Relevant Deterioration Research Articles

OS7.4 Calculating the net clinical benefit in brain tumor clinical trials by combining survival and health-related quality of life data using two methods: quality adjusted survival effect sizes (QASES) and joint modelling (JM)

Abstract BACKGROUND The impact of treatment on both the quality and the quantity of life, i.e. the ‘net clinical benefit’, should be considered to inform glioma patients and facilitate shared decision making. We applied two methods (i.e. Quality Adjusted Effect Sizes (QASES) and Joint Modelling (JM)) that combine survival and health-related quality of life (HRQoL) data into one outcome, to gain insight in the net clinical benefit of a treatment strategy. In addition, we assessed if both methods result in similar interpretations. MATERIAL AND METHODS We calculated the net clinical benefit in one randomized controlled trial, EORTC 26951 comparing radiotherapy (RT) + PCV chemotherapy versus RT alone, as a proof of concept for other trials. With the QASES method, effect sizes for differences in survival and HRQoL between treatment arms were calculated. Next, the combined effect size can be determined by weighing the emphasis put on survival or HRQoL (e.g. survival more important). JM allows simultaneous modeling of a longitudinal outcome (HRQoL), and a time-to event outcome (survival). HRQoL scales/items that were selected for primary analysis in the main study were also selected for this analysis: fatigue, global health, social functioning, communication deficit, seizures, physical functioning, and nausea/vomiting. RESULTS 288/386 patients completed baseline HRQoL forms and were included in the analysis. Overall survival (OS) was significantly longer with combined treatment (difference of 10.8 months). In contrast, the percentage of patients who experienced a clinically relevant deterioration (≥10 points) in nausea/vomiting, fatigue, social functioning and global health up to one year after treatment compared to baseline was larger in the RT+PCV arm. The QASES corresponded to a reduction in the median OS difference from 10.8 months to 6.8 months when adjusted for the HRQoL scales/items, when given equal weights to OS and HRQoL. JM analyses resulted in a theoretical loss of treatment effect in OS of 2–6% when adjusting for HRQoL. CONCLUSION Both methods showed that adjusting for the impact of treatment on a relevant HRQoL parameter reduced the survival benefit in the experimental treatment arm compared to standard treatment arm. Applying these methods may facilitate communicating the impact of treatment to patients in clinical practice.

One-Stop Management with Perfusion for Transfer Patients with Stroke due to a Large-Vessel Occlusion: Feasibility and Effects on In-Hospital Times.

In-hospital time delays lead to a relevant deterioration of neurologic outcomes in patients with stroke with large-vessel occlusions. At the moment, CT perfusion is relevant in the triage of late-window patients with stroke. We conducted this study to determine whether one-stop management with perfusion is feasible and leads to a reduction of in-hospital times. In this observational study, we report the first 15 consecutive transfer patients with stroke with externally confirmed large-vessel occlusions who underwent flat panel detector CT perfusion and thrombectomy in the same room. Preinterventional imaging consisted of noncontrast flat panel detector CT and flat panel detector CT perfusion, acquired with a biplane angiography system. The flat panel detector CT perfusion was used to reconstruct a flat panel detector CT angiography to confirm the large-vessel occlusions. After confirmation of the large-vessel occlusion, the patient underwent mechanical thrombectomy. We recorded time metrics and safety parameters prospectively and compared them with those of transfer patients whom we treated before the introduction of one-stop management with perfusion. Fifteen transfer patients underwent flat panel detector CT perfusion and were treated with mechanical thrombectomy from June 2017 to January 2019. The median time from symptom onset to admission was 241 minutes. Median door-to-groin time was 24 minutes. Compared with 23 transfer patients imaged with multidetector CT, it was reduced significantly (24 minutes; 95% CI, 19-37 minutes, versus 53 minutes; 95% CI, 44-66 minutes; P < .001). Safety parameters were comparable between groups. In this small series, one-stop management with perfusion led to a significant reduction of in-hospital times compared with our previous workflow.

SRSF11 Loss Leads to Aging-Associated Cognitive Decline by Modulating LRP8 and ApoE

RNA binding proteins, the key regulators in gene expression at the posttranscriptional level, remain largely uncharacterized with respect to aging and relevant cognitive deterioration. Here, we report that the levels of SFRS11 are substantially decreased in the prefrontal cortex (PFC) of aged brains. Notably, mice with SFRS11 deficiency in the PFC show impaired learning and memory. We demonstrate that SFRS11 directly binds to the 3' UTR of LRP8 mRNA, as well as to the third exon of apoE mRNA, resulting in stabilization of these mRNAs, eventually deactivating JNK signaling. Importantly, restoration of LRP8 and apoE reduces JNK signaling that is significantly enhanced in SFRS11-deficient cells. In addition, LRP8 and apoE rescue aging-like phenotypes induced by SFRS11 loss. Our findings demonstrate that age-dependent loss of SFRS11 in the PFC reduces levels of apoE and LRP8, leading to activation of the JNK pathway, ultimately influencing cognitive deficits.

Comparison of Growth Curve Estimates of Infants in São Tomé Island, Africa, with the WHO Growth Standards: A Birth Cohort Study.

This birth cohort study compared the infant growth curve estimates in São Tomé Island to the WHO growth standards. Despite this island belonging to a lower-middle-income country, there were several factors favorable for growth that were present. Four-hundred and seventy-five full-term singleton appropriate for-gestational-age infants were enrolled and followed-up to 24 months of age. Weight-for-age, length-for-age, weight-for-length, body mass index-for-age, head circumference-for-age, weight velocity, and length velocity curves were estimated and compared to the WHO standards. In the first 6 months of age, the weight gain was adequate in the presence of a high prevalence of exclusive breastfeeding. Thereafter, weight trajectories tracked close to the WHO standards, except for a progressive decline in the infants growing in higher percentiles, especially in girls. Median length at birth was below the median WHO standards, followed by an early postnatal velocity spurt, which probably reflected the transition from an unfavorable to a more favorable postnatal environment. Thereafter, linear growth faltering was observed without relevant deterioration up to 24 months of age, which was probably due to the presence of protective factors. These results may be useful to implement strategies to further approximate infant growth in São Tomé Island to the WHO standards.

MRI-Guided Ultrafocal HDR Brachytherapy for Localized Prostate Cancer: Median 4-Year Results of a feasibility study

For the treatment of localized prostate cancer, focal therapy has the potential to cure with fewer side effects than traditional whole-gland treatments. We report an update on toxicity, quality of life (QoL), and tumor control in our magnetic resonance imaging (MRI)-guided ultrafocal high-dose-rate brachytherapy cohort. Disease status was evaluated by systematic biopsies and 3T multiparametric MRI. The brachytherapy implant procedure under fused transrectal ultrasound/MRI guidance was followed by a 1.5T MRI for contour adjustments and catheter position verification. A single dose of 19Gy was delivered to the tumor with a margin of 5mm. Genitourinary (GU) toxicity, gastrointestinal (GI) toxicity, and erectile dysfunction (ED) were graded with the Common Terminology Criteria for Adverse Events version 4.0. QoL was measured with RAND-36, European Organisation for Research and Treatment of Cancer QLQ-C30 and PR25. International Prostate Symptom Scores and International Index of Erectile Function scores were obtained. Prostate-specific antigen level was monitored, with biochemical recurrence defined as nadir + 2ng/mL (Phoenix). Thirty patients with National Comprehensive Cancer Network low- (13%) to intermediate-risk (87%) prostate cancer were treated between May 2013 and April 2016. Median follow-up was 4years. Median age was 71years (interquartile range, 68-73) and median initial prostate-specific antigen level was 7.3ng/mL (5.2-8.1). Maximum Gleason score was 4+3=7 (in 2 patients). All tumors were radiologic (MRI) stage T2. No grade >2 GU or >1 GI toxicity occurred. International Prostate Symptom Scores only deteriorated temporarily. Mild pretreatment ED deteriorated to moderate/severe ED in 50% of patients. Long-term clinically relevant QoL deterioration was seen in sexual activity and tiredness, whereas emotional and cognitive functioning improved. At 4years, biochemical disease-free survival was 70% (95% confidence interval, 52%-93%), metastases-free survival was 93% (85%-100%), and overall survival was 100%. Of intraprostatic recurrences, 7 of 9 were out of field. Ultrafocal high-dose-rate brachytherapy conveys minimal GU or GI toxicity and has a marginal effect on QoL. An early decline in erectile function was seen. Tumor control outcomes are poor (biochemical disease-free survival of 70% [52%-93%] at 4years), most likely as a result of poor patient selection.

Clustering‐Based Resource Allocation mechanism in Long Term Evolution Advanced networks with auto‐encoder for feature learning

AbstractClustering‐Based Resource Allocation (CBRA) is a relatively recent approach applied in some communication network technologies that executes resource allocation rules by following patterns discovered in the user and traffic flow information. It is a useful option for classifying traffic and detecting the most suitable Quality‐of‐Service parameters to perform improved resource allocation, especially in mobile systems such as Long Term Evolution Advanced, which are growing in user demand. An open issue in the CBRA approach is the necessity to perform feature engineering manually (feature selection), which may cause loss of relevant system information and consequent deterioration of performance. In this research article, we present a novel CBRA mechanism that implements an auto‐encoder to perform feature learning, thus avoiding feature selection. The auto‐encoder, deployed at the early stages of the CBRA mechanism, transforms the user and traffic flow data into a shortened representation, preventing the curse of dimensionality while capturing the nonlinear correlations of the data. The simulation results indicate better cluster formation and performance improvement for real‐time video applications using the proposed mechanism.

Acute Leg and Trunk Muscle Fatigue Differentially Affect Strength, Sprint, Agility, and Balance in Young Adults.

Roth, R, Donath, L, Zahner, L, and Faude, O. Acute leg and trunk muscle fatigue differentially affect strength, sprint, agility, and balance in young adults. J Strength Cond Res 35(8): 2158-2164, 2021-How important leg or trunk muscles are for balance and sprint performance is still unexplored. Therefore, we separately fatigued the leg and trunk musculature and examined their contribution to strength, balance, sprint, and agility performance. Twenty-four healthy adults (12 women; age 22.9 [SD: 2.6] years; body mass 59 [10] kg; height 1.65 [0.09] m; and 12 men; age 22.7 [3.0] years; body mass 78 [9] kg; height 1.81 [0.06] m; at least 3 training sessions/week for at least 90 minutes) underwent a leg and a trunk fatigue procedure, each of 20-minute duration and a control condition at rest in a randomized order. Each condition was conducted individually on 3 separate days. Isokinetic leg and trunk strength, as well as static and dynamic balance, sprint, agility, and prone plank endurance, were assessed before and after each fatiguing protocol. Before assessment, a familiarization was conducted. Pairwise magnitude-based inference analyses showed likely relevant deterioration in leg (probability >87%; 0.36 < standardized mean differences [SMDs] < 0.92) and trunk (>88%, 0.28 < SMD < 0.74) fatigue procedures for all motor test parameters compared with the control condition, except for the 20-m sprint after the trunk fatigue procedure. Isokinetic strength testing revealed a large loss of strength in leg fatigue (particularly knee extension, 78%, SMD = 0.24) and trunk fatigue (trunk flexion, 100%, SMD = 1.36). Acute fatigue of leg and trunk muscles decreases performance in relevant measures of strength, balance, sprint, and agility. The impact of leg fatigue compared with trunk fatigue was larger in almost all measurements.

Permanent 125I prostate brachytherapy for castration‐resistant prostate cancer

To evaluate the clinical significance of permanent 125 I prostate brachytherapy in patients with castration-resistant prostate cancer. A retrospective study of 45 patients with castration-resistant prostate cancer from the Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu, China was carried out. Patients were divided into two groups according to different treatments: 21 patients received endocrine therapy alone (control group), and 24 patients underwent brachytherapy combined with endocrine therapy (treatment group). Prostate-specific antigen progression-free survival, cancer-specific survival, overall survival and quality of life of the two groups were compared. The median prostate-specific antigen progression-free survival and cancer-specific survival of the treatment group were 29months (interquartile range 25-37months) and 37months (interquartile range 30-50months), respectively. These were significantly longer than those of the control group (both P<0.05). Prostate-specific antigen (before androgen deprivation therapy and before brachytherapy), prostate volume, Gleason score, clinical stage and brachytherapy were associated with prostate-specific antigen progression-free survival and cancer-specific survival on univariate analysis. For the quality of life after treatment, urinary symptoms/problems at 1month after brachytherapy compared with the control group had a statistically significant difference and clinically relevant deterioration, but after 6months there were no statistically significant differences and clinically relevant deterioration. Compared with the control group, the physical functioning, social functioning, global health and general physical discomfort of the treatment group were significantly improved. Brachytherapy with 125 I seed implantation can effectively prolong survival of patients with castration-resistant prostate cancer and, to a certain extent, improve patients' quality of life.

Moderate Hypofractionation in Intermediate- and High-Risk, Localized Prostate Cancer: Health-Related Quality of Life From the Randomized, Phase 3 HYPRO Trial

The phase 3 Hypofractionated Irradiation for Prostate Cancer trial compared hypofractionated radiation therapy with conventionally fractionated radiation therapy in patients with localized prostate cancer. Similar 5-year relapse-free survival rates were achieved in both groups, but noninferiority of hypofractionation was not confirmed for genitourinary and gastrointestinal toxicity. Here, we present the secondary trial endpoint on patient-reported quality of life. A total of 820 patients with intermediate-risk or high-risk prostate cancer were randomized to hypofractionation (19 fractions of 3.4Gy) or conventional fractionation (39 fractions of 2.0Gy). Quality of life was measured using a validated questionnaire, the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Prostate Cancer 25 module. Subscales (score range, 0-100) on urinary symptoms, gastrointestinal symptoms, symptoms related to androgen deprivation therapy, sexual function, and sexual activity were analyzed. Changes from baseline of at least 5 points were considered clinically relevant. Inferiority of hypofractionation for separate subscales was rejected if the mean difference in the 3-year incidence of clinically relevant deterioration between treatments was <8.0%. A total of 697 men were eligible for this quality-of-life analysis. Baseline characteristics were comparable between both groups. At 3-year follow-up, the incidence of clinically relevant deterioration of urinary symptoms was 33% for both treatments (difference 0.49% in favor of conventional fractionation; 90% confidence interval, -7.20% to 8.18%). Such deterioration of gastrointestinal symptoms was reported in 38% of patients receiving hypofractionation versus 36% of patients receiving conventional fractionation (2.03% in favor of conventional fractionation; 90% confidence interval, -6.18% to 10.23%). Therefore, we could not demonstrate noninferiority of hypofractionation for genitourinary and gastrointestinal quality of life. For all other subscales, noninferiority of hypofractionation was demonstrated. Noninferiority of the hypofractionated treatment was not demonstrated for genitourinary and gastrointestinal quality of life, and therefore we cannot rule out that relevant differences may exist between both treatments. Noninferiority of hypofractionation was demonstrated for symptoms related to androgen deprivation therapy, sexual activity, and sexual function.

Sexual function and combined oral contraceptives - a randomised, placebo-controlled trial.

ObjectiveThe effect of combined oral contraceptives (COCs) on female sexuality has long been a matter of discussion, but placebo-controlled studies are lacking. Thus, the aim of the present study was to investigate if an oestradiol-containing COC influences sexual function.DesignInvestigator-initiated, randomised, double-blinded, placebo-controlled clinical trial where 202 healthy women were randomised to a combined oral contraceptive (1.5 mg oestradiol and 2.5 mg nomegestrol acetate) or placebo for three treatment cycles.MethodsSexual function at baseline and during the last week of the final treatment cycle was evaluated by the McCoy Female Sexuality Questionnaire. Serum and hair testosterone levels were assessed at the same time points.ResultsCompared to placebo, COC use was associated with a small decrease in sexual interest (COC median change score: −2.0; interquartile range (IQR): −5.0 to 0.5 vs placebo: −1.0; IQR: −3.0 to 2.0, P = 0.019), which remained following adjustment for change in self-rated depressive symptoms (B = −0.80 ± 0.30, Wald = 7.08, P = 0.008). However, the proportion of women who reported a clinically relevant deterioration in sexual interest did not differ between COC or placebo users (COC 18 (22.2%) vs placebo 16 (17.8%), P = 0.47). Change in other measured aspects of sexual function as well as total score of sexual function did not differ between the two treatments.ConclusionsThis study suggests that use of oestradiol-based COCs is associated with reduced sexual interest. However, the changes are minute, and probably not of clinical relevance.

A protocol for the development of a prediction model in mild traumatic brain injury with CT scan abnormality: which patients are safe for discharge?

BackgroundHead injury is an extremely common clinical presentation to hospital emergency departments (EDs). Ninety-five percent of patients present with an initial Glasgow Coma Scale (GCS) score of 13–15, indicating a normal or near-normal conscious level. In this group, around 7% of patients have brain injuries identified by CT imaging but only 1% of patients have life-threatening brain injuries. It is unclear which brain injuries are clinically significant, so all patients with brain injuries identified by CT imaging are admitted for monitoring. If risk could be accurately determined in this group, admissions for low-risk patients could be avoided and resources could be focused on those with greater need.This study aims to (a) estimate the proportion of GCS13–15 patients with traumatic brain injury identified by CT imaging admitted to hospital who clinically deteriorate and (b) develop a prognostic model highly sensitive to clinical deterioration which could help inform discharge decision making in the ED.MethodsA retrospective case note review of 2000 patients with an initial GCS13–15 and traumatic brain injury identified by CT imaging (2007–2017) will be completed in two English major trauma centres. The prevalence of clinically significant deterioration including death, neurosurgery, intubation, seizures or drop in GCS by more than 1 point will be estimated. Candidate prognostic factors have been identified in a previous systematic review. Multivariable logistic regression will be used to derive a prognostic model, and its sensitivity and specificity to the outcome of deterioration will be explored.DiscussionThis study will potentially derive a statistical model that predicts clinically relevant deterioration and could be used to develop a clinical risk tool guiding the need for hospital admission in this group.

Effects of land use change on ecosystem services value in West Jilin since the reform and opening of China

Land resources were the foundation of human survival and development. The change of land use altered the pattern of vegetation and landscape, caused the change of ecosystem structure and function and changed the value of regional ecosystem services. This study spatially and quantitatively explored the impact of land use change on the ecosystem service value in West Jilin since the reform and opening of China. The results showed that the main characteristic of land use change in West Jilin was area reduction in grassland and marsh and area increase in arable land and alkali-land. However, land use change in Period I (1976–2000) got a faster rate than in Period II (2000–2013). Land use change resulted in the ESV in West Jilin decreased by 1334 million yuan since the reform and opening up of China, with an annual loss of 39.2 million yuan in Period I and 30.2 million yuan in Period II. The conversion of marsh to other types land use was the primary land use reason for the decrease in ESV. Alkali-land expanded quickly in Period I, however, the trend of salinization turned to be curbed and the area of alkali-land began to decrease after 2000, which increased the ESV by about 234 million yuan. Due to the concern of local government and relevant scientific research departments, the ecological and environmental deterioration were meliorated and the decrease rate of ecosystem services value also slowed down. Excitingly, ESV even increased in some areas on account of land use was becoming more rational.

Effects of a population-based, person-centred and integrated care service on health, wellbeing and self-management of community-living older adults: A randomised controlled trial on Embrace.

ObjectiveTo evaluate the effects of the population-based, person-centred and integrated care service ‘Embrace’ at twelve months on three domains comprising health, wellbeing and self-management among community-living older people.MethodsEmbrace supports older adults to age in place. A multidisciplinary team provides care and support, with intensity depending on the older adults’ risk profile. A randomised controlled trial was conducted in fifteen general practices in the Netherlands. Older adults (≥75 years) were included and stratified into three risk profiles: Robust, Frail and Complex care needs, and randomised to Embrace or care as usual (CAU). Outcomes were recorded in three domains. The EuroQol-5D-3L and visual analogue scale, INTERMED for the Elderly Self-Assessment, Groningen Frailty Indicator and Katz-15 were used for the domain ‘Health.’ The Groningen Well-being Indicator and two quality of life questions measured ‘Wellbeing.’ The Self-Management Ability Scale and Partners in Health scale for older adults (PIH-OA) were used for ‘Self-management.’ Primary and secondary outcome measurements differed per risk profile. Data were analysed with multilevel mixed-model techniques using intention-to-treat and complete case analyses, for the whole sample and per risk profile.Results1456 eligible older adults participated (49%) and were randomized to Embrace (n(T0) = 747, n(T1) = 570, mean age 80.6 years (SD 4.5), 54.2% female) and CAU (n(T0) = 709, n(T1) = 561, mean age 80.8 years (SD 4.7), 55.6% female). Embrace participants showed a greater–but clinically irrelevant–improvement in self-management (PIH-OA Knowledge subscale effect size [ES] = 0.14), and a greater–but clinically relevant–deterioration in health (ADL ES = 0.10; physical ADL ES = 0.13) compared to CAU. No differences in change in wellbeing were observed. This picture was also found in the risk profiles. Complete case analyses showed comparable results.ConclusionsThis study found no clear benefits to receiving person-centred and integrated care for twelve months for the domains of health, wellbeing and self-management in community-living older adults.

Impairment Models for Performance Evaluation of Digital Modulations in the Millimeter Wave Range

The use of millimeter waves in wireless communication systems is expected to pave the way for solving the problem of spectrum scarcity currently experienced in lower frequencies, yet allowing for higher bit rates. However, impairments that are not of major concern in lower frequencies become relevant performance deterioration causes in the millimeter wave range, for instance the high signal attenuation and shadowing, as well as hardware-dependent impairments like phase noise, I-Q imbalance, and amplifier nonlinearities. In this tutorial article, the recent theory about these impairments are reviewed and applied to the development of models for assessing the performance of digital modulations in the millimeter wave range, under the separate and the joint effect of such impairments. The developed models are then used in the performance analysis of the&nbsp;M-ary frequency-shift keying (MFSK) modulation with non-coherent detection, and of the&nbsp;M-ary phase-shift keying (MPSK) and&nbsp;M-ary quadrature amplitude modulation (MQAM) with coherent detection. Simulation results bring out the different degrees of robustness of these modulations to the modeled impairments, highlighting the attractiveness of the&nbsp;MFSK and the 16QAM.

Verbal memory decline from hippocampal depth electrodes in temporal lobe surgery for epilepsy.

To explore whether patients with refractory mesial temporal lobe epilepsy risk aggravated verbal memory loss from intracranial electroencephalography (EEG) recording with longitudinal hippocampal electrodes in the language-dominant hemisphere. A long-term neuropsychological follow-up (mean 61.5 months, range 22-111 months) was performed in 40 patients after ictal registration with left hippocampal depth electrodes (study group, n = 16) or no invasive EEG, only extracranial registration (reference group, n = 24). The groups were equal with respect to education, age at seizure onset, epilepsy duration, and prevalence of pharmacoresistant temporal lobe epilepsy (TLE; 75%) versus seizure freedom (25%). Retrospective neuropsychological data from preoperative surgical workup (T1) and prospective follow-up neuropsychological data (T2) were compared. A ≥1 SD intrapatient decline was considered as clinically relevant deterioration of verbal memory. Significant decline in verbal memory was seen in 56% of the patients in the study group compared to 21% in the reference group. At T1, there were no statistical between-group differences in memory performance. At T2, between-group comparison showed significantly greater verbal memory decline for the study group (Claeson Dahl Learning and Retention Test, Verbal Learning: p = 0.05; Rey Auditory Verbal Learning Test, Total Learning: p = 0.04; Claeson Dahl Learning and Retention Test, Verbal Retention: p = 0.04). An odds ratio (OR) of 7.1 (90% confidence interval [CI] 1.3-37.7) for verbal memory decline was seen if right temporal lobe resection (R TLR) had been performed between T1 and T2. The difference between groups remained unchanged when patients who had undergone R TLR were excluded from the analysis, with a remaining aggravated significant decline in verbal memory performance for the study group compared to the reference group. Our results suggest a risk of verbal memory deterioration after the use of depth electrodes along the longitudinal axis of the hippocampus. Until this issue is further investigated, caution regarding depth electrodes in the language-dominant hemisphere hippocampus seems advisable.

Physical ExeRcise Following Esophageal Cancer Treatment (PERFECT) study: design of a randomized controlled trial

BackgroundFollowing esophagectomy, esophageal cancer patients experience a clinically relevant deterioration of health-related quality of life, both on the short- and long-term. With the currently growing number of esophageal cancer survivors, the burden of disease- and treatment-related complaints and symptoms becomes more relevant. This emphasizes the need for interventions aimed at improving quality of life. Beneficial effects of post-operative physical exercise have been reported in several cancer types, but so far comparable evidence in esophageal cancer patients is lacking. The aim of this study is to investigate effects of physical exercise on health-related quality of life in esophageal cancer patients following surgery.MethodsThe Physical ExeRcise Following Esophageal Cancer Treatment (PERFECT) study is a multicenter randomized controlled trial including 150 esophageal cancer patients after surgery with curative intent. Patients are randomly allocated to an exercise group or usual care group. The exercise group participates in a 12-week combined aerobic and resistance exercise program, supervised by a physiotherapist near the patient’s home-address. In addition, participants in the exercise group are requested to be physically active for at least 30 min per day, every day of the week. Participants allocated to the usual care group are asked to maintain their habitual physical activity pattern. The primary outcome is health-related quality of life (EORTC-QLQ-C30). Secondary outcomes include esophageal cancer specific quality of life, fatigue, anxiety and depression, sleep quality, work-related factors, cardiorespiratory fitness (VO2peak), muscle strength, physical activity, malnutrition risk, anthropometry, blood markers, recurrence of disease and survival. All questionnaire outcomes, diaries and accelerometers are assessed at baseline, post-intervention (12 weeks post-baseline) and 24 weeks post-baseline. Physical fitness, anthropometry and blood markers are assessed at baseline and post-intervention. In addition, adherence and safety are monitored throughout the exercise program.DiscussionThis randomized controlled trial investigates effects of physical exercise versus usual care in esophageal cancer patients after surgery. As the design of the exercise program closely resembles daily practice, this study can contribute both to evidence on effects of exercise in esophageal cancer patients, and to potential implementation strategies.Trial registrationTrial registration:Netherlands Trial Registry NTR5045Date of trial registration: January 19th, 2015Date and version study protocol: February 2017, version 1

Cardiovascular risk in advanced naïve HIV-infected patients starting antiretroviral therapy: Comparison of three different regimens - PREVALEAT II cohort

Background and aimsPREVALEAT (PREmature VAscular LEsions and Antiretroviral Therapy) II is a multicenter, longitudinal cohort study aimed at the evaluation of cardiovascular risk among advanced HIV-positive, treatment-naïve patients starting their first therapy. We hypothesized that these patients, present a higher cardiovascular (CV) risk. MethodsThe study included all consecutive naïve patients with less than 200 CD4 cells/ml starting antiretroviral therapy. Our primary objective was to evaluate changes in carotid intima- media thickness (IMT). Secondary endpoints included changes in flow mediated vasodilation (FMD), inflammatory markers, triglycerides and cholesterol. Patients were evaluated at time 0, and after 3, 6 and 12 months. ResultsWe enrolled 119 patients, stratified into three different groups: patients receiving atazanavir/ritonavir boosted (ATV/r) based regimens, efavirenz (EFV) based regimens and darunavir/ritonavir boosted (DRV/r) based regimens. At baseline, advanced naïve patients showed a relevant deterioration of CV conditions in terms of traditional CV risk factors, endothelial dysfunction and serum biomarkers. During the 12-month follow up period, mean blood lipids significantly increased: total cholesterol from 159 to 190 mg/dL, HDL-C from 31 to 41 mg/dL, and LDL-C from 99 to 117 mg/dL. D-dimers steadily decreased (median level 624 at baseline and 214 at T3), whereas ICAM and VCAM consistently raised. DRV/r and ATV/r determined a more marked decrease of D-dimers as compared to EFV. Regarding the epi-aortic changes (IMT >1 mm or presence of atherosclerotic plaques), patients in the DRV/r group were at risk of developing pathological IMT during the study (OR 6.0, 95% CI 0.9–36.9), as compared to EFV ones. ConclusionsCV risk was elevated in advanced naïve patients and tended to remain high in the first year of therapy.

P18.16 Changes in health-related quality of life and neurocognitive functioning in individual patients treated with stereotactic radiotherapy for brain metastases

Abstract Background: Stereotactic radiotherapy (SRT) is believed to result in a similar survival rate as whole-brain radiotherapy for treatment of brain metastases, with a less profound impact on cognition and health-related quality of life (HRQoL). Recently it has been shown that, on group level, brain metastases patients treated with SRT maintain their pre-treatment levels of cognition and HRQoL. Although stable on group level, this may not hold true for individual patients. Objective: We sought to evaluate changes in cognition and HRQoL on the individual patient level three and six months after SRT. Methods: A total of 55 patients completed HRQoL questionnaires and underwent neurocognitive testing prior to SRT and 3 and/or 6 months after SRT. The EORTC QLQ-C30 and BN20 questionnaires were used to assess HRQoL and a standardized test battery to assess neurocognitive functioning. Changes in HRQoL and cognition were evaluated on (1) a scale/domain level and (2) patient level. First, percentage of patients showing a clinically relevant improvement, stable score or deterioration on each of 8 predetermined HRQoL scales and 7 cognitive domains were calculated. Next, patients were categorized into 4 groups, separately for HRQoL and cognition: decline (only worsening of HRQoL or cognition), both (decline and improvement), stable (no detectable change in any scale/domain) and improvement (only improvement). Results: Three months after SRT, a decline in the 8 different HRQOL scales was observed in 16-61% of the patients, while 20-71% remained stable and 16-40% improved. Six months after SRT, 8-47% of the patients had worse scores on the 8 HRQoL scales, 18-75% the same scores and 11-34% better scores. On the 7 different neurocognitive functioning domains, only 3-8% of the patients worsened, 78-100% remained stable, while 3-17% showed an improvement three months after SRT. These percentages were similar six months after SRT; 8-20% of the patients deteriorated on the 7 domains, 73-100% remained stable and 4-8% improved. Changes in HRQoL and cognition on patient level were evaluated for two different time periods (0-3 months and 3-6 months). For HRQoL, 22% and 21% of the patients worsened in the period 0-3 and 3-6 months respectively, 64% and 58% both improved and deteriorated, 2% and 3% were stable and 12% and 18% showed improvement only. For cognition, the percentages were as follows: 14% and 33% showed a decline only, 6% and 4% both a decline and improvement, 67% and 50% stable scores and 14% and 13% an improvement only. Conclusion: In line with the results at group level, most brain metastases patients treated with SRT maintained their pre-treatment levels of cognition for at least 6 months. In contrast, changes in HRQoL scores for the different scales differed considerably on an individual patient level, and most patients showed both deterioration and improvement in various HRQoL scales in the first 6 months after SRT.

Health-related quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomised, double-blind, phase 3 trial

The EORTC 18071 phase 3 trial compared adjuvant ipilimumab with placebo in patients with stage III melanoma. The primary endpoint, recurrence-free survival, was significantly longer in the ipilimumab group than in the placebo group. Investigator-reported toxic effects of ipilimumab consisted mainly of skin, gastrointestinal, endocrine, and hepatic immune-related adverse events. Adjuvant treatment with ipilimumab in this setting was approved in October, 2014, by the US Food and Drug Administration based on the results of the primary outcome of this trial. Here, we report the results of the secondary endpoint, health-related quality of life (HRQoL), of this trial. EORTC 18071 was a multinational, double-blind, randomised, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis) in 19 countries worldwide. Participants were randomly assigned (1:1) centrally by an interactive voice response system, to receive either ipilimumab 10 mg/kg or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. HRQoL was assessed with the EORTC QLQ-C30 quality-of-life instrument at baseline, weeks 4, 7, 10, and 24, and every 12 weeks thereafter up to 2 years, irrespective of disease progression. Results were summarised by timepoint and in a longitudinal manner in the intention-to-treat population. Two summary scores were calculated for each HRQoL scale: the average score reported during induction (ipilimumab or placebo at a dose of 10 mg/kg, administered as one single dose at the start of days 1, 22, 43, and 64-ie, four doses in 3 weeks), and the average score reported after induction. A predefined threshold of a 10 point difference between arms was considered clinically relevant. The primary HRQoL endpoint was the global health scale, with the predefined hypothesis of no clinically relevant differences after induction between groups. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov, number NCT00636168. Between July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to treatment: 475 in the ipilimumab group and 476 in the placebo group. Compliance with completing the HRQoL questionnaire was 893 (94%) of 951 patients at baseline, 693 (75%) of 924 at week 24, and 354 (51%) of 697 at week 108. Patient mean global health scores during (77·32 [SD 17·36] vs 72·96 [17·82]; p=0·00011) and after induction (76·48 [17·52] vs 72·32 [18·60]; p=0·00067) were statistically significantly different between groups but were not clinically relevant. Mean global health scores differed most between the groups at week 7 (77 [SD 19] in the placebo group vs 72 [22] in the ipilimumab group) and week 10 (77 [20] vs 70 [23]). Mean HRQoL scores differed by more than 10 points at week 10 between treatment groups for diarrhoea (7·67 [SD 17·05] for placebo vs 18·17 [28·35] for ipilimumab) and insomnia (15·17 [22·53] vs 25·60 [29·19]). Despite increased toxicity, which led to treatment discontinuation for most patients during the induction phase of ipilimumab administration, overall HRQoL, as measured by the EORTC QLQ-C30, was similar between groups, as no clinically relevant differences (10 points or more) in global health status scores were observed during or after induction. Clinically relevant deterioration for some symptoms was observed at week 10, but after induction, no clinically relevant differences remained. Together with the primary analysis, results from this trial show that treatment with ipilimumab results in longer recurrence-free survival compared with that for treatment with placebo, with little impairment in HRQoL despite grade 3-4 investigator-reported adverse events. Bristol-Myers Squibb.

361O Patient-reported outcomes (PROs) in recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) treated with nivolumab (Nivo) or Investigator's Choice (IC): CheckMate 141

Background Patients (pts) with platinum-refractory R/M SCCHN have median survival :::6 mo and suffer from their disease and its treatment. Accordingly, maintaining quality of life (QoL) is a key treatment goal. PRO data were collected as exploratory endpoints in CheckMate 141 (NCT02105636), a randomized, open-label, phase 3 trial comparing nivo to IC (methotrexate, docetaxel, or cetuximab) in 361 pts with platinum-refractory R/M SCCHN. We report the first comparative results for PRO for nivo and IC in R/M SCCHN. Methods The European Organisation for Research and Treatment of Cancer QoL Questionnaire (EORTC QLQ-C30), EORTC Head and Neck Cancer module (QLQ- H&N35), and EQ-5D were administered at baseline (BL), wk 9, and then at 6-wk intervals during treatment. A clinically relevant score change or difference was regarded as 10 points for the EORTC subscales. Analysis of covariance (ANCOVA) was applied to compare mean score changes between arms. Proportional hazards regression was used to evaluate time to clinically relevant score deterioration (TTD). Results BL questionnaire completion rates for nivo and IC were rv80% and rv75%, respectively. Low IC completion rates precluded analysis of mean differences after wk 15. Overall, 129 pts completed a PRO measure at BL and during follow up. Nivo significantly delayed TTD (P < 0.05, 2-tailed) vs IC for global health; physical, role, cognitive, and social functioning; fatigue; dyspnea; and insomnia (EORTC QLQ-C30) as well as pain; sensory problems; and mouth opening problems (QLQ-H&N35). ANCOVA revealed statistically significant, clinically relevant differences favoring nivo at wks 9 and 15 for role and social functioning, fatigue, dyspnea, and appetite loss (EORTC QLQ-C30) as well as pain and sensory problems (QLQ-H&N35). Differences in mean values were observed for other PROs at wk 15 only. Conclusions Pts treated with nivo had delayed worsening of functioning and symptoms with PRO differences between arms favoring nivo up to rv4 mo of follow up. These results, as assessed through wk 15, suggest that pts receiving nivo maintained functioning for longer and had less pain, fatigue, and dyspnea on treatment as compared with IC. Clinical trial indentification NCT02105636; Study start date, May 2014 Legal entity responsible for the study Bristol-Myers Squibb Funding Bristol-Myers Squibb Disclosure N. Kiyota: Grants from research funding, Ono Pharmaceutical Co. Ltd, Eisai Co. Ltd, and Nippon Boehringer Ingelheim Co. Ltd; personal fees (honorarium and research funding), Ono Pharmaceutical Co. Ltd; payment for seminar presentation, BMS, Merck Serono, and Bayer. K. Harrington: Fees paid to research institution by BMS; personal fees from and fees paid to research institution by Merck and Amgen; personal fees from AstraZeneca and Pfizer. R.L. Ferris: Personal fees and advisory board member, Merck and Celgene; grants, personal fees and advisory board member, AZ/Medimmune and BMS; and grants, VentiRx. J.W. Shaw: Employee and shareholder, Bristol-Myers Squibb. F. Taylor: Employee of Adelphi Values, a consulting company that is being paid by BMS to analyze clinical trial PRO data. D. Turner- Bowker: Employee of Adelphi Values, which received funding to conduct this research. L. Morrissey: Employee of Adelphi Values, which was paid for the statistical analyses. K. Cocks: Employee of Adelphi Values, which consults with BMS. M. Gillison: Consulting for BMS, Lilly and Merck Inc. J. Guigay: Grants and advisory board member, Merck; grants, GlaxoSmithKline; advisory board member, Bristol-Myers Squibb and Innate Pharma. All other authors have declared no conflicts of interest.