Clinical Activity Research Articles

Circulating Proteins Associated with Anti-IL6 Receptor Therapeutic Resistance in the Sera of Patients with Severe COVID-19.

Circulating proteomes provide a snapshot of the physiological state of a human organism responding to pathogenic challenges and drug interventions. The outcomes of patients with COVID-19 and acute respiratory distress syndrome triggered by the SARS-CoV2 virus remain uncertain. Tocilizumab is an anti-interleukin-6 treatment that exerts encouraging clinical activity by controlling the cytokine storm and improving respiratory distress in patients with COVID-19. We investigate the biological determinants of therapeutic outcomes after tocilizumab treatment. Overall, 28 patients hospitalized due to severe COVID-19 who were treated with tocilizumab intravenously were included in this study. Sera were collected before and after tocilizumab, and the patient's outcome was evaluated until day 30 post-tocilizumab infusion for favorable therapeutic response to tocilizumab and mortality. Hyperreaction monitoring measurements by liquid chromatography-mass spectrometry-based proteomic analysis with data-independent acquisition quantified 510 proteins and 7019 peptides in the serum of patients. Alterations in the serum proteome reflect COVID-19 outcomes in patients treated with tocilizumab. Our results suggested that circulating proteins associated with the most significant prognostic impact belonged to the complement system, platelet degranulation, acute-phase proteins, and the Fc-epsilon receptor signaling pathway. Among these, upregulation of the complement system by activation of the classical pathway was associated with poor response to tocilizumab, and upregulation of Fc-epsilon receptor signaling was associated with lower mortality.

Extensivist: improving the delivery of enhanced health in older people’s care homes

BackgroundOlder people living in care homes are often frail and clinically complex. The Enhanced Health in Care Homes (EHCH) framework supports organisational and clinical strategies to deliver good care, promoting...

Increased choroidal stromal area in patients with active Graves’ ophthalmopathy based on binarisation method of optical coherence tomographic images

ObjectiveTo investigate the change in choroidal components of patients with Graves’ ophthalmopathy (GO) with different degrees of disease activity and severity by using the image binarisation method of optical coherence...

Exploring the Utility of a Novel Approach of Evaluating Application of a Validated Violence Risk Assessment Instrument.

Mental health nurses are often responsible for assessment/management of inpatient aggression. Validated instruments such as the Dynamic Appraisal of Situational Aggression (DASA), can aid risk assessment. However, limited attention has been paid to evaluating nurses' ability to administer risk assessment instruments. An entrustable professional activity may offer way of evaluating risk assessment clinical activities. DASA trainers' perceptions of the value and utility of an EPA were explored via collection of data through focus groups, with 17 participants from six countries. Thematic analysis was conducted to analyze the data. Three themes were interpreted: (1) DASA trainers-a way of knowing and being (2) An EPA-something you did not know you need until you see it; (3) The DASA-EPA supports the need for training and importance of integrity in assessment. Trainers engaged in innovative ways to ensure training is suitable and responsive to needs of nurses and their setting. Participants understood how an EPA could be used to evaluate DASA administration, monitor DASA use, provide feedback, and highlight the importance of training to ensure best practice.

Neoadjuvant letrozole and palbociclib in patients with HR-positive/HER2-negative early breast cancer and Oncotype DX Recurrence Score ≥18: DxCARTES study

The effect of the addition of cyclin-dependent kinases 4 and 6 inhibitors to endocrine therapy in terms of molecular downstaging remains undetermined. Switching from a high-risk to a low risk Recurrence Score (RS) group could provide useful information to identify patients who might not require chemotherapy. The purpose of this study was to assess the biological and clinical activity of letrozole plus palbociclib as neoadjuvant treatment for patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative early breast cancer with an initial Oncotype DX RS ≥18. Participants were women aged ≥18 years with HR-positive/HER2-negative, Ki67 ≥ 20%, stage II-IIIB early breast cancer with a baseline RS ≥18. Eligible patients with a pretreatment RS 18-25 (cohort A) and 26-100 (cohort B) received six 28-day cycles of letrozole (2.5 mg per day; plus goserelin if pre- or perimenopausal) plus palbociclib (125 mg per day; 3/1 schedule) before surgery. The primary endpoint for both cohorts was the proportion of patients who achieved an RS ≤25 at surgery or a pathological complete response (pCR). A total of 67 patients were enrolled, among which 65 were assessable for the primary endpoint (32 patients in cohort A and 33 in cohort B). At surgery, 22 (68.8%) patients in cohort A and 18 (54.5%) patients in cohort B had an RS ≤25 or a pCR [only 1 (3.0%) patient in cohort B], meeting the primary endpoint in cohort B (P < 0.01), but not in cohort A (P= 0.98). No new safety signals were identified. The efficacy of neoadjuvant treatment with letrozole plus palbociclib does not seem to depend on pretreatment RS for patients with RS ≥18. However, around half of patients with HR-positive/HER2-negative early breast cancer with an RS 26-100 at baseline achieved molecular downstaging with this regimen.

Prospective Comparison of FOCUS MUSE and Single-Shot Echo-Planar Imaging for Diffusion-Weighted Imaging in Evaluating Thyroid-Associated Ophthalmopathy.

To prospectively compare single-shot (SS) echo-planar imaging (EPI) and field-of-view optimized and constrained undistorted single-shot multiplexed sensitivity-encoding (FOCUS MUSE) for diffusion-weighted imaging (DWI) in evaluating thyroid-associated ophthalmopathy (TAO). SS EPI and FOCUS MUSE DWIs were obtained from 39 patients with TAO (18 male; mean ± standard deviation: 48.3 ± 13.3 years) and 26 healthy controls (9 male; mean ± standard deviation: 43.0 ± 18.5 years). Two radiologists scored the visual image quality using a 4-point Likert scale. The image quality score, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and apparent diffusion coefficient (ADC) of extraocular muscles (EOMs) were compared between the two DWIs. Differences in the ADC of EOMs were also evaluated. The performance of discriminating active from inactive TAO was assessed using receiver operating characteristic curves. The correlation between ADC and clinical activity score (CAS) was analyzed using Spearman correlation. Compared with SS EPI DWI, FOCUS MUSE DWI demonstrated significantly higher image quality scores (P < 0.001), a higher SNR and CNR on the lateral rectus muscle (LRM) and medial rectus muscle (MRM) (P < 0.05), and a non-significant difference in the ADC of the LRM and MRM. Active TAO showed higher ADC than inactive TAO and healthy controls with both SS EPI and FOCUS MUSE DWIs (P < 0.001). Inactive TAO and healthy controls did not show a significant ADC difference with both DWIs. Compared with SS EPI DWI, FOCUS MUSE DWI demonstrated better discrimination of active from inactive TAO (AUC: 0.925 vs. 0.779; P = 0.007). The ADC was significantly correlated with CAS in SS EPI DWI (r = 0.391, P < 0.001) and FOCUS MUSE DWI (r = 0.645, P < 0.001). FOCUS MUSE DWI provides better images for evaluating EOMs and better performance in diagnosing active TAO than SS EPI DWI. The application of FOCUS MUSE will facilitate the DWI evaluation of TAO.

Valemetostat for patients with relapsed or refractory peripheral T-cell lymphoma (VALENTINE-PTCL01): a multicentre, open-label, single-arm, phase 2 study.

Peripheral T-cell lymphomas are aggressive non-Hodgkin lymphomas with few treatment options for relapsed or refractory disease. Valemetostat tosylate (valemetostat) is a potent, novel, dual inhibitor of EZH2 and EZH1. We investigated the clinical activity and safety of valemetostat in patients with relapsed or refractory peripheral T-cell lymphoma, and its safety in patients with relapsed or refractory adult T-cell leukaemia/lymphoma. VALENTINE-PTCL01 was a multicentre, open-label, single-arm, phase 2 trial performed at 47 hospitals in 12 countries across Asia, Europe, North America, and Oceania. Patients with either peripheral T-cell lymphoma or adult T-cell leukaemia/lymphoma, aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-2 received oral valemetostat at 200 mg per day in continuous 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint for patients with peripheral T-cell lymphoma was the CT-based objective response rate by blinded independent central review (BICR) using 2014 Lugano response criteria. Patients who received valemetostat and had a confirmed eligible peripheral T-cell lymphoma subtype on central review were included in the efficacy analysis. The primary endpoint for patients with adult T-cell leukaemia/lymphoma was the safety and tolerability of valemetostat. Safety in both cohorts was assessed in all patients who received at least one dose of valemetostat. The trial is registered with ClinicalTrials.gov, NCT04703192, and EudraCT, 2020-004954-31, and is closed to enrolment. Between June 16, 2021, and Aug 10, 2022, 133 patients with relapsed or refractory peripheral T-cell lymphoma (median age 69·0 years [IQR 58·0-74·0]; 91 [68%] were male, and 42 [32%] were female) and 22 patients with adult T-cell leukaemia/lymphoma (66·5 years [54·0-73·0]; 15 [68%] were male, and seven [32%] were female) were enrolled. The median follow-up time was 12·3 months (95% CI 11·8-13·8). 52 (44%; 95% CI 35-53) of 119 efficacy-evaluable patients with relapsed or refractory peripheral T-cell lymphoma had an objective response. The most common grade 3-4 adverse events were thrombocytopenia (31 [23%] of 133 patients in the peripheral T-cell lymphoma group and 11 [50%] of 22 patients in the adult T-cell leukaemia/lymphoma group), anaemia (25 [19%] and ten [46%]), and neutropenia (23 [17%] and four [18%]). Serious treatment-emergent adverse events were reported in 53 (40%) patients with peripheral T-cell lymphoma and 15 (68%) patients with adult T-cell leukaemia/lymphoma; nine (7%) patients and one (5%) patient had a serious treatment-emergent adverse event considered to be treatment related, respectively. No treatment-related deaths were reported. These data show that treatment with valemetostat leads to durable responses in patients with relapsed or refractory peripheral T-cell lymphoma, with a manageable safety profile. Daiichi Sankyo.

451 (PB439): First results of a Phase 1 study evaluating safety, PK, PD and clinical activity of STC-15, aMETTL3 inhibitor, in patients with advanced malignancies

451 (PB439): First results of a Phase 1 study evaluating safety, PK, PD and clinical activity of STC-15, aMETTL3 inhibitor, in patients with advanced malignancies

Role of melatonin in rheumatoid arthritis: a narrative review

Melatonin, also known as methoxytryptamine-5-acetyl-N, is the main hormone secreted by the pineal gland. It shows that exogenous melatonin as a supplement can help improve sleep quality and act as an anti-inflammatory factor. Melatonin, in multiple ways, controls the immune system, including regulating inflammatory pathways, apoptosis signaling pathways, and regulating the circadian clock. CD4+ T helper (Th1), Th17, and regulatory T cells, which are the important cells in the immune system, are affected by melatonin. Studies did not demonstrate serious complications following the consumption of melatonin. Rheumatoid Arthritis (RA) is an autoimmune disease that causes a chronic inflammatory situation. RA is a systematic disease that affects multi-organ. The characteristic feature of RA is targeting symmetrically small joints. RA has an unknown etiology, and numerous immune cells, cytokines, interleukins, and inflammatory factors participate in the etiology of RA. In addition, oxidative stress and the relation of oxidative stress with clinical presentation and RA disease activity. Due to the following information, melatonin might be a possible supplementary treatment for RA. Some studies demonstrated that melatonin supplements have advantages in some autoimmune and inflammatory diseases. Studies suggest pro-inflammatory factors reduction and increase in anti-inflammatory agents with melatonin supplementation, while other studies have reported no considerable effects, and the results are controversial. Some clinical studies evaluate the impact of melatonin on RA disease clinical signs and symptoms, but they did not report any clinical improvements. Considering the lack of a definite conclusion due to the limited available evidence, future studies are suggested.

Ziftomenib in relapsed or refractory acute myeloid leukaemia (KOMET-001): a multicentre, open-label, multi-cohort, phase 1 trial

Ziftomenib (KO-539) is an oral selective menin inhibitor with known preclinical activity in menin-dependent acute myeloid leukaemia models. The primary objective of this study was to determine the recommended phase 2 dose in patients with relapsed or refractory acute myeloid leukaemia based on safety, pharmacokinetics, pharmacodynamics, and preliminary activity. KOMET-001 is a multicentre, open-label, multi-cohort, phase 1/2 clinical trial of ziftomenib in adults with relapsed or refractory acute myeloid leukaemia. Results of the phase 1 study, conducted at 22 hospitals in France, Italy, Spain, and the USA, are presented here and comprise the dose-escalation (phase 1a) and dose-validation and expansion (phase 1b) phases. Eligible patients were aged 18 years or older, had relapsed or refractory acute myeloid leukaemia, and had an Eastern Cooperative Oncology Group performance status of 2 or less. For phase 1a, patients (all molecular subtypes) received ziftomenib (50-1000 mg) orally once daily in 28-day cycles. For phase 1b, patients with NPM1 mutations or with KMT2A rearrangements were randomly assigned (1:1) using third-party interactive response technology to two parallel dose cohorts (200 mg and 600 mg ziftomenib). Primary endpoints were maximum tolerated dose or recommended phase 2 dose in phase 1a, and safety, remission rates, and pharmacokinetics supporting recommended phase 2 dose determination in phase 1b. Analyses were performed in all patients who received at least one dose of ziftomenib (modified intention-to-treat population). Phase 1a/1b is complete. This trial is registered with ClinicalTrials.gov, NCT04067336, and the EU Clinical Trials register, EudraCT 2019-001545-41. From Sept 12, 2019, to Aug 19, 2022, 83 patients received 50-1000 mg ziftomenib (39 [47%] were male and 44 [53%] were female). Median follow-up was 22·3 months (IQR 15·4-30·2). Of 83 patients, the most common grade 3 or worse treatment-emergent adverse events were anaemia (20 [24%]), febrile neutropenia (18 [22%]), pneumonia (16 [19%]), differentiation syndrome (12 [15%]), thrombocytopenia (11 [13%]), and sepsis (ten [12%]). Overall, 68 of 83 patients had serious adverse events, with two reported treatment-related deaths (one differentiation syndrome and one cardiac arrest). Differentiation syndrome rate and severity influenced the decision to halt enrolment of patients with KMT2A rearrangements. In Phase 1b, no responses were reported in patients treated at the 200 mg dose level. At the recommended phase 2 dose of 600 mg, nine (25%) of 36 patients with KMT2A rearrangement or NPM1 mutation had complete remission or complete remission with partial haematologic recovery. Seven (35%) of 20 patients with NPM1 mutation treated at the recommended phase 2 dose had a complete remission. Ziftomenib showed promising clinical activity with manageable toxicity in heavily pretreated patients with relapsed or refractory acute myeloid leukaemia. Phase 2 assessment of ziftomenib combination therapy in the upfront and relapsed or refractory setting is ongoing. Kura Oncology.

Southwest Oncology Group S0826: A phase 2 trial of SCH 727965 (NSC 727135, dinaciclib) in patients with stage IV melanoma.

Cell cycle inhibition is an established therapeutic approach for some cancers. A multicenter, single-arm, phase 2 trial (ClinicalTrials.gov identifier NCT00937937) of the cyclin-dependent kinase inhibitor SCH 727965 (NSC 747135; dinaciclib) was conducted in patients with metastatic melanoma to determine its clinical activity. Patients with metastatic melanoma of cutaneous or mucosal origin were eligible if they had zero to one previous treatments, a Zubrod performance status of 0-1, and adequate organ function. SCH 727965 50 mg/m2 was given intravenously every 3 weeks until progression. Co-primary end points were 1-year overall survival (OS) and 6-month progression-free survival (PFS). Seventy-two patients were enrolled from July 1, 2009, to November 1, 2010, at 24 institutions. Sixty-eight percent of patients had M1c disease, and 43% had elevated lactate dehydrogenase levels. Twenty-eight patients (39%) experienced grade 4 adverse events, including 20 cases of neutropenia. Sixty-seven patients were evaluable for response. There was a response in zero of 67 patients (95% confidence interval [CI], 0%-5%), and stable disease was observed in 21%. The estimated median PFS was 1.4 months (95% CI, 1.4-1.5 months), and the 6-month PFS rate was 6% (2%-13%). The median OS was 8.2 months (95% CI, 5.5-10.5 months), and the 1-year OS rate was 38% (95% CI, 26%-49%). This multicenter, US National Cancer Institute Cancer Therapy Evaluation Program-sponsored trial of SCH 727965 was conducted at a time when the current generation of effective therapies for melanoma were not available. Although the null hypothesis of 1-year OS was rejected, the minimal PFS impact and substantive toxicity indicated that this regimen lacks justification for further investigation as a single agent.

Establishing a Specialist Physiotherapy service with a Regional Specialist Memory Clinic

Abstract Background Patients with complex motor-cognitive syndromes (E.g. Dementia with Lewy Bodies, Corticobasal syndrome, Progressive Supranuclear Palsy and Huntington’s disease) present with a wide variety of symptoms. Accordingly, these patients have traditionally been managed under different services from Neurology-led movement disorder clinics to age-related services, without dedicated access to specialist physiotherapy input. Recognising this, the Model of Care for Dementia in Ireland recommended that all regional specialist memory services (RSMC) should have a dedicated Clinical Specialist Physiotherapist. The aim of this study was to provide an overview of clinic activity in the first six months of operation. Methods Physiotherapy referrals were collected from September 2023 to March 2024. Referral details were captured using Microsoft Excel and included patient demographics, reason for referral, diagnosis and previous physiotherapy input. Following triage of referrals, patients were placed in one of the following three care pathways: Results 63 referrals were generated. Of these, 15 patients were referred for pre-diagnostic assessment, 46 were referred for rehabilitation, and 2 were referred for secondary prevention. Of those referred for rehabilitation; 18 patients had a diagnosis of DLB, 27 had another form of atypical Parkinsonism, 1 patient had HD. 22 patients had previous physiotherapy input. Conclusion This is the first specialist physiotherapy service in Ireland within a RSMC. This presents a challenge as there is no specific physiotherapy care pathway established for this service elsewhere, but also opportunity for service development and innovation. This overview will help with strategic and service planning and enables KPIs to be established to ensure patients receive a quality service.

Alterations of the Gut Microbiome and TMAO Levels in Patients with Ulcerative Colitis.

Background: Ulcerative colitis (UC) is an idiopathic and heterogeneous large intestine disease, characterized by chronic mucosa and submucosa inflammation. Alteration of the intestinal microbiome in UC may be responsible for modifications in metabolite production. Aim: To investigate the microbiota status and trimethylamine-N-oxide (TMAO) metabolite levels in patients with UC according to clinical and endoscopic activity. Methods: As part of a grant project AP14871959 from September 2022 to October 2023, 31 patients with UC and 15 healthy volunteers over 18 years at the Clinic of NCJSC "KMU" were assessed for blood TMAO level and metagenomic sequencing of fecal microbiome. Results: A significant depletion of the main representatives of Bacteroides, Parabacteroides, Prevotella; and an increase in the relative abundance of the genera Actinomyces, Klebsiella, Limosilactobacillus, Streptococcus, Escherichia-Shigella were detected in patients with UC. The number of p_Actinobacteria (g_Collinsella) and p_Eubacterium (g_Xylanophilum) representatives with genes encoding TMA-trimethylamine conversion is significantly reduced in UC patients. TMAO levels were significantly lower in UC patients than in healthy individuals (0.233 µmol/L, p = 0.004). TMAO decreased with disease severity and significantly differed between patients with different activities (p = 0.034). Conclusions: The composition of the intestinal microbiome changes and the level of TMAO decreases in patients with UC at different activities.

The recurrence of disease activity after ocrelizumab discontinuation in multiple sclerosis

IntroductionOcrelizumab (OCR) is a highly effective treatment of multiple sclerosis (MS), and B cell repopulation profiles suggest that it might be used as an immune reconstitution therapy. However, data on disease recurrence after stopping treatment with OCR are scarce. Our objective was to evaluate the recurrence of disease activity after OCR discontinuation. MethodsIn this multicenter retrospective cohort study, we included MS patients who discontinued OCR, without switching to another treatment, for twelve months or more, after having received at least one full dosage of 600 mg. We defined focal inflammation as the occurrence of a clinical relapse or significant MRI activity (≥3 new T2 lesions or ≥2 contrast-enhancing lesions). ResultsWe included 53 MS patients; 41 relapsing remitting (RRMS), 5 secondary progressive (SPMS) and 7 primary progressive (PPMS) patients. Median follow-up period after OCR discontinuation was 16 months. We only observed focal inflammation after discontinuation in RRMS patients; 2.4 % (1/41) patients presented with significant MRI activity and matching clinical symptoms, and 7.3 % (3/41) patients presented with a suspected clinical relapse without radiological activity: a total of 9.8 % (4/41) at a median time of 17 months after the last infusion. DiscussionWe found focal inflammation after discontinuation of OCR in 4 (9.8 %) of the RRMS patients, of which 1 was radiologically confirmed. Our observations highlight that recurrence of focal inflammation seems low but discontinuation may not be appropriate for everyone. Further larger studies are important to determine the immune reconstitution therapy potential of OCR.

Neuropathic pain in spondyloarthritis: Decoding its prevalence, risk factors, and impact on disease activity

ObjectivesThis study aimed to evaluate the prevalence and characteristics of neuropathic pain in patients with various subtypes of spondyloarthritis (SpA), including axial SpA (axSpA), psoriatic arthritis (PsA), and undifferentiated peripheral SpA (p-SpA). Additionally, the study sought to identify potential risk factors associated with the presence or severity of neuropathic pain and to investigate its impact on clinical disease activity assessment. MethodsWe conducted a cross-sectional study at two tertiary rheumatology centers, enrolling patients diagnosed with SpA. Data on demographic and clinical characteristics, comorbidities, and current therapies were collected. Neuropathic pain was assessed using the PainDETECT Questionnaire (PD-Q) and the Neuropathic Pain Symptom Inventory (NPSI). Statistical analyses included descriptive statistics, t-tests, and Pearson's correlations to evaluate the relationships between neuropathic pain scores and clinical disease activity indices. ResultsThe study included 177 patients. Of these, 22.2% had a PD-Q score ≥19, showing a high likelihood of neuropathic pain, while 64.9% scored ≤12, suggesting the absence of significant neuropathic components. The mean PD-Q score was 11.5 ± 10.1. Subgroup analyses showed that females had significantly higher scores for paroxysmal and evoked pain (p < 0.05), and obese patients had significantly higher scores across all NPSI subscores (p < 0.05). Moderate positive correlations were found between neuropathic pain scores and clinical disease activity indices, such as DAPSA (r = 0.46, p < 0.0001) and ASDAS-CRP (r = 0.42, p < 0.01). ConclusionsNeuropathic pain is prevalent among patients with SpA and is significantly associated with disease activity assessments and management. This study highlights the importance of integrating neuropathic pain evaluation into the clinical assessment of SpA to tailor treatment approaches effectively and improve patient outcomes.

Nivolumab in patients with metastatic castration-resistant prostate cancer with and without DNA repair defects.

Despite the success of immune checkpoint inhibitors (ICIs) across various cancers, their efficacy in metastatic castration-resistant prostate cancer (mCRPC) is modest, except for a subset of patients who experience significant, yet unpredictable, benefits. DNA repair defects (DRD) are associated with higher neoantigen load, which may predict response. Our study explored the potential of DRD for enhanced responsiveness to the ICI nivolumab. We conducted a phase II, multi-center, single-arm trial evaluating nivolumab in post-docetaxel mCRPC patients. DRD was assessed using circulating tumor DNA (ctDNA). The primary endpoint was PSA50 response. Secondary endpoints included objective response rate (ORR), radiographic progression-free survival (rPFS), and overall survival (OS). Also, exploratory comprehensive genomic profiling was performed via whole-exome sequencing (WES) of tumor samples and matched normal tissue, alongside PD-L1 expression evaluation. Among the 38 enrolled patients, DRD was identifiable in 30.5% (11/36) through ctDNA and/or WES analysis. The overall PSA50 response rate was 10.5% (4/38). PSA50 response and ORR did not significantly differ between patients with and without DRD (18.2% vs. 8%; p = 0.57 and 50% vs. 17.6%, p= 0.27, respectively). Median PSA-PFS (1.9 vs. 2.8 months, p=0.52) and rPFS (3.4 vs. 5.5 months, p=0.7) were not statistically different between patients with and without DRD. Grade ≥ 3 adverse events were reported in 47.3% of participants. Nivolumab has clinical activity in a subset of mCRPC patients, however, DRD do not predicted response.These results highlight the necessity of identifying new biomarkers to more accurately determine mCRPC patients who might respond to ICIs.

Efficacy and safety of filgotinib in patients with moderately active rheumatoid arthritis and an inadequate response to methotrexate.

Clinical trials restricted to moderately active RA are limited. Filgotinib is approved for treating moderate to severe active RA. This post hoc analysis assessed efficacy and safety of filgotinib in moderately active RA. In FINCH 1, patients with active moderate to severe RA and inadequate response to methotrexate received filgotinib 200 mg or 100 mg (FIL200/FIL100) once daily, adalimumab 40 mg every 2 weeks, or placebo, all with methotrexate (n = 1,755). This subgroup analysis was conducted in patients with a moderate baseline Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP; >3.2 to ≤ 5.1; n = 425 [24.2%]). A higher proportion of patients achieved DAS28-CRP <2.6, Clinical Disease Activity Index (CDAI) remission (≤2.8), low disease activity (LDA) (DAS28-CRP ≤3.2 or CDAI ≤10), and American College of Rheumatology (ACR20/50/70) responses with FIL200 and FIL100 vs placebo at Weeks 12 and 24. Week 12 ACR20 response rates (primary end point) were 77.9%, 67.8%, and 43.8%, respectively. ∼75% of patients achieved DAS28-CRP LDA by week 24 with either filgotinib dose. FIL200 and FIL100 elicited greater improvements in patient-reported outcomes than placebo. The efficacy of filgotinib, maintained through week 52, was comparable to that of adalimumab. Frequency of adverse events (AEs) was similar with filgotinib and adalimumab. Infections were the most common AEs; incidence rates were 40-53% in active treatment groups. In this subpopulation with moderately active RA, the efficacy and safety of filgotinib were similar to those in the overall FINCH 1 population (patients with active moderate to severe RA). NCT02889796.

Teprotumumab for the Treatment of Thyroid Eye Disease: Why Should We Keep Our Eyes "Wide Open"?-A Clinical and Pharmacovigilance Point of View.

Objectives: Thyroid eye disease (TED) treatment has been recently revolutionized with the approval of teprotumumab, a targeted insulin growth factor 1 receptor (IGF1R) inhibitor. To date, teprotumumab is the only FDA-approved drug for treating TED. In this article, we would like to temper the current enthusiasm around IGF1R inhibitors. Methods: critical review of the literature by independent academic practitioners. Results: several questions should be raised. First, "how an orphan drug has become a blockbuster with annual sales exceeding $1 billion?" Teprotumumab infusions are expensive, costing about USD 45,000 for one infusion and USD 360,000 for eight infusions in a 75 kg patient. Teprotumumab approval was based on two randomized clinical trials investigating active (clinical activity score ≥ 4) TED patients. Despite this, teprotumumab was approved by the FDA for "the treatment of TED" without distinguishing between active and inactive forms. The second question is as follows: "how can a new drug, compared only to a placebo, become the new standard without being compared to historically established gold standard medical or surgical treatments?" Teprotumumab has never been compared to other medical treatments in active TED nor to surgery in chronic TED. Up to 75% of patients may experience proptosis regression after treatment discontinuation. Finally, ototoxicity has emerged as a potentially devastating side effect requiring frequent monitoring. Investigation into the long-term side effects, especially in women of childbearing age, is also warranted. Conclusions: Teprotumumab is undoubtedly a major treatment option in TED. However, before prescribing a drug, practitioners should assess its benefit/risk ratio based on the following: (i) evidence-based medicine; (ii) their empirical experience; (iii) the cost/benefit analysis; (iv) the long-term outcomes and safety profile.

Correlation between the Quantity and Type of Dietary Fiber with the Activity in Mexican Patients with Ulcerative Colitis (UC).

Background/Objective: Ingestion of dietary fiber can influence in the remission of patients with ulcerative colitis (UC). There are no current recommendations for fiber intake in UC; therefore, we evaluate the association between dietary fiber and the activity of the disease. Methods: Ours is a cross-sectional study in patients with a confirmed diagnosis of UC to whom a 24 h recall was applied; this allowed for the estimation and classification of type of dietary fiber. The patients were divided into two groups: (1) remission and (2) active UC. We analyzed the quantity and type of fiber with the grades of disease activity through Spearman correlation and logistic regression. Results: A total of 152 patients were included; it was found that those with clinically active UC consumed less total fiber (p = 0.016) and insoluble fiber (p = 0.018). Meanwhile, in endoscopic grade, the difference was for insoluble fiber (p = 0.038). Insoluble fiber had an inversely significant correlation with fecal calprotectin levels (r = -0.204; p = 0.018). Logistic regression showed that less than 11 g of insoluble fiber was a risk factor for clinical activity (OR = 2.37; 95% CI 1.107-5.019; p = 0.026). Conclusions: Consumption below the current recommendation of total and insoluble dietary fiber is associated with clinical activity of UC.

Abstract B175: Addressing the urgent demand for clinical research professionals through a novel training initiative

Abstract Training and retaining diverse, qualified clinical research professionals that reflect the demographics of the community is pivotal to design inclusive clinical protocols, recruit underrepresented populations, and increase generalizability of scientific advancements. The University of Chicago's Comprehensive Cancer Center (UCCCC) and the Professional Education (UCPE) office job market analysis found an urgent and growing—and chronically unmet—demand for clinical research professionals across the United States. Nearly 6,930 employers nationwide had active clinical trials job postings from May 2023-2024. Illinois is among the top ten states with unique clinical research job postings. Further, internal UChicago analysis revealed high turnover in entry-level clinical research positions, highlighting a competitive job market for qualified individuals. As 60% of all clinical research activities at UChicago are cancer-focused, the UCCCC pursued novel strategies to diversify, grow, and retain the clinical research workforce. The overarching goal is to optimize pathways from undergraduate programs to clinical research careers. City Colleges of Chicago (CCC) and the UCCCC’s Clinical Trials Support Office (CTSO), Office of Diversity, Equity, and Inclusion, and Office of Education are collaborating on a three-module Cancer Clinical Research Professionals (CCRP) Program to create new pathways into clinical research careers. The yearlong CCRP Program provides hands-on training and development opportunities to community college students interested in biomedicine via a 6-week summer internship, monthly academic year engagements, and a semester-long apprenticeship. The program expands CCC’s capacity to combine classroom learning with practical experience and professional opportunities, which are critical components of students’ education. It promotes career awareness, specialized skill development, and employment in cancer clinical research among CCC students, a diverse and highly motivated talent pool. The internship attracted 49 applicants in its first year. Out of 22 qualified applicants, 6 interns were selected and will begin their training in June 2024. Detailed findings from the internship evaluation will be available in September 2024. We expect the CCRP Program to be most students’ first experience with clinical research careers, greatly expanding their access to opportunities. Our evaluation will present lessons learned during the first year of the CCRP and plans to modify program components. Findings will also inform related training initiatives such as developing an Associate Degree in Clinical Research. We are confident that our forthcoming data will be of interest to other cancer centers and academic medical centers working to enhance their cancer clinical research workforce, which is essential for inclusive research and cancer health equity. Citation Format: Camilla Frost-Brewer, Aspen Ward, Lauren Wall, Megan Mekinda, Eileen Dolan, Jasmine Tiro, Matt Cohn. Addressing the urgent demand for clinical research professionals through a novel training initiative [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr B175.