Dose escalation study of a personalized peptide-based neoantigen vaccine (EVX-01) in patients with metastatic melanoma.

BACKGROUND: Neoantigens can serve as targets for T cell-mediated antitumor immunity via personalized neopeptide vaccines. Interim data from our clinical study NCT03715985 showed that the personalized peptide-based neoantigen vaccine EVX-01, formulated in the liposomal adjuvant, CAF09b, was safe and able to elicit EVX-01-specific T cell responses in patients with metastatic melanoma. Here, we present results from the dose-escalation part of the study, evaluating the feasibility, safety, efficacy, and immunogenicity of EVX-01 in addition to anti-PD-1 therapy. METHODS: Patients with metastatic melanoma on anti-PD-1 therapy were treated in three cohorts with increasing vaccine dosages (twofold and fourfold). Tumor-derived neoantigens were selected by the AI platform PIONEER and used in personalized therapeutic cancer peptide vaccines EVX-01. Vaccines were administered at 2-week intervals for a total of three intraperitoneal and three intramuscular injections. The study's primary endpoint was safety and tolerability. Additional endpoints were immunological responses, survival, and objective response rates. RESULTS: Compared with the base dose level previously reported, no new vaccine-related serious adverse events were observed during dose escalation of EVX-01 in combination with an anti-PD-1 agent given according to local guidelines. Two patients at the third dose level (fourfold dose) developed grade 3 toxicity, most likely related to pembrolizumab. Overall, 8 out of the 12 patients had objective clinical responses (6 partial response (PR) and 2 CR), with all 4 patients at the highest dose level having a CR (1 CR, 3 PR). EVX-01 induced peptide-specific CD4+ and/or CD8+T cell responses in all treated patients, with CD4+T cells as the dominating responses. The magnitude of immune responses measured by IFN-γ ELISpot assay correlated with individual peptide doses. A significant correlation between the PIONEER quality score and induced T cell immunogenicity was detected, while better CRs correlated with both the number of immunogenic EVX-01 peptides and the PIONEER quality score. CONCLUSION: Immunization with EVX-01-CAF09b in addition to anti-PD-1 therapy was shown to be safe and well tolerated and elicit vaccine neoantigen-specific CD4+and CD8+ T cell responses at all dose levels. In addition, objective tumor responses were observed in 67% of patients. The results encourage further assessment of the antitumor efficacy of EVX-01 in combination with anti-PD-1 therapy.

The Oxford digital multiple errands test (OxMET): Validation of a simplified computer tablet based multiple errands test.

Impairments in executive functioning are common following Acquired Brain Injury, though there are few screening tools which present a time efficient and ecologically valid approach to assessing the consequences of executive impairments. We present the Oxford Digital Multiple Errands Test (OxMET), a novel and simplified computer-tablet version of a Multiple Errands Test. We recruited 124 neurologically healthy controls and 105 stroke survivors to complete the OxMET task. Normative data and internal consistency were established from the healthy control data. Convergent and divergent validation was assessed in a mixed subset of 158 participants who completed the OxMET and OCS-Plus. Test-retest reliability was examined across a mixed subset of 39 participants. Finally, we investigated the known-group discriminability of the OxMET. The OxMET demonstrated very high internal consistency, and stable group level test-retest performance as well as good convergent and divergent validity. The OxMET demonstrated high sensitivity and good specificity in overall differentiation of stroke survivors from controls. The Oxford Digital Multiple Errands Test is a brief, easy to administer tool, designed to quickly screen for potential consequences of executive impairments in a virtual environment shopping task on a computer tablet. Initial normative data and validation within a chronic stroke cohort is presented.

Reliability of Pain Measurements Using Computerized Cuff Algometry: A DoloCuff Reliability and Agreement Study.

INTRODUCTION: Computerized pneumatic cuff pressure algometry (CPA) using the DoloCuff is a new method for pain assessment. Intra- and inter-rater reliabilities have not yet been established. Our aim was to examine the inter- and intrarater reliabilities of DoloCuff measures in healthy subjects. METHODS: Twenty healthy subjects (ages 20 to 29 years) were assessed three times at 24-hour intervals by two trained raters. Inter-rater reliability was established based on the first and second assessments, whereas intrarater reliability was based on the second and third assessments. Subjects were randomized 1:1 to first assessment at either rater 1 or rater 2. The variables of interest were pressure pain threshold (PT), pressure pain tolerance (PTol), and temporal summation index (TSI). Reliability was estimated by a two-way mixed intraclass correlation coefficient (ICC) absolute agreement analysis. Reliability was considered excellent if ICC > 0.75, fair to good if 0.4 < ICC < 0.75, and poor if ICC < 0.4. Bias and random errors between raters and assessments were evaluated using 95% confidence interval (CI) and Bland-Altman plots. RESULTS: Inter-rater reliability for PT, PTol, and TSI was 0.88 (95% CI: 0.69 to 0.95), 0.86 (95% CI: 0.65 to 0.95), and 0.81 (95% CI: 0.42 to 0.94), respectively. The intrarater reliability for PT, PTol, and TSI was 0.81 (95% CI: 0.53 to 0.92), 0.89 (95% CI: 0.74 to 0.96), and 0.75 (95% CI: 0.28 to 0.91), respectively. CONCLUSION: Inter-rater reliability was excellent for PT, PTol, and TSI. Similarly, the intrarater reliability for PT and PTol was excellent, while borderline excellent/good for TSI. Therefore, the DoloCuff can be used to obtain reliable measures of pressure pain parameters in healthy subjects.

Pain Sensitisation in Women with Active Rheumatoid Arthritis: A Comparative Cross-Sectional Study.

Objectives. In some rheumatoid arthritis (RA) patients, joint pain persists without signs of inflammation. This indicates that central pain sensitisation may play a role in the generation of chronic pain in a subgroup of RA. Our aim was to assess the degree of peripheral and central pain sensitisation in women with active RA compared to healthy controls (HC). Methods. 38 women with active RA (DAS28 > 2.6) and 38 female HC were included in, and completed, the study. Exclusion criteria were polyneuropathy, pregnancy, and no Danish language. Cuff Pressure Algometry measurements were carried out on the dominant lower leg. Pain threshold, pain tolerance, and pain sensitivity during tonic painful stimulation were recorded. Results. Women with active RA had significantly lower pain threshold (p < 0.01) and pain tolerance (p < 0.01) than HC. The mean temporal summation- (TS-) index in RA patients was 0.98 (SEM: 0.09) and 0.71 (SEM: 0.04) in HC (p < 0.01). Conclusion. Patients with active RA showed decreased pressure-pain threshold compared to HC. In addition, temporal summation of pressure-pain was increased, indicating central pain sensitization, at least in some patients. Defining this subgroup of patients may be of importance when considering treatment strategies.

The Relationship between Mechanical Hyperalgesia Assessed by Manual Tender Point Examination and Disease Severity in Patients with Chronic Widespread Pain: A Cross-Sectional Study.

The clinical utility of tender point (TP) examination in patients reporting chronic widespread pain (CWP) is the subject of contemporary debate. The objective of this study was to assess the relationship between mechanical hyperalgesia assessed by manual TP examination and clinical disease severity. 271 women with CWP were recruited from a clinical setting. Data collection included patient-reported symptoms, health-related quality of life variables, and observation-based measures of functional ability, muscle strength, 6-minute walk, and pressure pain thresholds measured by cuff algometry. TP examination was conducted according to ACR-guidelines. Relationships between disease variables and TP count (TPC) were analyzed with logistic regression in a continuum model, allowing the TPC to depend on the included disease variables and two regression models carried out for a TPC threshold level, varying between 1 and 17. The threshold analyses indicated a TPC threshold at 8, above which a large number of disease variables became consistently significant explanatory factors, whereas none of the disease variables reached a significance level in the continuum model. These results support the premise that the presence of mechanical hyperalgesia influences symptomatology in CWP and that the severity of clinical expression is related to a threshold of TPs, rather than being part of a continuum.

Temporal summation of pain and ultrasound Doppler activity as predictors of treatment response in patients with rheumatoid arthritis: protocol for the Frederiksberg hospitals Rheumatoid Arthritis, pain assessment and Medical Evaluation (FRAME-cohort) study.

INTRODUCTION: Chronic pain is common in rheumatoid arthritis (RA) and may still persist despite regression of objective signs of inflammation. This has led researchers to hypothesise that central pain sensitisation may play a role in the generation of chronic pain in RA. Application of the disease activity score DAS28 can classify some patients with active RA solely based on a high tender joint count and poor patient global health score. In such cases, intensified treatment with anti-inflammatory drugs would be expected to yield poorer results than in cases with DAS28 elevation due to a high score for swollen joints and C reactive protein (CRP). Evaluation of central pain sensitisation in patients with few inflammatory indices may be a predictive tool regarding the effect of anti-inflammatory treatment. Computerised pneumatic cuff pressure algometry (CPA) is a method for assessing temporal summation (ie, degree of central sensitisation). The main objective of this study was to examine the prognostic values of pressure pain-induced temporal summation, ultrasound Doppler activity and the interaction between them in relation to treatment response (DAS28-CRP change) in patients with RA initiating any anti-inflammatory therapy. METHOD AND ANALYSIS: 120 participants ≥18 years of age will be recruited. Furthermore, they must be either (1) diagnosed with RA, untreated with disease-modifying antirheumatic drugs for at least 6 months and about to initiate disease-modifying antirheumatic drug treatment or (2) about to begin or switch treatment with any biological drug for their RA. Data (clinical, imaging, blood samples, patient reported outcomes and CPA measurements) will be collected from each participant at baseline and after 4 months of anti-inflammatory treatment. ETHICS AND DISSEMINATION: This study has been approved by the ethics committee for the Copenhagen region (H-4-2013-007). Dissemination will occur through presentations and publication in international peer-reviewed journals.

Assessment of pressure-pain thresholds and central sensitization of pain in lateral epicondylalgia.

OBJECTIVE.: To assess pain sensitivity and spreading hyperalgesia in lateral epicondylalgia (LE). SUBJECTS.: Twenty-two women with LE, and 38 controls were included. OUTCOME MEASURES.: Computerized cuff pressure algometry was used for assessment of pressure-pain threshold and tolerance. The stimulus was applied using a single (stimulation-area: 241 cm(2) ) or double-chambered (stimulation-area: 482 cm(2) ) tourniquet on the arm and leg. Spatial summation was expressed as the ratio between pressure-pain thresholds to single and double cuff-chamber stimulation. During 10-minute constant pressure stimulation at intensity relative to the individual pain threshold, the pain intensity was continuously recorded using an electronic visual analogue scale (VAS), and from this the degree of temporal summation was estimated. For LE, a Doppler ultrasound examination of the elbow was made to identify inflammation. RESULTS.: In LE compared with controls the pressure-pain threshold and tolerance were on average reduced by respectively 31% (nonsignificant) and 18% (nonsignificant) on the lower arm and by 32% (P < 0.05) and 22% (P < 0.05) on the lower leg (spreading sensitization). Within the LE group, pressure-pain thresholds were on average reduced by 20% (P < 0.05) and pain tolerance by 10% (nonsignificant) on the painful compared with the asymptomatic side. Spatial summation (P < 0.01) and temporal summation (P < 0.05) was facilitated in LE compared with controls. In LE patients without signs of peripheral inflammation assessed by Doppler ultrasound, temporal summation was significantly stronger than in patients with ongoing inflammation (P < 0.01). CONCLUSION.: Patients with LE may be subgrouped based on pain hypersensitivity and Doppler ultrasound into clinically meaningful subgroups with varying duration of symptoms and different degrees of central sensitization. These groups may require different pain management strategies.

An international, randomized, double-blind, placebo-controlled, phase III trial of pregabalin monotherapy in treatment of patients with fibromyalgia.

OBJECTIVE: To evaluate the efficacy and safety of pregabalin monotherapy versus placebo for symptomatic pain relief and improvement of patient global assessment in patients with fibromyalgia (FM) enrolled from countries outside the United States. METHODS: This international, multicenter, double-blind, placebo-controlled trial randomly assigned 747 patients with FM to placebo or 300, 450, or 600 mg/day pregabalin twice daily for 14 weeks. Primary efficacy measures were endpoint mean pain scores and Patient Global Impression of Change (PGIC). Secondary outcomes included assessments of sleep and function. RESULTS: Patients in the 450 mg/day pregabalin group showed significant improvements versus placebo in endpoint mean pain score (-0.56; p = 0.0132), PGIC (73% improved vs 56% placebo; p = 0.0017), and function [Fibromyalgia Impact Questionnaire (FIQ) total score -5.85; p = 0.0012]. PGIC was also significant for 600 mg/day pregabalin (69% improved; p = 0.0227). Results for these endpoints were nonsignificant for pregabalin at 300 mg/day and for pain and FIQ score at 600 mg/day. Early onset of pain relief was seen, with separation from placebo detected by Week 1 in all pregabalin groups. All pregabalin doses demonstrated superiority to placebo on the Medical Outcomes Study-Sleep Scale Sleep Disturbance subscale and the Sleep Quality diary. Dizziness and somnolence were the most frequently reported adverse events. CONCLUSION: Pregabalin demonstrated modest efficacy in pain, global assessment, and function in FM at 450 mg/day, and improved sleep across all dose levels, but it did not provide consistent evidence of benefit at 300 and 600 mg/day in this study. Pregabalin was generally well tolerated for the treatment of FM. (Clinical trial registry NCT00333866).

Observation-based assessment of functional ability in patients with chronic widespread pain: a cross-sectional study.

Knowledge about functional ability, including activities of daily living (ADL), in patients with chronic widespread pain (CWP) and fibromyalgia (FMS) is largely based on self-report. The purpose of this study was to assess functional ability by using standardised, observation-based assessment of ADL performance and to examine the relationship between self-reported and observation-based measures of disability. A total of 257 women with CWP, 199 (77%) fulfilling the American College of Rheumatology tender point criteria for FMS, were evaluated with the Assessment of Motor and Process Skills (AMPS), an observation-based assessment providing linear measures of ADL motor and ADL process skill ability (unit: logits). A cutoff for effortless and independent ADL task performance is set at 2.0 for the motor scale and 1.0 for the process scale. A total of 248 (96.5%) had ability measures below the 2.00 ADL motor cutoff and 107 (41.6%) below the 1.00 ADL process cutoff, indicating increased effort and/or inefficiency during task performance as well as a potential need of assistance for community living. Mean ADL motor ability measure was 1.07 and was significantly lower in patients diagnosed with FMS than plain CWP (1.02 vs 1.27 logits, P=.001). Mean ADL process ability measure was 1.09 logits and was without difference between FMS and plain CWP (1.07 vs 1.16 logits, P=.064). Only weak to moderate correlations between self-reported functional ability and observation-based AMPS ability measures were observed. The results of the study support the notion of considerable performance difficulties in women with CWP. The everyday life problems are substantial and place the individual at risk of need of support for community living.

Self-reported somatosensory symptoms of neuropathic pain in fibromyalgia and chronic widespread pain correlate with tender point count and pressure-pain thresholds.

Widespread pain and pain hypersensitivity are the hallmark of fibromyalgia, a complex pain condition linked to central sensitization. In this study the painDETECT questionnaire (PDQ), validated to identify neuropathic pain and based on pain quality items, was applied in a cross-sectional sample of patients with chronic widespread pain (CWP). The aims of the study were to assess the patient-reported sensory neuropathic symptoms by PDQ and to correlate these with tender point (TP) count and pressure-pain thresholds. Eighty-one patients (75 F, 6 M) with CWP (ACR-criteria) filled in the PDQ. Manual TP examination was conducted according to ACR guidelines. Computerized cuff pressure algometry was used for the assessment of pressure-pain detection thresholds (PDT, unit: kPa) and pressure-pain tolerance thresholds (PTT, unit: kPa). Mean TP count was 14.32 (range: 2-18), mean PDQ score 22.75 (range: 5-37). Mean PDT was 8.8 kPa (range: 2-36) and mean PTT 30.9 kPa (range: 4-85). Deep-tissue hyperalgesia was the predominant somatosensory symptom reported in 83%, but other neuropathic symptoms were also frequent, e.g. burning 51% and prickling 47%. Statistically significant correlations were found between PDQ score and TP count: r=0.35 (p<0.01), and PDQ score and PDT: r=0.45 (p<0.01), and PTT: r=0.43 (p<0.01). The study indicates that pain in CWP has neuropathic features, and that the presence and number of tender points are associated with neuropathic pain symptoms. A high mean PDQ score was found to correlate with TP count and pressure-pain thresholds. The PDQ may become a useful tool assisting in the identification of central sensitization in patients with CWP and in the future diagnostic assessment fibromyalgia.

[Physiological changes in fibromyalgia]. / Fysiologiske aendringer ved fibromyalgi.

A number of physiological changes, some measurable as changes in biomarkers, have been described in fibromyalgia (FM). These include changes in cytokine serum levels and elevated levels of some neurotransmitters in the cerebrospinal fluid. None of these measurements have been validated for diagnosis or follow-up in FM. It is suggested that non-invasive methods which hold the potential to evaluate the severity of FM and serve as therapy targets should be developed in the future.

[Fibromyalgia as a neuropathic pain condition]. / Fibromyalgi som neurogen smertetilstand.

Fibromyalgia is characterised by chronic widespread pain and mechanical hyperalgesia. It is associated with a higher pain intensity, fewer pain-free intervals and more pronounced pain-related interference in function than other musculoskeletal pain conditions. Increasing evidence supports an underlying augmented central pain processing which includes sensitization of pain-transmitting neurons and dysfunction of pain inhibitory pathways. If this permanent change in the function of the nociceptive system is shown to equal fibromyalgia, the condition may be considered a neuropathic pain condition.

[Fibromyalgia, diagnosis and prevalence. Are gender differences explainable?]. / Fibromyalgi, diagnostik og praevalens. Kan kønsforskellen forklares?

Most non-inflammatory musculoskeletal diseases are more common in women than in men. Fibromyalgia is characterised by chronic generalised muscle pain. The male:female ratio is 1:9. Interacting factors including genetic, hormonal, environmental and behavioural elements may cause this condition, and there are possibly subgroups of which one has shown to be treatable. A different pathogenetic appearance in the two sexes may also be present. The gender difference may partly be explained by the fact that pressure pain test in tender points forms part of the diagnosis. This may leave some male fibromyalgia patients unrecognized.

Relationships between the fibromyalgia impact questionnaire, tender point count, and muscle strength in female patients with fibromyalgia: a cohort study.

OBJECTIVE: To test the hypothesis that fibromyalgia (FM) patients with reduced lower extremity strength are more symptomatic and tender than FM patients with normal muscle strength. METHODS: A total of 840 FM patients and 122 healthy subjects were evaluated between 1998 and 2005. All of the patients completed version 1 of the Fibromyalgia Impact Questionnaire (FIQ) and were assessed for tender points and knee muscle strength. All subjects underwent bilateral isokinetic knee muscle strength testing in flexion and extension. Normative knee muscle strength values were calculated from the healthy subjects, and the FM cohort was divided in 2 groups: 1) patients with normal muscle strength and 2) patients with low muscle strength (2 SDs below normal). The clinical characteristics of these 2 groups were compared. RESULTS: Significantly reduced knee muscle strength was found in 52% of the patients. There were no clinically significant differences between patients with low versus normal muscle strength. There were no clinically significant correlations between total FIQ score, tender point count, and muscle strength. Only 4.6% of the FIQ scores and 5.1% of the tender point counts were explained by muscle strength. CONCLUSION: Significantly reduced knee muscle strength was found in more than half of the patients. Patients with subnormal muscle strength were not more symptomatic or tender than patients with normal muscle strength. There were no clinically significant correlations between FIQ, tender point count, and muscle strength; therefore, reduced knee muscle strength appears to be a common objective abnormality in FM that is independent of measurements of disease activity. The implication of this finding in regard to the clinical assessment of FM needs further study.

Computerized cuff pressure algometry: A new method to assess deep-tissue hypersensitivity in fibromyalgia.

The aim of this study was to evaluate the use of computerized cuff pressure algometry (CPA) in fibromyalgia (FM) and to correlate deep-tissue sensitivity assessed by CPA with other disease markers of FM. Forty-eight women with FM and 16 healthy age-matched women were included. A computer-controlled, pneumatic tourniquet cuff was placed over the gastrocnemius muscle. The cuff was inflated, and the subject rated the pain intensity continuously on an electronic Visual Analogue Scale (VAS). The subject stopped the inflation at the pressure-pain tolerance and the corresponding VAS-score was determined (pressure-pain limit). The pressure at which VAS firstly exceeded 0 was defined as the pressure-pain threshold. Other disease markers (FM only): Isokinetic knee muscle strength, tenderpoint-count, myalgic score, Beck Depression Inventory, and Fibromyalgia Impact Questionnaire. Student's T-test was used to compare pressure-pain threshold and pressure-pain tolerance and the Mann-Whitney test to compare pressure-pain limit. Pearson's correlation was used to detect linear relationships. Pressure-pain threshold and pressure-pain tolerance assessed by CPA were significantly lower in FM compared to healthy controls. There was no difference in pressure-pain limit. CPA-parameters were significantly correlated to isokinetic muscle strength where more hypersensitivity resulted in lower strength. Pressure-pain threshold and pressure-pain tolerance assessed by CPA were significantly lower in patients with FM indicating muscle hyperalgesia. CPA was associated with knee muscle strength but not with measures thought to be influenced by psychological distress and mood.