Study protocol for OptimalTTF-2:enhancing Tumor Treating Fields with skull remodeling surgery for first recurrence glioblastoma: a phase 2, multi-center, randomized, prospective, interventional trial

Abstract Background OptimalTTF-2 is a randomized, comparative, multi-center, investigator-initiated, interventional study aiming to test skull remodeling surgery in combination with Tumor Treating Fields therapy (TTFields) and best physicians choice medical oncological therapy for first recurrence in glioblastoma patients. OptimalTTF-2 is a phase 2 trial initiated in November 2020. Skull remodeling surgery consists of five burrholes, each 15 mm in diameter, directly over the tumor resection cavity. Preclinical research indicates that this procedure enhances the effect of Tumor Treating Fields considerably. We recently concluded a phase 1 safety/feasibility trial that indicated improved overall survival and no additional toxicity. This phase 2 trial aims to validate the efficacy of the proposed intervention. Methods The trial is designed as a comparative, 1:1 randomized, minimax two-stage phase 2 with an expected 70 patients to a maximum sample size of 84 patients. After 12-months follow-up of the first 52 patients, an interim futility analysis will be performed. The two trial arms will consist of either a) TTFields therapy combined with best physicians choice oncological treatment (control arm) or b) skull remodeling surgery, TTFields therapy and best practice oncology (interventional arm). Major eligibility criteria include age ≥ 18 years, 1st recurrence of supratentorial glioblastoma, Karnofsky performance score ≥ 70, focal tumor, and lack of significant co-morbidity. Study design aims to detect a 20% increase in overall survival after 12 months (OS12), assuming OS12 = 40% in the control group and OS12 = 60% in the intervention group. Secondary endpoints include hazard rate ratio of overall survival and progression-free survival, objective tumor response rate, quality of life, KPS, steroid dose, and toxicity. Toxicity, objective tumor response rate, and QoL will be assessed every 3rd month. Endpoint data will be collected at the end of the trial, including the occurrence of suspected unexpected serious adverse reactions (SUSARs), unacceptable serious adverse events (SAEs), withdrawal of consent, or loss-to-follow-up. Discussion New treatment modalities are highly needed for first recurrence glioblastoma. Our proposed treatment modality of skull remodeling surgery, Tumor Treating Fields, and best practice medical oncological therapy may increase overall survival significantly. Trial registration ClinicalTrials.gov Identifier: NCT0422399 , registered 13. January 2020

Multimodal imaging of the distal interphalangeal-joint synovio-entheseal complex in psoriatic arthritis (MIDAS): a cross-sectional study on the diagnostic accuracy of different imaging modalities comparing psoriatic arthritis to psoriasis and osteoarthritis

Objective Can ultrasound (US), MRI and X-ray applied to the distal interphalangeal (DIP)-joint and synovio-entheseal complex (SEC) discriminate between patients with psoriatic arthritis (PsA), skin psoriasis (PsO) and hand osteoarthritis (OA)? Methods In this prospective, cross-sectional study, patients with DIP-joint PsA and nail involvement (n=50), PsO with nail involvement (n=12); and OA (n=13); were consecutively recruited. Risk ratios (RR) were calculated for US, MRI and X-ray findings of the DIP-joint and SEC between diagnoses. Results New bone formation (NBF) in US and MRI was a hallmark of OA, reducing the risk of having PsA (RR 0.52 (95% CI 0.43 to 0.63) and 0.64 (95% CI 0.56 to 0.74). The OA group was different from PsA and PsO on all MRI and X-ray outcomes reflected in a lower RR of having PsA; RR ranging from 0.20 (95% CI 0.13 to 0.31) for MRI bone marrow oedema (BMO) to 0.85 (95% CI 0.80 to 0.90) in X-ray enthesitis. No outcome in US, MRI or X-ray was significantly associated with a higher risk of PsA versus PsO, although there was a trend to a higher degree of US erosions and NBF in PsA. 82% of PsA and 67% of PsO was treated with disease modifying antirheumatic drugs which commonly reflects the clinical setting. Conclusion High grade of US, MRI and X-ray NBF reduce the RR of having PsA compared with OA. In PsA versus PsO patients, there was a trend for US to demonstrate more structural changes in PsA although this did not reach significance

Exercise therapy and patient education versus intra-articular saline injections in the treatment of knee osteoarthritis: an evidence-based protocol for an open-label randomised controlled trial (the DISCO trial)

BackgroundKnee osteoarthritis (OA) is a highly prevalent musculoskeletal condition causing pain, physical disability, and reduced quality of life. Exercise and patient education are non-pharmacological interventions for knee OA unanimously recommended a

In psoriatic arthritis fatigue is driven by inflammation, disease duration, and chronic pain: An observational DANBIO registry study

Objective Fatigue is one of the most significant symptoms, and an outcome of great importance, in patients with psoriatic arthritis (PsA), but associations between underlying components of fatigue experienced by patients in relation to the disease have been sparsely investigated. The objectives were to describe the degree of fatigue in PsA patients, and secondly to explore important components associated with fatigue. Methods We performed a cross-sectional survey including patients registered in the Danish nationwide registry DANBIO from December 2013 to June 2014. Principal component analysis was used to identify factors associated with fatigue. Results A total of 1,062 PsA patients were included in the study. A principal component analysis reduced co-variables into three components explaining 63% of fatigue in patients. The first component, contributing to 31% of fatigue, was composed of inflammatory factors including swollen and tender joints, doctors’ global assessment, elevated CRP, and high Pain Detect Questionnaire (PDQ) score; the second component, contributing to 17%, consisted of increasing age and long disease duration. The third component, contributing to 15%, consisted of high PDQ score, tender joint count, increasing age, and concomitant low CRP, suggestive of a chronic pain component consisting of central pain sensitization or structural joint damage. Conclusion Fatigue in PsA patients may be driven by clinical inflammatory factors, disease duration, and chronic pain in the absence of inflammation

In psoriatic arthritis fatigue is driven by inflammation, disease duration, and chronic pain: An observational DANBIO registry study

Objective Fatigue is one of the most significant symptoms, and an outcome of great importance, in patients with psoriatic arthritis (PsA), but associations between underlying components of fatigue experienced by patients in relation to the disease have been sparsely investigated. The objectives were to describe the degree of fatigue in PsA patients, and secondly to explore important components associated with fatigue. Methods We performed a cross-sectional survey including patients registered in the Danish nationwide registry DANBIO from December 2013 to June 2014. Principal component analysis was used to identify factors associated with fatigue. Results A total of 1,062 PsA patients were included in the study. A principal component analysis reduced co-variables into three components explaining 63% of fatigue in patients. The first component, contributing to 31% of fatigue, was composed of inflammatory factors including swollen and tender joints, doctors’ global assessment, elevated CRP, and high Pain Detect Questionnaire (PDQ) score; the second component, contributing to 17%, consisted of increasing age and long disease duration. The third component, contributing to 15%, consisted of high PDQ score, tender joint count, increasing age, and concomitant low CRP, suggestive of a chronic pain component consisting of central pain sensitization or structural joint damage. Conclusion Fatigue in PsA patients may be driven by clinical inflammatory factors, disease duration, and chronic pain in the absence of inflammation.</p

Change in psoriatic arthritis outcome measures impacts SF-36 physical and mental component scores differently: an observational cohort study

Objective The objective was to investigate interplay and physical and mental component scores between change (Δ) in health-related quality of life (HRQoL) quantified by the physical component score (PCS) and mental component score (MCS) retrieved from short-form health survey (SF-36), change in disease activity (ΔDAS28CRP) and manifestations of PsA. Methods PsA patients initiating new medical therapy were enrolled. Independent disease measures evaluating disease activity, enthesitis, psoriasis, pain and fatigue were collected at treatment initiation and after 4 months. Interplay between independent disease measures and dependent outcome measures, ΔPCS and ΔMCS, was described with univariate regression analyses. Multivariate regression analyses were applied to assess the impact of independent variables, such as individual disease outcome measures vs ΔDAS28CRP on ΔPCS and ΔMCS. Results One hundred and eight PsA patients were included. In the univariate regression analyses, improvement in fatigue, pain and disability were associated with improvement in ΔPCS (β; −2.08, −0.18 and −13.00, respectively; all P Conclusion In this PsA patient cohort, diminishing pain, disability and fatigue improved PCS and MCS significantly. Changes in enthesitis and psoriasis did not grossly impact HRQoL compared with DAS28CRP. Individual PsA manifestations influence HRQoL differently, which is important clinically when targeting treatment.</p

Change in psoriatic arthritis outcome measures impacts SF-36 physical and mental component scores differently: an observational cohort study.

Objective: The objective was to investigate interplay and physical and mental component scores between change (Δ) in health-related quality of life (HRQoL) quantified by the physical component score (PCS) and mental component score (MCS) retrieved from short-form health survey (SF-36), change in disease activity (ΔDAS28CRP) and manifestations of PsA. Methods: PsA patients initiating new medical therapy were enrolled. Independent disease measures evaluating disease activity, enthesitis, psoriasis, pain and fatigue were collected at treatment initiation and after 4 months. Interplay between independent disease measures and dependent outcome measures, ΔPCS and ΔMCS, was described with univariate regression analyses. Multivariate regression analyses were applied to assess the impact of independent variables, such as individual disease outcome measures Results: One hundred and eight PsA patients were included. In the univariate regression analyses, improvement in fatigue, pain and disability were associated with improvement in ΔPCS (β; -2.08, -0.18 and -13.00, respectively; all Conclusion: In this PsA patient cohort, diminishing pain, disability and fatigue improved PCS and MCS significantly. Changes in enthesitis and psoriasis did not grossly impact HRQoL compared with DAS28CRP. Individual PsA manifestations influence HRQoL differently, which is important clinically when targeting treatment. Trial registration: ClinicalTrials.gov, http://clinicaltrials.gov, NCT02572700