Clinical Activity Research Articles

Clinical disease activity index versus disease activity score (28 joints) for assessment of disease activity in obese patients of rheumatoid arthritis

Background: Measurement of disease activity by Disease Activity Score 28 joints -Erythrocyte Sedimentation Rate (DAS28-ESR), Disease Activity Score (28 joints)-C-Reactive Protein (DAS28-CRP), and Clinical Disease Activity Index (CDAI) has become an integral part of management of Rheumatoid Arthritis (RA), by ‘Treatment to Target’ approach. With the exception of CDAI, the other two use inflammatory markers ESR and CRP to measure disease activity. Obesity is also known to increase inflammatory markers like CRP. We undertake this study to examine if obesity confounds the disease activity measurement in RA leading to overestimation of disease activity. Methods: A cross-sectional observation study was conducted on one hundred patients of RA (40 obese and 60 non obese) in remission or low disease activity as defined by CDAI. They were divided into obese and non-obese groups based on Indian standards (BMI>25kg/m2). ESR and CRP were measured in both the groups. DAS28-ESR and DAS28-CRP were calculated and compared using relevant statistical tests. Results: DAS28-ESR and DAS-28-CRP scores were significantly higher in the obese subjects, despite both groups having comparable CDAI scores. Similar findings were also observed with inflammatory markers ESR and CRP, both being higher in obese patients. Conclusions: We conclude that indices incorporating inflammatory markers, like DAS28 overestimate disease activity in obese RA patients. Treatment decisions regarding escalation or addition of DMARDs should be taken after considering the same. CDAI appears to be better suited for disease activity measurements in obese RA patients as compared to DAS 28.

First-line avelumab plus chemotherapy in patients with advanced solid tumors: results from the phase 1b/2 JAVELIN Chemotherapy Medley study.

Chemotherapy can potentially enhance the activity of immune checkpoint inhibitors by promoting immune priming. The phase 1b/2 JAVELIN Chemotherapy Medley trial evaluated first-line avelumab + concurrent chemotherapy in patients with advanced urothelial carcinoma or nonsmall cell lung cancer (NSCLC). Avelumab 800 mg or 1200 mg was administered continuously every 3 weeks (Q3W) with standard doses of cisplatin + gemcitabine in patients with urothelial carcinoma, or carboplatin + pemetrexed in patients with nonsquamous NSCLC. Dual primary endpoints were dose-limiting toxicity (DLT; phase 1b) and confirmed objective response (phase 1b/2). In phase 1b, urothelial carcinoma and NSCLC cohorts received avelumab 800 mg (n=13 and n=6, respectively) or 1200 mg (n=6 each) + chemotherapy. In evaluable patients with urothelial carcinoma treated with avelumab 800 mg or 1200 mg + chemotherapy, DLT occurred in 1/12 (8.3%) and 1/6 (16.7%), respectively; no DLT occurred in the NSCLC cohort. In phase 2, 35 additional patients with urothelial carcinoma received avelumab 1200 mg + chemotherapy. Across all treated patients, safety profiles were similar irrespective of avelumab dose. Objective response rates (95% confidence internal) with avelumab 800 mg or 1200 mg + chemotherapy, respectively, across phase 1b/2, were 53.8% (25.1-80.8) and 39.0% (24.2-55.5) in urothelial carcinoma, and 50.0% (11.8-88.2) and 33.3% (4.3-77.7) in NSCLC. Preliminary efficacy and safety findings with avelumab + chemotherapy in urothelial carcinoma and NSCLC were consistent with previous studies of similar combination regimens. Conclusions about clinical activity are limited by small patient numbers. gov identifier, NCT03317496.

Bispecific T cell engager therapy for refractory rheumatoid arthritis.

Bispecific T cell engagers (BiTEs) kill B cells by engaging T cells. BiTEs are highly effective in acute lymphoblastic leukemia. Here we treated six patients with multidrug-resistant rheumatoid arthritis (RA) with the CD19xCD3 BiTE blinatumomab under compassionate use. Low doses of blinatumomab led to B cell depletion and concomitant decrease of T cells, documenting their engager function. Treatment was safe, with brief increase in body temperature and acute phase proteins during first infusion but no signs of clinically relevant cytokine-release syndrome. Blinatumomab led to a rapid decline in RA clinical disease activity in all patients, improved synovitis in ultrasound and FAPI-PET-CT and reduced autoantibodies. High-dimensional flow cytometry analysis of B cells documented an immune reset with depletion of activated memory B cells, which were replaced by nonclass-switched IgD-positive naïve B cells. Together, these data suggest the feasibility and potential for BiTEs to treat RA. This approach warrants further exploration on other B-cell-mediated autoimmune diseases.

Real-world utilization, patient characteristics, and treatment patterns among men with localized prostate cancer tested with the 17-gene genomic prostate score® (GPSTM) assay.

Descriptive study focusing on real-world utilization and characteristics of men with prostate cancer tested with the 17-gene Genomic Prostate Score® (GPS™) assay by linking administrative claims and electronic health record (EHR) data with GPS results. This retrospective, observational cohort study (January 1, 2013 to December 31, 2020) included men aged 40-80 years with localized prostate cancer claims, continuous enrollment in Optum's Integrated Claims data set, ≥1 day of EHR clinical activity, and a GPS result. Men were classified as undergoing definitive therapy (DT) (prostatectomy, radiation, or focal therapy) or active surveillance (AS). AS and DT distribution were analyzed across GPS results, National Comprehensive Cancer Network® (NCCN®) risk, and race. Costs were assessed 6 months after the first GPS result (index); clinical outcomes and AS persistence were assessed during the variable follow-up. All variables were analyzed descriptively. Of 834 men, 650 (77.9%) underwent AS and 184 (22.1%) DT. Most men had Quan-Charlson comorbidity scores of 1-2 and a tumor stage of T1c (index). The most common Gleason patterns were 3 + 3 (79.6%) (AS cohort) and 3 + 4 (55.9%) (DT cohort). The mean (standard deviation) GPS results at index were 23.2 (11.3) (AS) and 30.9 (12.9) (DT). AS decreased with increasing GPS result and NCCN risk. Differences between races were minimal. Total costs were substantially higher in the DT cohort. Most men with GPS-tested localized prostate cancer underwent AS, indicating the GPS result can inform clinical management. Decreasing AS with increasing GPS result and NCCN risk suggests the GPS complements NCCN risk stratification.

Primary care dentistry: Past, present and future

This article examines the past, present and future of primary care dentistry. It provides a historical background of primary care dentistry and describes stages of its evolution. It further reviews the purpose and mission of contemporary primary care dentistry and outlines a vision for the development of primary care dentistry in the future. The type and extent of innovations and technological advances that have impacted – and improved – primary care dentistry revolutionising clinical activities, ranging from early computerised tomography to modern digital systems and workflows are summarised. A discussion of current scientific evidence base pertinent to primary care dentistry highlighting the need for ‘effectiveness’ rather than ‘efficacy’ studies is included in order to provide research data pertinent to the primary care dentistry setting where most dental patients receive most of their care most of the time.

E074 Clinical features, disease activity and functional outcome of juvenile-onset, adult-onset and late-onset ankylosing spondylitis: a cross sectional study from India

Abstract Background/Aims Ankylosing spondylitis (AS) or radiographic axial spondyloarthritis (axial SpA) is reported to present with peripheral arthritis, less spinal symptoms, and more radiographic damage in juvenile onset (age at onset ≤16 years) as compared to adult-onset AS(age at onset <45 years). Functional outcome has varied depending on the population studied. In this cross-sectional study we compared clinical features, disease activity, and functional outcome among juvenile-onset AS (JoAS), adult-onset AS(AoAS), late-onset AS (LoAS). Methods Consenting patients fulfilling either the ASAS classification for axial SpA or 1984 modified New York criteria attending SpA clinic were included between May and June 2022. Data was collected by direct patient interview and clinical examination. Data collected: Clinical features, treatment, current disease activity by Bath AS disease activity index (BASDAI), current functional outcome by the Bath Ankylosing Spondylitis Functional Index (BASFI). Disease activity, functional outcome were compared among JoAS, AoAS, and LoAS. Study protocol was approved by the IEC. Results Of 73 patients (61 male), mean age 39.1±12.8 years, 10 (13.7%) were JoAS, 56 (76.7%) and 7 (9.6%) were AoAS and LoAS respectively. Only 30%, 59%, and 57% patients in JoAS, AoAS, and LoAS respectively were employed. There were no differences in the clinical presentation, namely back pain, neck pain, hip involvement, uveitis, and enthesitis among the three groups (Table 1). Majority received conventional-synthetic-DMARDs; only 2(20)%, 8(14.3), and 1(14.3) in the JoAS, AoAS, and LoAS group respectively had ever received TNF-inhibitors. Majority patients in all the groups had active disease (BASDAI>4 and ASDAS>1.3) and there was also no difference in the disease activity (at enrolment) between the groups. All patients with JoAS were positive for HLA-B27. Mean BASFI was not different between the groups, but poor functional outcome (BASFI >6) was observed in 5/10 (50%), 28/56 (50%), 5/9 (71.4%) patients of JoAS, AoAS, and LoAS respectively. Conclusion In a study involving a homogeneous cohort of Indian AS, there were no marked differences in clinical features, disease activity between JoAS, AoAS, and LoAS. Majority patients have poor functional outcomes which could be a direct effect of poor disease control due to lack of access to TNF inhibitors. Disclosure K. Modadugu: None. M.M. Thabah: None.

Drug Optimization in Patients with Mild-to-Moderate Ulcerative Colitis: A Global Survey.

Background/Objectives: The treatment of patients with mild-to-moderate ulcerative colitis (UC) is challenging. Although there are commonly used guidelines, therapy optimization is not standardized. We conducted a survey to investigate the management and treatment of patients with mild-to-moderate UC. Methods: Physicians with experience in treating inflammatory bowel diseases (IBD) were invited to participate in an anonymous, multiple-choice survey between June and July 2023. The survey addressed various issues of patient care such as patient monitoring, treatment optimization, follow-up, treatment decision making, and therapy de-escalation. Results: The survey included 222 physicians (59.9% men; mean age = 50.4 years) from 66 countries worldwide. Gastroenterologists were the most represented specialists (89.6%), followed by surgeons (3.2%), and internal medicine doctors (2.7%). Two-thirds of the participants (66.7%) had >10 years of experience in the field of IBD. The combination of oral (≥4 g/day) and rectal 5-aminosalicylic acid (5-ASA) was the preferred choice when optimizing therapy. Budesonide MMX (41.8%) and systemic steroids (39.9%) were preferred in patients who failed 5-ASA. Treatment decisions were predominantly based on endoscopic (99.0%) or clinical (59.8%) activity. A significant percentage of clinicians did not optimize therapy in the case of increased fecal calprotectin alone (45.1%) or radiological/ultrasound activity (39.8%) alone. Conclusions: The guidelines for the management of mild-to-moderate UC are well accepted in clinical practice. Endoscopic remission remains the main therapeutic target, followed by clinical remission. Fecal calprotectin and intestinal ultrasound still elicit complaints from physicians.

P127 Comparison of the Efficacy, Safety and Immunogenicity of a Proposed Biosimilar MSB11456 with Tocilizumab Reference Product in Moderate-to-Severe Rheumatoid Arthritis: Results of a Randomized Double-Blind Study

Abstract Background/Aims Tocilizumab is an anti-interleukin-6 receptor monoclonal antibody indicated for treating rheumatoid arthritis (RA) and other inflammatory diseases. MSB11456 is a proposed biosimilar to US-licensed tocilizumab and EU-approved tocilizumab. It has already shown equivalent pharmacokinetic, pharmacodynamic safety, tolerability, and immunogenicity profiles to these products given subcutaneously (SC) as a single dose in healthy volunteers. This Phase III, multi-centre, randomised, double-blind, multiple fixed-dose, parallel group study compared efficacy, safety and immunogenicity of MSB11456 and EU-approved tocilizumab administered SC in moderate-to-severe RA patients. Methods Patients were randomised to 162mg MSB11456 or EU-approved tocilizumab for 24 weeks (W). At W24, patients receiving EU-approved tocilizumab were re-randomised to continue treatment or switch to MSB11456 for up to W52. Safety evaluations were conducted up to W63. A change from baseline in Disease Activity Score-28 Joint Count-ESR (DAS28-ESR) at W24 was analysed, as the primary efficacy endpoint, using analysis of covariance to determine the least squares mean (LSM) difference between MSB11456 and EU-approved tocilizumab; equivalence was considered if the 90% confidence interval (CI) was entirely within the FDA equivalence interval -0.6 to 0.5. Secondary endpoints were 20% improvement in ACR core set measures at W24 and DAS28-ESR at W12. Additional endpoints included ACR50/70, change in DAS28-CRP, Simplified and Clinical Disease Activity Indexes, evaluation of immunogenicity up to W55 and safety up to W63. Results Clinically relevant LSM decreases from baseline in DAS28-ESR were observed from W2 up to W24 with both treatments. The 90% CI for LSM difference in the change from baseline in DAS28-ESR between treatments was fully included within the predefined equivalence interval, which demonstrated therapeutic equivalence of MSB11456 and EU-approved tocilizumab (Table 1). Other efficacy endpoint analyses supported this conclusion. No discernible patterns in the nature or frequency of treatment-emergent adverse events (TEAEs) were identified to suggest a difference between drugs. Anti-drug antibodies incidence was similar among treatment arms. Switching from EU-approved tocilizumab to MSB11456 had no clinically relevant impact on efficacy or safety. Conclusion Equivalent efficacy, immunogenicity and safety profiles of MSB11456 and EU-approved tocilizumab were demonstrated in moderate-to-severe RA patients, confirming equivalence between MSB11456 and the EU-approved tocilizumab. Disclosure A. Zubrzycka-Sienkiewicz: None. M. Misterska-Skora: None. M. Socik-Pojawa: None. K. Klama: None. M. Ullman: Other; Employee of Fresenius Kabi SwissBioSim - Sponsor of the study. C. Petit-Frere: Other; Employee of Fresenius Kabi SwissBioSim - Sponsor of the study. A. Illes: Other; Employee of Fresenius Kabi SwissBioSim - Sponsor of the study. P. Baker: Other; Employee of Fresenius Kabi SwissBioSim - Sponsor of the study. J. Monnet: Other; Employee of Fresenius Kabi SwissBioSim - Sponsor of the study. J. Morais: Other; Employee of Fresenius Kabi SwissBioSim - Sponsor of the study. J. Brzezicki: None.

P117 Efficacy of filgotinib in patients with rheumatoid arthritis: Week 156 results from a long-term extension study

Abstract Background/Aims In the treatment of RA, JAK inhibitors are a valuable option to meet remission or low disease activity (LDA) treatment targets following an inadequate response (IR) or intolerance to ≥ 1 conventional synthetic disease-modifying antirheumatic drug (DMARD). FIL is a JAK1 preferential inhibitor available in two doses for the treatment of moderate to severe RA. Objectives: To evaluate long-term efficacy of two doses of FIL in clinically relevant pt populations. Methods In this interim analysis, efficacy (non-responder imputation) of FIL 200 mg (FIL200) and 100 mg (FIL100) was assessed from LTE baseline (BL) to W156 in pts with an IR to methotrexate (MTX-IR) and biologics (bDMARD-IR), enrolled from FINCH 1 (NCT02889796) and 2 (NCT02873936) parent studies (PS), respectively, receiving ≥1 FIL dose in FINCH 4 (NCT03025308). Results Study design, BL characteristics and W48 outcomes for MTX-IR1 and bDMARD-IR2 pts were reported previously. For MTX-IR and bDMARD-IR pts who received FIL200 or FIL100 in the PS, W156 remission rates using Boolean 1.0 criteria were 20.5% and 15.8%, and 18.2% and 8.9%, respectively. Adopting the Boolean 2.0 criteria slightly increased remission rates for FIL200 and FIL100 at W156: +4.2% and +4.9% for MTX-IR pts, and +1.5% and +2.4% for bDMARD-IR pts, respectively. For pts rerandomized to FIL on entering the LTE, Boolean 2.0 criteria also increased remission rates vs Boolean 1.0. Both MTX-IR and bDMARD-IR pts maintained long-term Boolean remission through W156 with FIL200 and FIL100, irrespective of prior FIL. Results for Disease Activity Score 28 with C-reactive protein (DAS28-CRP) <2.6, Clinical Disease Activity Index (CDAI) ≤2.8, and Simplified Disease Activity Index (SDAI) ≤3.3, and mean change from PS BL in Health Assessment Questionnaire-Disability Index (HAQ-DI) and pain are shown (Table). Similar trends in efficacy were seen for LDA and ACR response criteria. Conclusion In FINCH 4, both FIL200 and FIL100 showed sustained efficacy up to W156 in clinically relevant pt populations. Boolean 2.0 criteria classified more pts in remission, in line with the range reported in the validation study. Disclosure M.H. Buch: Consultancies; AbbVie, CESAS Medical, Galapagos, Gilead, and Pfizer (all paid to host institution). Member of speakers’ bureau; AbbVie (paid to host institution). Grants/research support; Gilead (paid to host institution). D. Aletaha: Consultancies; AbbVie, Eli Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, Sandoz, and Sanofi. Member of speakers’ bureau; AbbVie, Eli Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, Sandoz, and Sanofi. Grants/research support; AbbVie, Eli Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, Sandoz, and Sanofi. R. Caporali: Consultancies; AbbVie, Fresenius, Galapagos, Lilly, Novartis, Pfizer, and UCB. Member of speakers’ bureau; AbbVie, Amgen, BMS, Celltrion, Fresenius, Galapagos, Janssen, Lilly, Novartis, Pfizer, and UCB. B. Combe: Consultancies; AbbVie, Galapagos, Gilead, Janssen, Lilly, Novartis, and Roche-Chugai. Member of speakers’ bureau; AbbVie, Celltrion, Galapagos, Janssen, Lilly, Pfizer, and Roche-Chugai. H. Schulze-Koops: Consultancies; AbbVie, Galapagos, Lilly, and Pfizer. Member of speakers’ bureau; AbbVie, Galapagos, Lilly, and Pfizer. J. Gottenberg: Consultancies; AbbVie, BMS, Galapagos, Gilead, Lilly, MSD, Novartis, and Pfizer. Grants/research support; BMS and Pfizer. Y. Tanaka: Member of speakers’ bureau; AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, GSK, Mitsubishi-Tanabe, and Pfizer. Grants/research support; AbbVie, Asahi-Kasei Pharma, Boehringer Ingelheim, Chugai, Daiichi-Sankyo, Eisai, Takeda. R. Blanco: Consultancies; AstraZeneca, Galapagos, Janssen, Novartis, and Pfizer. Member of speakers’ bureau; AbbVie, Amgen, BMS, Galapagos, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, and Sanofi. Grants/research support; AbbVie and Roche. T. Takeuchi: Consultancies; AbbVie GK, Astellas, Chugai, Eli Lilly Japan, Gilead Sciences, Inc., Janssen Pharm K.K., Mitsubishi-Tanabe, and Pfizer Japan Inc. Member of speakers’ bureau; AbbVie GK, AYUMI, BMS, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Gilead Sciences, Inc., Janssen Pharm K.K., Mitsubishi-Tanabe, Pfizer Japan Inc., and Sanofi K.K. Grants/research support; AbbVie GK, Asahi-Kasei Pharma, Astellas, AYUMI, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Mitsubishi-Tanabe, Nippon Kayaku, and UCB Japan. E. V. Ekoka Omoruyi: Consultancies; Galapagos and Janssen. Shareholder/stock ownership; UCB. K. Van Beneden: Shareholder/stock ownership; Galapagos. Other; Employee of Galapagos. V. Rajendran: Shareholder/stock ownership; Galapagos. Other; Employee of Galapagos. C. Watson: Shareholder/stock ownership; Galapagos. Other; Employee of Galapagos. F. De Leonardis: Other; Employee of Galapagos. P. Emery: Consultancies; AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Galapagos, Gilead, Lilly, Novartis, Pfizer, Roche, and Samsung. Member of speakers’ bureau; AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Galapagos, Gilead, Lilly, Novartis, Pfizer, and Samsung. Grants/research support; AbbVie, BMS, Lilly, Novartis, Pfizer, Roche, and Samsung.

OA02 Longitudinal high throughput proteomics identifies novel proteins associated with inflammation and future response in new-onset, treatment-naïve rheumatoid arthritis

Abstract Background/Aims Despite the availability of effective targeted therapies, only 20-30% achieve low disease activity and even fewer attain remission. There remains a pressing need to identify meaningful biomarkers and disease endotypes to enable precision medicine. We aimed to identify serum protein biomarkers that associate with RA inflammation and future remission in a treatment-naïve, new-onset RA trial cohort. Methods Serum from 105 patients from the ‘VEDERA’ trial (first-line tumour necrosis factor inhibitor + methotrexate [TNFi + MTX] versus methotrexate treat-to-target [MTX-TT]) at baseline, week 24 and 48 were analysed for 92 proteins using the Olink Target 96 Inflammation panel. Clinical and MSUS assessments completed at baseline, weeks 24 and 48 were used for the analyses. Clinical remission was defined as DAS28-ESR ≤ 2.6 and joint-level remission as absence of power Doppler ultrasound synovitis (PDUS). After adjusting for age, gender and seropositive status, Bayesian mixed effects regression (posterior estimates and 95% credible intervals reported) was used to identify association of (i) proteins with clinical disease activity (DAS28-ESR) and joint-level inflammation (total power Doppler ultrasound synovitis (PDUS) scores] and (ii) baseline proteins with future (week 24 or 48) clinical and joint-level remission. Results Longitudinally, out of 92 proteins, 10 and 14 were significantly associated with DAS28-ESR and total PDUS scores respectively, with 3 proteins in common: leukaemia inhibitory factor receptor (LIF-R); fractalkine (CX3CL1); interleukin-10 receptor alpha (IL-10RA). Baseline levels of 9 proteins were associated with future clinical remission (week 24 = 6 proteins; week 48 = 3 proteins) while 6 were associated with future PDUS status (week 24 = 4 proteins; week 48 = 3 proteins). Proteins that were associated with inflammation longitudinally and whose baseline levels associated with future remission included IL-17C, fibroblast growth factor 5 (FGF-5), lymphotoxin alpha and TNF. Posterior estimates and 95% credible intervals for above proteins are reported in Table 1. Conclusion Using longitudinal high-throughput proteomics in a treatment-naïve early onset RA cohort, this study sheds new light on known and novel protein associates of inflammation and future remission. With future validation, these biomarkers could provide mechanistic understanding and allow for individualised treatment strategies to improve outcomes. Disclosure R. Shukla: None. R. Wakefield: None. A. Tan: None. P. Emery: Consultancies; BristolMyersSquibb, AbbVie, Gilead, Galapagos, Eli Lilly, MSD, Pfizer, Novartis, Roche and Samsung. Grants/research support; AbbVie, Eli Lilly, Novartis, BristolMyersSquibb, Pfizer and Roche, outside the submitted work. D. Plant: None. M.H. Buch: Consultancies; AbbVie, Arxx Therapeutics, Boehringer Ingelheim, Galapagos, Gilead, and Pfizer; and speaker fees from AbbVie, CESAS Medical, Galapagos, Gilead, Medistream, and Pfizer. Grants/research support; grant support from Gilead.

Effect of simulation-based zoom learning on clinical decision-making among undergraduate nursing students and experiences of students and instructors: A mixed methods study

AimTo determine the effect of simulation-based Zoom learning (SBZL) on perceived capabilities and clinical decision-making skills among undergraduate nursing students and to explore experiences of the instructors and students participating in SBZL. BackgroundNursing is a practice profession and students acquire clinical decision-making skills in clinical settings. However, the COVID-19 pandemic has disrupted conventional clinical learning activities. In this study, the outcomes of implementing SBZL in an undergraduate programme to support students’ clinical learning were examined. DesignA mixed methods design was employed. MethodsThis study recruited 195 final-year students to participate in the SBZL programme, which was developed based on the NLN Jeffries Simulation Theory to guide its design, implementation and evaluation. Case scenarios were developed and simulated through Zoom. Students’ perceived capabilities, perceptions of the learning environment and clinical decision-making skills were assessed before and after SBZL. A historical control group of 226 previous final year students who had received a clinical practicum was included for comparison. Semi-structured interviews were conducted with 11 instructors and 19 students to explore their experiences of participating in SBZL. ResultsA total of 102 students completed the post-SBZL questionnaire. An increase in perceived creative thinking (mean difference = 0.24, p < 0.001) was observed post-SBZL. After SBZL, the perceptions of the learning environment were significantly improved. However, the SBZL group demonstrated lower perceived problem-solving capability than the control group (mean difference = 0.14, p = 0.007). Clinical decision-making was significantly improved in the SBZL group than in the control group (p < 0.001). Both the instructors and students reported positive experiences with SBZL, and highlighted challenges and factors for improving its implementation. ConclusionsSBZL showed improvement in perceived creative thinking, perceptions of the learning environment and clinical decision-making. This innovative teaching and learning method can be valuable for nursing education in various regions to prepare students for real-life roles. Tweetable abstractSimulation-based Zoom learning is better than traditional teaching in improving clinical decision-making skills among undergraduate nursing students.

Targeting CEACAM5-positive solid tumors using NILK-2401, a novel CEACAM5xCD47 κλ bispecific antibody.

Blocking the CD47 "don't eat me"-signal on tumor cells with monoclonal antibodies or fusion proteins has shown limited clinical activity in hematologic malignancies and solid tumors thus far. Main side effects are associated with non-tumor targeted binding to CD47 particularly on blood cells. We present here the generation and preclinical development of NILK-2401, a CEACAM5×CD47 bispecific antibody (BsAb) composed of a common heavy chain and two different light chains, one kappa and one lambda, determining specificity (so-called κλ body format). NILK-2401 is a fully human BsAb binding the CEACAM5 N-terminal domain on tumor cells by its lambda light chain arm with an affinity of ≈4 nM and CD47 with its kappa chain arm with an intendedly low affinity of ≈500 nM to enabling tumor-specific blockade of the CD47-SIRPα interaction. For increased activity, NILK-2401 features a functional IgG1 Fc-part. NILK-2401 eliminates CEACAM5-positive tumor cell lines (3/3 colorectal, 2/2 gastric, 2/2 lung) with EC50 for antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity ranging from 0.38 to 25.84 nM and 0.04 to 0.25 nM, respectively. NILK-2401 binds neither CD47-positive/CEACAM5-negative cell lines nor primary epithelial cells. No erythrophagocytosis or platelet activation is observed. Quantification of the pre-existing NILK-2401-reactive T-cell repertoire in the blood of 14 healthy donors with diverse HLA molecules shows a low immunogenic potential. In vivo, NILK-2401 significantly delayed tumor growth in a NOD-SCID colon cancer model and a syngeneic mouse model using human CD47/human SIRPα transgenic mice and prolonged survival. In cynomolgus monkeys, single doses of 0.5 and 20 mg/kg were well tolerated; PK linked to anti-CD47 and Fc-binding seemed to be more than dose-proportional for Cmax and AUC0-inf. Data were validated in human FcRn TG32 mice. Combination of a CEACAM5-targeting T-cell engager (NILK-2301) with NILK-2401 can either boost NILK-2301 activity (Emax) up to 2.5-fold or allows reaching equal NILK-2301 activity at >600-fold (LS174T) to >3,000-fold (MKN-45) lower doses. NILK-2401 combines promising preclinical activity with limited potential side effects due to the tumor-targeted blockade of CD47 and low immunogenicity and is planned to enter clinical testing.

Final phase 1 substudy results of ivosidenib for patients with mutant IDH1 relapsed/refractory myelodysplastic syndrome

AbstractIvosidenib is a first-in-class mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor and has shown efficacy and tolerability in patients with advanced mIDH1 hematologic malignancies, leading to approval in frontline and relapsed/refractory (R/R) mIDH1 acute myeloid leukemia populations. We report final data from a phase 1 single-arm substudy of patients with R/R mIDH1 myelodysplastic syndrome (MDS) after failure of standard-of-care therapies. Oral ivosidenib was taken once daily on days 1 through 28 in 28-day cycles. Primary objectives were to determine safety, tolerability, and clinical activity. The primary efficacy end point was the complete remission (CR) + partial remission (PR) rate. Nineteen patients were enrolled; 18 were included in the efficacy analysis. Treatment-related adverse events occurred in 8 (42.1%) patients, including a grade 1 QT interval prolongation in 1 (5.3%) patient and grade 2 differentiation syndrome in 2 (10.5%) patients. Rates of CR + PR and objective response (CR + PR + marrow CR) were 38.9% (95% confidence interval [CI], 17.3-64.3) and 83.3% (95% CI, 58.6-96.4), respectively. Kaplan-Meier estimates showed a 68.6% probability of patients in CR achieving a remission duration of ≥5 years, and a median overall survival of 35.7 months. Of note, 71.4% and 75.0% baseline red blood cell (RBC)- and platelet-transfusion–dependent patients, respectively, became transfusion independent (TI; no transfusion for ≥56 days); 81.8% and 100% of baseline RBC and platelet TI patients, respectively, remained TI. One (5.3%) patient proceeded to a hematopoietic stem cell transplant by data cutoff. In conclusion, ivosidenib is clinically active, with durable remissions and a manageable safety profile observed in patients with mIDH1 R/R MDS. This trial was registered at www.ClinicalTrials.gov as #NCT02074839.

BCR::ABL1 kinase N-lobe mutants confer moderate to high degrees of resistance to asciminib

AbstractSecondary kinase domain mutations in BCR::ABL1 represent the most common cause of resistance to tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukemia. The first 5 approved BCR::ABL1 TKIs target the adenosine triphosphate (ATP)–binding pocket. Mutations confer resistance to these ATP-competitive TKIs and those approved for other malignancies by decreasing TKI affinity and/or increasing ATP affinity. Asciminib, the first highly active allosteric TKI approved for any malignancy, targets an allosteric regulatory pocket in the BCR::ABL1 kinase C-lobe. As a non–ATP-competitive inhibitor, the activity of asciminib is predicted to be impervious to increases in ATP affinity. Here, we report several known mutations that confer resistance to ATP-competitive TKIs in the BCR::ABL1 kinase N-lobe that are distant from the asciminib binding pocket yet unexpectedly confer in vitro resistance to asciminib. Among these is BCR::ABL1 M244V, which confers clinical resistance even to escalated asciminib doses. We demonstrate that BCR::ABL1 M244V does not impair asciminib binding, thereby invoking a novel mechanism of resistance. Molecular dynamic simulations of the M244V substitution implicate stabilization of an active kinase conformation through impact on the α-C helix as a mechanism of resistance. These N-lobe mutations may compromise the clinical activity of ongoing combination studies of asciminib with ATP-competitive TKIs.

Intensive care unit follow-up clinic activities: a scoping review.

The importance of ongoing post-discharge follow-up to prevent functional impairment in patients discharged from intensive care units (ICUs) is being increasingly recognized. Therefore, we conducted a scoping review, which included existing ICU follow-up clinic methodologies using the CENTRAL, MEDLINE, and CINAHL databases from their inception to December 2022. Data were examined for country or region, outpatient name, location, opening days, lead profession, eligible patients, timing of the follow-up, and assessment tools. Twelve studies were included in our review. The results obtained revealed that the methods employed by ICU follow-up clinics varied among countries and regions. The names of outpatient follow-up clinics also varied; however, all were located within the facility. These clinics were mainly physician or nurse led; however, pharmacists, physical therapists, neuropsychologists, and social workers were also involved. Some clinics were limited to critically ill patients with sepsis or those requiring ventilation. Ten studies reported the first outpatient visit 1-3months after discharge. All studies assessed physical function, cognitive function, mental health, and the health-related quality of life. This scoping review revealed that an optimal operating format for ICU follow-up clinics needs to be established according to the categories of critically ill patients.

Datopotamab Deruxtecan in Advanced or Metastatic HR+/HER2- and Triple-Negative Breast Cancer: Results From the Phase I TROPION-PanTumor01 Study.

Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate consisting of a humanized antitrophoblast cell-surface antigen 2 (TROP2) monoclonal antibody linked to a potent, exatecan-derived topoisomerase I inhibitor payload via a plasma-stable, selectively cleavable linker. TROPION-PanTumor01 (ClinicalTrials.gov identifier: NCT03401385) is a phase I, dose-escalation, and dose-expansion study evaluating Dato-DXd in patients with previously treated solid tumors. The primary study objective was to assess the safety and tolerability of Dato-DXd. Secondary objectives included evaluation of antitumor activity and pharmacokinetics. Results from patients with advanced/metastatic hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer (BC) or triple-negative BC (TNBC) are reported. At data cutoff (July 22, 2022), 85 patients (HR+/HER2- BC = 41, and TNBC = 44) had received Dato-DXd. The objective response rate by blinded independent central review was 26.8% (95% CI, 14.2 to 42.9) and 31.8% (95% CI, 18.6 to 47.6) for patients with HR+/HER2- BC and TNBC, respectively. The median duration of response was not evaluable in the HR+/HER2- BC cohort and 16.8 months in the TNBC cohort. The median progression-free survival in patients with HR+/HER2- BC and TNBC was 8.3 and 4.4 months, respectively. All-cause treatment-emergent adverse events (TEAEs; any grade, grade ≥3) were observed in 100% and 41.5% of patients with HR+/HER2- BC and 100% and 52.3% of patients with TNBC. Stomatitis was the most common TEAE (any grade, grade ≥3) in both HR+/HER2- BC (82.9%, 9.8%) and TNBC (72.7%, 11.4%) cohorts. In patients with heavily pretreated advanced HR+/HER2- BC and TNBC, Dato-DXd demonstrated promising clinical activity and a manageable safety profile. Dato-DXd is currently being evaluated in phase III studies.

Ultrasonographic Evaluation of the Ankle Joint in Relation to Rheumatoid Factor Status and Disease Activity in Patients with Rheumatoid Arthritis

Abstract Background: Rheumatoid arthritis (RA) is a form of inflammatory disease whose clinical pattern is largely dependent on the presence of both anti-citrullinated protein antibodies and rheumatoid factor (RF). Although this is still debatable, seronegative RA seems to be a somewhat less serious condition. The present study aimed to evaluate ankle joint ultrasound in relation to RF status and disease activity in RA patients. Methods: A cross-sectional study involving RA patients from a single center was conducted. Laboratory test evaluations and clinical activity assessments were carried out. The ankle joint was examined using musculoskeletal ultrasound (US). Results: The study included 100 patients with established RA in total. Eighty-two patients tested positive for RF with a mean age of 42.3, whereas only 18 tested negative with a mean age of 39.6. Patients who tested positive for RF had a longer duration of illness (9.39 ± 5.39 vs. 4.56 ± 3.24). There were no differences in clinical activity scores between the seropositive and seronegative groups. The pathological US findings of any ankle joint showed no differences between the seropositive and seronegative groups. Patients with US findings of tibialis posterior tenosynovitis in the left ankle and synovitis and erosion in the right ankle, particularly in the tibiotalar and talonavicular joints, had significantly high Disease Activity Score 28-Erythrocyte sedimentation rate-scores. The increased disease activity was accompanied by significant erosions on both ankles. Conclusion: In terms of disease activity, there is no clinically significant difference between seropositive and seronegative RA patients. Sonographic ankle joint abnormalities do not appear to be associated with the patients’ RF status. High RA disease activity, on the other hand, is associated with synovitis and erosions, particularly in the talonavicular and tibiotalar joints, as well as tibialis posterior tenosynovitis.

Medical rehabilitation in dermatology : Goals, program content, and application process

Medical rehabilitation plays an important role in the management of patients with chronic dermatoses and dermato-oncological diseases. Which dermatological indications qualify for amedical rehabilitation? What forms need to be completed for asuccessful application? Which treatments are provided and what are goals to be accomplished during dermatological rehabilitation? Evaluation of current guidelines, directives, and recommendations as well as exemplary reviews. Dermato-oncological diseases and every chronic dermatological disease that is associated with alimitation of body functions and structures, activity and participation is eligible for medical rehabilitation. They include need, ability to absolve arehabilitation, and afavorable prognosis. Treatments range from therapy of the underlying dermatological condition to interdisciplinary treatment of comorbidities with the aim of restoring functional health. Medical rehabilitation follows aholistic approach and represents asignificant addition to outpatient and acute inpatient care, often leading to along-term improvement in clinical outcome, participation, and activity.

A phase I trial of autologous RAK cell immunotherapy in metastatic renal cell carcinoma

BackgroundTreatment of metastatic renal cell carcinoma (mRCC) remains a challenge worldwide. Here, we introduced a phase I trial of autologous RAK cell therapy in patients with mRCC whose cancers progressed after prior systemic therapy. Although RAK cells have been used in clinic for many years, there has been no dose-escalation study to demonstrate its safety and efficacy.MethodsWe conducted a phase I trial with a 3 + 3 dose-escalation design to investigate the dose-related safety and efficacy of RAK cells in patients with mRCC whose cancers have failed to response to systemic therapy (ChiCTR1900021334).ResultsAutologous RAK cells, primarily composed of CD8+ T and NKT cells, were infused intravenously to patients at a dose of 5 × 109, 1 × 1010 or 1.5 × 1010 cells every 28 days per cycle. Our study demonstrated general safety of RAK cells in a total of 12 patients. Four patients (33.3%) showed tumor shrinkage, two of them achieved durable partial responses. Peripheral blood analysis showed a significant increase in absolute counts of CD3+ and CD8+ T cells after infusion, with a greater fold change observed in naive CD8+ T cells (CD8+CD45RA+). Higher peak values of IL-2 and IFN-γ were observed in responders after RAK infusion.ConclusionThis study suggests that autologous RAK cell immunotherapy is safe and has clinical activity in previously treated mRCC patients. The improvement in peripheral blood immune profiling after RAK cell infusion highlights its potential as a cancer treatment. Further investigation is necessary to understand its clinical utility.

A Phase I Trial Evaluating the Addition of Lenalidomide to Patients with Relapsed/Refractory Multiple Myeloma Progressing on Ruxolitinib and Methylprednisolone.

Ruxolitinib (RUX), an orally administered selective Janus kinase 1/2 inhibitor, has received approval for the treatment of myelofibrosis, polycythemia vera, and graft-versus-host disease. We have previously demonstrated the anti-multiple myeloma effects of RUX alone and in combination with the immunomodulatory agent lenalidomide (LEN) and glucocorticosteroids both pre-clinically and clinically. This study aims to evaluate whether LEN can achieve clinical activity among patients with multiple myeloma progressing on the combination of RUX and methylprednisolone (MP). In this part of a phase I, multicenter, open-label study, we evaluated the safety and efficacy of RUX and MP for patients with multiple myeloma with progressive disease who had previously received a proteasome inhibitor, LEN, glucocorticosteroids, and at least three prior regimens; we also determined the safety and efficacy of adding LEN at the time of disease progression from the initial doublet treatment. Initially, all subjects received oral RUX 15 mg twice daily and oral MP 40 mg every other day. Those patients who developed progressive disease according to the International Myeloma Working Group criteria then received LEN 10 mg once daily on days 1-21 within a 28-day cycle in addition to RUX and MP, which were administered at the same doses these patients were receiving at the time progressive disease developed. Twenty-nine subjects (median age 64 years; 18 [62%] male) were enrolled in this part of the study and initially received the two-drug combination of RUX and MP. The median number of prior therapies was six (range 3-12). The overall response rate from this two-drug combination was 31% and the clinical benefit rate was 34%. The best responses were 1 very good partial response, 8 partial responses, 1 minor response, 12 stable disease, and 7 progressive disease. The median progression-free survival was 3.5 months (range 0.5-36.2months). The median time to response was 3.0 months. The median duration of response was 12.5 months (range 2.8-36.2 months). Twenty (69%) patients whoshowed progressive disease had LEN added to RUX and MP; all patients had prior exposure to LEN and all but one patient was refractory to their last LEN-containing regimen. After the addition of LEN, the overall response rate was 30% and the clinical benefit rate was 40%. The best responses of patients following the addition of LEN were 2 very good partial responses, 4 partial responses, 2 minor responses, 8 stable disease, and 4 progressive disease. The median time to response was 2.6 months (range 0.7-15.0 months). The median duration of response was not reached. The median progression-free survival following the addition of LEN was 3.5 months (range 0.3-25.9 months). For patients with multiple myeloma, treatment with RUX and MP is effective and well tolerated, and LEN can be used to extend the benefit of this RUX-based treatment. This study is registered with ClinicalTrials.gov, NCT03110822, and is ongoing.