IMRT - Biomarkers for dose escalation, dose de-escalation and personalized medicine in radiotherapy for head and neck cancer.

Radiotherapy (RT) is an integral component in the management of head and neck cancer. Despite progress in several respects, a noteworthy proportion of the treated patients do not achieve complete response after RT. Regardless of novel dose delivery technologies, RT for head and neck cancer is still associated with acute as well as late toxicity. These challenges could potentially be addressed by means of personalized treatment. In this paper, we discuss the possibilities for dose escalation, dose de-escalation and allocation to systemic concomitant treatment based on prognostic and predictive markers for tumor control as well as predictive markers for normal tissue radiosensitivity.

"Freshman's week": characteristics associated with participation and experiencing adverse effects.

BACKGROUND: "Freshman's week" (FW) is a Norwegian initiation ritual to higher education. Previous research has suggested that FW-participation is associated with better social adjustment to the student setting, as well as heavy alcohol use both during and after the event. In this study, we aimed to identify characteristics associated with participation in FW and characteristics associated with experiencing adverse effects of alcohol use during FW. METHODS: Students in the city of Bergen, Norway participated in a survey during fall 2015, shortly after FW. The current sample consisted of the first-year students (N = 4, 401, estimated response rate: 49%). The sample's mean age was 24 years (range: 17-73 years), 65% were females, and the majority were born in Norway (93%). Logistic regressions were conducted to identify characteristics associated with participation in FW and experiencing adverse effects. RESULTS: A total of 64% of the first-year students reported participation in FW, and 27% of these reported experiencing at least one adverse alcohol-related effect during FW. Participation in FW was positively associated with being single (OR = 1.29), extroversion (OR = 1.18), and alcohol use (OR = 1.28), and inversely associated with age (OR = 0.70), and having children (OR = 0.36). Several characteristics (e.g., alcohol use (OR = 1.84), extroversion (OR = 0.60), symptoms of depression (OR = 1.60)) were associated with an increased risk of experiencing adverse effects of alcohol use during participation. CONCLUSION: The current results suggest that initiatives for increasing the participation rate in FW, reducing alcohol use during FW, and decreasing the occurrence of adverse alcohol effects during FW are warranted. Aiming to reduce the focus on alcohol use during FW, and seeking to make FW more available and enjoyable for students with other priorities, students who do not match the stereotype of the typical first-year student, and less sociable students, might both increase participation rate and prevent the occurrence of adverse alcohol effects. Future studies should aim to develop and assess interventions designed to increase participation in FW and reduce the occurrence of adverse effects related to participation.

Tanning addiction: conceptualization, assessment and correlates.

BACKGROUND: Research into problematic tanning (or 'tanning addiction') has markedly increased over the past few years. Although several instruments exist to measure excessive tanning, most of these are psychometrically poor, are not theoretically anchored, and have been used mainly on small samples. OBJECTIVES: To develop a new tanning addiction scale based on a specific theoretical approach utilizing core addiction criteria. METHODS: A scale comprising seven items (salience/craving, tolerance, mood modification, relapse/loss of control, withdrawal, conflict and problems) was administered online to a cross-sectional convenience sample of 23 537 adults (mean ± SD age 35·8 ± 13·3 years). There was also assessment of demographic factors, the five-factor model of personality, and symptoms of obsessive-compulsive disorder, anxiety and depression. RESULTS: A confirmatory factor analysis showed that a one-factor model gave an optimal fit with the data collected [root mean square error of approximation = 0·050, 90% confidence interval (CI) 0·047-0·053; comparative fit index = 0·99; Tucker-Lewis index = 0·99]. High factor loadings (0·78-0·91, all P < 0·001) and coefficient omega indicator of reliability (ω = 0·94, 95% CI 0·94-0·94) were also found using the new scale. In a multiple linear regression analysis, tanning addiction was positively associated with being female, not being in a relationship, extraversion, neuroticism, anxiety and obsessive-compulsiveness. It was also found that educational level, intellect/openness and depression were inversely associated with tanning addiction. CONCLUSIONS: The new scale, the Bergen Tanning Addiction Scale (BTAS), showed good psychometric properties, and is the first scale to conceptualize tanning addiciton fully within a contemporary addiction framework. Given this, the BTAS may potentially assist future clinical practice in providing appropriate patient care, prevention and disease management.

Radiogenomics: the search for genetic predictors of radiotherapy response.

'Radiogenomics' is the study of genetic variation associated with response to radiotherapy. Radiogenomics aims to uncover the genes and biologic pathways responsible for radiotherapy toxicity that could be targeted with radioprotective agents and; identify genetic markers that can be used in risk prediction models in the clinic. The long-term goal of the field is to develop single nucleotide polymorphism-based risk models that can be used to stratify patients to more precisely tailored radiotherapy protocols. The field has evolved over the last two decades in parallel with advances in genomics, moving from narrowly focused candidate gene studies to large, collaborative genome-wide association studies. Several confirmed genetic variants have been identified and the field is making progress toward clinical translation.

Expression of neurotrophic factors in diabetic muscle--relation to neuropathy and muscle strength.

Diabetic polyneuropathy can lead to atrophy and weakness of distally located striated muscles due to denervation. Lack of neurotrophic support is believed to contribute to the development of diabetic neuropathy. In this study, we measured the expression of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), neurotrophin 4 (NT-4) and ciliary neurotrophic factor (CNTF) in muscle biopsies taken from the gastrocnemic and deltoid muscles in 42 diabetic patients and 20 healthy control subjects. To express the distal neuropathic gradient and to reduce interindividual variation, a distal/proximal ratio between expression levels in the gastrocnemic and deltoid muscles was calculated for all neurotrophic factors. Neuropathic status was determined by clinical examination, electrophysiological studies and quantitative sensory examination in diabetic patients, and muscle strength at both the shoulder and ankle was assessed by isokinetic dynamometry. Distal/proximal ratios for NT-3 were lower in diabetic patients [median (range) 110.7 (39.8-546.8)] than in controls [157.6 (63.3-385.4); (P < 0.05)], and in neuropathic diabetic patients [107.1 (39.8-326.0)] versus patients without neuropathy [134.5 (46.6-546.8); (P < 0.005)]. Further, ratios for NT-3 were related to muscle strength (r(s) = 0.41, P < 0.01) and showed a tendency towards a negative relationship to the combined score of all measures of neuropathy [Neuropathy rank-sum score (NRSS)] (r(s) = -0.27, P = 0.09). Similar trends were observed for ratios for NT-4. Ratios for NGF (r(s) = -0.32, P < 0.05) and BDNF (r(s) = -0.32, P < 0.05) were related to NRSS, but not to muscle strength. Ratios for CNTF were higher in diabetic patients [64.6 (23.7-258.7)] compared with controls [50.2 (27.2-186.4); (P < 0.05)], but showed no relationship to neither NRSS nor muscle strength. Our results show that the expression of NT-3 is reduced in striated muscles in diabetic patients and is related to muscle weakness and neuropathy. We suggest that lack of NT-3 contributes to insufficient re-innervation leading to the loss of muscle strength in diabetic neuropathy.

Accelerated atrophy of lower leg and foot muscles--a follow-up study of long-term diabetic polyneuropathy using magnetic resonance imaging (MRI).

AIMS/HYPOTHESIS: The aim of the study was to determine the loss of muscle volume in the lower leg and foot in long-term diabetic patients in relation to the presence of neuropathy. METHODS: We re-examined 26 type 1 diabetic patients who had participated in magnetic resonance imaging (MRI) studies on muscle volume in the lower leg and foot 9 to 12 years earlier. Re-examination involved MRI, isokinetic dynamometry, clinical examination, electrophysiological studies and quantitative sensory examinations. RESULTS: Annual loss of muscle volume of ankle dorsal and plantar flexors was 4.5 (5.5-3.9)% (median [range]) and 5.0 (7.0-4.2)% in neuropathic patients, 1.9 (3.2-1.0)% and 1.8 (2.6-1.3)% in non-neuropathic patients, and 1.7 (2.8-0.8)% and 1.8 (2.4-0.8)% in controls, respectively (p < 0.01). Annual change of volume and strength correlated for ankle dorsal flexors (r (s) = 0.73, p < 0.01) and for ankle plantar flexors (r (s) = 0.63, p < 0.05) in diabetic patients. In addition, annual change of muscle volume for dorsal and plantar flexors was related to the combined score of all measures of neuropathy (r (s) = -0.68, p < 0.02 and r (s) = -0.73, p < 0.01, respectively). Foot muscle volume declined annually by 3.0 (3.4-1.0)% in neuropathic patients and by 1.1 (4.0-0.2)% in non-neuropathic patients, both values being significantly different from controls (0.2 [-2.5 to 2.4]%). Loss of foot muscle volume was related to severity of neuropathy assessed at clinical evaluation (r (s) = -0.6, p < 0.05). CONCLUSIONS/INTERPRETATION: Muscular atrophy in long-term diabetic neuropathy occurs early in the feet, progresses steadily in the lower legs, relates to severity of neuropathy and leads to weakness at the ankle.

Risk of radiation-induced subcutaneous fibrosis in relation to single nucleotide polymorphisms in TGFB1, SOD2, XRCC1, XRCC3, APEX and ATM--a study based on DNA from formalin fixed paraffin embedded tissue samples.

PURPOSE: In two previously published studies, associations with risk of radiation-induced subcutaneous fibrosis were found for single nucleotide polymorphisms (SNP) in TGFB1 (transforming growth factor beta 1 gene), XRCC1 (X-ray repair cross-complementing 1 gene), XRCC3 (X-ray repair cross-complementing 3 gene), SOD2 (manganese superoxide dismutase gene) and ATM (gene of ataxia telangiectasia mutated). The present study was conducted to seek a confirmation of these findings. MATERIALS AND METHODS: Like the 41 patients previously investigated, the 120 subjects included in the present study were accrued from a historical cohort of 319 post-mastectomy radiotherapy patients. All patients received hypo-fractionated radiotherapy. The TGFB1 position--509, codons 10 and 25, XRCC1 codons 194, 280 and 399, XRCC3 codon 241, SOD2 codon 16, ATM codon 1853 and APEX (apurinic/apyrimidinic exonuclease gene) codon 148 polymorphisms were assessed based on archival histological material. Differences in fibrosis risk were quantified from dose-response assessments. RESULTS: For none of the investigated polymorphisms, significant associations with risk of subcutaneous fibrosis were observed. A detailed analysis did not reveal any obvious explanation for the discrepancy between the previous and the present study. CONCLUSION: The previously observed associations with risk of radiation-induced subcutaneous fibrosis could not be replicated in the present study. Further studies are needed to elucidate the influence of genetic variation upon normal tissue radiosensitivity.

Optimisation and validation of methods to assess single nucleotide polymorphisms (SNPs) in archival histological material.

BACKGROUND AND PURPOSE: An increasing amount of evidence indicates that single nucleotide polymorphisms (SNPs) may affect a variety of oncology related phenotypes. Occasionally, it is convenient to base studies addressing genotype-phenotype relationships on historical patient cohorts, from which only archival specimens are available. This study was conducted to validate protocols optimised for assessment of SNPs based on paraffin embedded, formalin fixed tissue samples. PATIENTS AND METHODS: In 137 breast cancer patients, three TGFB1 SNPs were assessed based on archival histological specimens. In 37 of these patients, the SNPs were also assessed using cultured fibroblasts and the assays were validated by direct comparison of the results. From the remaining 100 patients, only archival material was available. In these patients, the existence of a genetic linkage pattern between the assessed TGFB1 SNPs was used to provide an indirect validation of the genotyping results. Furthermore, two different methods for DNA extraction were compared (semi-automatic DNA extraction using the ABI Prism 6100 Nucleic Acid PrepStation versus Proteinase K digestion for 5 days followed by boiling and DNA precipitation). RESULTS: Assessment of SNPs based on archival histological material is encumbered by a number of obstacles and pitfalls. However, these can be widely overcome by careful optimisation of the methods used for sample selection, DNA extraction and PCR. Within 130 samples that fulfil the criteria for analysis a highly reliable SNP assessment was observed. The study demonstrated that different 'down-stream applications' ('single nucleotide primer extension' or 'TaqMan-based' real-time PCR) could be used as genotyping procedure. CONCLUSIONS: Reliable assessment of SNPs in formalin-fixed paraffin-embedded specimens is possible but a number of precautions should be carefully taken.

Organization in visual episodic memory: relationships between verbalized knowledge, strategy use, and performance.

Relationships between verbalized knowledge (metamemory), strategy use, and performance were examined in a memory task for visually presented episodes. Kindergarten, second-grade, and fifth-grade students were asked to reconstruct a sequence of pictures forming an episode from an array of original pictures and foils. The episodes varied on two dimensions; materials type and the logic of the sequence. Materials were either typical (familiar animal characters and scenes) or atypical (geometric figures) story materials. Sequences either readily conveyed a story (logical) or were rearranged to present a random ordering of pictures (illogical). Children were questioned about their use of a story line to help remember the picture sequences (general questioning) and were asked more specific questions concerning the reasons for their picture selection during the task (specific questioning). Children at all ages recalled logical sequences better than illogical ones. Second- and fifth-grade children recalled animal episodes better than geometric form episodes. Children at all ages showed a correspondence between strategy use and metamemory as assessed by verbalization of relationships among pictures during the specific questioning. However, when the more typical general question format was used to assess metamemory, strategy use preceded verbalized knowledge of strategy use.