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Background & Aims: Human allogeneic liver-derived progenitor cells (HALPC, HepaStem®; Promethera Biosciences, Mont-Saint-Guibert, Belgium) are an advanced therapy medicinal product that could potentially alleviate systemic inflammation and ameliorate liver function in patients with acute-on-chronic liver failure (ACLF) or acute decompensation of cirrhosis (AD). Methods: This open-label phase II study was conducted in 9 centres in Belgium, Spain, and Bulgaria between 2016 and 2019. The primary objective was to assess the safety of HALPC therapy up to Day 28 and the secondary objectives were to assess its safety and preliminary efficacy up to Month 3. Results: The 24 treated patients (mean age: 51 years) were mostly male with an alcoholic cirrhosis. On pre-infusion Day 1, 15 patients had ACLF and 9 patients had AD. Two of the 3 initial patients treated with high HALPC doses (∼5×106 cells/kg body weight [BW]) had severe adverse bleeding events attributed to treatment. In 21 patients subsequently treated with lower HALPC doses (0.6 or 1.2×106 cells/kg BW, 1 or 2 times 7 days apart), no serious adverse events were related to treatment, and the other adverse events were in line with those expected in patients with ACLF and AD. Overall, markers of systemic inflammation and altered liver function decreased gradually for the surviving patients. The Day-28 and Month-3 survival rates were 83% (20/24) and 71% (17/24), and at Month 3, no patient had ACLF. Conclusions: The treatment of patients with ACLF or AD with up to 2 doses of 1.2×106 HALPC/kg BW appeared safe. The results of this study support the initiation of a proof-of-concept study in a larger cohort of patients with ACLF to further confirm the safety and evaluate the efficacy of HALPC therapy. Clinical Trials Registration: EudraCT 2016-001177-32. Lay summary: Patients with liver cirrhosis may suffer from the rapid onset of organ failure or multiple organ failure associated with a high risk of death in the short term. This clinical study of 24 patients suggests that an advanced therapy based on the intravenous infusion of low doses of human allogeneic liver-derived progenitor cells is safe and supports the next phase of clinical development of this type of therapy., SCOPUS: ar.j, info:eu-repo/semantics/published

Background. In cells long non-coding RNAs (lncRNAs) control gene expression through various mechanisms, acting on different biological levels: chromatin remodeling, regulation of transcription, posttranscriptional modification. LncRNAs could also be transported via systemic circulation, encapsulated in extracellular vesicles called “exosomes” or in vesicle-free form, bounded to proteins or lipoproteins. Knowing the intracellular function of lncRNAs, it is reasonably speculated that in cancer patients their existence in bloodstream is more than just an extracellular release. It is thought to be a kind of an epigenetic mechanism, rendered by tumor cells, so the last could influence gene expression programs of normal cells in distance, creating tumor-friendly environment in other body compartments - a sine qua non for metastatic spread. Few studies have investigated in vivo circulating lncRNAs in breast cancer and even less have done it in the neoadjuvant setting. Goals and objectives. We decided to conduct a small exploratory study in patients with locally advanced breast cancer, focusing on changes in plasma lncRNAs during neoadjuvant therapy. The two main goals of the study are: 1. Assessing the effect of systemic anticancer treatment on epigenetic regulators such as circulating lncRNAs; 2. Testing the technical feasibility of using lncRNAs as plasma biomarkers. Our objectives include lncRNA profiling in circulation before onset as well as in the course of systemic therapy, followed by correlation analysis between distinct lncRNA signatures and clinicopathological features. Differential lncRNA expression will be assessed between patients and normal controls as well as among patient subgroups according to time of sampling, age, intrinsic breast cancer phenotype and response to therapy. LncRNAs of interest will be further examined in larger cohorts of patients and healthy controls. Design/materials/methods. This is a prospective, interventional, case-control clinical trial in two parts - exploration and validation. Patients eligibility criteria: age ≥ 18 years; females; histologically confirmed locally advanced breast cancer; multidisciplinary tumor board decision for neoadjuvant chemotherapy or chemotherapy plus targeted therapy; radiologically excluded distant dissemination; no concomitant malignancy; signed informed consent form (ICF). Healthy controls eligibility criteria: age ≥ 18 years; females; no oncologic history; signed ICF. For part I ten patients and two controls have already been recruited. Blood samples were taken from each patient twice - before onset of neoadjuvant therapy and before 4th cycle (in one patient the second sample was taken before 6th cycle), from control subjects blood was taken once. Plasma was immediately separated and frozen until RNA extraction. Next-generation RNA sequencing was performed with subsequent bioinformatics analysis on lncRNAs. Clinical and pathology information was obtained from each patient’s hospital file. In part II plasma will be collected in the same manner as in part I. Preselected lncRNAs from part I will be measured by real-time polymerase chain reaction. Statistics. This is an exploratory study with no empirical data and no formal planning for sample size. The correlation between lncRNAs and clinicopathological characteristics and the significance of the differences among groups will be assessed by parametric tests (Pearson correlation, Student’s t-test) and/or multivariate such (ANCOVA). Present and target accrual. Part I accrual has completed and bioinformatics data are expected. Part II accrual is ongoing with 15 patients already recruited. Target accrual for part II is 50 patients and 20 controls. Citation Format: Boris Krastev, Constanta Timcheva, Spartak Valev, Georgi Zhbantov, Mila Petrova, Teodora Karanikolova, Radostina Gencheva, Anika Ivanova, Ivaylo Stoykov, Georgi Stamenov. Investigating circulating lncRNAs in breast cancer patients on neoadjuvant systemic therapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-03-03.

To examine patient-reported outcomes (PROs) in patients with different rheumatoid arthritis (RA) disease activity levels and identify residual symptoms.Post hoc analyses of overall and Japanese data from two randomized controlled trials including RA patients with previous inadequate responses to methotrexate (NCT01710358) or no/minimal previous disease-modifying antirheumatic drug treatment (NCT01711359) (sponsor: Eli Lilly and Company). Week 24 assessments were disease activity (Simplified Disease Activity Index, Disease Activity Score/Disease Activity Score 28 joints-erythrocyte sedimentation rate) and PROs (pain visual analog scale [VAS], morning joint stiffness [MJS], Health Assessment Questionnaire-Disability Index, Functional Assessment of Chronic Illness Therapy-Fatigue, and Medical Outcomes Study Short Form 36 Health Survey Physical and Mental Component Scores).Patients achieving remission/low disease activity (LDA) at Week 24 had larger/significant improvements from baseline in pain, MJS, disability, fatigue, and physical and emotional quality of life versus patients with high/moderate disease activity. Some patients achieving remission and LDA, reported residual pain (pain VAS10 mm): 20.8-39.3% and 48.7-70.0% (overall study populations), 16.0-34.5% and 47.1-62.0% (Japanese patients). Residual MJS and fatigue were also reported.Remission/LDA were associated with improvements in PROs in overall and Japanese patient populations; however, some patients achieving remission had residual symptoms, including pain.

Objective To evaluate the long-term efficacy and safety of maintaining baricitinib monotherapy in patients with active rheumatoid arthritis (RA) originally treated with baricitinib monotherapy or switched from methotrexate (MTX) or the combination of baricitinib plus MTX to baricitinib monotherapy. Methods This is a post hoc analysis of patients from the RA-BEGIN study who entered a long-term extension, RA-BEYOND, and were assessed for up to 24 weeks. In RA-BEGIN, MTX-naive patients with early active RA were randomized to MTX monotherapy, baricitinib 4 mg monotherapy, or baricitinib 4 mg plus MTX. At week 52, all patients entering RA-BEYOND received baricitinib 4 mg monotherapy. MTX could be prescribed during RA-BEYOND at the investigator's discretion. Results Patients in RA-BEYOND who were not rescued in RA-BEGIN (n = 423) were evaluated. Of these, 47% continued baricitinib monotherapy and 53% added MTX, with similar proportions from the 3 original arms. Patients with lower disease activity at the RA-BEYOND baseline generally continued to do well with baricitinib monotherapy as assessed by the Simplified Disease Activity Index, the Clinical Disease Activity Index, and the Health Assessment Questionnaire disability index scores. Patients prescribed MTX had higher disease activity at the RA-BEYOND baseline and had improved disease activity after the addition of MTX. Safety outcomes were similar across treatment groups. Conclusion Many patients responded well to continued baricitinib monotherapy or to switching to baricitinib monotherapy from MTX monotherapy or baricitinib plus MTX, showing sustained or improved disease control. The groups of patients who had less disease control on their original therapies showed sustained or improved disease control with the addition of MTX to baricitinib.

e12644 Background: Though long considered “nonfunctional”, recent evidence is growing that non-coding RNAs, including long non-coding RNAs (lncRNAs), have an active role in tumor biology, mainly as gene expression regulators. Breast cancer is heterogeneous in nature and locally advanced cases are distinct entity in terms of curability. Being borderline between early and metastatic disease, long-term outcome here strongly depends on the efficacy of systemic therapy. To the best of our knowledge, no study has yet investigated global changes of circulating lncRNAs in this patient population during preoperative (neoadjuvant) treatment. Methods: We conducted a small transcriptomic trial on 10 locally advanced breast cancer patients, assessing lncRNA and messenger RNA (mRNA) expression in plasma samples before (S1) and after (S2) initiation of neoadjuvant therapy. Next-generation sequencing was performed with differential gene expression analysis between S1 and S2 groups. We assessed co-expression between lncRNAs and mRNAs, identifying mRNAs whose transcription was potentially regulated by lncRNAs, i.e. “lncRNA target genes”. In order to elucidate biological roles of these target mRNAs, we performed gene ontology (GO) and pathway analysis (Kyoto Encyclopedia of Genes and Genomes, KEGG). Results: 394 lncRNAs and 1085 mRNAs demonstrated statistically significant difference in expression between pretreatment and posttreatment samples. Co-expression analysis revealed positive correlation between 25 lncRNAs and 25 mRNAs located in cis, while potential trans interactions exceeded 105. GO evaluation of lncRNA target genes was significant for 44 terms: 28 for biological process (BP), 9 for cellular component (CC) and 7 for molecular function (MF). The most annotated terms for BP, MF and CC were respectively biosynthetic process, DNA-binding transcription factor activity and nucleus. KEGG analysis showed that 105 of 201 analyzed pathways were statistically significant with most prominent being pathways in cancer and transcriptional misregulation in cancer. Conclusions: Despite limited in size, present study provides broad view on transcriptional landscape in blood circulation, interrogating in vivo dynamics of systemic gene expression during neoadjuvant breast cancer treatment. It demonstrates that substantial number of circulating lncRNAs could be up- or downregulated in the course of therapy and this has the potential to control protein-coding genes that are tightly implicated in cancer biology.

Background Baricitinib (bari) is a reversible oral Janus kinase (JAK) inhibitor with selectivity for JAK1/JAK2 in development for treatment of patients (pts) with active rheumatoid arthritis (RA). In the 52-week (wk) Phase 3 RA-BEGIN study of MTX-naive pts, there were 3 arms: bari 4 mg once daily (QD), methotrexate (MTX) up to 20 mg weekly (QW), and the combination of bari plus MTX (bari+MTX). Nonresponders were rescued from week 24 onwards by receiving bari+MTX, regardless of original treatment. Bari monotherapy showed superior efficacy compared to MTX monotherapy and similar clinical efficacy to bari+MTX. Objectives Efficacy and safety were evaluated in pts from RA-BEGIN who switched from MTX or bari+MTX therapy to bari monotherapy upon entering the long-term extension (LTE) study (RA-BEYOND). Methods In RA-BEGIN, 588 pts were randomised 4:3:4 to MTX, bari monotherapy 4 mg, or bari+MTX. At Wk 52, pts could enter the LTE; all pts received bari 4 mg monotherapy. MTX could be added in the LTE by investigator decision. Seventy-seven percent of pts (451/588) enrolled in the LTE, of whom 423 had not been rescued in RA-BEGIN. This post hoc analysis evaluated clinical efficacy of pts who continued bari monotherapy compared to those in whom MTX was added within the first 24 wks of the LTE. Results Of these 423 pts, 200 (47%) remained on monotherapy at Wk 24 of the LTE and 223 pts started on MTX before wk 24. Most (193) had initiated MTX within 4 wks of starting the LTE study, evenly balanced from the 3 original arms of RA-BEGIN. Across study arms, pts who had MTX added in the LTE had worse disease control upon entry and during the LTE. Through 24 wks, statistically significant improvement in disease state was observed in the MTX-to-bari group regardless of whether or not MTX was added back. In the bari-to-bari monotherapy group, the addition of MTX led to lowered disease activity, which was statistically significant. No statistically significant changes in disease activity were observed in the pts who were switched from bari+MTX to bari monotherapy regardless of additional MTX therapy (Table 1). Exposure-adjusted incidence rates for total treatment-emergent adverse events, including non-serious infections, were lowest in the MTX-to-bari group. Clinically significant or consistent differences in SIE, SAEs, or AEs leading to study drug discontinuation were not seen in any of the arms, whether MTX was added or not. Conclusions Switching from MTX to bari monotherapy, maintaining bari monotherapy was associated with improvements in depths of disease control during the initial 24 wks post-switch. Disease control did not significantly change after withdrawal of MTX from combination therapy. Pts who entered the LTE with suboptimal disease control after treatment with bari monotherapy may benefit from the addition of MTX. Discontinuation of MTX in pts treated with combination during the index study was associated with maintenance of response. There were no differences in important measures of safety including events that are serious or led to discontinuation. Disclosure of Interest R. Fleischmann Grant/research support from: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Genetech, GlaxoSmithKline, Janssen, Eli Lilly and Company, Merck, Pfizer, Regeneron, Roche, Sanofi Aventis, UCB, Consultant for: AbbVie, Akros, Amgen, Bristol-Myers Squibb, Celgene, Genentech, GSK, Janssen, Eli Lilly and Company, Pfizer, Sanofi-Aventis, UCB, T. Takeuchi Consultant for: Pfizer Japan, Astra Zeneca KK, Eli Lilly Japan KK, Novartis Pharma KK, Daiichi Sankyo Co Ltd, Nipponkayaku Ltd, Janssen Pharma KK, Merck Serono Ltd, Takeda Pharma Ltd, Mitsubishi Tanabe Pharma, Astellas Pharm, Abbvie GK, Bristol-Myers KK, Asahi Kasei Medical KK, Speakers bureau: Celtrion, Nipponkayaku Ltd, Pfizer Japan, UCB Japan, Daiichi Sankyo Ltd, Takeda Pharma Ltd, Chugai Pharma Ltd, Abbvie GK, Bristol-Myers KK, Eisai Ltd, Mitsubishi Tanabe Pharma, Janssen Pharma KK, Astellas Pharma, M. Schiff Consultant for: Abbvie, Amgen, Antares, BMS, Eli Lilly and Company, J&J, Novartis, Novo Niordisk, Pfizer, Roche, UCB, Speakers bureau: Abbvie, BMS, D. Schlichting Employee of: Eli Lilly and Company, L. Xie Employee of: Eli Lilly and Company, M. Issa Employee of: Eli Lilly and Company, I. Stoykov Employee of: Eli Lilly and Company, J. Lisse Employee of: Eli Lilly and Company, P. Martinez-Osuna Employee of: Eli Lilly and Company, T. Rooney Employee of: Eli Lilly and Company, C. Zerbini Grant/research support from: Pfizer, Novartis, Eli Lilly and Company, Merck, Sanofi, Amgen, Celtrion, Consultant for: Merck, Pfizer, Sanofi, Eli Lilly and Company

Background Rheumatoid arthritis (RA) is a chronic disease associated with inflammatory activity and joint damage that result in disability, pain, and other impairments. The current recommendation is to assess disease activity based on composite indices with objective signs of inflammation (e.g. synovitis, acute phase reactants) and patient9s assessment of disease activity. The patient9s perception of disease impact and its treatment also facilitate shared decision-making about treatment. Objectives To compare patient-reported outcomes (PROs) for RA patients who achieved low disease activity (LDA) or remission based upon the DAS28-ESR compared to those with moderate and high disease activity (MDA and HDA) in this post-hoc analysis of a randomized, double-blind phase 3 clinical trial, RA-BEAM 1 . Methods 1305 patients were randomized to placebo (N=488), adalimumab (N=330) or baricitinib 4 mg (N=487). Patients with observed DAS28-ESR values at Week 24 (N=1,010) were divided into 4 disease activity groups: HDA (DAS28-ESR>5.1), MDA (3.2 Results Patients with HDA and MDA at Week 24 had greater baseline pain and HAQ-DI scores and lower PCS and MCS scores than patients achieving LDA or remission at Week 24. Lower disease activity at Week 24 was associated with improvement in pain, HAQ-DI, SF-36 PCS and MCS at Week 24. Among patients who achieved remission, residual pain was observed, with close to 40% still experiencing some level of pain and 20% of patients in remission at Week 24 had a residual pain score>20. Sensitivity analyses using other clinical measures (DAS28-CRP, SDAI, CDAI) to define disease activity confirmed the findings. Conclusions Improving patient disease activity is associated with improved health-related quality of life. Patients who achieved remission had greater improvement in PROs but residual pain remained. Further research is needed to understand the treatment differences in the association between disease activity and PROs among different therapies. References Taylor PC, Keystone E, van der Heijde D, et al. Baricitinib Versus Placebo or Adalimumab in Patients with Active Rheumatoid Arthritis (RA) and an Inadequate Response to Background Methotrexate Therapy: Results of a Phase 3 Study. Arthritis Rheum 2015;67(Suppl 10):3928. Disclosure of Interest M. Dougados Grant/research support from: Abbvie, Pfizer, Eli Lilly and Company, Novartis, UCB, Merck, Roche, BMS, Consultant for: Abbvie, Pfizer, Eli Lilly and Company, Novartis, UCB, Merck, Roche, BMS, B. Zhu Employee of: Eli Lilly and Company, A. Tang Employee of: Eli Lilly and Company, A. Quebe Employee of: Eli Lilly and Company, I. Stoykov Employee of: Eli Lilly and Company, Z. Cai Employee of: Eli Lilly and Company, M. Ishida Employee of: Eli Lilly and Company, C. Gaich Employee of: Eli Lilly and Company

Background: Baricitinib, an oral JAK1/JAK2 inhibitor, improves disease activity with an acceptable safety profile in patients with active rheumatoid arthritis (RA). We report efficacy and safety data for baricitinib as monotherapy or in combination with methotrexate (MTX), compared with MTX, in[for full text, please go to the a.m. URL]

Objectives To assess baricitinib on patient-reported outcomes (PROs) in patients with moderately to severely active rheumatoid arthritis, who had insufficient response or intolerance to >= 1 tumour necrosis factor inhibitors (TNFis) or other biological disease-modifying antirheumatic drugs (bDMARDs).Methods In this double-blind phase III study, patients were randomised to once-daily placebo or baricitinib 2 or 4 mg for 24 weeks. PROs included the Short Form36, EuroQol 5-D, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient's Global Assessment of Disease Activity (PtGA), patient's assessment of pain, duration of morning joint stiffness (MJS) and Work Productivity and Activity Impairment Questionnaire-Rheumatoid Arthritis. Treatment comparisons were performed with logistic regression for categorical measures or analysis of covariance for continuous variables.Results 527 patients were randomised (placebo, 176; baricitinib 2 mg, 174; baricitinib 4 mg, 177). Both baricitinib-treated groups showed statistically significant improvements versus placebo in most PROs. Improvements were generally more rapid and of greater magnitude for patients receiving baricitinib 4 mg than 2 mg and were maintained to week 24. At week 24, more baricitinib-treated patients versus placebo-treated patients reported normal physical functioning (HAQ-DI = 1 tumour necrosis factor inhibitors (TNFis) or other biological disease-modifying antirheumatic drugs (bDMARDs).Methods In this double-blind phase III study, patients were randomised to once-daily placebo or baricitinib 2 or 4 mg for 24 weeks. PROs included the Short Form36, EuroQol 5-D, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient's Global Assessment of Disease Activity (PtGA), patient's assessment of pain, duration of morning joint stiffness (MJS) and Work Productivity and Activity Impairment Questionnaire-Rheumatoid Arthritis. Treatment comparisons were performed with logistic regression for categorical measures or analysis of covariance for continuous variables.Results 527 patients were randomised (placebo, 176; baricitinib 2 mg, 174; baricitinib 4 mg, 177). Both baricitinib-treated groups showed statistically significant improvements versus placebo in most PROs. Improvements were generally more rapid and of greater magnitude for patients receiving baricitinib 4 mg than 2 mg and were maintained to week 24. At week 24, more baricitinib-treated patients versus placebo-treated patients reported normal physical functioning (HAQ-DI = 3.56; p

Background: To describe changes in health-related quality of life (HRQoL) of postmenopausal women with osteoporosis treated with teriparatide for up to 18 months and followed-up for a further 18 months, and to assess the influence of recent prior and incident fractures. Methods: The European Forsteo Observational Study (EFOS) is an observational, prospective, multinational study measuring HRQoL using the EQ-5D. The primary objective was to assess changes in HRQoL during 36 months in the whole study population. A secondary post-hoc analysis examined fracture impact on HRQoL in four subgroups classified based on recent prior fracture 12 months before baseline and incident clinical fractures during the study. Changes from baseline were analysed using a repeated measures model. Results: Of the 1581 patients, 48.4% had a recent prior fracture and 15.6% of these patients had an incident fracture during follow-up. 10.9% of the 816 patients with no recent prior fracture had an incident fracture. Baseline mean EQ-VAS scores were similar across the subgroups. In the total study cohort (n = 1581), HRQoL (EQ-VAS and EQ-5D index scores) improved significantly from baseline to 18 months and this improvement was maintained over the 18-month post-teriparatide period. Improvements were seen across all five EQ-5D domains during teriparatide treatment that were maintained after teriparatide was discontinued. Subjects with incident clinical fractures had significantly less improvement in EQ-VAS than those without incident fractures. Recent prior fracture did not influence the change in EQ-VAS during treatment. Conclusions: EFOS is the first longitudinal study in women with severe postmenopausal osteoporosis in the real world setting to show a substantial improvement in HRQoL during teriparatide treatment that was sustained during subsequent treatment with other medications. The increase in HRQoL was lower in the subgroups with incident fracture but was not influenced by recent prior fracture. The results should be interpreted in the context of the design of an observational study.