaluated construct validity, while 3 studies considered criterion and 1 study reported both content and criterion validity. CONCLUSIONS This review provides a synthesis to aid in choosing intensity of end of life care measures based on their previous use but simultaneously highlights the crucial need for more validation studies and consensus in the field.

Tree Species Composition and Harvest Intensity Affect Herbivore Density and Leaf Damage on Beech, Fagus sylvatica, in Different Landscape Contexts

Most forests are exposed to anthropogenic management activities that affect tree species composition and natural ecosystem processes. Changes in ecosystem processes such as herbivory depend on management intensity, and on regional environmental conditions and species pools. Whereas influences of specific forest management measures have already been addressed for different herbivore taxa on a local scale, studies considering effects of different aspects of forest management across different regions are rare. We assessed the influence of tree species composition and intensity of harvesting activities on arthropod herbivores and herbivore-related damage to beech trees, Fagus sylvatica, in 48 forest plots in three regions of Germany. We found that herbivore abundance and damage to beech trees differed between regions and that – despite the regional differences - density of tree-associated arthropod taxa and herbivore damage were consistently affected by tree species composition and harvest intensity. Specifically, overall herbivore damage to beech trees increased with increasing dominance of beech trees – suggesting the action of associational resistance processes – and decreased with harvest intensity. The density of leaf chewers and mines was positively related to leaf damage, and several arthropod groups responded to beech dominance and harvest intensity. The distribution of damage patterns was consistent with a vertical shift of herbivores to higher crown layers during the season and with higher beech dominance. By linking quantitative data on arthropod herbivore abundance and herbivory with tree species composition and harvesting activity in a wide variety of beech forests, our study helps to better understand the influence of forest management on interactions between a naturally dominant deciduous forest tree and arthropod herbivores.

The Sensitivity of Physiological Measures to Phobic and Nonphobic Fear Intensity

We investigated whether amygdala activation, autonomic responses, respiratory responses, and facial muscle activity (measured over the brow and cheek [fear grin] regions) are all sensitive to phobic versus nonphobic fear and, more importantly, whether effects in these variables vary as a function of both phobic and nonphobic fear intensity. Spider-phobic and comparably low spider-fearful control participants imagined encountering different animals and rated their subjective fear while their central and peripheral nervous system activity was measured. All measures included in our study were sensitive to variations in subjective fear, but were related to different ranges and positions on the subjective fear level continuum. Left amygdala activation, heart rate, and facial muscle activity over the cheek region captured fear intensity variations even within narrowly described regions on the fear level continuum (here within extremely low levels of fear and within considerable phobic fear). Skin conductance and facial muscle activity over the brow region did not capture fear intensity variations within low levels of fear: skin conductance mirrored only extreme levels of fear, and activity over the brow region distinguished phobic from nonphobic fear but also low-to-moderate and high phobic fear. Finally, respiratory measures distinguished phobic from nonphobic fear with no further differentiation within phobic and nonphobic fear. We conclude that a careful consideration of the measures to be used in an investigation and the population to be examined can be critical in order to obtain significant results.

Facial Feedback Affects Perceived Intensity but Not Quality of Emotional Expressions

Motivated by conflicting evidence in the literature, we re-assessed the role of facial feedback when detecting quantitative or qualitative changes in others’ emotional expressions. Fifty-three healthy adults observed self-paced morph sequences where the emotional facial expression either changed quantitatively (i.e., sad-to-neutral, neutral-to-sad, happy-to-neutral, neutral-to-happy) or qualitatively (i.e. from sad to happy, or from happy to sad). Observers held a pen in their own mouth to induce smiling or frowning during the detection task. When morph sequences started or ended with neutral expressions we replicated a congruency effect: Happiness was perceived longer and sooner while smiling; sadness was perceived longer and sooner while frowning. Interestingly, no such congruency effects occurred for transitions between emotional expressions. These results suggest that facial feedback is especially useful when evaluating the intensity of a facial expression, but less so when we have to recognize which emotion our counterpart is expressing.