Longer Treatment Research Articles

Clinical moderators and predictors of cognitive-behavioral therapy by guided-self-help versus therapist-led for binge-eating disorder: Analysis of aggregated clinical trials.

Cognitive-behavioral therapy (CBT)-therapist-led (CBTth) and guided-self-help (CBTgsh)-has efficacy for binge-eating disorder (BED) but many patients do not benefit sufficiently. We examined predictors and moderators for these two CBT methods. Data were aggregated from randomized controlled trials (RCTs) testing psychosocial treatments for BED in the U.S. Predictors and moderators of outcomes (treatment completion and binge-eating remission) were examined in N=457 participants who received either CBTgsh (N=164) or CBTth (N=293). Analyses, adjusting for demographic/clinical variables, indicated CBTth was significantly superior to CBTgsh for treatment completion (odds ratio [OR]=20.0) and remission (OR=14.6). For remission, analyses revealed significant predictors (age, treatment length, Weight Concern), a moderator (weight concern [OR=5.13]), and a significant interaction between CBT-type and treatment length (OR=2.66). For CBTgsh, longer treatment was associated with less remission, whereas for CBTth, longer treatment was associated with greater remission. For CBTgsh, 44.1% with low weight concern versus 56.3% with high weight concern achieved remission whereas for CBTth, 43.5% with high weight concern and 61.0% with low weight concern achieved remission. Analyses of aggregated RCT BED data, adjusting for demographic/clinical characteristics, indicated superiority (large effect-sizes) in treatment outcomes of CBTth over CBTgsh and that Weight Concern moderated outcomes.

P–403 Sodium tungstate increases embryo adhesion through a direct effect on endometrial cells

Abstract Study question Does sodium tungstate treatment induce a change in endometrial cells’ capacity to implant trophoblasts? Summary answer Administration of sodium tungstate to endometrial cells increases trophoblast adhesion. What is known already Sodium tungstate (ST) has shown its capacity to modulate the activity of cytokines, such as leptin, an activator of an obligatory signalling cascade in the embryo-implantation process. STAT3, a signal transducer molecule critical for the embryo implantation process, is also known to be activated by ST. Still, ST’s effect on implantation using biological systems has never been studied. Embryo implantation process and endometrium roles are complicated to study in vivo due to a lack of animal models and appropriate techniques. In vitro techniques using immortalised cell lines allows a first approach to study early implantation stages, such as embryo adhesion. Study design, size, duration An in vitro study was carried out using a human endometrial carcinoma cell line (HEC–1-A) treated with sodium tungstate for 24 and 48h, and choriocarcinoma cell spheroids (JAr). Different times of treatment and concentrations were studied. Each experiment was performed in triplicate. Participants/materials, setting, methods Confluent endometrial HEC–1-A cultures were treated with ST at concentrations (0–150mM) and withaferin A (1mM), negative control for embryo adhesion. After the treatment period, HEC–1-A cultures were washed with ST-free culture medium to eliminate ST. Immediately, 15 JAr trophoblast spheroids were added to cultures and coincubated with gentle agitation for 30, 60 and 90 minutes. An inverted light microscope was used to count adhered and floating spheroids, and determine the trophoblast adherence ratio. Main results and the role of chance HEC–1-A cells treated with ST showed normal morphology and growth at all doses except 150mM. At the highest dose tested, the cells’ culture was still viable (negative blue trypan staining) and maintained morphology, but the adhesion to the plate surface was affected. Doses from 0.15 to 15mM were used to perform adhesion assays. HEC–1-A cells treated with ST for 24h showed an increased capacity to adhere JAr trophoblast spheroids. Adhesion rates reached significant differences at doses of 1.5 and 15mM after 60 and 90 minutes of coincubation. After 90 minutes, untreated cells reached 32.8% adhesion rate, while 1.5 and 15mM ST-treated cells reached 54.6% and 53.4% respectively (p < 0.05 ST vs untreated). Thus, the increment of trophoblast adhesion rate induced by ST reached 66%. Lower adhesion rates were observed after 60 minutes of coincubation but were also significant with a relative increase of 49.1% at 1.5mM and 50.5% at 1.5mM when compared with untreated cells (p < 0.05) Longer treatments (48h) showed similar trends to 24h-treatments, but with a lower extent of ST effect on HEC–1-A receptivity. Maximum adhesion rates were also observed at 90 minutes of coincubation and 1.5 and 15mM doses. The Mean adhesion rate increase was >40% with both doses. Limitations, reasons for caution: The current study is the first approach to evaluate sodium tungstate effect on endometrium using an in vitro model. Future research using in vivo models should be performed to assess sodium tungstate effect on endometrium receptivity and its potential as a fertility treatment. Wider implications of the findings: We conclude that the direct effect of sodium tungstate on endometrial cells increases embryo adhesion rate. These results open a new research line to a potential treatment in human reproduction management with sodium tungstate to solve the unmet need of inducing embryo implantation. Trial registration number Not applicable

Effect of Two Essential Oils From the Asteraceaes Family Against Ectomyelois Ceratoniae Zell. (Lepidoptera, Pyralidae): Case Of Artemisia Herba-Alba Asso. And Artemisia Compestris L.

The current work was done Artemisia herba-alba and Artemisia compestris essential oils harvested from the Eastern Algerian Sahara, their insecticidal characteristics against the eggs and adults of the date moth Ectomyelois ceratoniae. Indeed, two treatment modes were used; by contact application on eggs and by inhalation against adults. It appears from the results that the hatch rates were less than the hatching rate recorded in the control (96% ±00.00). The hatching rate reported on eggs treated by the highest dose (160 μl/ml) of Artemisia herba-alba and Artemisia compestris essential oils are 16.66 ± 08.81 and 37.77 ± 13.47 respectively. Statistical treatment results by the Chi-square test (χ2), attest that the treatment by A. herba-alba and Artemisia compestris essential oils at the same dose (160 μl/ml) affect significantly (χ2 = 35.62, p = 0.00 and χ2 = 21.17, p = 0.00 respectively) the hatching rate compared to the control. The sensitivity of adults to essential oils is expressed by 100% mortality rates obtained after 10 min of treatment by the highest doses (80 μl/ml and 160 μl/ml) of A. herba-alba essential oils, the same mortality rates (100%) were notified with the same doses (80 μl/ml and 160 μl/ml) after 20 min and 15 min of treatment by Artemisia compestris essential oils respectively. The dose-dependent mortality data revealed that there was a significant difference between the five doses of A. herba-alba essential oil tested except at the last treatment time (20 min) for which it was appeared p = 0.571, while for A. compestris essential oil, a significant difference was recorded with p varying between 0.00 and 0.003. The lowest LD50 value (0.09 μl/ml and 16.71 μl/ml) were noted during the longest treatment time (20 min), while the highest LD50 value (75.85 μl/ml and 263.7 μl/ml) were found during the shortest time (5 min) of A. herba-alba and A. compestris respectively. J. Bio-Sci. 29(2): 09-17, 2021 (December)

Delayed adjuvant imatinib in patients with high risk of recurrence of gastrointestinal stromal tumor after radical surgery: a retrospective cohort study.

To investigate the impact of delayed adjuvant imatinib on GIST patients with high risk of recurrence. Adult GIST patients were retrospectively collected from our hospital between 2011 and 2018, and patients having high risk of recurrence were included for subsequent analyses. The primary endpoint was recurrence-free survival (RFS). According to the interval between the radical surgery and the beginning of adjuvant imatinib, 222 patients were divided into three groups: group A (≤ 2months, n = 41), group B (2-≤ 4months, n = 113), and group C (4-≤ 6months, n = 68). Univariate, multivariate, and survival analyses all showed that patients in group A had significantly more favorable RFS than those in group C but not group B, and patients taking adjuvant imatinib for over 12months were also associated with longer RFS comparing to adjuvant imatinib of ≤ 12months. When stratified by the duration of adjuvant imatinib, no significant differences were found in RFS among groups A, B, and C for adjuvant imatinib of ≤ 12months. While for adjuvant imatinib of over 12months, both groups A and B had significantly more favorable RFS than group C, and no significant difference in RFS was found between group A and B. Delayed postoperative adjuvant imatinib for over 4months in patients with high risk of recurrence of GIST may lead to worse RFS, and longer treatment with shorter delay has best results.

Efficacy and predictive factors of cyclosporine A in alopecia areata: a systematic review with meta-analysis

Introduction Drugs for alopecia areata (AA) can induce hair regrowth, but do not change the disease course. Dual properties of cyclosporine A (CsA) as hypetrichotic and immunosuppressive agent have encouraged use in AA. We aimed to determine the most meaningful efficacy of CsA and reveal features helping enhance its efficacy and reduce relapses. Method Efficacy of CsA and predictive factors were investigated. Cochrane, MEDLINE, Pubmed and Embase databases were searched. Results 2,189 papers were retrieved. Based on 344 patients, mean proportion of responders was 73%. CsA monotherapy showed proportion of hair regrowth of 66%, whereas CsA combined with systemic corticosteroids yielded 78%. Overall efficacy in studies with duration of CsA treatment <6 months was: 74% (53–88%), while in those with duration ≥6 months was: 73% (47–89%). Recurrence with CsA monotherapy was 55% (6–96%) whereas when CsA was combined with systemic corticosteroids it was 28% (6–72%). Conclusion CsA confers a favorable therapeutic effect and concomitant use of steroids slightly enhances efficacy, but it dramatically decreases relapses. Longer treatments seem to lead to less relapse likelihood, but daily dose does not influence recurrence. Optimal CsA dosage is 5 mg/kg/day in single therapy regimen, whereas it is 3 mg/kg/day in the steroid-associated regimen. KEY POINTS What is already known about this subject? Most treatments for alopecia areata have not been critically evaluated. Current outcomes about the efficacy and relapse rate of cyclosporine A (CsA) are inconsistent and predictive factors about the clinical response are lacking. What this study adds? CsA confers a favorable therapeutic hair regrowth. Longer treatment seems to lead to less likelihood of relapse of AA, but the daily dose does not exert any effect on the recurrence of the disease. The concomitant use of corticosteroids broadly decreases relapses, and it also enhances efficacy. Impact on clinical practice The combination with corticosteroids is the most predictive feature to prevent relapse of AA, followed by the duration of CsA therapy. The daily dose of CsA is the feature with the least or null impact on the clinical course of AA.

Obinutuzumab Plus Chemotherapy Compared with Rituximab Plus Chemotherapy in Previously Untreated Italian Patients with Advanced Follicular Lymphoma at Intermediate-High Risk: A Cost-Effectiveness Analysis.

ObjectiveTo assess the cost-effectiveness of obinutuzumab (O-chemo) in comparison to rituximab (R-chemo) in patients with untreated advanced follicular lymphoma (FL) at intermediate or high risk from an Italian National Health Service (NHS) perspective.MethodsA previously developed four-state Markov model was adapted to estimate lifetime clinical outcomes and costs of Italian patients with advanced FL and an FL international predictive index score ≥2 in treatment with O-chemo and R-chemo. Life expectancy was derived from the GALLIUM and PRIMA clinical trials. Progression-free survival (PFS), early progressive disease (PD), and treatment duration were extrapolated by fitting parametric distributions to empirical data in GALLIUM and late PD to data in PRIMA. Expected survival was weighed by published utilities. Costs updated to 2020 Euros and health gains occurring after the first year were discounted at an annual 3% rate. Probabilistic sensitivity analysis (PSA) was carried out.ResultsO-chemo was associated with an incremental survival increase (0.97 life-years [LYs]), even when weighted for quality (0.88 quality-adjusted LYs [QALYs]), and incremental costs (around €15,000), driven by longer treatment during PFS state relative to R-chemo. The incremental cost-effectiveness ratio and incremental cost-utility ratio are both widely accepted by the Italian NHS (around €15,500/LY and €17,000/QALY gained, respectively). PSA simulations confirmed the robustness of results given sensible variations in assumptions.ConclusionO-chemo has superior clinical efficacy compared to rituximab, and should be considered a cost-effective option in first-line treatment of patients with advanced FL at intermediate or high risk in Italy. Incremental cost-effectiveness ratios are below the threshold considered affordable by developed countries.

Abstract LB064: Long-term application of TTFields in anaplastic astrocytoma - a case study

Abstract Background: Anaplastic astrocytomas WHO III° (AA) represent diffusely infiltrating, high grade gliomas (HGG). Despite advancements in the molecular characterization of HGG treatment options are limited and are often in analogy to grade IV glioblastoma treatment. Tumor Treating Fields therapy (TTF) is an established modality for newly diagnosed and recurrent glioblastoma (GBM) shown to significantly improve progression-free and overall survival. While TTF is under investigation in grade III gliomas in several clinical trials, we present an exemplary case of an AA undergoing mid-term TTF therapy and adjuvant chemotherapy to explore treatment adherence, feasibility and safety. Methods: We present case details of a patient from our specialized neurosurgical oncology center, with an anaplastic astrocytoma (WHO grade III) who began TTF treatment at first diagnosis while being in the adjuvant chemotherapy phase at the time of TTF commencement. We describe treatment details and the course of disease under continuous and ongoing TTF therapy. Results: In December 2016 a 43year-old male patient was diagnosed with an anaplastic astrocytomaIDH 1/2 mutant, MGMT promoter-hypermethylation without 1p/19q codeletion. After biopsy and consequent partial tumor resection, he received concomitant radiochemotherapy and adjuvant chemotherapy with temozolomide. TTF was started six months after initial diagnosis. He has now completed 1328 days of treatment with an average daily usage of 90% and has survived 48 months from first diagnosis (cutoff January, 8th, 2021). Since beginning TTF, he has undergone temozolomide treatment for 6 cycles. He continues TTF without further adjuvant therapy. The patient is symptomatically stable and his quality of life is maintained. Significant adverse events or longer treatment interruptions have not occurred. Conclusion: The treatment with TTFields was well tolerated and seems to be feasible in this patient with an anaplastic astrocytoma. Considering the long treatment duration and favorable average daily usage, this treatment might be suitable for a long-term treatment in high grade gliomas. Ongoing clinical trials will provide more information on safety and efficacy for the use of TTFields in patients with grade III gliomas. Citation Format: Darko Markovic. Long-term application of TTFields in anaplastic astrocytoma - a case study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB064.

The Effect of Probiotic and Omega-3 Supplements on Total Oxidant and Total Antioxidant Levels in Experimental Colitis

Objective: Treatment of inflammatory bowel disease (IBD) usually involves medical therapy. For this reason, it is recommended to seek alternative treatment methods such as nutritional therapy. The aim of the study is to evaluate the effects of probiotics and omega-3 fatty acids on total oxidant and total antioxidant levels in an experimental colitis model.Methods: Mice were randomly divided into five groups (n= 10/group) as healthy group, colitis group, group treated with probiotics (VSL#3), group treated with omega-3 (w-3), and group treated with both probiotics and omega-3. To induce experimental colitis, 200 mg/kg dinitrobenzene sulfonic acid (DNBS) + 30% ethanol combination was rectally administered to anesthetized mice. Total oxidant (TOS) and total antioxidant (TAS) levels were measured at the tissue level.Results: Lower concentrations of TOS were observed in the probiotics groups (2.11±0.23 mmol H2O2 Eq/L), probiotics+omega-3 (2.56±1.18 mmol H2O2 Eq/L), and omega-3 (3.02±1.88 mmol H2O2 Eq/L) groups compared to the colitis group (3.11±0.91 mmol H2O2 Eq/L) (p&amp;gt;0.05). Higher TOS and TAS level were observed in the control colitis group compared to other groups; however, the differences were not statistically significant.Conclusion: Our findings showed that TAS and TOS levels were positively affected by the use of probiotic supplements in IBD. It was determined that using w-3 alone was ineffective in decreasing TOS levels. Studies with higher dosages and longer treatment.

BET Inhibitors in Chronic Lymphocytic Leukemia: JQ1 Synergizes with Venetoclax in Promoting Apoptosis

▪Background: The bromodomain and extra terminal BET family proteins (BRD2, BRD3, BRD4 and the testis-specific BRDT) play a critical role in mediating gene transcription and have been considered as highly promising targets in several diseases including cancer. Specifically, BET inhibitors block the transcription of key oncogenes (BCL2, C-MYC and CDK6) through the displacement of BRDs and other epigenetic modifiers from chromatin. However, while BET inhibitors were consistently described as highly effective drugs in in vitro experiments, few reports and clinical trials have already demonstrated the rapid emergence of BET inhibitors resistance.Aim: We examined the efficacy of the BET inhibitor JQ1 in CLL samples, upon short and prolonged treatments, to assess its efficacy and the potential development of resistances.Methods: MEC-1/EHEB CLL cell lines (p53 wild-type EHEB and p53-mutated MEC-1 cell lines) and primary CD19 positive lymphocytes from CLL patients were subjected to short and prolonged treatment with the BET inhibitor JQ1. Responses were measured in terms of proliferation, cell-cycle and apoptosis.Results: Treatment of CLL cell lines with the BET inhibitor JQ1 was associated with block of proliferation, cell cycle arrest and apoptosis. Molecularly, JQ1 treatment was associated to c-Myc down-modulation. Notably, treatment with JQ1 caused also loss of viability of primary patient-purified CLL cells. However, starting from 48 hours of JQ1 treatment in CLL cell lines, we observed a compensatory increase of BRDs mRNA levels, which was associated to the development of resistant clones after longer treatments (30 days). These data demonstrate that resistance to BET inhibitors can rapidly emerge and suggest that a combination therapy with other drugs should be explored. Interestingly, we observed that JQ1 was also able to modulate BCL-2 expression in CLL. We therefore assessed the effect of a combination therapy based on JQ1 in association with the BCL-2 inhibitor, Venetoclax. Intriguingly, co-treatment with JQ1 and Venetoclax significantly increased apoptosis demonstrating a synergic action.Conclusions: Our data demonstrated for the first time that: i) CLL may be effectively targeted by BET inhibitors; ii) short term treatment with BET inhibitors rapidly results in the upregulation of additional BRD family members; iii) prolonged treatment is associated with the development of resistance; IV) BET proteins modulate BCL-2 and c-MYC expression also in CLL; V) the combination therapy based of JQ1 administration in association with Venetoclax is extremely effective in CLLDiscussion: Here, we show that JQ1 treatment results in growth inhibition and apoptosis of CLL cells by down-modulating the expression of the pro-survival genes, C-MYC and BCL-2. Furthermore, our data show that treatment with JQ1 is only effective for a short time while the co-treatment with Venetoclax exerts a synergistic lethality effect in CLL. These data suggest the efficacy of a combination therapy with JQ1 and Venetoclax in refractory TP53 mutated CLL patients. DisclosuresSaglio:Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria.

Rock physical and chemical alterations during the in-situ interaction between fracturing fluid and Silurian organic-rich shales in China

Hydraulic fracturing has been proved to be an effective way to unlock shale gas resources. During this process, fracturing fluid comes into contact with shale reservoirs and interact with the rocks. This could cause alteration of the pore systems in shales, thereby affecting gas transport and production. To illustrate this geochemical process and identify the physical and chemical alterations of shales, fluid-shale interaction at in-situ conditions is studied for typical marine organic-rich shales from the Silurian Longmaxi Formation in the Sichuan Basin, using actual fracturing fluid and deionized water over a 5-day period. The minerals and pore structures before and after the reaction were examined by X-ray diffraction (XRD), field emission scanning electron microscope (FE-SEM), QEMSCAN, computed tomography (CT) scanning, nitrogen adsorption testing and organic geochemical analysis. Results showed that, the fracturing fluid and deionized water caused indiscernible changes to the organic matter, but a variety of alterations on carbonate minerals. Calcites and dolomites were markedly dissolved, but quartzs, albites and illites remained relatively unaltered. More dolomites crystals were precipitated in the deionized water-shale interaction than in the fracturing fluid-shale interaction, and some of the fractures seemed to be filled by flocculation of friction reducers or deposited mineral particles. The fracturing fluid could enlarge the pore volumes and improve pore connectivity, and the invasion depth of fracturing fluid after 120 h’ was around 60 μm. The dissolved pores and loosening/shedding of particles detected by CT increased through time, and the calculated 3D pore volume increased by 67% at 24 h, 117% at 72 h, and 430% at 120 h compared to that of the initial sample. The XRD and nitrogen adsorption data indicated that new pore volumes increased with higher contents of carbonate minerals in the sample and longer treatment by fracturing fluid. The mineral and pore-scale alterations of shale reservoirs indicated that fracturing fluid-shale interaction (FFSI) enlarged the reservoir reconstruction volume, increased well performance during shut-in period and should be considered as part of the well treatment optimization process.

Dual antiplatelet therapy after percutaneous coronary intervention: Personalize the duration.

The recommended duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention with a drug-eluting stent has changed from 1 year for all to a more personalized approach based on the patient's risks of ischemia and bleeding. The trend is toward shorter treatment in view of lower rates of late and very late stent thrombosis with newer drug-eluting stents and the risk of bleeding with DAPT. But some patients at high risk of ischemic events and low risk of bleeding may benefit from longer treatment.

PMH3 Effects of Antidepressants on Health-Related Quality of Life in Patients with Major Depressive Disorder; A Secondary Analysis Using Perform-J Study

Major depressive disorder (MDD) and other mental diseases greatly affect the quality of life (QOL), but little is known about longitudinal QOL health status in MDD patients. The aim of this study was to investigate the temporal trends of QOL in MDD patients treated with antidepressants in Japan. The Prospective Epidemiological Research on Functioning Outcomes related to Major Depressive Disorder in Japan (PERFROM-J) study was used, in which patients initiating antidepressant treatment (n=518) were observed for 6 months. Patient’s QOL was assessed at baseline, month 1, month 2, and month 6 using the 5-level version of EQ-5D questionnaire, which consists of 5 items (Mobility, Self-care, Usual Activities, Pain/Discomfort, and Anxiety/Depression), and overall health state measured by VAS. Proportions for each dimension of EQ-5D were described, and Paretian Classification of Health Changes (PCHC) from baseline were assessed at each time point. Each dimension of EQ-5D-5L improved over the course of antidepressant treatment, and the proportion of patients rating no problems increased from baseline to month 6 with 12.8% (Mobility), 9.9% (Self-care), 30.5% (Usual Activities), 25.6% (Pain/Discomfort), and 28.7% (Anxiety/Depression). However, approximately half of the patients claimed problems (rating 2-5) for daily activities (51.3%), pain/discomfort (51.0%), and anxiety/depression (62.9%) 6 months after initiation of antidepressant treatment, which were dimensions considered related to depression. The PCHC analysis showed that more than half of the patients had “improved (improvement on at least one EQ-5D dimension and no worsening on any other dimension)” their QOL 1 month after initiating antidepressant treatment. The temporal trends in QOL of Japanese MDD patients initiating antidepressant was demonstrated by EQ-5D-5L. At 6 months after initiation of antidepressant treatment, there was room for improvement in dimensions related to MDD. Longer treatment may be required to further improve quality of life.

Cannabinoid Activity-Is There a Causal Connection to Spasmolysis in Clinical Studies?

Cannabinoid drugs are registered for postoperative nausea and emesis, Tourette syndrome and tumor-related anorexia, but are also used for spasticity and pain relief, among other conditions. Clinical studies for spasmolysis have been equivocal and even conclusions from meta-analyses were not consistent. This may be due to uncertainty in diagnostic criteria as well as a lack of direct spasmolytic activity (direct causality). In this review we used the Hill criteria to investigate whether a temporal association is causal or spurious. Methods: A systematic literature search was performed to identify all clinical trials of cannabinoids for spasticity. Studies were evaluated for dose dependency and time association; all studies together were analyzed for reproducibility, coherence, analogy and mechanistic consistency. A Funnel plot was done for all studies to identify selection or publication bias. Results: Twenty-seven studies were included in this meta-analysis. The spasmolytic activity (effect strength) was weak, with a nonsignificant small effect in most studies and a large effect only in a few studies (“enriched” studies, low patient numbers). No dose dependency was seen and plotting effect size vs. daily dose resulted in a slope of 0.004. Most studies titrated the cannabinoid to the optimum dose, e.g., 20 mg/d THC. The effect decreased with longer treatment duration (3–4 months). The spasmolytic effect is consistent for different European countries but not always within a country, nor is the effect specific for an etiology (multiple sclerosis, spinal cord injury, others). For other criteria like plausibility, coherence or analogous effects, no data exist to support or refute them. In most studies, adverse effects were frequently reported indicating a therapeutic effect only at high doses with relevant side effects. Conclusions: Current data do not support a specific spasmolytic effect; a general decrease in CNS activity analogous to benzodiazepines appears more likely. Whether individual patients or specific subgroups benefit from cannabinoids is unclear. Further studies should compare cannabinoids with other, nonspecific spasmolytic drugs like benzodiazepines.

Unsulfated biotechnological chondroitin by itself as well as in combination with high molecular weight hyaluronan improves the inflammation profile in osteoarthritis in vitro model.

Several studies suggest that inflammation has a pivotal role during the progression of osteoarthritis (OA) and cytokines have been identified as the main process mediators. This study aimed to explore the ability to modulate the main OA pro‐inflammatory biomarkers of novel gels (H‐HA/BC) based on high molecular weight hyaluronan (H‐HA) and unsulfated biotechnological chondroitin (BC). For the first time, BC was tested also in combination with H‐HA on human primary cells isolated from pathological knee joints. Specifically, the experiments were performed using an OA in vitro model based on human chondrocytes and synoviocytes. To evaluate the anti‐inflammatory effects of H‐HA/BC in comparison with H‐HA and BC single gels, NF‐kB, COMP‐2, MyD88, MMP‐13 and a wide range of cytokines, known to be specific biomarkers in OA (e.g., IL‐6, IL‐8, and TNF‐α), were evaluated. In addition, cell morphology and proliferation occurring in the presence of either H‐HA/BC or single components were assessed using time‐lapse video microscopy. It was shown that synovial fluids and cells isolated from OA suffering patients, presented a cytokine pattern respondent to an ongoing inflammation status. H‐HA and BC significantly reduced the levels of 23 biomarkers associated with cartilage damage. However, H‐HA/BC decreased significantly 24 biological mediators and downregulated 19 of them more efficiently than the single components. In synoviocytes cultures, cytokine analyses proved that H‐HA/BC gels re‐established an extracellular environment more similar to a healthy condition reducing considerably the concentration of 11 analytes. Instead, H‐HA and BC significantly modulated 7 (5 only with a longer treatment) and 8 biological cytokines, respectively. Our results suggest that H‐HA/BC beyond the viscosupplementation effect typical for HA‐based gels, can improve the inflammation status in joints and thus could be introduced as a valid protective and anti‐inflammatory intraarticular device in the field of Class III medical devices for OA treatments.

P299 Loss-of-response to anti-tumour necrosis factor-α critically depends on treatment duration in patients with Inflammatory Bowel Disease

Abstract Background Inflammatory bowel disease (IBD) is often managed with anti-tumour necrosis factor-α (anti-TNFα) compounds, but only few studies have reported on long-term outcomes. We aimed to determine whether the incidence of loss-of-response decreases with longer treatment duration. Methods In a multicentre, retrospective cohort study of patients with IBD who received anti-TNFα for at least 4 months between 2011-2019, we compared incidence rates of loss-of-response between different intervals of treatment duration and performed parametric survival modelling to assess changes with longer treatment duration. Cox regression analysis was performed to identify predictors of loss-of-response. Secondary outcomes included overall anti-TNFα discontinuation and dose escalation. Results We included 900 anti-TNFα treatment episodes in 746 individual patients, with up to 9 years of follow-up. During follow-up, the most frequently observed reason for anti-TNFα discontinuation was loss-of-response (Figure 1), which occurred in 231 (25.7%) episodes, with presence of anti-drug antibodies in 67/231 (29%). Within the first year, the incidence of loss-of-response was threefold higher than after four years of treatment (17.3% versus 4.7% per patient-year, p&amp;lt;0.001). The incidence of overall drug discontinuation (28.6% versus 14.0% per patient-year, p&amp;lt;0.001) and dose escalations (36.5% versus 6.4% per patient-year, p&amp;lt;0.001) also decreased significantly from the first year to after four years, respectively. Risk factors for loss-of-response included stricturing or penetrating Crohn’s disease (adjusted hazard ratio [aHR] 1.67, 95% CI 1.14 – 2.44), while male sex (aHR 0.74, 95% CI 0.56 – 0.98) and concomitant immunomodulators (aHR 0.73, 95% CI 0.54 – 0.98) were protective. Conclusion Long-term use of anti-TNFα maintenance treatment is associated with a reduced risk of loss-of-response in patients with IBD.

Optimal treatment duration of bevacizumab (BEV) combined with carboplatin and paclitaxel in patients (pts) with primary epithelial ovarian (EOC), fallopian tube (FTC) or peritoneal cancer (PPC): A multicenter open-label randomized 2-arm phase 3 ENGOT/GCIG trial of the AGO Study Group, GINECO, and NSGO (AGO-OVAR 17/BOOST, GINECO OV118, ENGOT Ov-15, NCT01462890).

5501 Background: GOG-0218 established the addition of BEV 15 mg/kg every 3 weeks (q3w) for 15 months to standard front-line chemotherapy for advanced ovarian cancer, but the optimal BEV duration remained unknown. We report primary results from a randomized phase 3 trial designed to address this question. Methods: Eligible pts with FIGO stage IIB–IV EOC, FTC, or PPC and ECOG PS ≤2 underwent primary cytoreductive surgery followed by 6 cycles of chemotherapy (paclitaxel 175 mg/m2 + carboplatin AUC 5 q3w) and BEV (15 mg/kg q3w). Pts were randomized to receive BEV for either 15 months (standard arm BEV15) or 30 months (experimental arm BEV30), stratified by FIGO stage/residual tumor (stage IIB–IIIC/no residual tumor vs stage IIB–IIIC/residual tumor or stage IV). The primary endpoint was investigator-assessed progression-free survival (PFS) according to RECIST v1.1. Secondary endpoints were overall survival (OS), objective response rate, quality of life, safety, and tolerability. The trial was designed with 80.2% power to detect a hazard ratio (HR) of 0.66 favoring BEV30 (2-sided log-rank test, 5% significance level, 10% dropout rate) after 697 PFS events. The trial was funded by F. Hoffmann-La Roche Ltd., performed according to ENGOT model A. Results: From Nov 2011 to Aug 2013, 927 women (83% with EOC) from 161 centers were randomized. Baseline characteristics were balanced between arms; median age was 61 years, 96% had ECOG PS 0/1, 58% had no residual tumor, and 77% had high-grade serous histology. Serious adverse events of special interest for BEV occurred in 51/448 pts (11%) vs 61/442 pts (14%) receiving BEV15 vs BEV30, respectively: hypertension (2.7%/4.5%), thromboembolic event (2.2%/3.2%), fistula (3.1%/1.1%), gastrointestinal perforation (0.2%/0.9%), proteinuria (0.7%/1.4%), hemorrhage (0.2%/0.9%), and myocardial infarction (0%/1.1%). Efficacy is shown in the table. Conclusions: Longer treatment with BEV for up to 30 months improves neither PFS nor OS in pts with primary EOC, FTC, or PPC. Therefore BEV treatment duration of 15 months remains standard of care. Clinical trial information: NCT01462890. [Table: see text]

Early safety and efficacy from a phase I open-label clinical trial of CD137(4-1BB) agonistic antibody LVGN6051 as monotherapy and in combination with pembrolizumab.

2521 Background: LVGN6051, a monoclonal antibody against CD137 (also known as 4-1BB or TNFRSF9) with an engineered Fc capable of selectively binding to the Fcγ receptor IIB, acts as a conditional CD137 agonist, resulting in immune activation optimally in tumor microenvironment ( Qi, Nat. Commun. 2019 ). In preclinical models, LVGN6051 demonstrated robust anti-tumor efficacy and safety as a single agent and in combination with anti-PD-1 antibodies. Therefore, we have initiated this first-in-human study of LVGN6051 alone or in combination with pembrolizumab for the treatment of advanced or metastatic malignancy. Methods: This study includes accelerated dose escalation monotherapy up to 2 mg/kg of LVGN6051, and traditional 3 + 3 design for higher doses of LVGN6051 alone or in combination with pembrolizumab. Then, this study will enroll patients with specific types of malignancies following Simon’s two-stage design. Both agents are administered once every 3 weeks. Primary objectives of this study were to define the safety profile and to establish the recommended phase 2 dose (RP2D) of LVGN6051 alone or in combination with pembrolizumab. Pharmacokinetics, immunogenicity, pharmacodynamics and clinical efficacy will be also evaluated. Results: At the cut-off date on January 18, 2021, 16 subjects have been enrolled into the monotherapy cohorts (n=12, no DLT observed up to 7 mg/kg), and the combination cohort (n=4, ongoing at LVGN6051 2 mg/kg and pembrolizumab 200 mg, one DLT observed). No treatment-related adverse event (TRAE) was observed in monotherapy. Treatment-emergent adverse events (TEAE) in combination included increased ALT/AST, thrombocytopenia, and fatigue. In the combination cohort, one patient with predominant hepatic metastases and history of intermittent grade 2 hepatic impairment experienced grade 3 increased ALT/AST (DLT) on cycle 1 day 15 that were resolved to her baseline without corticosteroids on cycle 1 day 18. TRAE included increased ALT/AST, thrombocytopenia, neutropenia, nausea and fatigue. Seven of 10 evaluable patients in the monotherapy cohorts demonstrated stable disease with the longest treatment being 8+ months. Tumor reductions by &gt;10% were observed in melanoma and neuroendocrine tumor on monotherapy. One patient with metastatic head and neck squamous cell carcinoma who had progressed on an anti-PD-L1 based therapy showed an immune partial response (iPR) for 6+ months to the combination therapy. Conclusions: Preliminary evidence showed that LVGN6051 was well tolerated and tumor shrinkages were observed. While we continue assessing its safety profile, antitumor activity was observed in the LVGN6051 and pembrolizumab cohort. The favorable safety profile and preliminary antitumor activity warrant further evaluation in patients with advanced malignancies. Clinical trial information: NCT04130542.

When to perform curettage after uterine artery embolization for cesarean scar pregnancy: a clinical study

BackgroundProphylactic uterine artery embolization (UAE) combined with subsequent curettage is suggested as an effective and minimally invasive treatment strategy for cesarean scar pregnancy (CSP) with a high bleeding risk. However, the timing of curettage after UAE remains to be studied. Thus, we aimed to identify the optimal time interval to perform curettage after UAE in patients with CSP.MethodsWe conducted a retrospective cohort study in a large medical center for women and children in Southwest China. CSP patients treated by UAE combined with subsequent curettage were included and grouped by the treatment time interval between these two procedures. The clinical outcomes among arms were compared by univariate and multivariable analysis.ResultsOur study included 314 CSP patients who received this combination treatment in our department from January 2014 to December 2019. The median time interval between UAE and curettage was 48 h, with a range of 12-168 h among all participants. Thirty-two patients (10.2%) experienced intraoperative hemorrhage (blood loss ≥200 mL). Intrauterine balloon tamponade was used in 17 cases (5.4%). In 14 cases (4.5%), the procedure was converted to laparoscopy (or laparotomy). In the cohort study, patients with longer treatment intervals had more intraoperative blood loss and a higher incidence of complications than those with shorter intervals (P < 0.05). The rates of intraoperative bleeding were 5.0% for patients who received curettage within 24 h after UAE (Arm 1) and 19.4% for those who had a treatment interval longer than 72 h (Arm 4). In the multivariable logistic regression model of bleeding, a treatment interval > 72 h had an adjusted odds ratio of 3.37 (95% confidence interval: 1.40-8.09).ConclusionWe suggest that curettage not be delayed longer than 72 h after UAE in this combined treatment of CSP.

The Marine Natural Product Furospinulosin 1 Induces Apoptosis in MDA-MB-231 Triple Negative Breast Cancer Cell Spheroids, But Not in Cells Grown Traditionally with Longer Treatment

Cancer cells grown in spheroid conditions interact with each other and the extracellular matrix, providing a better representation of the in vivo environment than two-dimensional cultures and are a more clinically relevant model. A discrete screening of genetically diverse marine samples in the spheroid assay led to the identification of a novel activity for the known compound furospinulosin 1. This compound shows activity against MDA-MB-231 triple negative breast cancer cells grown as spheroids and treated for 24 or 48 h. No cytotoxicity was seen in traditional two-dimensional adherent cultures treated for a longer time (72 h). A reverse phase protein array (RPPA) confirmed the limited activity of the compound in cells grown traditionally and revealed changes in protein expression when cells are grown as spheroids that are associated with better clinical prognosis. Analysis of the RPPA data through the Broad institute’s connectivity map suggested the hypothesis that furospinulosin 1 functions as an MEK inhibitor. Analysis of the RPPA data through STRING supports the apoptosis observed. The selectivity exhibited by furospinulosin 1 for triple negative breast cancer cells only when grown as spheroids makes it an interesting compound with strong therapeutic potential that merits further study.

A Retrospective Cohort Study on the Clinical Course of Patients With Moderate-Type COVID-19.

Background: A large number of people contracted moderate-type COVID-19 around the world. However, to our knowledge no studies have covered the clinical course of patients with moderate-type COVID-19. This study describes the clinical course of moderate-type patients with COVID-19 from Wuhan City and Yiyang City, and explores factors relevant to the length of hospitalization and symptoms relief.Methods: The study analyzed the clinical course of 107 moderate-type patients with COVID-19 from the outbreak area (Wuhan) and the imported area (Yiyang), and used automatic linear modeling and multivariate linear regression analysis to explore the factors relevant to the length of hospitalization and symptoms relief. Furthermore, we created a scoring system to value the length of hospitalization and symptoms relief.Results: Lymphopenia, elevated C-reactive protein, increased LDH, bilateral lung GGO (ground glass opacity), and lung consolidation were more likely to appear in ordinary inpatients with moderate-type COVID-19 from Wuhan (P < 0.05), compared to infected medical staff from Wuhan and ordinary inpatients with moderate-type COVID-19 from Yiyang. Meanwhile, the length of hospitalization and symptoms relief was longer in ordinary patients with moderate-type COVID-19 from Wuhan (P < 0.05). Onset of symptoms to admission, ESR, leucocytes count, and bilateral lung GGO were linearly related to the length of hospitalization (P < 0.05); onset of symptoms to admission, leucocytes count, bilateral lung GGO, and lung consolidation were linearly related to the length of symptoms relief (P < 0.05). By using the scoring system, we found that the time of hospitalization and symptoms relief lengthened as the scores increased.Conclusions: This study described the clinical course of patients with moderate-type COVID-19, and found that ordinary patients with moderate-type COVID-19 in outbreak areas were more serious and needed stronger treatment and longer treatment time. Onset of symptoms to admission, ESR, leucocytes count, and bilateral lung GGO can be effective predictors of the length of hospitalization. And onset of symptoms to admission, leucocytes count, bilateral lung GGO, and lung consolidation can be effective predictors of the amount of time until symptoms relief. Most importantly, we have created a scoring system, which could contribute to the diagnosis and treatment of COVID-19.