Patient-Reported Outcomes as Independent Prognostic Factors for Survival in Oncology: Systematic Review and Meta-Analysis.

OBJECTIVES: Assessment of patient-reported outcomes (PROs) in oncology is of critical importance because it provides unique information that may also predict clinical outcomes. METHODS: We conducted a systematic review of prognostic factor studies to examine the prognostic value of PROs for survival in cancer. A systematic literature search was performed in PubMed for studies published between 2013 and 2018. We considered any study, regardless of the research design, that included at least 1 PRO domain in the final multivariable prognostic model. The protocol (EPIPHANY) was published and registered in the International Prospective Register of Systematic Reviews (CRD42018099160). RESULTS: Eligibility criteria selected 138 studies including 158 127 patients, of which 43 studies were randomized, controlled trials. Overall, 120 (87%) studies reported at least 1 PRO to be statistically significantly prognostic for overall survival. Lung (n = 41, 29.7%) and genitourinary (n = 27, 19.6%) cancers were most commonly investigated. The prognostic value of PROs was investigated in secondary data analyses in 101 (73.2%) studies. The EORTC QLQ-C30 questionnaire was the most frequently used measure, and its physical functioning scale (range 0-100) the most frequent independent prognostic PRO, with a pooled hazard ratio estimate of 0.88 per 10-point increase (95% CI 0.84-0.92). CONCLUSIONS: There is convincing evidence that PROs provide independent prognostic information for overall survival across cancer populations and disease stages. Further research is needed to translate current evidence-based data into prognostic tools to aid in clinical decision making.

Consistency matters: measurement invariance of the EORTC QLQ-C30 questionnaire in patients with hematologic malignancies.

PURPOSE: To ensure that observed differences in the scores of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) reflect actual differences in health-related quality of life (HRQoL) rather than measurement bias, measurement invariance needs to be established. We investigated the assumption of measurement invariance of the EORTC QLQ-C30 in patients with hematological malignancies across age, sex, comorbidity, disease type, and time. METHODS: We used a large database of patients with hematological malignancies, which included HRQoL data collected with the EORTC QLQ-C30. We used the structural equation modeling approach to test for measurement (metric and scalar) invariance across groups (age, sex, comorbidity, disease) and time (baseline, 1 month and 2 month follow-up). Longitudinal invariance was examined in a subgroup of patients diagnosed with myelodysplastic syndromes. RESULTS: Confirmatory factor analyses demonstrated full measurement invariance for age and comorbidity and over time, while support for partial scalar invariance was obtained for sex and disease. Violations of invariance for sex were observed for items of the physical functioning scale and the emotional functioning scale, while for disease type, violations of invariance were observed for items of the physical functioning scale, emotional functioning scale, and the cognitive functioning scale. CONCLUSIONS: Our findings support measurement invariance of the EORTC QLQ-C30 in a large sample of patients with hematological malignancies. The results showed that the number of non-invariant items was negligible, suggesting that this questionnaire is a valid and robust measurement tool in patients with hematological malignancies, also for comparisons across groups and time.

Duration of immunity against heterologous porcine parvovirus 1 challenge in gilts immunized with a novel subunit vaccine based on the viral protein 2.

BACKGROUND: Porcine parvovirus 1 (PPV1) is widespread in commercial pig farms worldwide and has a significant impact to the swine industry. Long-lasting immunity achieved by means of vaccination is the main tool to prevent PPV1 infection and its associated clinical signs. Here we evaluated the duration of immunity (DOI) conferred by a novel subunit vaccine based on the viral protein (VP) 2 of PPV1, named ReproCyc® ParvoFLEX. The DOI was assessed at 6 months post-vaccination following the standard vaccination scheme (phase I) or after re-vaccination (phase II) with a single injection administered 24 weeks after the basic vaccination scheme. A total of 46, five to six-month-old gilts, free of PPV1 and porcine reproductive and respiratory syndrome virus (PRRSV), were randomly assigned to 6 groups (three in each phase): the negative control groups were inoculated with sodium chloride (NaCl), the vaccinated groups were immunized with the PPV1 subunit vaccine and the strict controls were neither treated nor challenged. Subsequently, the negative control and vaccinated groups from each phase were challenged with a heterologous PPV1 strain. Infection of fetuses was the primary outcome parameter for efficacy, though other supportive parameters were PPV1 viremia and serological status of the gilts and the condition of their fetuses (i.e. normal, autolytic, or mummified). RESULTS: All gilts vaccinated against PPV1 tested seropositive at challenge and viremia after challenge was detectable only in the non-vaccinated animals. In this regard, fetuses positive to PPV1 by PCR were only found in litters from non-vaccinated sows. CONCLUSIONS: These results point out that the immunity developed by the PPV1 subunit vaccine is effective in terms of preventing viremia, transplacental infection of fetuses and fetal death caused by PPV1 infection. ReproCyc® ParvoFLEX was demonstrated to protect fetuses against heterologous PPV1 challenge with a DOI of 6 months after vaccination.

Validation of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 Summary Score in Patients With Hematologic Malignancies.

OBJECTIVES: We investigated the validity of the recently developed European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) summary score in patients with hematologic malignancies. Specifically, we evaluated the adequacy of a single-factor measurement model for the QLQ-C30, and its known-groups validity and responsiveness to change over time. METHODS: We used confirmatory factor analysis to test the single-factor model of the QLQ-C30, using baseline QLQ-C30 data (N = 2134). The QLQ-C30 summary score was compared to the original QLQ-C30 scales using general (age, sex, Eastern Cooperative Oncology Group performance status, comorbidity) and disease-specific (red blood cell transfusion dependency) groups. Repeated measurements allowed us to investigate responsiveness to change in a subgroup of patients with acute myeloid leukemia. RESULTS: The single-factor model of the QLQ-C30 exhibited adequate fit in patients with hematologic malignancies. Known-group comparisons generally supported the construct validity of the summary score when using more general grouping variables (sociodemographics, broad clinical parameters). Nevertheless, when groups were formed on the basis of disease-specific variables (eg, transfusion dependency), the summary score performed less well the some of the original, separate scales of the QLQ-C30. CONCLUSION: Our findings provide support for the validity of the single-factor model of the EORTC QLQ-C30 in patients with hematologic malignancies. Specifically, the results suggest that the summary score can be used as an endpoint in this population when symptom- or other health domain-specific hypotheses are not available.

Raising the standards of patient-centered outcomes research in myelodysplastic syndromes: Clinical utility and validation of the subscales of the QUALMS from the MDS-RIGHT project.

BACKGROUND: Clinical decision-making for patients with myelodysplastic syndromes (MDS) is challenging, and both disease and treatment effects heavily impact health-related quality of life (HRQoL) of these patients. Therefore, disease-specific HRQoL measures can be critical to harness the patient voice in MDS research. METHODS: We report a prospective international validation study of the Quality of Life in Myelodysplasia Scale (QUALMS) with a main focus on providing information on the psychometric characteristics of its three subscales: physical burden (QUALMS-P), emotional burden (QUALMS-E), and benefit finding (QUALMS-BF). The analysis is based on patients enrolled from three European countries and Israel, participating to the MDS-RIGHT Project. The scale structure and psychometric properties of the QUALMS were assessed. RESULTS: Overall, 270 patients with a median age of 74 years were analyzed and the majority of them (60.3%) had a low MDS-Comorbidity Index score. Results of the confirmatory factor analysis supported the underlying scale structure of the QUALMS, which, in addition to a total score, includes three subscales: QUALMS-P, QUALMS-E, and the QUALMS-BF. The QUALMS-P exhibited the highest Cronbach's alpha coefficients. Discriminant validity analysis indicated good results with the QUALMS-P and QUALMS-E distinguishing between patients with different performance status, comorbidity, anemia, and transfusion dependency status. No floor and ceiling effects were observed. Responsiveness to change analysis supported the validity of the measure. Patients with a hemoglobin (Hb) level of <11 g/dL at study entry, who subsequently showed an improvement in their Hb levels, also reported a mean score change of 9 and 8 points (scales ranging between 0 and 100) in the expected direction of the QUALMS-E and QUALMS-P, respectively. CONCLUSIONS: Our study provides additional validation data on the QUALMS from the international MDS-RIGHT Project. The use of this disease-specific HRQoL measure may contribute to raise quality standards of patient-centered outcomes research in MDS.

Acute promyelocytic leukaemia long-term survivors: higher fatigue and greater overall symptom burden.

OBJECTIVE: We aimed to investigate the association of fatigue with severity of other key cancer symptoms, as well as symptom interference with daily activities and outlook on life, in long-term survivors of acute promyelocytic leukaemia (APL). METHODS: The study sample consisted of APL survivors (n=244), with a median time from diagnosis of 14.3 years (IQR=11.1-16.9 years), previously enrolled in a long-term follow-up study. Symptom severity and symptom interference were assessed using the well-validated MD Anderson Symptom Inventory (MDASI). Fatigue was evaluated with the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire. RESULTS: Higher fatigue burden was associated with increased affective symptoms, memory problems, drowsiness, sleep disturbances, shortness of breath and pain. Higher levels of fatigue were also associated with higher scores across all interference items of the MDASI. Overall, symptoms interfered most with mood, but among APL survivors with high levels of fatigue, symptoms interfered most with enjoyment of life. Multivariable regression analysis confirmed the independent association between fatigue and all symptom severity items of the MDASI. CONCLUSIONS: The current findings show that long-term APL survivors who report higher fatigue also experience a greater overall symptom burden and a substantial impact on performance of daily activities. Further studies are needed to examine whether interventions aimed at reducing fatigue could also reduce overall symptom burden.

The EORTC QLU-C10D was more efficient in detecting clinical known group differences in myelodysplastic syndromes than the EQ-5D-3L.

BACKGROUND: The aim was to investigate the relative validity of the preference-based measure EORTC QLU-C10D in comparison with the EQ-5D-3L in myelodysplastic syndromes (MDS) patients. METHODS: We used data from an international multicentre, observational cohort study of MDS patients. Baseline EORTC QLU-C10D and EQ-5D-3L scores were used and index scores calculated for Italy, Australia, and the UK. Criterion validity was established by Spearman and intraclass correlations (ICC) and Bland-Altman plots. Construct validity was established by the instruments' ability to discriminate known groups, i.e. groups whose health status is expected to differ. RESULTS: We analyzed data from 619 MDS patients (61.1% male; median age 73.8 years). Correlations between theoretically corresponding domains were largely higher than between unrelated domains. ICCs and Bland-Altman plots indicated moderate to good criterion validity. Ceiling effects were lower for the QLU-C10D (4.7%) than for the EQ-5D-3L (22.6%). The EQ-5D-3L failed to discriminate known-groups in two and the QLU-C10D in one of the comparisons; the QLU-C10D's efficiency in doing so was higher in clinical known-groups. Results were comparable between the countries. CONCLUSIONS: The QLU-C10D may be suitable to generate health utilities for economic research in MDS. Responsiveness and minimal important differences need yet to be established.

Physical activity and health-related quality of life in multiple myeloma survivors: the PROFILES registry.

OBJECTIVES: To investigate whether physical activity (PA) is associated with health-related quality of life (HRQOL) outcomes in multiple myeloma (MM) survivors up to 11 years after diagnosis. METHODS: We used data from the Patient Reported Outcomes Following Initial treatment and Long term Evaluation of Survivorship registry. We included 175 MM survivors diagnosed between 1999 and 2009 as registered by the Netherlands Cancer Registry. Sixty-four per cent (n=112/175) of patients who received the questionnaires, completed the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and the EORTC QLQ-MY20. Patients were classified into two groups: physically active and not physically active patients. Univariable and multivariable linear regression models were used to evaluate associations between PA and HRQOL outcomes. RESULTS: Physically active patients reported a statistically significant higher global health status/HRQOL (p=0.001), lower fatigue (p=0.002) and fewer side effects of treatments (p=0.001), than not physically active patients. PA was not associated with psychological symptoms (ie, anxiety and depressive symptoms) (anxiety: p=0.139; depressive symptoms: p=0.073). Exploratory analyses performed on the other scales of the EORTC QLQ-C30 indicated statistically significant better outcomes in several functional and symptom subscales for physically active patients. CONCLUSIONS: These findings might contribute to a better understanding of the relationship between PA and disease specific HRQOL aspects in MM survivors. Prospective studies are warranted to further elucidate on the beneficial effects of PA on HRQOL outcomes of MM survivors.

Time to health-related quality of life improvement analysis was developed to enhance evaluation of modern anticancer therapies.

OBJECTIVES: Major advances have recently been made in the treatments of cancer, which now also have the potential to improve patients' health-related quality of life (HRQOL). We propose the time to HRQOL improvement (TTI) and the time to sustained HRQOL improvement (TTSI) as potentially important cancer outcomes to be used in longitudinal HRQOL analyses. STUDY DESIGN AND SETTING: As proof of principle, we defined TTI and TTSI, using the Fine-Gray model to include competing risks in estimates, in a case study in real life of a cohort of newly diagnosed patients with cancer receiving a targeted therapy. HRQOL was evaluated before and during therapy with six assessments over a 24-month period, using the well-validated European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30. RESULTS: For each assessed HRQOL domain, we assessed TTI and TTSI and estimated the cumulative incidence of patients' clinically meaningful improvements, also accounting for the occurrence of competing events. CONCLUSION: TTI and TTSI are potentially important outcomes in the era of modern anticancer therapies. The analysis of TTI and TTSI by competing risks approach will further add to the statistical methods that can be used to inform on the impact of cancer therapies on patients' HRQOL.

Psychopathy traits and reinforcement sensitivity theory: Prepulse inhibition and ERP responses.

This study examined the associations between Reinforcement Sensitivity Theory (RST-PQ, Corr & Cooper, 2016) and psychopathy traits (LSRPS, Levenson et al., 1995) in university students. The aim was to identify psychopathy and RST traits associated with prepulse inhibition (PPI) of acoustic startle and ERP responses by using two prepulse-stimulus intensities (70 and 85 dB) combined with a 105 dB startle pulse (200 ms prepulse-plus-pulse interval). The higher intensity prepulse produced a larger PPI, although both prepulse stimuli reliably activated the startle system. Higher Primary Psychopathy was associated with a higher Defensive-Fight trait and both measures were associated with larger PPI. A principal components factor analysis disclosed an N1-startle factor that was a significant predictor of both reward reactivity and Goal-Drive Persistence scores. Results appear in line with Newman's response modulation hypothesis emphasizing the engagement of attention and recognition of stimulus salience, which may be disrupted in psychopathy.

A novel subunit vaccine based on the viral protein 2 of porcine parvovirus: safety profile in bred pigs at different stages of the reproduction cycle and in offspring.

Porcine parvovirus 1 (PPV1) viral protein (VP) 2 is the primary antigen responsible for inducing specific protective immunity, so it is a desirable target for development of recombinant subunit vaccines to prevent PPV1 disease. The objective of this study was to evaluate repeated doses of a novel VP2-based PPV1 subunit vaccine, namely ReproCyc® ParvoFLEX, for safety in bred pigs and in offspring under experimental settings. Therefore, the investigation of safety at all breeding stages was evaluated in four independent studies involving: pre-breeding gilts (study A), breeding-age gilts and boars (study B), early and late gestating sows and offspring (study C) and lactating sows and offspring (study D). In all four studies, animals were free from PPV1 based on serology and PCR prior to inclusion. All studies comprised one or two vaccinated groups that received the PPV1 subunit vaccine and a negative control group. Thus, safety was established due to the lack of significant differences between the vaccinated groups and the corresponding unvaccinated (negative control) groups. Gilts, sows and boars were evaluated for local and systemic reactions after vaccination as well as for reproductive performance. The survival rate and average daily weight gain (ADWG) from birth to weaning in offspring was evaluated in studies C and D. Additionally, serology was determined in studies A, C and D. The vaccine was shown to be safe with no relevant significant differences between vaccinated and unvaccinated groups in any experiment. Therefore, repeated doses of ReproCyc® ParvoFLEX were safe in target animals at different stages of the reproductive cycle and in offspring, placing this vaccine as a suitable candidate for mass vaccination programs in breeding herds.

Resting Frontal Asymmetry and Reward Sensitivity Theory Motivational Traits.

The revised reinforcement sensitivity theory (rRST) of personality has conceptualized three main systems: the behavioural approach system (BAS), behavioural inhibition system (BIS), and fight-flight-freeze system (FFFS). Research links greater relative left-frontal activity with BAS-related tendencies and impulsivity and greater relative right-frontal activity with "withdrawal" motivation that included both BIS and FFFS. Although rRST has addressed the separation of FFFS and BIS, much of personality neuroscience research does not indicate which system is related to right frontal activity. We administered the Reinforcement Sensitivity Theory of Personality Questionnaire (RST-PQ) to measure the BAS and its facets (goal-drive persistence, reward interest, reward reactivity, and impulsivity), BIS, and the withdrawal FFFS. We examined the association of RST-PQ traits with resting electroencephalogram (EEG) alpha-asymmetry in female participants (N = 162) by considering the influence of experimenter's gender. In the total group, that included two subgroups with experimenters of different gender, BAS-impulsivity was related to greater left- than right-frontal activity, and FFFS, but not BIS, was related to greater relative right-frontocentral activity. These associations remained significant for the subgroup with a young same-sex experimenter, but not with opposite-sex experimenter.

The late posterior negativity in episodic memory: A correlate of stimulus retrieval?

We investigated whether the late posterior negativity (LPN) is a component linked to stimulus retrieval or rather to complex, higher-order stimulus evaluation processes or response preparation processes. Participants performed three separate tasks across separate sessions: an encoding task, a memory recognition task, and a visual discrimination task. In the visual discrimination task, the difficulty of stimulus evaluation was manipulated via stimuli varying in complexity (easy vs. moderately difficult) and duration of stimulus presentation (short vs. long). Three indices of the LPN peak were examined: amplitude, latency, and width. The LPN was present in all three tasks, with maximum amplitudes at occipital sites. Results of the visual discrimination task showed that the LPN amplitude is modulated by task difficulty. No latency differences were observed between short and long presentations, suggesting that the LPN is not related to response preparation. Consequently, we compared the LPN associated with short presentations of easy and difficult stimuli with the LPN of the encoding and memory task. The LPN amplitude was more negative in the memory task compared to the other tasks. Latency and width of the LPN were modulated by stimulus complexity, with increased latency and width in the encoding and memory task relative to the visual discrimination task. Overall, these findings suggest that the LPN is not a component linked to stimulus retrieval and response preparation, but rather to complex, higher-order stimulus evaluation processes, which are modulated by task difficulty.

Extraversion and behavioural approach system in stimulus analysis and motor response initiation.

In this study, we attempt to validate previous findings on extraversion-related differences in speed of sensorimotor processing and to extend them into Behavioural Approach System (BAS) subtraits within the framework of the revised Reinforcement Sensitivity Theory (rRST) of personality. Here, we assessed psychological traits of extraversion (E), four BAS facets (Goal-Drive Persistence, BAS-GDP; Reward Interest, BAS-RI; Reward Reactivity, BAS-RR; Impulsivity, BAS-I), Behavioural Inhibition System (BIS), and Fight-Flight-Freeze System (FFFS) in 51 volunteers (28 women). Stimulus-locked lateralized readiness potential (S-LRP), response-locked LRP (R-LRP), stimulus-locked and response-locked forearm electromyogram (S-EMG and R-EMG), and P3 components of the event-related potentials (ERPs), were recorded during the performance of a two-choice Go/NoGo visual letter-digit discrimination task varying in task difficulty. High extraverts, relative to introverts and individuals high relative to low on BAS-RI, were more likely to exhibit shorter S-LRP latencies and stimulus- and response-locked EMG latencies. Additionally, high BAS-I had a shorter R-RLP latency than low BAS-I participants for the difficult task. High FFFS levels were associated with longer S-LRP and S-EMG latencies, while high BIS levels had larger response accuracy. Extraverts, relative to introverts, along with those high relative to low on BAS-RR and BAS-I, exhibited smaller P3 amplitudes. The faster cortical premotor initiation, found in individuals high on extraversion, BAS-RI and low on FFFS, may account for their faster peripheral motor response initiation and execution. Smaller P3 amplitudes in extraverts and individuals high on BAS-RR and BAS-I may indicate reduced perceptual processing capacity in these individuals.

BIS/BAS sensitivity and emotional modulation in a prepulse-inhibition paradigm: A brain potential study.

We investigated whether prepulse inhibition (PPI) is sensitive to emotion modulation vis-à-vis individual differences in the sensitivity of the behavioral inhibition system (BIS) and behavioral activation system (BAS). Participants (n=50) performed a PPI task while recording the eyeblink reflex and auditory evoked potentials (i.e., N100 and P200). The results showed an increase in PPI from positive to negative stimuli at parietal sites, for both the N100 and P200. The N100 wave of the auditory evoked potential was sensitive to emotional valence high in arousal, whereas the P200 wave was sensitive to emotional valence low in arousal. Importantly, individual differences in BAS sensitivity, but not BIS sensitivity, influenced the emotional modulation of the startle response and PPI. This influence was most evident for the N100. Our findings are consistent with previous reports showing that PPI is sensitive to emotion modulation. The current results extent previous findings by highlighting the importance of the combined influence of valence and arousal. The findings indicate that state and trait emotions bias selective encoding of affective stimuli thereby priming behavioral output.

When caterpillars attack: biogeography and life history evolution of the Miletinae (Lepidoptera: Lycaenidae).

Of the four most diverse insect orders, Lepidoptera contains remarkably few predatory and parasitic species. Although species with these habits have evolved multiple times in moths and butterflies, they have rarely been associated with diversification. The wholly aphytophagous subfamily Miletinae (Lycaenidae) is an exception, consisting of nearly 190 species distributed primarily throughout the Old World tropics and subtropics. Most miletines eat Hemiptera, although some consume ant brood or are fed by ant trophallaxis. A well-resolved phylogeny inferred using 4915 bp from seven markers sampled from representatives of all genera and nearly one-third the described species was used to examine the biogeography and evolution of biotic associations in this group. Biogeographic analyses indicate that Miletinae likely diverged from an African ancestor near the start of the Eocene, and four lineages dispersed between Africa and Asia. Phylogenetic constraint in prey selection is apparent at two levels: related miletine species are more likely to feed on related Hemiptera, and related miletines are more likely to associate with related ants, either directly by eating the ants, or indirectly by eating hemipteran prey that are attended by those ants. These results suggest that adaptations for host ant location by ovipositing female miletines may have been retained from phytophagous ancestors that associated with ants mutualistically.