Similar Clinical Response Research Articles

Efficacy and Safety of Advanced Therapies in Moderately-to-Severely Active Ulcerative Colitis: a Systematic Review and Network Meta-analysis.

This study aimed to compare the efficacy and safety of biologics and small molecules for treatment of adults with moderately-to-severely active ulcerative colitis (UC). A systematic literature review was conducted to identify randomised controlled trials evaluating approved and emerging targeted therapies for patients with UC. A Bayesian network meta-analysis (NMA) approach was applied. Outcomes assessed included clinical response and remission, endoscopic mucosal healing, and safety. Thirty studies were included in the NMA following a feasibility assessment comparing approved induction dosing regimens and 22 studies comparing approved maintenance dosing regimens. In the biologic/Janus kinase inhibitor (JAKi)-naïve population, induction studies showed similar clinical response and remission rates across most interventions, with upadacitinib demonstrating significant improvements versus most other interventions. For maintenance studies, mirikizumab demonstrated significant improvements in clinical response and remission versus most other interventions. In the biologic/JAKi-experienced population, no significant differences were observed between most interventions in induction studies, except for significantly improved clinical response and remission for mirikizumab versus adalimumab, and upadacitinib demonstrated significant improvement versus all other interventions. Few differences between active treatments were observed in maintenance studies. In both populations, all active interventions had similar efficacy in terms of endoscopic mucosal healing in both induction and maintenance studies. Regardless of prior treatment exposure, similar rates of serious adverse events were seen across all active interventions in the induction period. Among the available interventions, owing to its favourable efficacy and safety profile, mirikizumab has a relevant role in the long-term treatment of UC.

Systematic Review and Meta-Analysis of Clinical Efficacy and Safety of Meropenem-Vaborbactam versus Best-Available Therapy in Patients with Carbapenem-Resistant Enterobacteriaceae Infections.

Antimicrobial resistance is increasingly concerning, causing millions of deaths and a high cost burden. Given that carbapenemase-producing Enterobacterales are particularly concerning due to their ability to develop structural modifications and produce antibiotic-degrading enzymes, leading to high resistance levels, we sought to summarize the available data on the efficacy and safety regarding the combination of meropenem-vaborbactam (MV) versus the best available therapy (BAT). Articles related to our objective were searched in the PubMed and Scopus databases inception to July 2024. To assess the quality of the studies, we used the Cochrane risk-of-bias tool, RoB2. The outcomes were pooled as a risk ratio (RR) and a 95% confidence interval (95%CI). A total of four published studies were involved: one retrospective cohort study and three phase 3 trials, including 432 patients treated with MV and 426 patients treated with BAT (mono/combination therapy with polymyxins, carbapenems, aminoglycosides, colistin, and tigecycline; or ceftazidime-avibactam; or piperacillin-tazobactam). No significant difference in the clinical response rate was observed between MV and the comparators at the TOC (RR = 1.29, 95%CI [0.92, 1.80], p = 0.14) and EOT (RR = 1.66, 95%CI [0.58, 4.76], p = 0.34) visits. MV was associated with a similar microbiological response as the comparators at TOC (RR = 1.63, 95%CI [0.85, 3.11], p = 0.14) and EOT assessment (RR = 1.16, 95%CI [0.88, 1.54], p = 0.14). In the pooled analysis of the four studies, 28-day all-cause mortality was lower for MV than the control groups (RR = 0.47, 95%CI [0.24, 0.92], p = 0.03). MV was associated with a similar risk of adverse events (AEs) as comparators (RR = 0.79, 95%CI [0.53, 1.17], p = 0.23). Additionally, MV was associated with fewer renal-related AEs than the comparators (RR = 0.32, 95%CI [0.15, 0.66], p = 0.002). MV was associated with a similar risk of treatment discontinuation due to AEs (RR = 0.76, 95%CI [0.38, 1.49], p = 0.42) or drug-related AEs (RR = 0.56, 95%CI [0.28, 1.10], p = 0.09) as the comparators. In conclusion, MV presents a promising therapeutic option for treating CRE infections, demonstrating similar clinical and microbiological responses as other comparators, with potential advantages in mortality outcomes and renal-related AEs.

Organ preservation after neoadjuvant long-course chemoradiotherapy versus short-course radiotherapy

Potential differences in organ preservation between total neoadjuvant therapy (TNT) regimens integrating long-course chemoradiotherapy (LCCRT) and short-course radiotherapy (SCRT) in rectal cancer remain undefined. This natural experiment arose from a policy change in response to the COVID-19 pandemic during which our institution switched from uniformly treating patients with LCCRT to mandating that all patients be treated with SCRT. Our study includes 323 locally advanced rectal adenocarcinoma patients treated with LCCRT-based or SCRT-based TNT from January 2018 to January 2021. Patients who achieved clinical complete response were offered organ preservation with watch-and-wait (WW) management. The primary outcome was 2-year organ preservation. Additional outcomes included local regrowth, distant recurrence, disease-free survival (DFS), and overall survival (OS). Patient and tumor characteristics were similar between LCCRT (n= 247) and SCRT (n= 76) cohorts. Median follow-up was 31 months. Similar clinical complete response rates were observed following LCCRT and SCRT (44.5% versus 43.4%). Two-year organ preservation was 40% [95% confidence interval (CI) 34% to 46%] and 31% (95% CI 22% to 44%) among all patients treated with LCCRT and SCRT, respectively. In patients managed with WW, LCCRT resulted in higher 2-year organ preservation (89% LCCRT, 95% CI 83% to 95% versus 70% SCRT, 95% CI 55% to 90%; P= 0.005) and lower 2-year local regrowth (19% LCCRT, 95% CI 11% to 26% versus 36% SCRT, 95% CI 16% to 52%; P= 0.072) compared with SCRT. The 2-year distant recurrence (10% versus 6%), DFS (90% versus 90%), and OS (99% versus 100%) were similar between WW patients treated with LCCRT and SCRT, respectively. While WW eligibility was similar between cohorts, WW patients treated with LCCRT had higher 2-year organ preservation and lower local regrowth than those treated with SCRT, yet similar DFS and OS. These data support induction LCCRT followed by consolidation chemotherapy as the preferred TNT regimen for patients with locally advanced rectal cancer pursuing organ preservation.

A secukinumab dose-escalation study in patients with ankylosing spondylitis not achieving inactive disease after 16 weeks of treatment.

To investigate the clinical response at week 52 in patients with ankylosing spondylitis (AS) who received secukinumab 300 vs 150 mg after inadequate response to 150 mg at week 16. ASLeap (NCT03350815) was a randomized, double-blind, parallel-group, multicentre, phase 4 trial. After 16 weeks of open-label secukinumab 150 mg (Treatment Period 1), patients who did not achieve inactive disease (Ankylosing Spondylitis Disease Activity Score [ASDAS] <1.3) at both Weeks 12 and 16 were considered to have an inadequate response and were randomized 1:1 to receive secukinumab 300 or 150 mg every 4 weeks until week 52 (Treatment Period 2). The primary efficacy variable was achievement of ASDAS <1.3 at week 52 using week 16 as baseline. Safety was evaluated by the incidence of treatment-emergent adverse events through week 52. Of 322 patients treated with secukinumab in Treatment Period 1, 207 (64.3%) had inadequate response. Similar proportions of patients with inadequate response randomized to secukinumab 300 mg (n = 101) and 150 mg (n = 105) in Treatment Period 2 completed the study (83.8% and 84.3%, respectively). At week 52, 8.8% and 6.7% of patients receiving secukinumab 300 and 150 mg, respectively, achieved ASDAS <1.3. The incidence of treatment-emergent adverse events was similar in both groups through week 52. No new safety signals were observed. Patients with AS who did not achieve ASDAS <1.3 after receiving secukinumab 150 mg for 16 weeks experienced similar clinical response and safety through week 52 regardless of dose escalation. ClinicalTrials.gov, NCT03350815.

Entecavir vs. tenofovir disoproxil fumarate in the treatment of chronic hepatitis B patients with severe acute exacerbation.

The efficacy of different nucleos(t)ide analogs in the treatment of chronic hepatitis B virus (CHB) with severe acute exacerbation (SAE) remained unclear. Thus, this study aimed to compare the short-term efficacy of tenofovir disoproxil fumarate (TDF) and entecavir (ETV) in patients having CHB with SAE. We analyzed consecutive patients with treatment-naive CHB receiving TDF (n = 36) or ETV (n = 65) for SAE. The primary endpoint was overall mortality or receipt of liver transplantation (LT) by 24 weeks. The secondary endpoints are the comparison of ETV vs. TDF influences on renal function and virological and biochemical responses at 4, 12, 24, and 48 weeks. The baseline characteristics were comparable between the two groups. By 24 weeks, 8 (22%) patients in the TDF group and 10 (15%) patients in the ETV group had either died (n = 15) or received LT (n = 3) ( P = 0.367). Cox-regression multivariate analysis revealed age ( P = 0.003), baseline international normalized ratio of prothrombin time ( P = 0.024), and early presence of hepatic encephalopathy ( P = 0.003) as independent factors associated with mortality or LT. The two groups of patients achieved comparable biochemical and virological responses at 48 weeks. No significant difference was found in the estimated glomerular filtration rate (eGFR) between the TDF and the ETV groups. However, a significant reduction in the eGFR at 48 weeks, as compared with the baseline, was found in each group. TDF and ETV achieved similar short-term clinical outcomes and treatment responses in CHB patients with SAE.

Systematic review and meta-analysis for the 2024 update of the Japan College of Rheumatology clinical practice guidelines for the management of rheumatoid arthritis.

The aim of this article is to update evidence on the efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) and provide information to the taskforce for the 2024 update of the Japan College of Rheumatology clinical practice guidelines for the management of rheumatoid arthritis (RA). We searched various databases for randomised controlled trials on RA published until June 2022, with no language restriction. For each of the 15 clinical questions, two independent reviewers screened the articles, evaluated the core outcomes, and performed meta-analyses. Subcutaneous injection of methotrexate (MTX) showed similar efficacy to oral MTX in MTX-naïve RA patients. Ozoralizumab combined with MTX improved drug efficacy compared to the placebo in RA patients with inadequate response (IR) to conventional synthetic DMARD (csDMARD). Rituximab with and without concomitant csDMARDs showed similar efficacy to other biological DMARDs (bDMARDs) in bDMARD-IR RA patients. Combined Janus kinase inhibitors and MTX achieved similar clinical responses and equal safety during a 4-year period compared to tumour necrosis factor inhibitors in MTX-IR RA patients. Biosimilars showed efficacy equivalent to that of the original bDMARDs in csDMARD-IR and bDMARD-IR RA patients. This systematic review provides latest evidence for the 2024 update of the Japan College of Rheumatology clinical practice guidelines for RA management.

P106 Do high rheumatoid factor titres impact response to tumour necrosis factor inhibitors? Comparison of certolizumab pegol and adalimumab in patients with rheumatoid arthritis and high titres of rheumatoid factor: a post hoc analysis of a phase 4 trial.

Abstract Background/Aims In patients with rheumatoid arthritis (RA), high rheumatoid factor (RF) titres are considered a poor prognostic factor and are associated with higher disease activity, risk of radiographic progression and decreased response to TNF inhibitors (TNFis). Recent data suggests that patients with RA and high RF titre may achieve and maintain greater clinical improvement with TNFis without a crystallisable fragment (Fc) compared to TNFis with an Fc. In this analysis of the EXXELERATE trial, we assessed efficacy outcomes of certolizumab pegol (CZP), a PEGylated Fc-free TNFi, versus adalimumab (ADA; Fc-containing TNFi) in patients with RA and high RF titres. Methods The phase 4 EXXELERATE trial (NCT01500278) compared the efficacy and safety of CZP to ADA. Patients were randomised 1:1 to CZP 200 mg every two weeks (Q2W) plus methotrexate (MTX) or ADA 40 mg Q2W plus MTX. At Week 12 (Wk), patients were classified as responders or non-responders; non-responders were switched to the other TNFi with possible follow-up to Wk104. Here, we report drug plasma concentrations, mean disease activity score (DAS)28-CRP score and proportion of patients achieving low disease activity (LDA; threshold: DAS28-CRP ≤2.7) to Wk104. Results are stratified by RF titre quartile (≤Q3: ≤203 IU/mL; &amp;gt;Q3: &amp;gt;203 IU/mL; measured by Roche Tina-quant®) and reported as observed data. Results Baseline data by RF quartile were available for 453 CZP-randomised patients (≤Q3: n = 334; &amp;gt;Q3: n = 119) and 454 ADA-randomised patients (≤Q3: n = 347; &amp;gt;Q3 n = 107). Baseline characteristics were similar between CZP- and ADA-randomised patients across the RF titre quartiles. At Wk12, 66 CZP-treated patients switched to ADA and 59 ADA-treated patients switched to CZP. At Wk104, mean ADA concentrations were 22.9% lower in patients with RF &amp;gt;Q3 (mean [SD] 4.8 [3.0]) vs those with RF ≤Q3 (6.2 [4.0]); in CZP-treated patients, this difference was smaller (13.0%) in patients with RF &amp;gt;Q3 (23.3 [15.4]) vs those with RF ≤Q3 (26.7 [13.1]). For patients in RF ≤Q3, mean DAS28-CRP scores were similar between CZP- and ADA-treated patients through Wks0-104 (mean [SD] DAS28 at Wk104: 2.48 [1.18] CZP vs 2.49 [1.14] ADA). However, for patients in RF &amp;gt;Q3, mean [SD] DAS28-CRP scores were nominally lower in CZP- vs ADA-treated patients (Wk104: 2.50 [1.18] CZP vs 2.93 [1.22] ADA). A similar pattern was observed for the proportion of patients achieving LDA at Wk104 (≤Q3: 64.8% CZP vs 65.1% ADA; &amp;gt;Q3: 65.7% CZP vs 48.3% ADA). Conclusion CZP-treated patients with RA and high titre RF had similar drug concentrations and clinical responses to patients with RA and low titre RF, a pattern not observed in ADA-treated patients. These data, together with previous reports where CZP showed consistent efficacy irrespective of baseline RF titre, suggest CZP may be a suitable therapy for patients with RA and high RF titre. Disclosure J.S. Smolen: Honoraria; AbbVie, Amgen, AstraZeneca, Astro, Bristol-Myers Squibb, Celgene, Celltrion, Chugai, Gilead, ILTOO, Janssen, Lilly, Merck Sharp &amp; Dohme, Novartis-Sandoz, Pfizer, R-Pharma, Roche, Samsung, Sanofi, and UCB Pharma. Grants/research support; AbbVie, AstraZeneca, Eli Lilly, Novartis and Roche. Other; Editor of Annals of the Rheumatic Diseases, Co-editor of Rheumatology 7E/8E, Convenor of EULAR Task Forces and T2T Task Forces. P.C. Taylor: Consultancies; AbbVie, Biogen, Eli Lilly, Fresenius, Galapagos, Gilead, GSK, Janssen, Nordic Pharma, Pfizer, Sanofi and UCB Pharma. Grants/research support; Galapagos. Y. Tanaka: Honoraria; AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Chugai, Eisai, Eli Lilly, Gilead, GSK, Pfizer, Taiho, Taisho. Member of speakers’ bureau; AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Chugai, Eisai, Eli Lilly, Gilead, GSK, Pfizer, Taiho and Taisho. Grants/research support; Chugai, Eisai, Mitsubishi-Tanabe, Taisho. C. Cara: Shareholder/stock ownership; UCB Pharma. Other; Employee of UCB Pharma. B. Lauwerys: Shareholder/stock ownership; UCB Pharma. Other; Employee of UCB Pharma. R. Xavier: Consultancies; AbbVie, AstraZeneca, Janssen, Organon, UCB Pharma. Member of speakers’ bureau; AbbVie, AstraZeneca, Janssen, Organon, and UCB Pharma. J.R. Curtis: Consultancies; AbbVie, Amgen, BMS, Corrona, Crescendo, Genentech, Janssen, Pfizer, Roche, UCB Pharma. Grants/research support; AbbVie, Amgen, BMS, Corrona, Crescendo, Genentech, Janssen, Pfizer, Roche, UCB Pharma. T.R. Mikuls: Consultancies; Horizon Therapeutics, Pfizer, Sanofi, UCB Pharma. Royalties; Elsevier, Wolters Kluwer Health (UpToDate). Grants/research support; Horizon Therapeutics. M. Weinblatt: Consultancies; AbbVie, Aclaris, Amgen, Aqtual, BMS, CorEvitas, Eli Lilly, GSK, Gilead, Horizon, Johnson and Johnson, Prometheus, Pfizer, Rani, Revolo, Sanofi, Scipher, Sci Rhom, Set Point, UCB Pharma. Grants/research support; AbbVie, Aqtual, BMS, Janssen.

Ceftaroline Fosamil for the Treatment of Methicillin-Resistant Staphylococcus Aureus Bacteremia: A Real-World Comparative Clinical Outcomes Study.

Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia results in substantial morbidity and mortality. As current treatments often lead to unsatisfactory outcomes, evidence guiding alternative treatment options is needed. This study evaluated real-world clinical outcomes of ceftaroline fosamil for the treatment of MRSA bacteremia. This retrospective study included adults hospitalized with MRSA bacteremia between 2011 and 2019. Patients were classified according to treatment with ceftaroline fosamil (ceftaroline), vancomycin, or daptomycin: Group 1, ceftaroline; Group 2, vancomycin or daptomycin (without ceftaroline); Group 3, combination therapy with ≥ 2 of these three agents. Clinical outcomes were compared using propensity-score-adjusted odds ratios (ORs) from logistic regression models. Overall, 24,479 patients were included (Group 1, n=532; Group 2, n=21,555; Group 3, n=2392). Mean age was 59.6, 60.8, and 57.4 years in Groups 1, 2, and 3, respectively. Mean post-index treatment length of stay was 8.8, 8.8, and 8.0 days, respectively. The most frequent line of therapy was ceftaroline first-line (42.1%), vancomycin or daptomycin first-line (95.4%), and combination therapy third-line or later (67.8%) in Groups 1, 2, and 3, respectively. Compared with Group 2, Groups 1 and 3 had similar favorable clinical responses {odds ratio [OR]=1.18 [95% confidence interval (CI) 0.98-1.44], p=0.08; OR=1.20 [95% CI 0.97-1.47], p=0.09, respectively} and were less likely to switch treatment (both p<0.001). Compared with Group 2, Group 1 was more likely to undergo 30-day all-cause readmission [OR=1.38 (95% CI 1.06-1.80), p=0.02], whereas this was less likely for Group 3 [OR=0.77 (95% CI 0.58-1.00), p=0.05]. Patients receiving ceftaroline more often had favorable clinical responses than those receiving vancomycin or daptomycin monotherapy. In the absence of large-scale randomized controlled trials, these real-world data provide insights into the potential role of ceftaroline for treating MRSA bacteremia.

Ceftobiprole mono-therapy versus combination or non-combination regimen of standard antibiotics for the treatment of complicated infections: A systematic review and meta-analysis

ObjectiveVarious bacteria produce complicated infections that are difficult to treat worldwide. Ceftobiprole is effective against resistant Gram-positive and Gram-negative bacteria. MethodsThis review assessed effectiveness and safety of ceftobiprole monotherapy for severe infections. A systematic review and meta-analysis of randomized controlled trials comparing clinical cure, microbiological cure, and safety of ceftobiprole alone to a combination or non-combination antibiotic regimen was conducted. Until December 20, 2022, we searched a major databases. ResultsThis study includes 4168 patients from six trials. Ceftobiprole and comparator-received patients had similar clinical responses for all patient population. Also, the eradication rate of all organisms and specific pathogenic bacteria in microbiologically examined patients was comparable between the groups. Ceftobiprole induced more gastrointestinal side events than comparable drugs, mostly nausea [OR 1.91 (1.26-2.90), p=<0.01]. While skin-related adverse events were significantly associated with comparator antibiotics [6 trials, 4062 patients; OR 0.77 (0.60-0.99), p=0.03]. Conclusion: Ceftobiprole monotherapy is effective and safe for severe infections caused by Gram-positive or Gram-negative bacteria.

(235) False Negative Penile Duplex Sonography: Results of Cavernovenous Leakage Surgery in 41 Patients with Normal End-Diastolic Velocity. The Need for Venous Leak Hemodynamic Criteria Re-Evaluation?

Abstract Introduction In cavernovenous leakage (CVL), blood entering corpora cavernosa escapes too early due to abnormal venous network, for erections to develop or maintain. CVL diagnosis relies on persisting blood flow velocity in cavernosal arteries at the end of diastole (EDV), with a consensus 5 cm/s cut-off value at pharmacologically-challenged penile duplex sonography (PC-PDS). Objective We present clinical, hemodynamic characteristics, and response to surgery of 41 patients with severe ED resistant to PDE5Is, with EDV5 cm/s at PC-PDS, considered non pathologic, but with CVLs identified by gold standard pharmacologically-challenged penile CT-cavernography. Methods Prospectively collected data from 41 consecutive patients with ED resistant to PDE5Is, with cavernosal artery EDV5 cm/s (Group A), were compared to data from 130 patients with EDV&amp;gt;5 cm/s (Group B). CVLs in Group A were detected by PC-PDS on deep dorsal vein or penile superficial veins after intracavenosal injection of Prostaglandin E1 plus Papaverine. All patients had refused a penile implant and underwent CVL intervention consisting in open surgery and embolization during the same procedure. Inter-group comparison used a T-test of means, pre- and post-operative data comparison a paired t-test. Results Patients in Group A were younger than in Group B (mean age 38.2±14.0 and 45.9±11.6 years, respectively, p&amp;lt;.0022). Pharmacologic Erection Hardness Score (EHS) was higher (2.9±.7 vs. 2.4±.6, p&amp;lt;.0001), EDV velocity was less (1.6±2.2 vs. 15.1±2.2 cm/s, p&amp;lt;.0001) in Group A than B, respectively. Pre-operative IIEF5 score was higher in Group A than in B (13.3±5.3 and 9.4±4.8, respectively, p&amp;lt;.0181). Other pre-operative erection parameters were otherwise similar in the two groups (morning erection EHS and frequency, masturbation and sexual intercourse EHS, percentage of successful penetration (p&amp;lt;.498, .543, .682, .510, .289, respectively). Patients in Group A and B responded similarly to surgery, with a similar pharmacologic EHS increase at systematic three-month post-operative PC-PDS (0.77±.94 vs. .81±.67, p&amp;lt;.80). Mixing Group A and B 171 patients, at the end of the 29.8±20.4-month follow-up, a significant improvement on all clinical parameters was observed: IIEF-5 score had increased from 9.7±5.1 to 15.5±6.0 (p&amp;lt;.0001), clinical EHS during sexual intercourse from 2.0±.7 to 3.3±.7 (p&amp;lt;.0001), penetration success rate from 22.3±31.7 to 70.1±37.2% (p&amp;lt;.0001), mean EHS during masturbation from 2.11±.67 to 3.04±.75 (p&amp;lt;.0001), morning erection EHS from .95±1.24 to 2.12±1.37 (p&amp;lt;.0001), before and after surgery, respectively. There was no statistically significant difference between Group A and B regarding all these parameters, demonstrating similar clinical responses to surgery. Conclusions Patients with EDV5 cm/s may have CVL evidenced by PC-PDS flow analysis directly on veins, and gold standard PC-PCTC. Their erection disability is severe. They respond well to combined open and embolization surgery, a confirmation that they suffer CVL. EDV criterium misses CVL in as much as one patient out of four with actual CVL in our series. Since false negative diagnosis has severe, life-long, patient and partner implications, hemodynamic criteria for CVL diagnosis should be debated in the field of sexual medicine. Disclosure No.

P872 PREDICT UC: Optimising Infliximab Induction therapy for Acute Severe Ulcerative Colitis – A Randomised Controlled Trial

Abstract Background The optimal dosing strategy of infliximab (IFX) in Acute Severe Ulcerative Colitis (ASUC) is unknown. We compared intensified and standard dose IFX strategies in ASUC. Methods In this open-label randomised trial (NCT02770040), patients from 13 Australian centres with intravenous steroid-refractory ASUC were randomised to receive a first dose of 10mg/kg or 5mg/kg IFX in a 1:2 ratio. Patients in the 10mg/kg group (intensified induction [II]) received a second dose at day 7 or earlier at time of non-response; all 5mg/kg patients were re-randomised 1:1 to standard (SI) or accelerated induction (AI), which produced three induction groups: II, SI and AI. SI patients received 5mg/kg at week 0, 2 and 6, with an extra 5mg/kg dose before day 7 if non-response. AI patients received 5mg/kg at week 0, 1 and 3, with the week 1 dose increased to 10mg/kg and given earlier if non-response. Primary outcome: clinical response by day 7 (reduction in Lichtiger score to &amp;lt;10, with decrease of ≥3 points and improvement in rectal bleeding and stool frequency to ≤4/day). Secondary outcomes compared induction regimens until month 3. Analysis was by intention to treat. Results Between July 2016 &amp; September 2021, 138 patients were randomised; 46 received a first IFX dose of 10mg/kg and 92 received 5mg/kg. Primary outcome: day 7 clinical response was observed in 65% (30/46) of 10mg/kg vs 61% (56/92) of 5mg/kg patients (P=0.76). In the 5mg/kg group, the rate of day 7 response was numerically lower in those with albumin &amp;lt;25g/L vs ≥25g/L [47% (15/32) vs 68% (41/60), P=0.07]. No difference in clinical response was observed in the 10mg/kg group when stratified by albumin [64% (9/14) vs 66% (21/32) P&amp;gt;0.99]. There was no difference in time to clinical response, change in Lichtiger score or CRP from baseline to day 7. Two patients who received 10mg/kg IFX underwent colectomy in the first 7 days vs 0 in the 5mg/kg group (P=0.21). Comparison of induction regimens (II, SI &amp; AI): no difference in clinical remission rates between weeks 2 and 6 were observed. AI and II groups had higher rates of combined clinical and biochemical remission compared to SI between weeks 2 and 6 (P=0.042). At 3 months, there was no difference in rates of endoscopic and steroid-free remission, as well as rates of colectomy (II 7%; SI 12%; AI 19%, P=0.20). Conclusion In steroid-refractory ASUC, a first dose of 10mg/kg or 5mg/kg IFX achieved similar clinical response rates by day 7. Patients receiving intensified or accelerated induction achieved clinical and biochemical remission earlier compared to standard induction; however, outcomes at three months were similar. Patients with a lower albumin may benefit from proactive intensified dosing strategies.

Efficacy and safety of novel carbapenem-β-lactamase inhibitor combinations: imipenem-cilastatin/relebactam results from randomized controlled trials.

Gram-negative bacteria is a global public health problem. Treatment options include novel beta-lactamase inhibitors. The objective of this study was to collect information on the efficacy and safety of novel β-lactamase inhibitor combinations such as imipenem-cilastatin/relebactam (IMI/REL). In order to comprehensively evaluate the clinical, microbiological, and adverse events outcomes, a meta-analysis was conducted on clinical trials comparing novel β-lactamase inhibitor combinations with existing comparator therapies. Four studies comprising 948 patients were included in the analysis. IMI/REL therapy demonstrated similar clinical responses to comparators across various treatment visits, including discontinuation of intravenously administered therapy visits [DCIV, RR = 1.00 (0.88, 1.12)], early follow-up visits [EFU, RR = 1.00 (0.89, 1.14)], late follow-up visits [LFU, RR = 1.00 (0.88, 1.13)]. Moreover, no significant difference in the microbiologic response of MITT patients was observed between IMI/REL and comparators across DCIV [RR = 0.99 (0.89, 1.11)], EFU [RR = 1.01 (0.95, 1.07)], and LFU visits [RR = 1.00 (90.94, 1.07)]. In terms of safety, therapy with IMI/REL and comparators exhibited similar risks of at least one adverse event (AE), drug-related AEs, and discontinuation due to AEs. The incidence of serious AEs (SAEs) was significantly lower in the IMI/REL group compared to the comparison groups. The predominant AEs were gastrointestinal disorders, with no significant difference observed between the IMI/REL group and comparators. The clinical and microbiologic response to IMI/REL in the treatment of bacterial infection was comparable to that of the comparator. Furthermore, the incidence of AEs and the tolerability of IMI/REL were similar among the comparators. Based on these findings, IMI/REL can be considered as a viable alternative treatment option.

Effect of Body Weight on Response to Nasal Glucocorticoid Treatment in Allergic Rhinitis.

Allergic rhinitis is among the most common chronic diseases in the world. Obesity can lead to a chronic systemic inflammatory process. In this study, we evaluated the effects of body weight on the response to treatment of allergic rhinitis with nasal corticosteroids. Two groups of patients diagnosed with allergic rhinitis were compared: one composed of obese patients and one composed of normal weight patients. Nasal endoscopy, peak nasal inspiratory flow, quality of life, the VAS, SNOT22, and NOSE-5 questionnaires, and the concentration of nasal cytokines (INF-γ, TNF-ᾳ, IL-4, IL-5, IL-6, and IL-10) through nasal brushing were evaluated before and after treatment with 400 mcg/day nasal beclomethasone. No differences were identified between the groups in nasal endoscopy, peak nasal inspiratory flow, the VAS, SNOT22, and NOSE-5 questionnaires, or in the cytokines INF-γ, TNF-ᾳ, IL-4, IL-5, IL-6, and IL-10 prior to nasal corticosteroid treatment. Both groups showed improvement in the VAS, SNOT-22, and NOSE-5 questionnaires and an increase in peak nasal inspiratory volumes after treatment. In the eutrophic group, there was an increase in INF-γ and IL-5 after treatment. When comparing the variation in cytokines before and after treatment between groups, IL-10 was the cytokine that showed altered behavior dependent on weight. Obesity did not seem to impact nasal symptoms and physiology and presented a similar clinical response to treatment with nasal corticosteroids to normal weight patients. However, obese patients had an impaired anti-inflammatory response during treatment with nasal corticosteroids.

Patients Age 40 Years and Younger With Multiple Myeloma Have the Same Prognosis as Older Patients: An Analysis of Real-World Patients' Evidence From Latin America

PURPOSE Multiple myeloma (MM) is a highly heterogeneous, incurable disease most frequently diagnosed in the elderly. Therefore, data on clinical characteristics and outcomes in the very young population are scarce. PATIENTS AND METHODS We analyzed clinical characteristics, response to treatment, and survival in 103 patients with newly diagnosed MM age 40 years or younger compared with 256 patients age 41-50 years and 957 patients age 51 years or older. RESULTS There were no statistical differences in sex, isotype, International Scoring System, renal involvement, hypercalcemia, anemia, dialysis, bony lesions, extramedullary disease, and lactate dehydrogenase (LDH). The most used regimen in young patients was cyclophosphamide, bortezomib, dexamethasone, followed by cyclophosphamide, thalidomide, dexamethasone and bortezomib, thalidomide, dexamethasone. Of the patients age 40 years or younger, only 53% received autologous stem-cell transplant (ASCT) and 71.1% received maintenance. There were no differences in overall survival (OS) in the three patient cohorts. In the multivariate analysis, only high LDH, high cytogenetic risk, and ASCT were statistically associated with survival. CONCLUSION In conclusion, younger patients with MM in Latin America have similar clinical characteristics, responses, and OS compared with the elderly.

The Clinical Characteristics and Prognosis of Exon 2 Mutations in Familial Mediterranean Fever

Objective: It is unclear whether exon 2 mutations are variations or a mutations that causes the disease. This study aimed to evaluate the clinical features and prognosis exon 2 mutations in Familial Mediterranean Fever. Methods: The clinical features, disease severity and prognosis of all patients with at least one exon 2 mutations were evaluated retrospectively. These data were compared seperately for homozygous (Group 1), heterozygous (Group 2), compound heterozygous (Group 3), and complex alleles (Group 4), and the data were compared by grouping patients into those with and without exon 10 mutations. Results: There were a total of 119 patients with exon 2 mutations, including 11.7% in Group 1, 36.1% in Group 2, 21.8% in Group 3, and 30.2% in Group 4 were similar in terms of demographic data, clinical characteristics, and disease course. When compared patients with exon 10 mutations (+) to those with exon 10 mutations (-), the exon 10 mutations (+) group had a higher presence of chest pain (100%, p=0.02) and a significantly higher mean Pras severity score (6.66±1.87, 6.01±1.40; p=0.02). Additionally, a higher number of patients with exon 10 mutation (-) achieved remission with treatment (76 (67.9%), 36 (32.1%); p=0.03). Conclusion: Exon 2 mutations have a milder course and higher remission rates but they should be considered as Familial Mediterranean Fever disease because of their similar clinical presentation and response to colchicine treatment with exon 10 mutations. Early treatment and close follow-up should be performed.

The evidence framework of traditional Chinese medicine injection (Aidi injection) in controlling malignant pleural effusion: A clustered systematic review and meta-analysis

IntroductionAidi injection (Aidi), a traditional Chinese medicine injection, is often practiced to control malignant pleural effusion (MPE). ObjectivesWe performed a registered systematic review and meta-analysis (PROSPERO: CRD42022337611) to clarify the clinical role of Aidi in MPE, reveal optimal combinations of Aidi and chemical agents, their indications, therapeutic route and usage, and demonstrate their clinical effectiveness and safety. MethodologyAll randomized controlled trials (RCTs) about Aidi in controlling MPE were collected from Chinese and English databases (up to October 2022). We clustered them into multiple homogenous regimens, evaluated the risk-of-bias at outcome level using a RoB 2, extracted and pooled the data using meta-analysis or descriptive analysis, and finally summarized their evidence quality. ResultsAll 56 studies were clustered into intrapleural administration with Aidi alone or plus chemical agents, and intravenous administration with Aidi for MPE. Intrapleural administration with Aidi alone displayed similar clinical responses on Cisplatin (DDP) alone. Only administration with Aidi plus DDP significantly improved complete response and quality of life, and displayed a low pleurodesis failure, disease progression, hematotoxicity, gastrointestinal and hepatorenal toxicity. For patients with moderate to massive effusion, Karnofsky Performance Status score ≥ 50 or anticipated survival time ≥3 months, Aidi (50 ml to 80 ml each time, one time each week and three to eight times) plus DDP (20 to 30 mg, 40 to 50 mg, or 60 to 80 mg each time) significantly improved clinical responses. Most results had moderate to low quality. ConclusionsCurrent evidences indicate that Aidi, a pleurodesis agent, plays an interesting clinical role in controlling MPE. Aidi plus DDP perfusion is a most commonly used regimen, which shows a significant improvement in clinical responses. These findings also provide an indication and possible optimal usage for rational drug use.

Comparative efficacy and optimal duration of first-line antibiotic regimens for acute otitis media in children and adolescents: a systematic review and network meta-analysis of 89 randomized clinical trials.

Antibiotic use for acute otitis media (AOM) is one of the major sources of antimicrobial resistance. However, the effective minimal antibiotic duration for AOM remains unclear. Moreover, guidelines often recommend broad ranges (5-10days) of antibiotic use, yet the clinical impact of such a wide window has not been assessed. We systematically searched PubMed/MEDLINE, Embase, Scopus, Web of Science, and Cochrane Library from database inception to 6 October 2021. Network meta-analysis was conducted on randomized controlled trials that assessed antibiotic treatment for AOM in children (PROSPERO CRD42020196107). For amoxicillin and amoxicillin-clavulanate, 7-day regimens were noninferior to 10-day regimens in clinical responses [amoxicillin: risk ratio (RR) 0.919 (95% CI 0.820-1.031), amoxicillin-clavulanate: RR 1.108 (0.957-1.282)], except for ≤ 2years. For the third-generation cephalosporins, 7-day and 10-day regimens had similar clinical responses compared to placebo [7-day: RR 1.420 (1.190-1.694), 10-day: RR 1.238 (1.125-1.362) compared to placebo]. However, 5-day regimens of amoxicillin-clavulanate and third-generation cephalosporins were inferior to 10-day regimens. Compared to amoxicillin, a shorter treatment duration was tolerable with amoxicillin-clavulanate. Our findings indicated that 10days of antibiotic use may be unnecessarily long, while the treatment duration should be longer than 5days. Otherwise, 5-day regimens would be sufficient for a modest treatment goal. Our findings revealed that the current wide range of recommended antibiotic durations may have influenced the clinical outcome of AOM, and a narrower antibiotic duration window should be re-established.

Abstract 3190: ALA-CART induces global transcriptional changes leading to enhanced potency and persistence of CAR T cells against both lymphoid and myeloid acute leukemias

Abstract Chimeric antigen receptor (CAR) T cell therapy has revolutionized cancer treatment, demonstrating clinical success in B-cell malignancies that are refractory to standard therapies. Relapses after CAR therapy has demonstrated the limitations of current CAR T cell therapies to target antigen-low tumors and induce consistent persistence. Furthermore, the success of CAR T cell therapy in B-lineage malignancies has not yet been translated to acute myeloid leukemia (AML). The targeting of myeloid-restricted antigens, such as CD33, with standard 2nd generation CAR T cells has not yielded similar clinical responses as ALL. Therefore, we hypothesize that novel CAR T cell strategies will be required to improve responses in non-B cell malignancies. We identified that CAR T cells inefficiently activate the scaffolding protein LAT in response to low levels of antigen, leading to diminished efficacy. We designed a bicistronic construct consisting of a clinically active 2nd generation CD22-BBz CAR along with a novel Adjunctive LAT Activating CAR incorporating the intracellular signaling domain of LAT (ALA-CART) to overcome this deficiency of signaling in CAR T cells. In xenograft models, 22ALA-CART cells completely eradicated CD22-low leukemia, which is not responsive to standard CD22-BBz CAR T cells. We have extended these findings to CD19-directed ALA-CART cells, which eradicate CD19-low leukemia that is otherwise resistant to standard CD19-BBz CAR T cells. To understand how ALA-CART improves responses to antigen-low leukemia, we evaluated the in vivo potency of ALA-CART relative to 2nd generation CARs and found ALA-CART cells could eradicate ALL in xenograft models at lower doses than standard CAR T cells. RNA-Seq analysis demonstrated global differences in ALA-CART cells in the resting state reflecting a less differentiated state, which corresponded to an enrichment of T stem cell memory cells and enhanced in vivo persistence. Stimulation through the ALA-CART receptor led to widespread changes in transcription factor activity in T cells which were distinct from standard CAR activation, particularly inducing significantly lower interferon response factor activity which has been associated with CAR T cell failure in patients. As strategies targeting myeloid lineage-restricted antigens with 2nd generation CAR T cells have not yet produced the clinical success seen with ALL-directed CAR therapy, we tested whether the ALA-CART platform could improve the activity of CD33-directed CAR T cells. CD33 ALA-CART cells demonstrated improved in vivo potency and exhibited enhanced memory potential like our results with ALL-directed ALA-CART. Thus, through the reversal of signaling deficits intrinsic to 2nd generation CARs, the ALA-CART platform improves the potency and persistence of CAR T cell therapy against both lymphoid and myeloid acute leukemias. Citation Format: Catherine Danis, Lillie Leach, Christopher Ebmeier, Amanda Novak, Etienne Danis, M. Eric Kohler. ALA-CART induces global transcriptional changes leading to enhanced potency and persistence of CAR T cells against both lymphoid and myeloid acute leukemias [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3190.

Constructing metabolism-protein interaction relationship to identify glioma prognosis using deep learning

Glioma is heterogeneous disease that requires classification into subtypes with similar clinical phenotypes, prognosis or treatment responses. Metabolic-protein interaction (MPI) can provide meaningful insights into cancer heterogeneity. Moreover, the potential of lipids and lactate for identifying prognostic subtypes of glioma remains relatively unexplored. Therefore, we proposed a method to construct an MPI relationship matrix (MPIRM) based on a triple-layer network (Tri-MPN) combined with mRNA expression, and processed the MPIRM by deep learning to identify glioma prognostic subtypes. These Subtypes with significant differences in prognosis were detected in glioma (p-value < 2e-16, 95% CI). These subtypes had a strong correlation in immune infiltration, mutational signatures and pathway signatures. This study demonstrated the effectiveness of node interaction from MPI networks in understanding the heterogeneity of glioma prognosis.

Real-World Treatment Patterns and Effectiveness of Targeted and Immune Checkpoint Inhibitor-Based Systemic Therapy in BRAF Mutation-Positive NSCLC

IntroductionBRAF mutations (present in 2%–3% of NSCLC) are a known oncogenic driver and emerging therapeutic target. There is a scarcity of real-world data describing the clinical characteristics, treatment patterns, and effectiveness of targeted BRAF-inhibiting and immune checkpoint inhibitor (ICI)-based systemic therapies, yet this is required for appropriate treatment decisions that optimize patient outcome. MethodsDemographic, clinical, treatment, and outcome data of patients with BRAF mutation-positive NSCLC diagnosed between 2018 and 2022 were identified from the Glans-Look Lung Cancer Research database and included in this analysis. ResultsA total of 53 BRAF mutation-positive patients were identified (V600E, n = 35; non-V600E, n = 18). Furthermore, 46 patients (87%) were diagnosed with metastatic disease, of whom 61% were treated with systemic anticancer therapy, which significantly improved overall survival (34.1 versus 2.2 mo, p = 0.01). ICI-based regimens were found to have effectiveness in the first-line setting for both V600E and non-V600E cohorts (objective response rate: 38%–43%; real-world calculations of median progression-free survival: 10.5–10.8 mo, respectively). Dual-targeted BRAF/MEK inhibition was also found to have effectiveness in the first-line setting for V600E patients (objective response rate: 33%, real-world calculations of median progression-free survival: 15.2 mo). ConclusionsThis study of real-world patients with BRAF mutations confirms the importance of effective systemic therapies. Both dual-targeted BRAF/MEK inhibition and ICI-based regimens have evidence of benefit in this population revealing that real-world populations can experience similar clinical response and outcome to clinical trial cohorts on these treatment regimens. Future studies to clarify the role of co-mutations on response to both dual-targeted BRAF/MEK inhibition and ICI-based regimens may be important to treatment selection and optimization of patient outcome.