(Pre)treatment risk factors for late fatigue and fatigue trajectories following radiotherapy for breast cancer.

Fatigue is common in breast-cancer survivors. Our study assessed fatigue longitudinally in breast cancer patients receiving adjuvant radiotherapy (RT) and aimed to identify risk factors associated with long-term fatigue and underlying fatigue trajectories. Fatigue was measured in a prospective multicenter cohort (REQUITE) using the Multidimensional Fatigue Inventory (MFI-20) and analyzed using mixed models. Multivariable logistic models identified factors associated with fatigue dimensions at 2 years post-RT and latent class growth analysis identified individual fatigue trajectories. A total of 1443, 1302, 1203 and 1098 patients completed the MFI-20 at baseline, end of RT, after 1 and 2 years. Overall, levels of fatigue significantly increased from baseline to end of RT for all fatigue dimensions (P < .05) and returned to baseline levels after 2 years. A quarter of patients were assigned to latent trajectory high (23.7%) and moderate (24.8%) fatigue classes, while 46.3% and 5.2% to the low and decreasing fatigue classes, respectively. Factors associated with multiple fatigue dimensions at 2 years include age, BMI, global health status, insomnia, pain, dyspnea and depression. Fatigue present at baseline was consistently associated with all five MFI-20 fatigue dimensions (ORGeneralFatigue = 3.81, P < .001). From latent trajectory analysis, patients with a combination of factors such as pain, insomnia, depression, younger age and endocrine therapy had a particularly high risk of developing early and persistent high fatigue years after treatment. Our results confirmed the multidimensional nature of fatigue and will help clinicians identify breast cancer patients at higher risk of having persistent/late fatigue so that tailored interventions can be delivered.

Developmental analysis of SV2 in the embryonic chicken corneal epithelium.

Intraepithelial corneal nerves (ICNs) help protect the cornea as part of the blink reflex and by modulating tear production. ICNs are also thought to regulate the health and homeostasis of the cornea through the release of trophic factors. Disruption to these nerves can lead to vision loss. Despite their importance little is known about how corneal nerves function and even less is known about how the cornea is initially innervated during its embryonic development. Here, we investigated the innervation of the embryonic chicken cornea. Western blot and immunohistochemistry were used to characterize the localization of the synaptic vesicle marker SV2, a molecule thought to be involved in the release of trophic factors from sensory nerves. The data show that both SV2 and synaptotagmin co-localize to ICNs. Nerves in the conjunctiva also contained SV2 and synaptotagmin, but these were localized to below the basal layers of the conjunctiva epithelium. SV2 isolated from corneal epithelium migrates in western blot at a heavier weight than SV2 isolated from brain, which suggests a role in vesicle targeting, as the deglycosylating enzyme PnGase does not affect corneal SV2.

Cardiorespiratory and perceptual responses to self-regulated and imposed submaximal arm-leg ergometry.

PURPOSE: This study compared cardiorespiratory and perceptual responses to exercise using self-regulated and imposed power outputs distributed between the arms and legs. METHODS: Ten males (age 21.7 ± 3.4 years) initially undertook incremental arm-crank ergometry (ACE) and cycle ergometry (CYC) tests to volitional exhaustion to determine peak power output (Wpeak). Two subsequent tests involved 20-min combined arm-leg ergometry (ALE) trials, using imposed and self-regulated protocols, both of which aimed to elicit an exercising heart rate of 160 beats min-1. During the imposed trial, arm and leg intensity were set at 40% of each ergometer-specific Wpeak. During the self-regulated trial, participants were asked to self-regulate cadence and resistance to achieve the target heart rate. Heart rate (HR), oxygen uptake ([Formula: see text]), pulmonary ventilation ([Formula: see text]), and ratings of perceived exertion (RPE) were recorded continuously. RESULTS: As expected, there were no differences between imposed and self-regulated trials for HR, [Formula: see text], and [Formula: see text] (all P ≥ 0.05). However, central RPE and local RPE for the arms were lower during self-regulated compared imposed trials (P ≤ 0.05). Lower RPE during the self-regulated trial was related to preferential adjustments in how the arms (33 ± 5% Wpeak) and legs (46 ± 5% Wpeak) contributed to the exercise intensity. CONCLUSIONS: This study demonstrates that despite similar metabolic and cardiovascular strain elicited by imposed and self-regulated ALE, the latter was perceived to be less strenuous, which is related to participants doing more work with the legs and less work with the arms to achieve the target intensity.

Prevalence and location of bone spurs in anterior ankle impingement: A cadaveric investigation.

Anterior ankle impingement (AAI) results from repetitive microtrauma leading to pain and decreased dorsiflexion due to spur formation and synovial hypertrophy. Information about the prevalence of anterior spur formation in a large population, and the individual contributions of the talus and tibia to osseous impingement, is limited. A total of 670 ankle specimens from 344 individuals (n = 111 females, n = 233 males) aged 20 to 40 years at the time of death were examined. Matching tibia and talus were opposed and any spurring causing impingement was recorded. Spur locations were measured and ratios calculated to allow for inter-specimen comparison between: (1) medial-to-lateral and anterior-to-posterior spur location versus dimensions of talar neck width, and (2) medial-to-lateral spur location to dimensions of distal anterior tibial width. Differences in spur prevalence in relation to sex, race, height and age were identified by univariant and multivariable statistical analyses. Bony impingement was observed in 21% (n = 72) of specimens, with bilateral involvement in 8% (n = 27). For ankles with AAI, spurs were seen on the talus only in 61%, on the tibia only in 14%, and on both the tibia and talus in 26%. Spurs were significantly more prevalent in males (P = 0.001) and with increasing specimen age (P = 0.002). There were no significant differences related to specimen height or race. Spurs were predominately located on the anterolateral talus (78%) and the anterolateral portion of the distal tibial margin (80%). AAI was present in 21% of young osseous specimens and was significantly more prevalent in males and with increasing specimen age. Clin. Anat. 31:1144-1150, 2018. © 2018 Wiley Periodicals, Inc.

Nuclear ferritin mediated regulation of JNK signaling in corneal epithelial cells.

Corneal epithelial (CE) cells are exposed to environmental insults (e.g., UV-irradiation), yet they suffer little damage. Our previous studies suggest that chicken CE cells have a novel form of protection involving having ferritin in a nuclear location where it can bind to DNA and sequester free iron. Here we describe another potential nuclear ferritin-mediated protective mechanism: the down-regulation of the JNK signaling pathway. The JNK pathway has been shown by others to promote apoptosis in response to cell damage and also to be activated in CE cell lines following exposure to UV radiation. Here we show in COS7 reporter cell lines that the expression of ferritin in a nuclear localization significantly down-regulates the JNK pathway (p = 5.7 × 10(-6)), but has no effect on the NFkB or the Erk pathways. In organ cultures of embryonic chicken corneas, we observed that inhibiting the synthesis of nuclear ferritin in CE cells, using the iron-chelating molecule deferoxamine, led to an increase in JNK signaling, as measured by phospho-JNK levels compared to CE cells with nuclear ferritin. Furthermore, the chemical inhibition of the JNK pathway using the molecule AS601245 decreased the production of nuclear ferritin. Taken together, these observations suggest that in CE cells a feedback-loop exists in which JNK signaling increases the production of nuclear ferritin and, in turn, nuclear ferritin decreases the activity of the JNK signaling pathway.

The Shoulder Objective Practical Assessment Tool: Evaluation of a New Tool Assessing Residents Learning in Diagnostic Shoulder Arthroscopy.

PURPOSE: To design and validate an objective practical assessment tool for diagnostic shoulder arthroscopy that would provide residents with a method to evaluate their progression in this field of surgery and to identify specific learning needs. METHODS: We designed and evaluated the shoulder Objective Practical Assessment Tool (OPAT). The shoulder OPAT was designed by us, and scoring domains were created using a Delphi process. The shoulder OPAT was trialed by members of the British Elbow & Shoulder Society Education Committee for internal consistency and ease of use before being offered to other trainers and residents. Inter-rater reliability and intrarater reliability were calculated. One hundred forty orthopaedic residents, of varying seniority, within 5 training regions in the United Kingdom, were questioned regarding the tool. A pilot study of 6 residents was undertaken. RESULTS: Internal consistency was 0.77 (standardized Cronbach α). Inter-rater reliability was 0.60, and intrarater reliability was 0.82. The Spearman correlation coefficient (r) between the global summary score for the shoulder OPAT and the current assessment tool used in postgraduate training for orthopaedic residents undertaking diagnostic shoulder arthroscopy equaled 0.74. Of the residents, 82% agreed or strongly agreed when asked if the shoulder OPAT would be a useful tool in monitoring progression and 72% agreed or strongly agreed with the introduction of the shoulder OPAT within the orthopaedic domain. CONCLUSIONS: This study shows that the shoulder OPAT fulfills several aspects of reliability and validity when tested. Despite the inter-rater reliability being 0.60, we believe that the shoulder OPAT has the potential to play a role alongside the current assessment tool in the training of orthopaedic residents. CLINICAL RELEVANCE: The shoulder OPAT can be used to assess residents during shoulder arthroscopy and has the potential for use in medical education, as well as arthroscopic skills training in the operating theater.

Automated design of paralogue ratio test assays for the accurate and rapid typing of copy number variation.

MOTIVATION: Genomic copy number variation (CNV) can influence susceptibility to common diseases. High-throughput measurement of gene copy number on large numbers of samples is a challenging, yet critical, stage in confirming observations from sequencing or array Comparative Genome Hybridization (CGH). The paralogue ratio test (PRT) is a simple, cost-effective method of accurately determining copy number by quantifying the amplification ratio between a target and reference amplicon. PRT has been successfully applied to several studies analyzing common CNV. However, its use has not been widespread because of difficulties in assay design. RESULTS: We present PRTPrimer (www.prtprimer.org) software for automated PRT assay design. In addition to stand-alone software, the web site includes a database of pre-designed assays for the human genome at an average spacing of 6 kb and a web interface for custom assay design. Other reference genomes can also be analyzed through local installation of the software. The usefulness of PRTPrimer was tested within known CNV, and showed reproducible quantification. This software and database provide assays that can rapidly genotype CNV, cost-effectively, on a large number of samples and will enable the widespread adoption of PRT. AVAILABILITY: PRTPrimer is available in two forms: a Perl script (version 5.14 and higher) that can be run from the command line on Linux systems and as a service on the PRTPrimer web site (www.prtprimer.org).

Dimitrios Zambakis' Scientific Hypothesis on the Transmission of Leprosy.

Dimitrios Zambakis was an acclaimed physician at his time, most recognized for his work on leprosy. He theorized that leprosy was a hereditary disease, receiving many awards for his work including the Cholera Medal of Honour (1854), Château-Villard Prize from the Faculty of Medicine in Paris (1898), The Montyon Prize, and the title of Pasha. However, his theory was routinely argued against and was later proven to be invalid. Leprosy is regarded as a contagious disease spread by contact and is not hereditary. The last name appears to be spelled in various ways (Zambakis, Zambaco). For this paper, "Dimitrios Zambakis" will be used.

Analysis of Neurosurgery Influencers on Instagram: Trends and Patterns of the Neurosurgeon's Social Media Footprint.

OBJECTIVE: Social media outlets such as Instagram have recently become a popular tool for medical professionals to disseminate medical information to a large public audience. In this study, we identify the top neurosurgery influencers on Instagram and analyze trends between content type, audience interaction, and user engagement. METHODS: A list of neurosurgeon Instagram profiles based on the number of followers, user engagement, and average interaction were compiled. Outcome variables such as the numbers of followers, likes, comments, hashtags, caption words, user engagement, and average user activity were collected and analyzed. The most recent 30 posts from each included profile were stratified into categories on the basis of type of content. RESULTS: A total of 73 neurologic surgeon "influencer" Instagram profiles met our inclusion and exclusion criteria (67 male [91.8%]; 6 female [8.2%]). Of the most recent 30 posts for each influencer, clinical and professional posts represented the majority (67.4%), while lifestyle and patient posts made up 30.3% and 2.3%, respectively. In comparison to the rest of the field (n = 43), the 30 profiles with the most followers had a significantly higher average interaction (418.77 vs. 126.79; P < 0.001), number of uploads (578.87 vs. 184.58; P = 0.004), average number of likes given in the top posts (770.71 vs. 2150.40; P < 0.001), average posts per week (2.40 vs. 1.12; P = 0.041), and average posts per month (9.91 vs. 4.02.; P = 0.015). CONCLUSIONS: Neurosurgeon influencers on Instagram post content that predominantly features educational and academic subject matter. Post content regarding the individual's personal life or extracurricular activities made up a lesser portion of content, and there were few posts categorized as patient testimonials.

Guillain-Barré syndrome after elective lateral lumbar interbody fusion.

Complications following lateral retroperitoneal transpsoas lumbar fusion (LLIF) surgery include femoral nerve apraxia, bowel/bladder injury, ureteral injury, and potentially, as illustrated in this case report, Guillain-Barré syndrome. Guillain-Barré syndrome (GBS) is an autoimmune inflammatory condition that typically presents after infection, or, less frequently, post-operatively. We report a case of GBS following elective lumbar fusion through the lateral retroperitoneal transpsoas approach (LLIF). A 56-year-old patient presented with left lower extremity (LLE) weakness on post-operative day 12. EMG showed bilateral upper extremity muscle recruitment, worse distally. Following a treatment with intravenous immunoglobulin (IVIG), the patient gradually improved, and her condition was favorable at 6-month post-operative follow-up. CSF analysis and EMG should be part of the workup for patients presenting with lower extremity neuropathy following LLIF.

Contouring variation affects estimates of normal tissue complication probability for breast fibrosis after radiotherapy.

BACKGROUND: Normal tissue complication probability (NTCP) models can be useful to estimate the risk of fibrosis after breast-conserving surgery (BCS) and radiotherapy (RT) to the breast. However, they are subject to uncertainties. We present the impact of contouring variation on the prediction of fibrosis. MATERIALS AND METHODS: 280 breast cancer patients treated BCS-RT were included. Nine Clinical Target Volume (CTV) contours were created for each patient: i) CTV_crop (reference), cropped 5 mm from the skin and ii) CTV_skin, uncropped and including the skin, iii) segmenting the 95% isodose (Iso95%) and iv) 3 different auto-contouring atlases generating uncropped and cropped contours (Atlas_skin/Atlas_crop). To illustrate the impact of contour variation on NTCP estimates, we applied two equations predicting fibrosis grade ≥ 2 at 5 years, based on Lyman-Kutcher-Burman (LKB) and Relative Seriality (RS) models, respectively, to each contour. Differences were evaluated using repeated-measures ANOVA. For completeness, the association between observed fibrosis events and NTCP estimates was also evaluated using logistic regression. RESULTS: There were minimal differences between contours when the same contouring approach was followed (cropped and uncropped). CTV_skin and Atlas_skin contours had lower NTCP estimates (-3.92%, IQR 4.00, p < 0.05) compared to CTV_crop. No significant difference was observed for Atlas_crop and Iso95% contours compared to CTV_crop. For the whole cohort, NTCP estimates varied between 5.3% and 49.5% (LKB) or 2.2% and 49.6% (RS) depending on the choice of contours. NTCP estimates for individual patients varied by up to a factor of 4. Estimates from "skin" contours showed higher agreement with observed events. CONCLUSION: Contour variations can lead to significantly different NTCP estimates for breast fibrosis, highlighting the importance of standardising breast contours before developing and/or applying NTCP models.

Comparing symptom reporting by prostate cancer patients and healthcare professionals in the international multicentre REQUITE study.

INTRODUCTION: Previous studies showed that healthcare professionals and patients had only moderate to low agreement on their assessment of treatment-related symptoms. We aimed to determine the levels of agreement in a large cohort of prostate cancer patients. METHODS: Analyses were made of data from 1,756 prostate cancer patients treated with external beam radiotherapy (RT) and/or brachytherapy in Europe and the USA and recruited into the prospective multicentre observational REQUITE study. Eleven pelvic symptoms at the end of RT were compared after translating patient-reported outcomes (PROs) into CTCAE-based healthcare professional ratings. Gwet's AC2 agreement coefficient and 95% confidence intervals were calculated for each symptom. To compare severity of grading between patients and healthcare professionals, percent agreement and deviations for each symptom were graphically depicted. Stratified and sensitivity analyses were conducted to identify potential influencing factors and to assess heterogeneity and robustness of results. RESULTS: The agreement for the 11 pelvic symptoms varied from very good (AC2 > 0.8: haematuria, rectal bleeding, management of sphincter control) to poor agreement (AC2 ≤ 0.2: proctitis and urinary urgency). Fatigue had a negative impact on the agreement. Patients tended to grade symptoms more severely than healthcare professionals. Information on sexual dysfunction was missing more frequently in healthcare professional assessment than PROs. CONCLUSION: Agreement was better for observable than subjective symptoms, with patients usually grading symptoms more severely than healthcare professionals. Our findings emphasize that PROs should complement symptom assessment by healthcare professionals and be taken into consideration for clinical decision-making to incorporate the patient perspective.

Genome-wide association study of treatment-related toxicity two years following radiotherapy for breast cancer.

BACKGROUND AND PURPOSE: Up to a quarter of breast cancer patients treated by surgery and radiotherapy experience clinically significant toxicity. If patients at high risk of adverse effects could be identified at diagnosis, their treatment could be tailored accordingly. This study was designed to identify common single nucleotide polymorphisms (SNPs) associated with toxicity two years following whole breast radiotherapy. MATERIALS AND METHODS: A genome-wide association study (GWAS) was performed in 1,640 breast cancer patients with complete SNP, clinical, treatment and toxicity data, recruited across 18 European and US centres into the prospective REQUITE cohort study. Toxicity data (CTCAE v4.0) were collected at baseline, end of radiotherapy, and annual follow-up. A total of 7,097,340 SNPs were tested for association with the residuals of toxicity endpoints, adjusted for clinical, treatment co-variates and population substructure. RESULTS: Quantile-quantile plots showed more associations with toxicity above the p < 5 × 10-5 level than expected by chance. Eight SNPs reached genome-wide significance. Nipple retraction grade ≥ 2 was associated with the rs188287402 variant (p = 2.80 × 10-8), breast oedema grade ≥ 2 with rs12657177 (p = 1.12 × 10-10), rs75912034 (p = 1.12 × 10-10), rs145328458 (p = 1.06 × 10-9) and rs61966612 (p = 1.23 × 10-9), induration grade ≥ 2 with rs77311050 (p = 2.54 × 10-8) and rs34063419 (p = 1.21 × 10-8), and arm lymphoedema grade ≥ 1 with rs643644 (p = 3.54 × 10-8). Heritability estimates across significant endpoints ranged from 25% to 39%. Our study did not replicate previously reported SNPs associated with breast radiation toxicity at the pre-specified significance level. CONCLUSIONS: This GWAS for long-term breast radiation toxicity provides further evidence for significant association of common SNPs with distinct toxicity endpoints.

Corneal microprojections in coleoid cephalopods.

The cornea is the first optical element in the path of light entering the eye, playing a role in image formation and protection. Corneas of vertebrate simple camera-type eyes possess microprojections on the outer surface in the form of microridges, microvilli, and microplicae. Corneas of invertebrates, which have simple or compound eyes, or both, may be featureless or may possess microprojections in the form of nipples. It was previously unknown whether cephalopods (invertebrates with camera-type eyes like vertebrates) possess corneal microprojections and, if so, of what form. Using scanning electron microscopy, we examined corneas of a range of cephalopods and discovered nipple-like microprojections in all species. In some species, nipples were like those described on arthropod compound eyes, with a regular hexagonal arrangement and sizes ranging from 75 to 103 nm in diameter. In others, nipples were nodule shaped and irregularly distributed. Although terrestrial invertebrate nipples create an antireflective surface that may play a role in camouflage, no such optical function can be assigned to cephalopod nipples due to refractive index similarities of corneas and water. Their function may be to increase surface-area-to-volume ratio of corneal epithelial cells to increase nutrient, gas, and metabolite exchange, and/or stabilize the corneal mucous layer, as proposed for corneal microprojections of vertebrates.

No Association Between Polygenic Risk Scores for Cancer and Development of Radiation Therapy Toxicity.

PURPOSE: Our aim was to test whether updated polygenic risk scores (PRS) for susceptibility to cancer affect risk of radiation therapy toxicity. METHODS AND MATERIALS: Analyses included 9,717 patients with breast (n=3,078), prostate (n=5,748) or lung (n=891) cancer from Radiogenomics and REQUITE Consortia cohorts. Patients underwent potentially curative radiation therapy and were assessed prospectively for toxicity. Germline genotyping involved genome-wide single nucleotide polymorphism (SNP) arrays with nontyped SNPs imputed. PRS for each cancer were generated by summing literature-identified cancer susceptibility risk alleles: 352 breast, 136 prostate, and 24 lung. Weighted PRS were generated using log odds ratio (ORs) for cancer susceptibility. Standardized total average toxicity (STAT) scores at 2 and 5 years (breast, prostate) or 6 to 12 months (lung) quantified toxicity. Primary analysis tested late STAT, secondary analyses investigated acute STAT, and individual endpoints and SNPs using multivariable regression. RESULTS: Increasing PRS did not increase risk of late toxicity in patients with breast (OR, 1.000; 95% confidence interval [CI], 0.997-1.002), prostate (OR, 0.99; 95% CI, 0.98-1.00; weighted PRS OR, 0.93; 95% CI, 0.83-1.03), or lung (OR, 0.93; 95% CI, 0.87-1.00; weighted PRS OR, 0.68; 95% CI, 0.45-1.03) cancer. Similar results were seen for acute toxicity. Secondary analyses identified rs138944387 associated with breast pain (OR, 3.05; 95% CI, 1.86-5.01; P = 1.09 × 10-5) and rs17513613 with breast edema (OR, 0.94; 95% CI, 0.92-0.97; P = 1.08 × 10-5). CONCLUSIONS: Patients with increased polygenic predisposition to breast, prostate, or lung cancer can safely undergo radiation therapy with no anticipated excess toxicity risk. Some individual SNPs increase the likelihood of a specific toxicity endpoint, warranting validation in independent cohorts and functional studies to elucidate biologic mechanisms.

High weekly integral dose and larger fraction size increase risk of fatigue and worsening of functional outcomes following radiotherapy for localized prostate cancer.

Introduction: We hypothesized that increasing the pelvic integral dose (ID) and a higher dose per fraction correlate with worsening fatigue and functional outcomes in localized prostate cancer (PCa) patients treated with external beam radiotherapy (EBRT). Methods: The study design was a retrospective analysis of two prospective observational cohorts, REQUITE (development, n=543) and DUE-01 (validation, n=228). Data were available for comorbidities, medication, androgen deprivation therapy, previous surgeries, smoking, age, and body mass index. The ID was calculated as the product of the mean body dose and body volume. The weekly ID accounted for differences in fractionation. The worsening (end of radiotherapy versus baseline) of European Organisation for Research and Treatment of Cancer EORTC) Quality of Life Questionnaire (QLQ)-C30 scores in physical/role/social functioning and fatigue symptom scales were evaluated, and two outcome measures were defined as worsening in ≥2 (WS2) or ≥3 (WS3) scales, respectively. The weekly ID and clinical risk factors were tested in multivariable logistic regression analysis. Results: In REQUITE, WS2 was seen in 28% and WS3 in 16% of patients. The median weekly ID was 13.1 L·Gy/week [interquartile (IQ) range 10.2-19.3]. The weekly ID, diabetes, the use of intensity-modulated radiotherapy, and the dose per fraction were significantly associated with WS2 [AUC (area under the receiver operating characteristics curve) =0.59; 95% CI 0.55-0.63] and WS3 (AUC=0.60; 95% CI 0.55-0.64). The prevalence of WS2 (15.3%) and WS3 (6.1%) was lower in DUE-01, but the median weekly ID was higher (15.8 L·Gy/week; IQ range 13.2-19.3). The model for WS2 was validated with reduced discrimination (AUC=0.52 95% CI 0.47-0.61), The AUC for WS3 was 0.58. Conclusion: Increasing the weekly ID and the dose per fraction lead to the worsening of fatigue and functional outcomes in patients with localized PCa treated with EBRT.

Development and Optimization of a Machine-Learning Prediction Model for Acute Desquamation After Breast Radiation Therapy in the Multicenter REQUITE Cohort.

Purpose: Some patients with breast cancer treated by surgery and radiation therapy experience clinically significant toxicity, which may adversely affect cosmesis and quality of life. There is a paucity of validated clinical prediction models for radiation toxicity. We used machine learning (ML) algorithms to develop and optimise a clinical prediction model for acute breast desquamation after whole breast external beam radiation therapy in the prospective multicenter REQUITE cohort study. Methods and Materials: Using demographic and treatment-related features (m = 122) from patients (n = 2058) at 26 centers, we trained 8 ML algorithms with 10-fold cross-validation in a 50:50 random-split data set with class stratification to predict acute breast desquamation. Based on performance in the validation data set, the logistic model tree, random forest, and naïve Bayes models were taken forward to cost-sensitive learning optimisation. Results: One hundred and ninety-two patients experienced acute desquamation. Resampling and cost-sensitive learning optimisation facilitated an improvement in classification performance. Based on maximising sensitivity (true positives), the "hero" model was the cost-sensitive random forest algorithm with a false-negative: false-positive misclassification penalty of 90:1 containing m = 114 predictive features. Model sensitivity and specificity were 0.77 and 0.66, respectively, with an area under the curve of 0.77 in the validation cohort. Conclusions: ML algorithms with resampling and cost-sensitive learning generated clinically valid prediction models for acute desquamation using patient demographic and treatment features. Further external validation and inclusion of genomic markers in ML prediction models are worthwhile, to identify patients at increased risk of toxicity who may benefit from supportive intervention or even a change in treatment plan.

Overview of health-related quality of life and toxicity of non-small cell lung cancer patients receiving curative-intent radiotherapy in a real-life setting (the REQUITE study).

OBJECTIVES: Radiotherapy-induced toxicity may negatively impact health-related quality of life (HRQoL). This report investigates the impact of curative-intent radiotherapy on HRQoL and toxicity in early stage and locally-advanced non-small cell lung cancer patients treated with radiotherapy or chemo-radiotherapy enrolled in the observational prospective REQUITE study. MATERIALS AND METHODS: HRQoL was assessed using the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire up to 2 years post radiotherapy. Eleven toxicities were scored by clinicians using the Common Terminology Criteria for Adverse Events (CTCAE) version 4. Toxicity scores were calculated by subtracting baseline values. Mixed model analyses were applied to determine statistical significance (p ≤ 0.01). Meaningful clinical important differences (MCID) were determined for changes in HRQoL. Analysis was performed on the overall data, different radiotherapy techniques, multimodality treatments and disease stages. RESULTS: Data of 510 patients were analysed. There was no significant change in HRQoL or its domains, except for deterioration in cognitive functioning (p = 0.01). Radiotherapy technique had no significant impact on HRQoL. The addition of chemotherapy was significantly associated with HRQoL over time (p <.001). Overall toxicity did not significantly change over time. Acute toxicities of radiation-dermatitis (p =.003), dysphagia (p =.002) and esophagitis (p <.001) peaked at 3 months and decreased thereafter. Pneumonitis initially deteriorated but improved significantly after 12 months (p =.011). A proportion of patients experienced meaningful clinically important improvements and deteriorations in overall HRQoL and its domains. In some patients, pre-treatment symptoms improved gradually. CONCLUSIONS: While overall HRQoL and toxicity did not change over time, some patients improved, whereas others experienced acute radiotherapy-induced toxicities and deteriorated HRQoL, especially physical and cognitive functioning. Patient characteristics, more so than radiotherapy technique and treatment modality, impact post-radiotherapy toxicity and HRQoL outcomes. This stresses the importance of considering the potential impact of radiotherapy on individuals' HRQoL, symptoms and toxicity in treatment decision-making.

The correlation between pre-treatment symptoms, acute and late toxicity and patient-reported health-related quality of life in non-small cell lung cancer patients: Results of the REQUITE study.

BACKGROUND AND PURPOSE: To investigate the association between clinician-scored toxicities and patient-reported health-related quality of life (HRQoL), in early-stage (ES-) and locally-advanced (LA-) non-small cell lung cancer (NSCLC) patients receiving loco-regional radiotherapy, included in the international real-world REQUITE study. MATERIALS AND METHODS: Clinicians scored eleven radiotherapy-related toxicities (and baseline symptoms) with the Common Terminology Criteria for Adverse Events version 4. HRQoL was assessed with the European Organization for Research and Treatment of Cancer core HRQoL questionnaire (EORTC-QLQ-C30). Statistical analyses used the mixed-model method; statistical significance was set at p = 0.01. Analyses were performed for baseline and subsequent time points up to 2 years after radiotherapy and per treatment modality, radiotherapy technique and disease stage. RESULTS: Data of 435 patients were analysed. Pre-treatment, overall symptoms, dyspnea, chest wall pain, dysphagia and cough impacted overall HRQoL and specific domains. At subsequent time points, cough and dysphagia were overtaken by pericarditis in affecting HRQoL. Toxicities during concurrent chemo-radiotherapy and 3-dimensional radiotherapy had the most impact on HRQoL. Conversely, toxicities in sequential chemo-radiotherapy and SBRT had limited impact on patients' HRQoL. Stage impacts the correlations: LA-NSCLC patients are more adversely affected by toxicity than ES-NSCLC patients, mimicking the results of radiotherapy technique and treatment modality. CONCLUSION: Pre-treatment symptoms and acute/late toxicities variously impact HRQoL of ES- and LA-NSCLC patients undergoing different treatment approaches and radiotherapy techniques. Throughout the disease, dyspnea seems crucial in this association, highlighting the additional effect of co-existing comorbidities. Our data call for optimized radiotherapy limiting toxicities that may affect patients' HRQoL.