Terms Of Clinical Response Research Articles

Association Between Single-Dose and Longer Term Clinical Response to Stimulants in Attention-Deficit/Hyperactivity Disorder: A Systematic Review of Randomized Controlled Trials.

Objectives: Stimulants, such as methylphenidate (MPH) and amphetamines, represent the first-line pharmacological option for attention-deficit/hyperactivity disorder (ADHD). Randomized controlled trials (RCTs) have demonstrated beneficial effects at a group level but could not identify characteristics consistently associated with varying individual response. Thus, more individualized approaches are needed. Experimental studies have suggested that the neurobiological response to a single dose is indicative of longer term response. It is unclear whether this also applies to clinical measures. Methods: We carried out a systematic review of RCTs testing the association between the clinical response to a single dose of stimulants and longer term improvement. Potentially suitable single-dose RCTs were identified from the MED-ADHD data set, the European ADHD Guidelines Group RCT Data set (https://med-adhd.org/), as updated on February 1, 2024. Quality assessment was carried out using the Cochrane Risk of Bias (RoB) 2.0 tool. Results: A total of 63 single-dose RCTs (94% testing MPH, 85% in children) were identified. Among these, only a secondary analysis of an RCT tested the association between acute and longer term clinical response. This showed that the clinical improvement after a single dose of MPH was significantly associated with symptom improvement after a 4-week MPH treatment in 46 children (89% males) with ADHD. The risk of bias was rated as moderate. A further RCT used near-infrared spectroscopy, thus did not meet the inclusion criteria, and reported an association between brain changes under a single-dose and longer term clinical response in 22 children (82% males) with ADHD. The remaining RCTs only reported single-dose effects on neuropsychological, neuroimaging, or neurophysiological measures. Conclusion: This systematic review highlighted an important gap in the current knowledge. Investigating how acute and long-term response may be related can foster our understanding of stimulant mechanism of action and help develop stratification approaches for more tailored treatment strategies. Future studies need to investigate potential age- and sex-related differences.

Abstract 6443: Enhanced detection of ctDNA molecular response for immunotherapy treated non-small cell lung cancer through analyses of cell-free and matched white blood cell DNA

Abstract Introduction: Immune checkpoint inhibitors (ICIs) have greatly improved clinical outcomes for patients with non-small cell lung cancer (NSCLC), however, programmed death-ligand 1 (PD-L1) and tumor mutation burden (TMB) have failed to consistently predict therapeutic response and outcomes in this population. There remains a critical unmet need to identify patients who are likely to experience clinical benefit from treatment, particularly as additional treatment regimens become available. Longitudinal cell-free tumor DNA (ctDNA) assessments have recently been applied as a strategy to identify molecular response (mR) and better predict long term clinical response. Through this real-world analysis of NSCLC, we explore the technical and biological considerations associated with determination of ctDNA mR through matched cell-free and white blood cell (WBC) DNA analyses and apply this optimized approach to assess therapeutic response to ICIs. Methods: Plasma from 50 patients with advanced or metastatic NSCLC who received ICIs from 2017-2019 at Hospital del Mar had detectable pre-treatment ctDNA and underwent analysis using the 521 gene PGDx elio plasma complete liquid biopsy assay. Patient blood was collected prior to the start of ICI therapy, early on-treatment (median 4 weeks; range 2.4-9 weeks) and longitudinally throughout clinical follow-up and disease progression. Matched WBCs were also analyzed for each patient to identify alterations arising from germline polymorphisms and clonal hematopoiesis (CH). mR was calculated as the percent change in mean variant allele frequency of the tumor-specific alterations assessed at the early on-treatment timepoint compared to the pre-treatment timepoint, and compared to radiographic response, progression-free, and overall survival (OS). Results: Best overall response for patients within the cohort was 4% complete response, 26% partial response, 34% stable disease, and 36% progressive disease. The removal of germline or CH variants allowed for improved characterization of tumor-specific somatic alterations and associations with radiographic and survival-based endpoints. With the integrated ctDNA and matched WBC approach, we observed a mR rate of 34% (17/50) with a median OS of 36.8 months compared to 9.2 months for patients experiencing molecular progression at the early on-treatment timepoint (HR 5.6, 95% CI 2.4-12.7, p<0.001, log-rank test). Specifically, of all patients that survived ≤12 months after initiation of treatment, 84% (21/25) were categorized as experiencing molecular progression through early on-treatment ctDNA analyses. Conclusions: This real-world study of ICI treated, advanced NSCLC highlights the opportunity afforded through integrated analyses of ctDNA and matched WBCs to accurately determine mR and the associations with radiographic response and OS. Citation Format: Jennifer B. Jackson, Pedro Rocha, James R. White, Andrew P. Georgiadis, Ellen L. Verner, Amy Greer, Rafael Bach Mora, Laura Masfarré Pintó, Nil Navarro, Álvaro Taus, Beatriz Bellosillo Paricio, Sergi Clavé, Mark T. Sausen, Edurne Arriola. Enhanced detection of ctDNA molecular response for immunotherapy treated non-small cell lung cancer through analyses of cell-free and matched white blood cell DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6443.

P685 Effectiveness of a second-line anti-TNFɑ agent compared to a different mechanism of action after first anti-TNFɑ failure in ulcerative colitis: CambiaCU Study

Abstract Background Ulcerative colitis (UC) is a chronic and relapsing disease for which the number of biological therapies available are increasing over the years. Data comparing the effectiveness of a second anti-TNFɑ (aTNF) and the switch to a different mechanism of action (MoA) such as Ustekinumab (UST), Vedolizumab (VDZ), Filgotinib or Tofacibinib (JAK) is lacking. Methods We performed a multicenter and retrospective study (6 Andalusian sites) in which patients diagnosed of UC who had failed a first biological therapy with an aTNF and started a second-line biological therapy with another aTNF or a different MoA (UST, VDZ, JAK) were included. Clinical response and remission were assessed at weeks 16 and 52. The aim of our study was to evaluate the effectiveness of a second-line biological therapy with aTNF compared to a different MoA after a first aTNF failure. Results 185 UC patients were included. There were no differences in the demographic data except for disease duration (9 years with MoA vs 13 years in aTNF, p=0.02). As first aTNF, infliximab (IFX) was the most common in both groups (49% MoA group, 56% second aTNF), followed by adalimumab (ADA) (48% MoA group, 33% second aTNF). In the second aTNF group, immunomodulators were significatively more used (60% vs 38%, p=0.003). There were no differences in the concomitant use of steroids. 80 patients received a different MoA (37 VDZ, 24 UST, 7 JAK) and 105 a second aTNF (34 IFX, 60 ADA, 11 golimumab). At week 16, 52% of patients were in clinical response (70% with another MoA vs 54% with second aTNF, p=0.07; IFX 65%, ADA 53%, VDZ 68%, UST 71%, JAK 74%, p=0.07), being 15.6% more likely to achieve response with another MoA. Clinical remission at week 16 was obtained by 36% (39% with another MoA vs 33% with second aTNF, p=0.6; IFX 47%, ADA 30%, VDZ 35%, UST 46%, JAK 37%, p=0.1). At week 52, 48% achieved clinical response (51% with another MoA vs 45% with second aTNF, p=0.8; IFX 50%, ADA 42%, VDZ 49%, UST 54%, JAK 53%, p=0.5) and 39% were in clinical remission (40% with another MoA vs 38% with second aTNF, p=0.53; IFX 50%, ADA 32%, VDZ 35%, UST 38%, JAK 53%; p=0.06) (figure 1). When the effectiveness is analyzed by first aTNF used, independently of the aTNF, subsequent use of a different MoA achieves better results although not significant compared to a second aTNF. Partial Mayo and calprotectin showed a significant decrease at weeks 16 and 52 in both groups. Hemoglobin and albumin levels remained similar during follow-up in both groups. Conclusion Second-line biological therapy is effective regardless of biological therapy used in UC, but switching to a different MoA tend to achieve better results in terms of clinical response and remission compared to a second aTNF.

P776 A Prospective, Multicenter, Single-arm, Observational Study to Evaluate the Safety and Effectiveness of Vedolizumab in Real-world Clinical Practice in China: Interim Analysis of Safety results

Abstract Background Crohn's disease (CD) and ulcerative colitis (UC) are categorized as inflammatory bowel disease [IBD] usually treated by corticosteroids, immunomodulators and biologics, etc. Vedolizumab, a gut-selective α4β7 integrin antibody, has been approved in China for IBD patients who are intolerant /lost response to conventional therapies or TNF-α inhibitors. Of late, there is a paucity of data on the safety and effectiveness of vedolizumab in real-world clinical practice in China. This study evaluates the safety and effectiveness of vedolizumab in adult patients with UC or CD Here, we present the first interim analysis. Methods In this multicenter, single arm, prospective, observational, real-world study (NCT04872491), adults (aged >18 years) with UC or CD were administered intravenous vedolizumab 300 mg at week 0, 2, 6, and thereafter every 8 weeks. Incidence of adverse events (AEs), serious AEs (SAEs), Treatment-related AEs (TRAEs) and AEs of special interest (AESIs) were the primary endpoints Patients with administration of at least 1 dose of VDZ were included and observed 18 weeks after completion of the study or early termination, up to maximum of 72 weeks. AESIs included infections, malignancies, infusion-related reactions, and hypersensitivity. The secondary endpoints included the effectiveness of vedolizumab in terms of clinical response, clinical remission and endoscopic remission assessed at week 14 and week 54 after vedolizumab initiation. Results A total of 307 patients (UC, n=245; CD, n=62) with a median age of 41 years (range: 18-86) were included in the interim analysis. Median duration was 883 days (UC: 1035 days; CD: 731 days) and 105 days (UC: 107 days; CD: 99 days) for IBD and vedolizumab exposure, respectively. A total of 105 (34.20%) patients (UC: 35.92%; CD: 27.42%) developed 225 AEs and the most frequent AEs were infections and infestations (16.61%) followed by gastrointestinal disorders (GID) (14.66%) and general disorders (GD) (4.56%). Colitis and pyeria were the most common GID and GD, respectively occurred in 7(2.28%) patients each (Table 1). Forty-one TRAEs were observed and ten AEs lead to study discontinuation. Total 13 AESIs and 34 SAEs were reported and at least one AESI was reported in 10 patients. No deaths were reported during the study (Table 2). A total of 79.19% (118/149) and 34.48% (10/29) patients with UC and CD respectively, achieved clinical response at week 14 (±4 weeks). Clinical remission and endoscopic remission was achieved by 2/2 and 1/1 patients with UC, respectively at week 54 (±4 weeks). Conclusion Vedolizumab demonstrated favorable safety profile and treatment effectiveness among Chinese adult patients with UC or CD in real-world clinical practice.

A prospective randomized half-body study: 308 nm LED light vs. 308 nm excimer laser for localized psoriasis.

Psoriasis is a chronic skin disease affecting approximately 3.2% of the population. The 308 nm light emitting diode (LED) is a novel, portable, and cost-effective light source, may have potential in the treatment of localized psoriasis patients in a home setting. To compare the clinical and dermoscopic responses in localized psoriatic patients undergoing localized phototherapy with 308 nm LED light and excimer laser. Twenty-two patients with mild-to-moderate psoriasis and symmetrical skin lesions were included in this prospective, randomized, left-to-right body trial. The target lesions were randomly treated with either LED light or excimer laser twice a week for 12 weeks. The responses were evaluated by the local psoriasis severity index (LPSI) scores, and dermoscopic features of the target lesions were examined and analyzed. Out of the 22 included psoriasis patients, 10 successfully completed the 12 weeks study. Both treatment sides showed similar clinical improvement in terms of clinical response, as evidenced by a LPSI 50 rate of 70% on the LED side and 80% on the excimer side, p > 0.05. Furthermore, the dermoscopic features also exhibited comparable improvement. The efficacy and safety of 308 nm LED light therapy are comparable to 308 nm excimer laser therapy. Moreover, given the portability and cost-effectiveness of 308 nm LED light, it holds great promise as a home phototherapy in the treatment of psoriasis.

777-P: Early Weight Loss and Late Metabolic Outcomes in Tirzepatide-Treated Participants with Type 2 Diabetes

Tirzepatide (TZP), a novel, once-weekly GIP/GLP-1 receptor agonist, significantly improved glycemic control with robust weight loss vs comparators in the SURPASS 1-5 trials. The aim of this analysis was to assess whether the magnitude of early weight loss with TZP (<5% or ≥5% at Week 8) would be associated with different clinical response in terms of HbA1c and weight at Week 40/42 across the SURPASS 1-5 trials. These phase 3 trials included participants with type 2 diabetes receiving TZP as monotherapy or add-on to background antihyperglycemic medications. This post-hoc analysis used pooled data from all TZP arms (5, 10, and 15 mg) across trials. Participants achieving ≥5% early weight loss at Week 8 had lower HbA1c and weight at baseline, and experienced greater reductions in HbA1c and weight at Week 40/42 vs those achieving <5% early weight loss (Table). Among participants achieving ≥5% early weight loss, greater proportions met HbA1c <7% and ≤6.5%, ≥10% weight loss, and the composite endpoint of HbA1c <7% and ≥10% weight loss. Early weight loss with TZP predicts greater reductions of HbA1c and weight at Week 40/42. However, even the one third of participants achieving <5% weight loss early in the course of therapy are likely to meet the ADA/EASD dual treatment goals of HbA1c <7% and ≥10% weight loss. Disclosure I.Lingvay: Advisory Panel; Novo Nordisk A/S, Lilly Diabetes, Boehringer-Ingelheim, Sanofi, Consultant; Carmot Therapeutics, Inc., Merck Sharp & Dohme Corp., Janssen Scientific Affairs, LLC, Pfizer Inc., Intercept, Intarcia, Valeritas, TargetRWE, Shionogi, Zealand Pharma, Structure, Bayer, Research Support; Novo Nordisk A/S, Boehringer-Ingelheim. F.Giorgino: Advisory Panel; Boehringer-Ingelheim, Amarin Corporation, Medtronic, Roche Diabetes Care, Sanofi, Bayer Inc., Novo Nordisk, Consultant; Novo Nordisk, Lilly, Research Support; Lilly, Roche Diabetes Care, AlfaSigma, Speaker's Bureau; Abbott, Boehringer-Ingelheim, Lilly, Sanofi, Medscape. L.Van gaal: Advisory Panel; Merck Sharp & Dohme Corp., Speaker's Bureau; Boehringer Ingelheim Pharma GmbH&Co.KG, Eli Lilly and Company, Novo Nordisk. M.Liu: Consultant; Eli Lilly and Company. Á.Rodríguez: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. A.Torcello-gomez: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. J.I.Kiljanski: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. Funding Eli Lilly and Company

#6738 ALCOHOL LOCK IN CRBSI: A PANACEA

Abstract Background and Aims CRBSI is a dreaded complication of permcath, with a reported incidence of 1.1 – 5.5 episodes/1000 days. Many of these patients especially those infected with Staphylococcus aureus, Pseudomonas aeruginosa or fungal growth require catheter removal. 70% alcohol possibly breaks the biofilm in the catheter and exposes hidden bacteria to antibiotics. This study was done to find the usefulness of 70% alcohol lock in patients with established CRBSI. Method All dialysis patients in our centre with permcath as vascular access were the subjects of the study. All patients were given heparin lock after each dialysis session. CRBSI was diagnosed as per CDC/IDSA criteria. All patients with CRBSI in addition to antibiotics were also given 70% alcohol lock (2 ml in each port) for 3 consecutive days. Outcome of these patients in term of clinical response and need for catheter removal was studied. The catheter outcome of this group was compared with our patients (retrospective controls) who were given only antibiotics and not given alcohol lock. Results Over last two years 166 permcaths were placed in our institution. Eighty nine of them continued dialysis in our centre. Their total follow up period was 12028 days (30-720 days). There were 18 episodes of CRBSI in 14 of these patients (1.5 episodes per 1000 catheter days). Three of these patients (16.67%) required catheter removal, rest all improved with antibiotics and alcohol lock. Over a follow up of 150 days (30 -420 days), these patients have been doing well and there has been no episode of catheter leak or break or block. On comparing with our retrospective control of 22 patients with CRBSI, who were not given alcohol lock, 15 (68.18%) required catheter removal (P = 0.001). Conclusion The present study though on small numbers, shows that alcohol lock works as a boon in the setting of established CRBSI. It avoids catheter removal in majority of patients.

Evaluation of ICI sensitivity for pembrolizumab in combination with anti-platelet therapy for patients with recurrent or metastatic squamous cell carcinoma of the head and neck (HNSCC).

6041 Background: This study was proposed to elucidate the impact of combining anti-platelet therapy with an immune checkpoint inhibitor (ICI) in altering the CD8+ T cell function in patients with head and neck squamous cell carcinoma (HNSCC). With a total enrollment of 15 of out an expected 20 patients, this report characterizes the findings thus far from the ongoing study. Methods: This crossover trial consisted of two different treatment regimens for two groups. Regimen A involved treatment with a PD-1 inhibitor pembrolizumab (200 mg iv over 30 min) every 3 weeks in combination of daily aspirin (81 mg orally) and clopidogrel (75 mg orally) for a total of 6 weeks. Regimen B involved pembrolizumab monotherapy (200 mg iv over 30 min) every 3 weeks for two cycles. Thus far, 15 patients with recurrent or metastatic HNSCC were randomized into the two groups, with Group 1 receiving Regimen A followed by Regimen B, while Group 2 received Regimen B followed by Regimen A. In addition to clinical endpoint, in depth analysis of the peripheral blood mononuclear cells (PBMCs) was also implemented using samples obtained prior to treatment, in between regimens, and at the end of treatment. These samples were then analyzed using a spectral flow cytometer panel specific for human CD8+ T cells. Given the 75 percent accrual, we performed analysis with the obtained clinical samples and data. Results: Of the 15 patients enrolled into the study, 14 remained on study and completed the trial till endpoint. All 14 patients presented with no overtly significant adverse events (AEs). In terms of clinical response, we observed in Group 1 patients (n=7) a total of 1 CR (complete response), 1 PR (partial response), 2 SD (stable disease), and 3 PD (progressive disease), while Group 2 (n=7) presented with 2 PR, 2 SD, and 3 PD. Spectral flow analysis performed on Group 1 patient samples revealed an increase in the Ki67+PD1+ proliferative subset post combination treatment (p value < 0.05, paired Student’s t-test). This finding indicates a potential increase in proliferation among CD8+ T cells after antigen stimulation that may pertain to the combination of anti-PD-1 and anti-platelet therapy. In addition, a higher frequency of Ki67+TIGIT+ CD8+ population (p value < 0.05, paired Student’s t-test) was also observed after combination therapy compared to pre-treatment; however, this level was not sustained after combination therapy was ceased, implying that ongoing anti-platelet therapy may be necessary for augmenting ICI. Conclusions: Combination of anti-PD1 and anti-platelet therapy demonstrates potential for remodeling the immune compartment pertaining to CD8+ T cells without resulting in overt toxicity. Further analysis of the effects of this combination regimen will be essential to better characterize tumor specific impact. Clinical trial information: NCT03245489 .

Matching-Adjusted Indirect Comparisons of Filgotinib vs Vedolizumab, Tofacitinib, and Ustekinumab for Moderately to Severely Active Ulcerative Colitis.

Where head-to-head trials are lacking, indirect comparative effectiveness can aid treatment decisions. We conducted matching-adjusted indirect comparisons of clinical outcomes with filgotinib vs recently approved comparators (vedolizumab, tofacitinib, ustekinumab) in patients with moderately to severely active ulcerative colitis (UC). Individual patient data from the SELECTION trial (NCT02914522) for filgotinib 200 mg were weighted to match average baseline characteristics of active treatment and placebo arms in comparator trials. Efficacy outcomes were compared for biologic-naive and biologic-experienced subgroups in induction and maintenance populations, if data were available. Safety and health-related quality of life outcomes were compared in the overall maintenance population. Filgotinib had a similar effect on efficacy outcomes compared with tofacitinib, ustekinumab, and subcutaneous vedolizumab in both the induction and maintenance populations. Filgotinib showed improved clinical response vs intravenous (IV) vedolizumab (odds ratio, 2.4; 95% confidence interval [CI], 1.0 to 5.5; P < .05) among the biologic-experienced induction population, and improved corticosteroid-free clinical remission (odds ratio, 15.2; 95% CI, 1.6 to 139.9; P < .05) among the biologic-naive maintenance population. Improved efficacy outcomes were reported with filgotinib compared with ustekinumab among the maintenance population. Higher estimates of serious adverse events were reported for filgotinib compared with vedolizumab IV 300 mg and tofacitinib 5 mg; however, imbalances were noted in their placebo groups. Health-related quality of life outcomes were similar between filgotinib and comparators. Matching-adjusted indirect comparison results suggest superiority of filgotinib 200 mg over vedolizumab IV in terms of clinical response and corticosteroid-free clinical remission in certain patient populations, noting small sample sizes and wide CIs, which may aid the selection of advanced therapies for moderately to severely active UC. A potential increased risk of serious adverse events was reported for filgotinib 200 mg vs vedolizumab IV and tofacitinib 5 mg, but findings should be interpreted with caution owing to underlying imbalances observed between the placebo groups of SELECTION and comparator trials.

Clinical and immunogenomic outcomes of consolidative cytoreductive nephrectomy in patients with metastatic renal cell carcinoma treated with immune checkpoint blockade.

720 Background: Immune checkpoint blockade (ICB) alone and in combination has dramatically improved outcomes in metastatic renal cell carcinoma (RCC). We performed in-depth clinical, histopathologic and immunogenomic analysis of a cohort of RCC patients treated with upfront ICB followed by delayed consolidative cytoreductive nephrectomy. This highly selected cohort included extreme responders defined by complete pathologic response and no evidence of disease at more than 25 months of follow-up. Methods: Clinicopathologic data was collected from 32 patients who received ICB (alone or combined with anti-VEGF therapy) and then subsequently underwent resection of primary tumor. Immunogenomic analysis was performed on select pre-treatment and nephrectomy tissue using targeted next-generation sequencing (MSK-IMPACT) and immunohistochemical (IHC) staining analyses. We further performed single-cell (sc)RNA sequencing of both peripheral blood and residual tumor tissue (where available), including 4 patients who demonstrated complete pathologic response. The Kaplan-Meier method was used to calculate survival outcomes. Results: All 32 patients underwent successful consolidative surgery and were further stratified based on evidence of radiographic progression, with 13 pts (40.6%) demonstrating no evidence of disease after surgery. The most common histopathology was clear cell RCC (n=29, 90.6%). Half the patients received dual ICB (CTLA-4/PD-1) (n=16, 50%), while the rest received an immunotherapy agent plus an anti-VEGF agent (n=13, 40.6%) or a single immunotherapy agent (n=3, 9.4%). Median follow-up for the cohort was 33.1 mo. (95%CI: 20.5-42.5) and median OS was 45.2 mo. (95%CI:23.9 – NR). Median OS for those who had progressive disease after CN was 25.5 (95%CI: 16.4- NR). At a median follow-up of 25.5 mo. in patients without evidence of disease after CN, 24-month survival rate was 100%. On pathologic evaluation, those without evidence of disease had a median of 8% (IQR: 0-35%) residual viable tumor. Mutational analysis revealed enrichment for BAP1 (n=3, 20.0% vs. n=0, 0%) and SETD2 (n=7, 46.7% vs. n=0, 0%) in progressive patients. scRNAseq and scTCRseq analysis of peripheral blood revealed distinct expansion of Natural Killer (NK), CD4 subsets and unique T cell clonal expansions amongst long term responders. Additionally, we identified an inverse relationship between NK cell populations and B cell infiltration in long term responders. Conclusions: Delayed cytoreductive nephrectomy in select patients is associated with favorable outcomes, especially in those who demonstrate complete response after surgery. Examination of this population offers opportunities for identification of unique tissue and peripheral based biomarkers for long term clinical responses in metastatic RCC.

Adverse reactions after treatment with dasatinib in chronic myeloid leukemia: Characteristics, potential mechanisms, and clinical management strategies.

Dasatinib, a second-generation tyrosine kinase inhibitor, is recommended as first-line treatment for patients newly diagnosed with chronic myeloid leukemia (CML) and second-line treatment for those who are resistant or intolerant to therapy with imatinib. Dasatinib is superior to imatinib in terms of clinical response; however, the potential pulmonary toxicities associated with dasatinib, such as pulmonary arterial hypertension and pleural effusion, may limit its clinical use. Appropriate management of dasatinib-related severe events is important for improving the quality of life and prognosis of patients with CML. This review summarizes current knowledge regarding the characteristics, potential mechanisms, and clinical management of adverse reactions occurring after treatment of CML with dasatinib.

Combination therapy is not associated with improved rates of clinical or endoscopic remission in patients with inflammatory bowel disease treated with ustekinumab or vedolizumab: a retrospective study.

Management of inflammatory bowel disease (IBD) involves biological agents, often in combination with thiopurines or methotrexate. The aim of our study was to compare clinical and endoscopic outcomes in IBD patients treated with vedolizumab or ustekinumab, as monotherapy or in combination with thiopurines or methotrexate. We conducted a retrospective cohort study of all patients aged ≥18 years with a diagnosis of ulcerative colitis or Crohn's disease, commenced on vedolizumab or ustekinumab between October 2015 and March 2022. Primary outcome was clinical remission or response calculated by partial Mayo score (remission: <3; response: improvement >1) for ulcerative colitis or Harvey-Bradshaw index (<5, >2 respectively) for Crohn's disease over 1 year. Secondary endpoints were treatment failure, relapse, endoscopic remission at 1 year. Statistical analysis was done using 2-sample Student's t and chi-square tests. A total of 159 IBD patients were included in the study, 85 (53%) on vedolizumab and 74 (47%) on ustekinumab. For those on vedolizumab, 61 (72%) patients had ulcerative colitis, and 24 (28%) has Crohn's disease. All patients on ustekinumab had Crohn's disease. Mean disease duration in was 9.4 and 13.5 years respectively. There was no difference in clinical response or remission for vedolizumab or ustekinumab monotherapy compared to combination therapy at 1 year. There was also no difference in treatment failure, relapse or endoscopic remission. Combining vedolizumab or ustekinumab with an immunomodulator is not superior to monotherapy in terms of clinical response or endoscopic remission up to 1 year in IBD.

Efficacy and safety of vedolizumab for inflammatory bowel diseases: A systematic review and meta-analysis of randomized controlled trials.

Background:Vedolizumab is a humanized monoclonal antibody that inhibits gut-selective α4β7 integrins on the surface of leukocytes, preventing their trafficking into the gastrointestinal tract, and ultimately achieves the effect of suppressing intestinal inflammation. This study aimed to evaluate the efficacy and safety of vedolizumab in the treatment of inflammatory bowel disease.Methods:After a systematic review of relevant studies, the pooled relative risk (RR) and 95% confidence intervals (CIs) were calculated to evaluate the effect. Heterogeneity was explored using sensitivity analysis, univariate meta-regression, and subgroup analysis. Potential publication bias was evaluated using Egger test and trim-and-fill method.Results:Nine randomized controlled trials involving 4268 participants were included in the meta-analysis. During induction therapy, vedolizumab was more effective than placebo in treating active ulcerative colitis and Crohn disease in terms of clinical response (RR = 1.55, 95%CI: 1.35–1.78), clinical remission (RR = 1.90, 95%CI: 1.50–2.41), and mucosal healing (RR = 1.53, 95%CI: 1.21–1.95). A superior effect in terms of durable Clinical or Crohn disease Activity Index-100 response (RR = 1.65, 95%CI: 1.20–2.26), clinical remission (RR = 1.92, 95%CI: 1.48–2.50), and glucocorticoid-free remission (RR = 2.22, 95%CI: 1.71–2.90) was found during maintenance treatment. Vedolizumab was not associated with any adverse events and was as safe as placebo in terms of the risk of serious adverse reactions.Conclusions:Vedolizumab may be safe and effective as an induction and maintenance therapy for the treatment of inflammatory bowel disease; however, further studies are needed to validate this conclusion.

Switching from adalimumab originator to biosimilars in hidradenitis suppurativa: What's beyond cost-effectiveness?

In the last years, adalimumab biosimilars have represented a commonly used alternative to the originator agent in the treatment of moderate to severe hidradenitis suppurativa. As of today, studies investigating the switch from adalimumab originator to biosimilar, following pharmacoeconomic policies, are lacking. Herein we present a real-life setting retrospective study aimed at assessing the safety and efficacy of this switch in 37 patients, evaluated for 12 months in terms of IHS4 (International Hidradenitis Suppurativa Severity Score System) and HiSCR (Hidradenitis Suppurativa Clinical Response). Overall, no significant differences emerge between adalimumab originator and biosimilar in terms of clinical response following non-medical switch. High discontinuation rates (43.2%) raise questions on patients' compliance to the new drug regimen, as severe pain at the injection site represents a substantial cause of biosimilar discontinuation (i.e., 31.5% of the cases). In selected cases, rechallenge with adalimumab originator may represent a valid option, as 66.6% (n=8) of the patients who switched back to the former agent have benefited in terms of tolerability and efficacy. Carefully integrating pharmacoeconomic policies with a thorough assessment regarding the benefit-risk ratio of a nonmedical switch from originator to biosimilars remains essential to provide each HS patient with the best therapeutic option.

Vagus Nerve Stimulation in Treatment-Resistant Depression: A Case Series of Long-Term Follow-up.

Vagus nerve stimulation (VNS) has been shown to be effective for treatment-resistant depression (TRD). However, long-term (>5 years) studies on the efficacy and tolerability of this treatment have been lacking. Here, we report a long-term clinical follow-up of 5 patients with severe and long-standing TRD, who received a VNS implant. Of the initial 6 patients with TRD implanted with VNS at our center, 5 of them were followed for 6 to 12 years after implantation. Primary efficacy outcomes were clinical response and improved functioning at follow-up visits. The primary safety outcome was all-cause discontinuation, and the secondary safety outcomes were the number and the severity of adverse events. The VNS implant was associated with a sustained response (>10 years) in terms of clinical response and social, occupational, and psychological functioning in 3 patients. Two patients dropped out after 6 and 7 years of treatment, respectively. Vagus nerve stimulation was well tolerated by all patients, who reported only mild adverse effects. One patient, who discontinued concomitant drug treatment, had a hypomanic episode in the 10th year of treatment. The parameters of the VNS device were fine-tuned when life stressors or symptom exacerbation occurred. Our case series showed that VNS can have long-term and durable effectiveness in patients with severe multiepisode chronic depression, and this could be associated with its neuroplastic effects in the hippocampus. In light of good general tolerability, our findings support VNS as a viable treatment option for TRD.

Correlation of antibiotics prescribing appropriateness based on the pharmaceutical care network europe (PCNE) method and clinical response in Community-Acquired Pneumonia

The use of antibiotics as the main standard of pneumonia treatment is usually prescribed in high quantities. Inappropriate selection of antibiotics can lead to bacterial resistance, treatment failure, and the emergence of DRPs (Drug-Related Problems). This study aims to determine the suitability of antibiotic prescribing using the PCNE method and to determine the correlation between the suitability of antibiotic prescribing and clinical response. This study was analyzed using a retrospective analytic cohort study method with data collection of adult Community-Acquired Pneumonia patients medical record, who were hospitalized in private hospital in Yogyakarta from January to December 2019. In addition, this study also assessed antibiotic prescribing according to the PCNE V8.02 method toward patients’ clinical response (the number of leukocyte, temperature, and respiratory rate) after take the antibiotics. The correlation according to antibiotic prescribing analyzed according to chi-square method. The results showed that a total of 52 antibiotic regimens obtained in the evaluation of antibiotic prescribing according to the PCNE method were 21.5% suitable and 78.8% not suitable. Thus, the results of the correlation test for the accuracy of antibiotic prescribing and clinical response to the number of leukocytes showed a significant relationship (p&lt;0.05). However in this study, none significant correlation was found in antibiotic prescription and clinical response in terms of temperature and respiratory rate (p&lt;0.05).

Update on ozanimod for ulcerative colitis.

Treating moderate to severe ulcerative colitis (UC) has been enriched by the increasing number of drugs available for this disease. However, failure of conventional therapies, an incomplete response, or loss of response to biologics is experienced in many UC patients. Thus, there is still a growing need for new drugs in the therapeutic arsenal for UC. Ozanimod is a sphingosine-1-phosphate (S1P) receptor modulator which has been recently approved for UC therapy. In this review, we focus on the mechanism of action of ozanimod hydrochloride in preclinical studies of intestinal inflammation as well as its clinical effectiveness and safety in moderate to severe UC patients. In this population, ozanimod was shown to be significantly more effective than placebo to induce clinical remission. Additionally, in terms of clinical response, corticosteroid-free remission, endoscopic improvement and mucosal healing, ozanimod performed significantly better than placebo in this population. No significant safety concerns about ozanimod emerged from clinical trials in UC.

Radiothérapie des cancers du col de l'utérus de stade IVA dans le service de Radiothérapie de l'Hôpital Aristide le Dantec de Dakar

INTRODUCTION: The management of stage IVA cervical cancer is based on radio-chemotherapy followed by utero-vaginal brachytherapy. In this study, we evaluate the results of external radiotherapy on stage IVA cervical cancer. MATERIALS AND METHODS: This was a retrospective, descriptive study. It covered all patients with stage IVA carcinoma of the cervix who received external radiotherapy at the Joliot Curie Institute of the Aristide Le Dantec Hospital from January 2018 to December 2019. RESULTS: We found 164 clinical records of patients, of which 24 patients had stage IVA, (14.3% of all cases). The average age of our patients was 51 years ± 12.13. Seventeen patients (70.9%) had an altered general condition on admission. The predominant histological type was squamous cell carcinoma found in 22 cases (91.6%). Anemia was found in 14 patients, (58.4%). Neo-adjuvant chemotherapy was performed in 21 of our patients (87.5%). Radiotherapy was exclusive in 20 patients (83.3%) and concomitant radio-chemotherapy was performed in 4 patients (16.7%). Normo-fractionated radiotherapy with curative intent was performed in 13 patients (54.2%), and hypo-fractionated radiotherapy with palliative intent was performed in the other 11 patients (45.8%). An objective response was found in 17 cases (70.8%) including 8 in patients who received hypo-fractionated radiotherapy and 9 in patients treated with normo-fractionated radiotherapy at a curative dose. Five patients (20.8%) had acute toxicity and 7 (29.2%) late toxicity. After 3 years of follow-up, 5 patients (29.2%) had loco-regional progression, 9 patients (37.5%) presented loco-regional recurrence and 4 patients (16.7%) presented distant metastases. Overall survival was 26.8% at 3 years. CONCLUSION: Normo-fractionated radiotherapy does not seem superior to palliative hypo-fractionated radiotherapy in terms of clinical response in stage IVA cervical cancer. KEYWORDS: Carcinoma; Uterine cervix; External radiotherapy.

Evaluation of hospitalized Covid-19 patients who received tocilizumab treatment in terms of clinical response, prognosis, and side effects

Aim: In this study, we aimed to evaluate the clinical response, prognosis, and side effects of tocilizumab treatment among moderate, severe, and critical patients hospitalized due to coronavirus disease 2019 pneumonia. Materials and methods: Retrospectively, 48 adult patients were included. Age, gender, co-morbid conditions, chest CT findings, and treatment modalities were recorded, and laboratory findings and the necessity of oxygen on the first, third and seventh day of tocilizumab were evaluated. Results: While receiving tocilizumab, 34 (70.8%) of the patients were hospitalized in the intensive care unit, and 14 (29.1%) were in an inpatient clinic. On the seventh day, mean lymphocyte counts, mean C- reactive levels, and oxygen saturations were improved significantly (p: &lt;0.001). All 14 patients whose tocilizumab treatment was initiated in an inpatient clinic survived, and none of them had needed an intensive care unit admission. The overall mortality rate was 45.8% (22/48). The average day of death was 16.6±12.6 (6 to 53). Among patients whose tocilizumab treatment was started in an intensive care unit, the mortality rate was 64.7% (22/34). Factors that were found to be significantly associated with mortality were as; hospitalization in an intensive care unit while receiving tocilizumab, receiving non-invasive/invasive mechanical ventilation, having bacterial superinfection, and high involvement in CT imaging (&gt; 50%) at presentation. No serious side effects were observed during/after tocilizumab treatment. Conclusions: In patients with moderate disease who have clinical signs of deterioration, starting early tocilizumab treatment may prevent admission to intensive care, reduce the necessity for supplemental oxygen, and improve clinical and laboratory response. Keywords: SARS-CoV-2, tocilizumab, mortality

Anti-reflux mucosectomy for refractory gastroesophageal reflux disease: a systematic review and meta-analysis.

Background and study aims Anti-reflux mucosectomy (ARMS) is an emerging endoscopic treatment for refractory gastroesophageal reflux disease (GERD). We conducted a systematic review and meta-analysis to evaluate the safety and efficacy ARMS in refractory GERD. Methods A comprehensive search of multiple databases (through March 2020) was performed to identify studies that reported outcomes of ARMS for refractory GERD. Outcomes assessed included technical success, clinical response, and adverse events (AEs). Clinical response was defined as discontinuation (complete) or reduction (partial) of proton pump inhibitors post-ARMS at follow up. Results A total of 307 patients (mean age 46.9 [8.1] years, 41.5 % females) were included from 10 studies. The technical success and clinical response rates were 97.7 % (95 % confidence interval [CI], 94.6–99.0) and 80.1 % (95 % CI, 61.6–91.0), respectively. The pooled rate of complete and partial clinical response was 65.3 % (95 % CI, 51.4–77.0) and 21.5 % (95 % CI, 14.2–31.2), respectively. The rate of AEs was 17.2 % (95 % CI, 13.1–22.2) with most common AE being dysphagia/esophageal stricture followed by bleeding with rates of 11.4 % and 5.0 %, respectively. GERD health-related quality of life (GERD-HRQL) (mean difference [MD] = 14.9, P < 0.001), GERD questionnaire (GERD-Q) (MD = 4.85, P < 0.001) and mean acid exposure time (MD = 2.39, P = 0.01) decreased significantly post-ARMS as compared to pre-procedure. There was no difference in terms of clinical response and AEs between ARMS and ARMS with banding on subgroup analysis. Conclusions ARMS is a safe and effective procedure for treatment of refractory GERD with high rates of clinical response, acceptable safety profile and significant improvement in GERD-related quality of life. Prospective studies are needed to validate our findings.