Open-source distributed learning validation for a larynx cancer survival model following radiotherapy

Introduction: Prediction models are useful to design personalised treatment. However, safe and effective implementation relies on external validation. Retrospective data are available in many institutions, but sharing between institutions can be challenging due to patient data sensitivity and governance or legal barriers. This study validates a larynx cancer survival model performed using distributed learning without any sensitive data leaving the institution. Methods: Open-source distributed learning software based on a stratified Cox proportional hazard model was developed and used to validate the Egelmeer et al. MAASTRO survival model across two hospitals in two countries. The validation optimised a single scaling parameter multiplied by the original predicted prognostic index. All analyses and figures were based on the distributed system, ensuring no information leakage from the individual centres. All applied software is provided as freeware to facilitate distributed learning in other institutions. Results: 1745 patients received radiotherapy for larynx cancer in the two centres from Jan 2005 to Dec 2018. Limiting to a maximum of one missing value in the parameters of the survival model reduced the cohort to 1095 patients. The Harrell C-index was 0.74 (CI95%, 0.71–0.76) and 0.70 (0.66–0.75) for the two centres. However, the model needed a scaling update. In addition, it was found that survival predictions of patients undergoing hypofractionation were less precise. Conclusion: Open-source distributed learning software was able to validate, and suggest a minor update to the original survival model without central access to patient sensitive information. Even without the update, the original MAASTRO survival model of Egelmeer et al. performed reasonably well, providing similar results in this validation as in its original validatio

Delineation uncertainties of tumour volumes on MRI of head and neck cancer patients

Background: During the last decade, radiotherapy using MR Linac has gone from research to clinical implementation for different cancer locations. For head and neck cancer (HNC), target delineation based only on MR images is not yet standard, and the utilisation of MRI instead of PET/CT in radiotherapy planning is not well established. We aimed to analyse the inter-observer variation (IOV) in delineating GTV (gross tumour volume) on MR images only for patients with HNC. Material/methods: 32 HNC patients from two independent departments were included. Four clinical oncologists from Denmark and four radiation oncologists from Australia had independently contoured primary tumour GTVs (GTV-T) and nodal GTVs (GTV-N) on T2-weighted MR images obtained at the time of treatment planning. Observers were provided with sets of images, delineation guidelines and patient synopsis. Simultaneous truth and performance level estimation (STAPLE) reference volumes were generated for each structure using all observer contours. The IOV was assessed using the DICE Similarity Coefficient (DSC) and mean absolute surface distance (MASD). Results: 32 GTV-Ts and 68 GTV-Ns were contoured per observer. The median MASD for GTV-Ts and GTV-Ns across all patients was 0.17 cm (range 0.08–0.39 cm) and 0.07 cm (range 0.04–0.33 cm), respectively. Median DSC relative to a STAPLE volume for GTV-Ts and GTV-Ns across all patients were 0.73 and 0.76, respectively. A significant correlation was seen between median DSCs and median volumes of GTV-Ts (Spearman correlation coefficient 0.76, p < 0.001) and of GTV-Ns (Spearman correlation coefficient 0.55, p < 0.001). Conclusion: Contouring GTVs in patients with HNC on MRI showed that the median IOV for GTV-T and GTV-N was below 2 mm, based on observes from two separate radiation departments. However, there are still specific regions in tumours that are difficult to resolve as either malignant tissue or oedema that potentially could be improved by further training in MR-only delineation

Intratumoral heterogeneity of microRNA expression in rectal cancer

Introduction: An increasing number of studies have investigated microRNAs (miRNAs) as potential markers of diagnosis, treatment and prognosis. So far, agreement between studies has been minimal, which may in part be explained by intratumoral heterogeneity of miRNA expression. The aim of the present study was to assess the heterogeneity of a panel of selected miRNAs in rectal cancer, using two different technical approaches. Materials and Methods: The expression of the investigated miRNAs was analysed by real-time quantitative polymerase chain reaction (RT-qPCR) and in situ hybridization (ISH) in tumour specimens from 27 patients with T3-4 rectal cancer. From each tumour, tissue from three different luminal localisations was examined. Inter- and intra-patient variability was assessed by calculating intraclass correlation coefficients (ICCs). Correlations between RT-qPCR and ISH were evaluated using Spearman's correlation. Results: ICCsingle (one sample from each patient) was higher than 50% for miRNA-21 and miRNA-31. For miRNA-125b, miRNA-145, and miRNA-630, ICCsingle was lower than 50%. The ICCmean (mean of three samples from each patient) was higher than 50% for miRNA-21(RT-qPCR and ISH), miRNA-125b (RT-qPCR and ISH), miRNA-145 (ISH), miRNA-630 (RT-qPCR), and miRNA-31 (RT-qPCR). For miRNA-145 (RT-qPCR) and miRNA-630 (ISH), ICCmean was lower than 50%. Spearman correlation coefficients, comparing results obtained by RT-qPCR and ISH, respectively, ranged from 0.084 to 0.325 for the mean value from each patient, and from -0.085 to 0.515 in the section including the deepest part of the tumour. Conclusion: Intratumoral heterogeneity may influence the measurement of miRNA expression and consequently the number of samples needed for representative estimates. Our findings with two different methods suggest that one sample is sufficient for adequate assessment of miRNA-21 and miRNA-31, whereas more samples would improve the assessment of miRNA-125b, miRNA-145, and miRNA-630. Interestingly, we found a poor correlation between the expression estimates obtained by RT-qPCR and ISH, respectively

Caries prevalence and tooth loss in Hungarian adult population: results of a national survey

<p>Abstract</p> <p>Background</p> <p>Oral health is basicly important for the well-being of people. Thus, it is strongly suggested to organize epidemiological surveys in order to gain representative data on oral condition of the given population. The purpose of the cross-sectional study was to determine the results on tooth loss and caries prevalence of Hungarian adults in different age groups.</p> <p>Methods</p> <p>Altogether 4606 persons (2923 women, 1683 men) participated in the study who were classified into different age groups: 19 [less than or equal to], 20–24, 35–44, 45–64, 65–74, [greater than or equal to]75 year olds. Probands were selected randomly from the population attending the compulsory lung screening examinations. The participants were examined by calibrated dentists, according to the WHO (1997) criteria. In order to produce representative data, the chosen localities for these examinations covered the capital, the largest towns, the villages, and case weights were used for the statistical evaluation.</p> <p>Results</p> <p>The mean values of DMF-T were found between 11.79±5.68 and 21.90±7.61 These values were significantly higher in women compared to men (p < 0.05). In all age groups the values of M were the highest. Except for the women in the groups of 35–44 and 45–64 year olds, these values showed an increasing tendency both in women and men by age (from 5.50±6.49, and 4.70±4.08 to 21.52±9.07 and 18.41±8.89 respectively). The values of D components reached the highest values in 45–64 year olds (4.54±2.12 and 4.22±2.81, by gender, respectively), then in the older age groups there was a high reduction in these values (in 65–74 year olds: 2.72±1.88 and 1.36±2.48; in 75 or more than 75 year olds: 1.05±1.41 and 1.03±1.76 by gender, respectively). The ratio of D and F values was the highest in the age group of 65–74 year olds (2.12), the lowest ratio could be calculated in 20–34 year olds (0.65).</p> <p>Data showed some decrease in caries experience in 35–44 years of age between 2000 and 2004. The prevalence of persons with 21 or more teeth had been increased from 65.6% to 73.1%. This positive tendency has not been occured in prevalence of edentulousness in this age group: the prevalence of edentulous persons changed from 1.4 to 1.9%. In 65–74 year olds the level of edentulousness became lower, from 25.9 to 14.8% and the prevalence of persons with 21 or more teeth is higher (22.6%) than it was in 2000 (13.0%).</p> <p>Conclusion</p> <p>Present data from Hungary show some slight decrease in caries experience between 35–44 years of age, although this positive tendency has not been occured in prevalence of edentulousness in this age group. A positive tendency could be experienced in the group of 65–74 year olds in edentulousness and in number of teeth, but further efforts are needed to reach a better situation.</p

The influence of visual flow and perceptual load on locomotion speed

Visual flow is used to perceive and regulate movement speed during locomotion. We assessed the extent to which variation in flow from the ground plane, arising from static visual textures, influences locomotion speed under conditions of concurrent perceptual load. In two experiments, participants walked over a 12-m projected walkway that consisted of stripes that were oriented orthogonal to the walking direction. In the critical conditions, the frequency of the stripes increased or decreased. We observed small, but consistent effects on walking speed, so that participants were walking slower when the frequency increased compared to when the frequency decreased. This basic effect suggests that participants interpreted the change in visual flow in these conditions as at least partly due to a change in their own movement speed, and counteracted such a change by speeding up or slowing down. Critically, these effects were magnified under conditions of low perceptual load and a locus of attention near the ground plane. Our findings suggest that the contribution of vision in the control of ongoing locomotion is relatively fluid and dependent on ongoing perceptual (and perhaps more generally cognitive) task demands

Identification and analysis of miRNAs in human breast cancer and teratoma samples using deep sequencing

<p>Abstract</p> <p>Background</p> <p>MiRNAs play important roles in cellular control and in various disease states such as cancers, where they may serve as markers or possibly even therapeutics. Identifying the whole repertoire of miRNAs and understanding their expression patterns is therefore an important goal.</p> <p>Methods</p> <p>Here we describe the analysis of 454 pyrosequencing of small RNA from four different tissues: Breast cancer, normal adjacent breast, and two teratoma cell lines. We developed a pipeline for identifying new miRNAs, emphasizing extracting and retaining as much data as possible from even noisy sequencing data. We investigated differential expression of miRNAs in the breast cancer and normal adjacent breast samples, and systematically examined the mature sequence end variability of miRNA compared to non-miRNA loci.</p> <p>Results</p> <p>We identified five novel miRNAs, as well as two putative alternative precursors for known miRNAs. Several miRNAs were differentially expressed between the breast cancer and normal breast samples. The end variability was shown to be significantly different between miRNA and non-miRNA loci.</p> <p>Conclusion</p> <p>Pyrosequencing of small RNAs, together with a computational pipeline, can be used to identify miRNAs in tumor and other tissues. Measures of miRNA end variability may in the future be incorporated into the discovery pipeline as a discriminatory feature. Breast cancer samples show a distinct miRNA expression profile compared to normal adjacent breast.</p

Infection after primary hip arthroplasty: A comparison of 3 Norwegian health registers

Background and purpose: The aim of the present study was to assess incidence of and risk factors for infection after hip arthroplasty in data from 3 national health registries. We investigated differences in risk patterns between surgical site infection (SSI) and revision due to infection after primary total hip arthroplasty (THA) and hemiarthroplasty (HA). Materials and methods: This observational study was based on prospective data from 2005–2009 on primary THAs and HAs from the Norwegian Arthroplasty Register (NAR), the Norwegian Hip Fracture Register (NHFR), and the Norwegian Surveillance System for Healthcare–Associated Infections (NOIS). The Norwegian Patient Register (NPR) was used for evaluation of case reporting. Cox regression analyses were performed with revision due to infection as endpoint for data from the NAR and the NHFR, and with SSI as the endpoint for data from the NOIS. Results: The 1–year incidence of SSI in the NOIS was 3.0% after THA (167/5,540) and 7.3% after HA (103/1,416). The 1–year incidence of revision due to infection was 0.7% for THAs in the NAR (182/24,512) and 1.5% for HAs in the NHFR (128/8,262). Risk factors for SSI after THA were advanced age, ASA class higher than 2, and short duration of surgery. For THA, the risk factors for revision due to infection were male sex, advanced age, ASA class higher than 1, emergency surgery, uncemented fixation, and a National Nosocomial Infection Surveillance (NNIS) risk index of 2 or more. For HAs inserted after fracture, age less than 60 and short duration of surgery were risk factors of revision due to infection. Interpretation: The incidences of SSI and revision due to infection after primary hip replacements in Norway are similar to those in other countries. There may be differences in risk pattern between SSI and revision due to infection after arthroplasty. The risk patterns for revision due to infection appear to be different for HA and THA

Smoking behaviour predicts tobacco control attitudes in a high smoking prevalence hospital: A cross-sectional study in a Portuguese teaching hospital prior to the national smoking ban

<p>Abstract</p> <p>Background</p> <p>Several studies have investigated attitudes to and compliance with smoking bans, but few have been conducted in healthcare settings and none in such a setting in Portugal. Portugal is of particular interest because the current ban is not in line with World Health Organization recommendations for a "100% smoke-free" policy. In November 2007, a Portuguese teaching-hospital surveyed smoking behaviour and tobacco control (TC) attitudes before the national ban came into force in January 2008.</p> <p>Methods</p> <p>Questionnaire-based cross-sectional study, including all eligible staff. Sample: 52.9% of the 1, 112 staff; mean age 38.3 ± 9.9 years; 65.9% females. Smoking behaviour and TC attitudes and beliefs were the main outcomes. Bivariable analyses were conducted using chi-squared and MacNemar tests to compare categorical variables and Mann-Whitney tests to compare medians. Multilogistic regression (MLR) was performed to identify factors associated with smoking status and TC attitudes.</p> <p>Results</p> <p>Smoking prevalence was 40.5% (95% CI: 33.6-47.4) in males, 23.5% (95% CI: 19.2-27.8) in females (p < 0.001); 43.2% in auxiliaries, 26.1% in nurses, 18.9% among physicians, and 34.7% among other non-health professionals (p = 0.024). The findings showed a very high level of agreement with smoking bans, even among smokers, despite the fact that 70.3% of the smokers smoked on the premises and 76% of staff reported being frequently exposed to second-hand smoke (SHS). In addition 42.8% reported that SHS was unpleasant and 28.3% admitted complaining. MLR showed that smoking behaviour was the most important predictor of TC attitudes.</p> <p>Conclusions</p> <p>Smoking prevalence was high, especially among the lower socio-economic groups. The findings showed a very high level of support for smoking bans, despite the pro-smoking environment. Most staff reported passive behaviour, despite high SHS exposure. This and the high smoking prevalence may contribute to low compliance with the ban and low participation on smoking cessation activities. Smoking behaviour had greater influence in TC attitudes than health professionals' education. Our study is the first in Portugal to identify potential predictors of non-compliance with the partial smoking ban, further emphasising the need for a 100% smoke-free policy, effective enforcement and public health education to ensure compliance and promote social norm change.</p

Trabecular Reorganization in Consecutive Iliac Crest Biopsies when Switching from Bisphosphonate to Strontium Ranelate Treatment

BACKGROUND: Several agents are available to treat osteoporosis while addressing patient-specific medical needs. Individuals' residual risk to severe fracture may require changes in treatment strategy. Data at osseous cellular and microstructural levels due to a therapy switch between agents with different modes of action are rare. Our study on a series of five consecutively taken bone biopsies from an osteoporotic individual over a six-year period analyzes changes in cellular characteristics, bone microstructure and mineralization caused by a therapy switch from an antiresorptive (bisphosphonate) to a dual action bone agent (strontium ranelate). METHODOLOGY/PRINCIPAL FINDINGS: Biopsies were progressively taken from the iliac crest of a female patient. Four biopsies were taken during bisphosphonate therapy and one biopsy was taken after one year of strontium ranelate (SR) treatment. Furthermore, serum bone markers and dual x-ray absorptiometry measurements were acquired. Undecalcified histology was used to assess osteoid parameters and bone turnover. Structural indices and degree of mineralization were determined using microcomputed tomography, quantitative backscattered electron imaging, and combined energy dispersive x-ray/µ-x-ray-fluorescence microanalysis. CONCLUSIONS/SIGNIFICANCE: Microstructural data revealed a notable increase in bone volume fraction after one year of SR treatment compared to the bisphosphonate treatment period. Indices of connectivity density, structure model index and trabecular bone pattern factor were predominantly enhanced indicating that the architectural transformation from trabecular rods to plates was responsible for the bone volume increase and less due to changes in trabecular thickness and number. Administration of SR following bisphosphonates led to a maintained mineralization profile with an uptake of strontium on the bone surface level. Reactivated osteoclasts designed tunneling, hook-like intratrabecular resorption sites. The appearance of tunneling resorption lacunae and the formation of both mini-modeling units and osteon-like structures within increased plate-like cancellous bone mass provides additional information on the mechanisms of strontium ranelate following bisphosphonate treatment, which may deserve special attention when monitoring a treatment switch

pO polarography, contrast enhanced color duplex sonography (CDS), [18F] fluoromisonidazole and [18F] fluorodeoxyglucose positron emission tomography: validated methods for the evaluation of therapy-relevant tumor oxygenation or only bricks in the puzzle of tumor hypoxia?

<p>Abstract</p> <p>Background</p> <p>The present study was conducted to analyze the value of ([¹⁸F] fluoromisonidazole (FMISO) and [¹⁸F]-2-fluoro-2'-deoxyglucose (FDG) PET as well as color pixel density (CPD) and tumor perfusion (TP) assessed by color duplex sonography (CDS) for determination of therapeutic relevant hypoxia. As a standard for measuring tissue oxygenation in human tumors, the invasive, computerized polarographic needle electrode system (pO₂histography) was used for comparing the different non invasive measurements.</p> <p>Methods</p> <p>Until now a total of 38 Patients with malignancies of the head and neck were examined. Tumor tissue pO₂was measured using a pO₂-histograph. The needle electrode was placed CT-controlled in the tumor without general or local anesthesia. To assess the biological and clinical relevance of oxygenation measurement, the relative frequency of pO₂readings, with values ≤ 2.5, ≤ 5.0 and ≤ 10.0 mmHg, as well as mean and median pO₂were stated. FMISO PET consisted of one static scan of the relevant region, performed 120 min after intravenous administration. FMISO tumor to muscle ratios (FMISO_T/M) and tumor to blood ratios (FMISO_T/B) were calculated. FDG PET of the lymph node metastases was performed 71 ± 17 min after intravenous administration. To visualize as many vessels as possible by CDS, a contrast enhancer (Levovist^®, Schering Corp., Germany) was administered. Color pixel density (CPD) was defined as the ratio of colored to grey pixels in a region of interest. From CDS signals two parameters were extracted: color hue – defining velocity (v) and color area – defining perfused area (A). Signal intensity as a measure of tissue perfusion (TP) was quantified as follows: TP = v_mean× A_mean.</p> <p>Results</p> <p>In order to investigate the degree of linear association, we calculated the Pearson correlation coefficient. Slight (|r| > 0.4) to moderate (|r| > 0.6) correlation was found between the parameters of pO₂polarography (pO₂readings with values ≤ 2.5, ≤ 5.0 and ≤ 10.0 mmHg, as well as median pO₂), CPD and FMISO_T/M. Only a slight correlation between TP and the fraction of pO₂values ≤ 10.0 mmHg, median and mean pO₂could be detected. After exclusion of four outliers the absolute values of the Pearson correlation coefficients increased clearly. There was no relevant association between mean or maximum FDG uptake and the different polarographic- as well as the CDS parameters.</p> <p>Conclusion</p> <p>CDS and FMISO PET represent different approaches for estimation of therapy relevant tumor hypoxia. Each of these approaches is methodologically limited, making evaluation of clinical potential in prospective studies necessary.</p