Shorter Duration Of Therapy Research Articles

Communication Intervention in South Africa: Advocating for the Listening and Spoken Language Approach.

Adhering to Early Hearing Detection and Intervention (EHDI) guidelines is critical for the timely identification and management of infants with hearing impairment. Early intervention specifically focusses on family-centred communication interventions, of which the Listening and Spoken Language-South Africa (LSL-SA) approach is available for children with hearing impairment in South Africa. Studies have evidenced significant benefits for children with hearing impairment enrolled in LSL-SA compared to those enrolled in Traditional Speech-Language Therapy (TSLT), that is, age-equivalent communication outcomes, shorter duration of therapy until discharge, meritorious academic performance and integration into a hearing society. Despite these positive outcomes related to the LSL-SA approach, significant contextual barriers hinder effective implementation nationwide.Contribution:The successful implementation of EHDI guidelines in South Africa hinges on overcoming barriers through tailored healthcare strategies and contextualised delivery. Adapting frameworks such as LSL-SA to fit the local context is crucial for advancing equitable access to EHDI services, positively impacting children with hearing impairment and their families. This article highlights the systemic challenges in South Africa in optimising resources by adopting linguistically appropriate and culturally responsive early intervention approaches to champion hearing healthcare initiatives. Effective collaboration among diverse stakeholders is essential for enhancing the uptake of EHDI guidelines and translating policy into impactful communication interventions. Implementing the core principles of the LSL-SA approach will not only ensure access to this specialised service for suitable candidates but may also alleviate specific barriers to EHDI implementation within TSLT approaches.

Human Serum Albumin-Coated 10B Enriched Carbon Dots as Targeted "Pilot Light" for Boron Neutron Capture Therapy.

Boron neutron capture therapy (BNCT) is a physiologically focused radiation therapy that relies on nuclear capture and fission processes. BNCT is regarded as one of the most promising treatments due to its excellent accuracy, short duration of therapy, and low side effects. The creation of novel boron medicines with high selectivity, ease of delivery, and high boron-effective load is a current research topic. Herein, boron-containing carbon dots (BCDs) and their human serum albumin (HSA) complexes (BCDs-HSA) are designed and synthesized as boron-containing drugs for BNCT. BCDs (10B: 7.1 wt%) and BCDs-HSA exhibited excitation-independent orange fluorescent emission which supported the use of fluorescence imaging for tracking 10B in vivo. The introduction of HSA enabled BCDs-HSA to exhibit good biocompatibility and increased tumor accumulation. The active and passive targeting abilities of BCDs-HSA are explored in detail. Subcutaneous RM-1 tumors and B16-F10 tumors both significantly decrease with BNCT, which consists of injecting BCDs-HSA and then irradiating the area with neutrons. In short, this study provides a novel strategy for the delivery of boron and may broaden the perspectives for the design of boron-containing carbon dots nanomedicine for BNCT.

Tirbanibulin as a Novel Treatment in Actinic Keratosis: A Literature Review

Introduction and purpose: Actinic keratosis (AK) is a common dermatological condition that primarily affects fair-skinned individuals due to cumulative ultraviolet light exposure, potentially leading to squamous cell carcinoma (SCC). AK therapy is divided into two main branches: lesion-directed therapy (cryotherapy, lasers, and surgical methods) and field cancerization-directed therapy (photodynamic therapy and topical agents). Unfortunately, the occurrence of local skin reactions (LSRs) and the therapy duration counted in weeks disrupt patient compliance. This study aims to review the clinical trials concerning the efficacy, safety, and adverse effects of tirbanibulin, a novel promising treatment for AK, which led to its approval and therapeutic development. Materials and methods: Literature available in PubMed and GoogleScholar databases were reviewed using the following keywords: actinic keratosis; actinic keratosis treatment; tirbanibulin. Results: Tirbanibulin's mechanism involves inducing apoptosis by inhibiting microtubule polymerization, which distinguishes it from other treatments that often cause significant inflammation. Clinical trials demonstrate its high efficacy in clearing AK lesions with a favorable safety profile, leading to regulatory approval. The ease of use and short therapy duration (5 days) ensure patient compliance and satisfaction with the treatment. Conclusion: Further longitudinal studies are necessary to confirm the long-term benefits and positioning of tirbanibulin in AK therapy. Raising public awareness about AK and the importance of early treatment with effective options like tirbanibulin is crucial for improving public health outcomes.

Results of the JRS-I LRA0401 and LRB0402 Japan Rhabdomyosarcoma Study Group trials for low-risk embryonal rhabdomyosarcoma.

Failure-free survival (FFS) rates of low-risk patients with rhabdomyosarcoma improved in Intergroup Rhabdomyosarcoma Study IV after the escalation of cyclophosphamide total dose to 26.4g/m2. However, this dose may increase the risk of adverse events, including infertility, in some patients. The JRS-I LRA0401 and LRB0402 protocols aimed to reduce the cyclophosphamide dose to 9.6g/m2 and 17.6g/m2, respectively, without decreasing the FFS rates. Subgroup-A patients received eight cycles (24weeks) of vincristine, actinomycin D, and 1.2g/m2/cycle cyclophosphamide. Subgroup-B patients received eight cycles (24weeks) of vincristine, actinomycin D, and 2.2g/m2/cycle cyclophosphamide, followed by six cycles (24weeks) of vincristine and actinomycin D. Group II/III patients in both subgroups received radiotherapy. In subgroup A (n = 12), the 3-year FFS rate was 83% (95% confidence interval [CI], 48-96), and the 3-year overall survival (OS) rate was 100%. Only one isolated local recurrence was observed (8.3%). There were no unexpected grade-4 toxicities and no deaths. In subgroup B (n = 16), the 3-year FFS and OS rates were 88% (95% CI, 59-97) and 94% (95% CI, 63-99), respectively. There were no unexpected grade 4 toxicities and no deaths. Shorter duration therapy using vincristine, actinomycin D, and lower dose cyclophosphamide with or without radiotherapy for patients with low-risk subgroup A rhabdomyosarcoma (JRS-I LRA0401 protocol) and moderate reduction of cyclophosphamide dose for patients with low-risk subgroup B rhabdomyosarcoma (JRS-I LRB0402 protocol) did not compromise FFS.

A retrospective study of the efficacy of sulbactam in the treatment of patients with extensively drug-resistant Acinetobacter baumannii infections.

Sulbactam (SBT) is one of the most significant treatments for patients with extensively drug-resistant Acinetobacter baumannii (XDR-AB). However, the efficacy and safety of SBT and its high dose regimen has not been well documented. This retrospective study aimed to assess the efficacy and safety of SBT-based treatment, particularly at high-dose (≥ 6g/day), for XDR-AB infection. A total of 52 XDR-AB infected patients treated with intravenous SBT at Peking Union Medical College Hospital were included. The primary outcome was 28-day all-cause mortality, while the secondary outcome was 14-day clinical response and the time of response. The formulation of SBT in our study is 0.5g per vial. Among the patients, the 28-day all-cause mortality rate was 36.5% (19/52), and the favorable 14-day clinical response rate was 59.6% (31/52). The 28-day mortality was independently associated coinfection with gram-positive bacteria (GPB) and a shorter duration of therapy. Patients with intracranial infection might have a longer survival time. A favorable 14-day clinical response was associated with the dose of SBT, and a longer treatment duration. However, the higher creatinine clearance (CrCl) associated with a worse clincal response. In addition, a higher SBT dosage was significantly correlated with a shorter time to clinical response. No adverse effects related were reported. The single-agent formulation of SBT emerges as a promising alternative for the treatment of XDR-AB infection, such as intracranial infection, particularly at high doses (≥ 6g/day). Besides, longer duration of treatment correlates with higher survival rate and better favorable clinical response. Higher CrCl negatively correlates with favorable clinical response.

Endocrine therapy of short duration prevents local and contralateral recurrence of ductal carcinoma in situ of the breast: A multicenter retrospective cohort study in China.

Endocrine therapy of short duration prevents local and contralateral recurrence of ductal carcinoma in situ of the breast: A multicenter retrospective cohort study in China.

Short versus long duration of ceftaroline combination therapy and outcomes in persistent or high-grade MRSA bacteremia: A retrospective single-center study.

Methicillin-resistant Staphylococcus aureus (MRSA) is associated with high mortality rates. Despite antibiotic therapy, persistent bacteremia is challenging to treat. Combination therapy with ceftaroline has emerged as a potential treatment option; however, the optimal duration and clinical implications after bacteremia clearance are unknown. This retrospective cohort study examined patients with high-grade or persistent MRSA bacteremia who were treated with ceftaroline combination therapy at the University of New Mexico Hospital between January 2014 and June 2021. Patients were categorized into short- (<7 days) or long-duration (≥7 days) groups based on the duration of combination therapy after bacteremia clearance. Outcomes included 30-day all-cause mortality, bacteremia recurrence, post-bacteremia clearance length of stay, and adverse events. A total of 32 patients were included in this study. The most common sources of bacteremia were bone/joint and endovascular (28.1%, 9/32 each). The median duration of combination therapy after clearance was seven days (IQR 2.8, 11). Patients in the long-duration group had a lower Charlson comorbidity index (1.0 vs 5.5, p = 0.017) than those in the short-duration group. After adjusting for confounders, there was no significant difference in the 30-day all-cause mortality between the groups (AOR 0.17, 95% CI 0.007-1.85, p = 0.18). No association was found between combination therapy duration and recurrence (OR 2.53, 95% CI 0.19-inf, p = 0.24) or adverse drug events (OR 3.46, 95% CI 0.39-74.86, p = 0.31). After controlling for total hospital length of stay, there was no significant difference in the post-bacteremia clearance length of stay between the two groups (p = 0.37). Prolonging ceftaroline combination therapy after bacteremia clearance did not significantly improve outcomes in patients with persistent or high-grade MRSA bacteremia. The limitations of this study warrant cautious interpretation of its results. Larger studies are needed to determine the optimal duration and role of combination therapy for this difficult-to-treat infection.

One- versus three-month dual antiplatelet therapy in high bleeding risk patients undergoing percutaneous coronary intervention for non-ST-segment elevation acute coronary syndromes.

A short dual antiplatelet therapy (DAPT) duration has been proposed for patients at high bleeding risk (HBR) undergoing drug-eluting coronary stent (DES) implantation. Whether this strategy is safe and effective after a non-ST-segment elevation acute coronary syndrome (NSTE-ACS) remains uncertain. We aimed to compare the impact of 1-month versus 3-month DAPT on clinical outcomes after DES implantation among HBR patients with or without NSTE-ACS. This is a prespecified analysis from the XIENCE Short DAPT programme involving three prospective, international, single-arm studies evaluating the safety and efficacy of 1-month (XIENCE 28 USA and Global) or 3-month (XIENCE 90) DAPT among HBR patients after implantation of a cobalt-chromium everolimus-eluting stent. Ischaemic and bleeding outcomes associated with 1- versus 3-month DAPT were assessed according to clinical presentation using propensity score stratification. Of 3,364 HBR patients (1,392 on 1-month DAPT and 1,972 on 3-month DAPT), 1,164 (34.6%) underwent DES implantation for NSTE-ACS. At 12 months, the risk of the primary endpoint of death or myocardial infarction was similar between 1- and 3-month DAPT in patients with (hazard ratio [HR] 1.09, 95% confidence interval [CI]: 0.71-1.65) and without NSTE-ACS (HR 0.88, 95% CI: 0.63-1.23; p-interaction=0.34). The key secondary endpoint of Bleeding Academic Research Consortium (BARC) Type 2-5 bleeding was consistently reduced in both NSTE-ACS (HR 0.57, 95% CI: 0.37-0.88) and stable patients (HR 0.84, 95% CI: 0.61-1.15; p-interaction=0.15) with 1-month DAPT. Among HBR patients undergoing implantation of an everolimus-eluting stent, 1-month, compared to 3-month DAPT, was associated with similar ischaemic risk and reduced bleeding at 1 year, irrespective of clinical presentation.

Short versus prolonged duration of therapy for Pseudomonas aeruginosa bacteraemia: a systematic review and meta-analysis

The optimal duration of therapy for Pseudomonas aeruginosa bloodstream infection (PSA-BSI) is unknown, with prolonged therapy frequently favored due to severity of infection, patient complexity, risk of multi-drug resistance, and high mortality. We therefore conducted a systematic review and meta-analysis of studies with head-to-head comparison of short versus prolonged therapy for PSA-BSI. A comprehensive search including Ovid MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus was performed. We pooled risk ratios using DerSimonian-Laird random effects model and performed subgroup analysis of outcomes including all-cause mortality, recurrent infection, and composite of these outcomes among patients receiving short versus prolonged therapy for PSA-BSI. Heterogeneity was assessed by the I2-index. Risk of bias for cohort studies was assessed using ROBINS-I tool. Of the 908 identified studies, six were included in the systematic review and five studies with head-to-head comparison of treatment duration were assessed in the meta-analysis, totalling 1746 patients. No significant difference in propensity score-weighted composite outcome (30-day all-cause mortality or recurrent infection) was noted between patients receiving short or prolonged therapy, with a pooled RR risk ratio of 0.80 (95% CI confidence interval 0.51-1.25, P=0.32; I2 = 0%). Additionally, duration of therapy did not impact individual outcomes of 30-day all-cause mortality or recurrent/persistent infection. Our meta-analysis demonstrated that short duration of antimicrobial therapy may have similar efficacy to prolonged treatment for PSA-BSI. Future randomized trials will be necessary to definitively determine optimal management of PSA bacteraemia.

Rechallenge in idiosyncratic drug-induced liver injury: An analysis of cases in two large prospective registries according to existing definitions

IntroductionData on positive rechallenge in idiosyncratic drug-induced liver injury (DILI) are scarce. We aim to analyse the clinical presentation, outcome and drugs associated with positive rechallenge in two DILI registries. MethodsCases from the Spanish and Latin American DILI registries were included. Demographics, clinical characteristics and outcome of cases with positive rechallenge according to CIOMS/RUCAM and current definitions were analysed. ResultsOf 1418 patients with idiosyncratic DILI, 58 cases had positive rechallenge (4.1%). Patients with positive rechallenge had shorter duration of therapy (p=0.001) and latency (p=0.003). In patients with rechallenge, aspartate transaminase levels were increased (p=0.026) and showed a prolonged time to recovery (p=0.020), albeit no differences were seen in terms of fatal outcomes. The main drug implicated in rechallenge was amoxicillin-clavulanate (17%). The majority of re-exposure events were unintentional (71%). Using both existing definitions of positive rechallenge, there were four cases which exclusively fulfilled the current criteria and five which only meet the historical definition. All cases of positive rechallenge, irrespective of the pattern of damage, fulfilled the criteria of either alanine transaminase (ALT) ≥3 times the upper limit of normal (ULN) and/or alkaline phosphatase (ALP) ≥2 times ULN. ConclusionsEpisodes of rechallenge were characterised by shorter duration of therapy and latency, and longer time to resolution, but did not show an increased incidence of fatal outcome. Based on our findings, ALT ≥3 times ULN and/or ALP ≥2 times ULN, regardless of the pattern of damage, is proposed as a new definition of rechallenge in DILI.

Shorter versus longer duration of antimicrobial therapy for early Lyme disease: A systematic review and meta-analysis

BackgroundAntibiotic therapy for patients with early Lyme disease is necessary to prevent later-stage Lyme disease complications. This systematic review and meta-analysis compares shorter versus longer antibiotic regimens in treating early Lyme disease. MethodsA systematic search of PubMed, Embase, and Cochrane Central Register of Controlled Trials was conducted up to November 2023. We examined treatment failure, complete response, and photosensitivity. Short vs. long therapy was defined as ≤10 days vs. >10 days. Subgroup analyses included antibiotic type and varying treatment durations. Analysis utilized RStudio 4.1.2. PROSPERO registration: CRD42023423876. ResultsSeven studies, encompassing 1,462 patients, were analyzed. No significant differences in treatment failure, 12-month complete response, final visit complete response were found between short and long durations of antibiotic therapy. Subgroup and sensitivity analyses corroborated these findings. ConclusionShorter and longer antibiotic regimens for early Lyme disease show similar efficacy, highlighting the potential of ≤10-day courses, as effective treatment options.

WUTSUP-02-II-Neo-Dis-Tis: Investigating the efficacy and safety of neoadjuvant tislelizumab plus disitamab vedotin with adjuvant tislelizumab in upper urinary tract carcinoma—A phase II multi-center study.

TPS718 Background: Upper tract urothelial carcinoma (UTUC) and urothelial bladder cancer (UBC) are frequently referred to as “disparate twins” despite their common tissue origin. They exhibit varying biological behaviors, prognostic outcomes, and responses to treatment. It is crucial to conduct dedicated clinical trials for UTUC as a separate entity rather than relying solely on UBC study results, giving that UTUC lags in evidence quantity and quality compared to UBC. Despite the superior outcomes of neoadjuvant treatment over adjuvant treatment in UBC trials, the currently available evidence for neoadjuvant therapy of UTUC remains limited in quantity and diversity, as the largest trial, POUT, is focused on adjuvant therapy. Additionally, the limited number of neoadjuvant trials for UTUC primarily utilize chemotherapy-based regimens, with little investigation into combination therapies. Of note, UTUC patients frequently have impaired renal functions, making a chemotherapy-independent approach a desirable alternative. On the other hand, given the short duration of neoadjuvant therapy, a combination therapy strategy appears to be necessary, especially with the increasing interest in immune therapy maintenance after surgery. Tislelizumab has demonstrated efficacy in patients with advanced or metastatic urothelial carcinoma. Disitamab Vedotin, a HER2-targeting antibody-drug conjugate (ADC), has demonstrated robust clinical efficacy in metastatic urothelial carcinoma patients with HER2 2+ or 3+ expression. Disitamab Vedotin in combination with PD-1 immunotherapy has shown remarkable results in locally advanced or metastatic urothelial carcinoma, regardless of HER2 expression, indicative of a synergistic effect between ADC and PD-1 immunotherapy. In this study, we aim to conduct a prospective phase II trial to investigate the efficacy and safety of neoadjuvant tislelizumab plus Disitamab Vedotin followed by adjuvant tislelizumab in patients with high-risk UTUC. Methods: This multi-center phase II trial aims to enroll 45 patients with histologically confirmed UTUC at clinical stage cT2-4N0M0 or cT1-4N1-2M0. Neoadjuvant therapy includes 4 cycles of Tislelizumab (200mg for each 3-week cycle) in combination with Disitamab Vedotin (2.0mg/kg for each 3-week cycle). Radical nephroureterectomy (including bladder cuff resection and regional lymph node dissection if indicated) will be performed if there is no obvious contraindication within 3-6 weeks after the final neoadjuvant therapy administration. Postoperative adjuvant treatment with 8 cycles of tislelizumab will be provided. The primary endpoint is pathological complete response rate. Secondary endpoints include overall survival, local recurrence free survival, distant metastasis free survival, FACT–G. Clinical trial information: ChiCTR2300067836 .

P769 Impact of discontinuation of anti-TNF therapy: A long term follow-up data of risks and predictors relapse in a large Indian cohort

Abstract Background Discontinuation of anti-TNF therapy in IBD is an important consideration in TB endemic low resource settings of the developing world. There are no established guidelines on withdrawal of biologics. A proper exit strategy on when and how biologics can be stopped is therefore warranted. We aimed to identify risk factors and rates of relapse post withdrawal in a large real-life cohort of patients from India. Methods Prospectively collected data of consecutive patients treated with anti-TNFs from the IBD registry of a large tertiary care centre was analyzed. Demographics,baseline disease characteristics,reasons for discontinuation, response to anti-TNF,and relapse rate after withdrawal were analysed. Time to event analysis was done to evaluate relapse rates over time. Cox proportional hazard analysis and non-parametric tests were performed to identify risk factors of relapse. Results Of 8300 patients, only 725(8.7%),(Median age-36y,IQR:26-47,61.2% male,61.2%CD, 32%UC, IBD-U 1.8%) received anti-TNFs. 445 (61.3%) discontinued with median follow up of 54 m(IQR:31-81). Reasons for discontinuation were primary non-response(64,14.3%);secondary loss of response (44,9.8%);financial constraints(27,6.1%);TB reactivation (18,4%), side effects(17,3.2%); infusion reactions(20,4.4%);non-compliance(4,0.9%), and COVID lockdown (6,1.3%). Overall, 232/445 (52%) were in clinical and endoscopic remission while stopping anti-TNFs with median follow up of 41 months(IQR:24.5-67). Relapse rates at 1,2,3,4, and 5 years after discontinuation were 16%,5.6%,5.2%,2.6% and 1.3% respectively. Overall,161/232(69%) patients remained in remission(Fig1A). Patients who stopped after clinical and endoscopic remission had higher likelihood of maintaining remission after discontinuation of biologics (Log-rank test,p=0.001). On multivariate analysis, fistulizing disease(p=0.03), prior history of bowel surgery (p=0.019), immunomodulator usage (p=0.001) and shorter duration of therapy (p=0.017) were associated with significantly higher rate of relapse(Table1). Cumulative time to relapse was significantly longer in those with or without endoscopic remission (median 17.3 vs 7 months;p=0.04)(Fig1B). On the other hand, shorter disease duration (p=0.001) and absence of extra-intestinal manifestations (p=0.009) were associated with lower risks of relapse. Conclusion 60% of patients discontinued anti-TNF therapy in this real world cohort. However, long-term cumulative relapse rates were low(30%), particularly in non-fistulizing disease, with no history of bowel surgery or extra intestinal manifestations and in endoscopic remission. A definite exit strategy appears feasible and would be a practical and affordable management approach.

Risk factors for clonal hematopoiesis of indeterminate potential in people with HIV: a report from the REPRIEVE trial

AbstractClonal hematopoiesis of indeterminate potential (CHIP), the clonal expansion of myeloid cells with leukemogenic mutations, results in increased coronary artery disease (CAD) risk. CHIP is more prevalent among people with HIV (PWH), but the risk factors are unknown. CHIP was identified among PWH in REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) using whole-exome sequencing. Logistic regression was used to associate sociodemographic factors and HIV-specific factors with CHIP adjusting for age, sex, and smoking status. In the studied global cohort of 4486 PWH, mean age was 49.9 (standard deviation [SD], 6.4) years; 1650 (36.8%) were female; and 3418 (76.2%) were non-White. CHIP was identified in 223 of 4486 (4.97%) and in 38 of 373 (10.2%) among those aged ≥60 years. Age (odds ratio [OR], 1.07; 95% confidence interval [CI], 1.05-1.09; P < .0001) and smoking (OR, 1.37; 95% CI, 1.14-1.66; P < .001) associated with increased odds of CHIP. Globally, participants outside of North America had lower odds of CHIP including sub-Saharan Africa (OR, 0.57; 95% CI, 0.4-0.81; P = .0019), South Asia (OR, 0.45; 95% CI, 0.23-0.80; P = .01), and Latin America/Caribbean (OR, 0.56; 95% CI, 0.34-0.87; P = .014). Hispanic/Latino ethnicity (OR, 0.38; 95% CI, 0.23-0.54; P = .002) associated with significantly lower odds of CHIP. Among HIV-specific factors, CD4 nadir <50 cells/mm3 associated with a 1.9-fold (95%CI, 1.21-3.05; P = .006) increased odds of CHIP, with the effect being significantly stronger among individuals with short duration of antiretroviral therapy (ART; OR, 4.15; 95% CI, 1.51-11.1; P = .005) (Pinteraction= .0492). Among PWH at low-to-moderate CAD risk on stable ART, smoking, CD4 nadir, North American origin, and non-Hispanic ethnicity associated with increased odds of CHIP. This trial was registered at www.ClinicalTrials.gov as NCT02344290.

Impact of Opioid Use on Duration of Therapy and Overall Survival for Patients with Advanced Non-Small Cell Lung Cancer Treated with Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICI) have significantly improved outcomes in advanced non-small cell lung cancer (NSCLC). We evaluated the effect of opioid use on outcomes in patients receiving ICI either alone or with chemotherapy. We conducted a retrospective review of 209 patients with advanced NSCLC who received an ICI at the University of Virginia between 1 February 2015 and 1 January 2020. We performed univariate and multivariate analyses to evaluate the impact of opioid use on duration of therapy (DOT) and overall survival (OS). Patients with no or low opioid use (n = 172) had a median DOT of 12.2 months (95% CI: 6.9-17.4) compared to 1.9 months (95% CI: 1.8-2.0) for those with high opioid use (n = 37, HR 0.26 95% CI: 0.17-0.40, p < 0.001). Patients with no or low opioid use had a median OS of 22.6 months (95% CI: 14.8-30.4) compared to 3.8 months (95% CI: 2.7-4.9) for those with high opioid use (HR 0.26 95% CI: 0.17-0.40 p < 0.001). High opioid use was associated with a shorter DOT and worse OS. This difference remained significant when accounting for possible confounding variables. These data warrant investigation of possible mechanistic interactions between opioids, tumor progression, and ICIs, as well as prospective evaluation of opioid-sparing pain management strategies, where possible.

Thiazole Heterocycle: An Incredible and Potential Scaffold in Drug Discovery and Development of Antitubercular Agents

AbstractIn 2020, 15 million people were diagnosed with tuberculosis (TB), and 2.4 million died. Additionally, the TB situation is worse with multidrug resistance (MDR) and extended‐drug resistance (XDR)‐TB. Research into innovative anti‐tubercular drugs with improved MDR‐TB activity, lower toxicity, and shorter therapy duration is crucial for solving this issue. Fortunately, numerous novel potential anti‐tubercular candidates are currently under clinical trials. Most of these candidates have five‐membered rings and are most likely effective against sensitive and resistant strains. This review discusses current developments in the five‐membered heterocyclic thiazole ring, emphasizing its anti‐tubercular properties, toxicity, structure‐activity relationship, and mechanism of action. Thiazole ring has a wide range of biological activities and thus gained much synthetic interest. Due to the popularity of thiazole as an anti‐tubercular moiety, it combined with other medicinally active chemical functionality and nuclei to design and synthesize novel hybrid analogues with maximum activity and minimal toxicity. In this review we have done the literature survey of the past 10 years, and compiled the structural and functional studies of thiazole as an anti‐tubercular agent with its potent chemical entities showing prominent pharmacological action.

Immune Profiling and Responses of Smoldering Multiple Myeloma Patients Treated in a Phase Ib Study of Pvx-410 Vaccine Targeting XBP1/CD138/CS1 Antigens, and Citarinostat, a Histone Deacetylase Inhibitor (HDACi) with and without Lenalidomide

BACKGROUND AND SIGNIFICANCE Immunoparesis plays an important role in the progression of smoldering multiple myeloma (SMM). Therapies that augment the immune response may prevent or slow the progression to symptomatic multiple myeloma. We have previously shown that PVX-410, a multi-peptide cancer vaccine (OncoPep., Inc.) targeting XBP1/CD138/CS1, is immunogenic in SMM, as a single therapy and in combination with lenalidomide. Here, we investigated whether co-administration of PVX-410 with an oral HDAC inhibitor, citarinostat, +/- lenalidomide enhances vaccine specific immune response in patients with SMM. STUDY DESIGN AND METHODS This 2-cohort phase 1b multicenter study accrued 16 adults (≥18 years) with HLA-A2 + SMM and high risk of progression to active MM. Patients received citarinostat in combination with PVX-410 (double combination cohort) and with PVX-410 and lenalidomide (triple combination cohort). PVX-410 was given as six doses of 0.8 mg biweekly (weeks 0, 2, 4, 6, 8, and 10) via subcutaneous injection followed by a single dose of PVX-410 during follow-up visits at month 1, 2, 3, 6, and 9; 3 cycles of citarinostat (180 mg QD PO for 21 days every 28 days) and lenalidomide (25 mg on Days 1-21 every 28 days) were given to patients in the double and triple combination cohorts respectively in conjunction with the initial 6 doses of PVX-410. Patients were followed post-treatment for 12 months. Peripheral blood (PB) and bone marrow (BM) samples at baseline and month one after treatment were analyzed by single-cell RNA sequencing. T-cell receptor and B-cell receptor sequencing were also performed to investigate T cell and B-cell clonal expansion before and after treatment. Flow cytometric analyses of anti-MM functionality of the XBP1/CD138/CS1-specific CD8 + cytotoxic T lymphocytes (CTL) was performed at various timepoints from baseline up to 12-month post-treatment. The development of antigen-specific memory CD8 + CTL through upregulation of 41BB and production of Th1-type of cytokines (IFN-g, IL-2, TNF-a) were evaluated by flow cytometry. Deep whole genome sequencing was performed on subsets of CD138 + cells from BM isolates to corroborate our findings. RESULTS We screened 16 SMM patients; 15 (94%) received treatment (7 with the double and 8 with the triple combination). By the end of the 12-month post-treatment follow-up period no patients progressed to symptomatic myeloma in the double combination cohort; one patient in the triple combination cohort withdrew by month 3 for disease progression. Most patients receiving the double combination had stable disease (SD) as their best clinical response (n=5), one had partial response (PR) and one minimal response (MR). Triple combination therapy resulted in better clinical response including PR (n=2), MR (n=4) and SD (n=2). Single-cell transcriptomic analyses of 21 PB samples from 13 patients and 15 BM samples from 11 patients at baseline and month one after treatment is in progress. Immune monitoring studies on 125 samples from 15 different patients at various timepoints from baseline up to 12-month post-treatment are ongoing. Fourteen patients (100%) had at least one treatment-related adverse event (trAEs), mostly grade 1-2 in severity. The most common trAEs among patients receiving double vs triple combination were fatigue (71% vs 63%), injection site reactions (43% vs 50%), neutropenia (57% vs 38%), anemia (29% vs 38%), and diarrhea (0% vs 50%). There was one grade 3 trAE: specifically, a thromboembolic event in one patient who was receiving lenalidomide and despite aspirin prophylaxis, but who fully recovered. DISCUSSION The combination of PVX-410 with citarinostat, with and without lenalidomide is generally safe in this patient population. The objective clinical response was relatively modest given the short duration of therapy: longer follow up is needed to assess the impact on progression to active myeloma. PB and marrow transcriptome profiling along with the immunogenicity studies are in progress and will be presented. We will evaluate whether PB mononuclear cells have the potential to replace BM as a surrogate for genetic and immunological surveillance in SMM, as we anticipate that further understanding of the immune alterations among patients with SMM and the response to immunomodulatory therapy may provide insight on early intervention and prevention of progression to symptomatic disease.

2267. Evaluation of Antibiotic Prescribing Trends from a Dental Clinic After Implementation of a Dental Antimicrobial Stewardship Initiative

Abstract Background Inappropriate antibiotic prescribing by dentists is as high as 80% and in the U.S., dentists rank third for writing the most antibiotic prescriptions. At NewYork-Presbyterian Brooklyn Methodist (NYP-BMH), the Antimicrobial Stewardship Program (ASP) and Division of Dental Medicine collaborated to create a clinical practice guideline regarding antibiotic use in dentistry that was implemented in May 2021 and is reinforced with annual education to dental prescribers. The purpose of this study is to compare outpatient antibiotic prescribing trends pre- and post-guideline implementation. Methods Patients presenting to NYP-BMH dental clinic for an emergent indication and prescribed an antibiotic from January-April of 2019-2021 (pre) and January-April of 2022 (post) were included. The primary outcome was appropriateness of antibiotic therapy. Secondary outcomes included a comparison of antibiotic selection, dosing and duration of therapy. A subgroup analysis of patients with reported penicillin allergies was conducted to compare alternative agents prescribed. Results A total of 119 patients in the pre and 100 patients in the post-guideline period were included. The primary outcome of appropriate antibiotic prescriptions significantly improved after guideline implementation (pre 45% vs post 64%, p&amp;lt; 0.01). The majority of antibiotic indications were treatment-related and the most common dental diagnosis was caries. The most common antibiotic prescribed in the study was amoxicillin. Compared to pre-guideline, there was significant decreased utilization of penicillin VK (pre 3.4% vs post 0%, p=0.05) and amoxicillin-clavulanate post-guideline (pre 16% vs post 8%, p=0.02). A wide variety of dosing regimens were utilized with more guideline-concordant regimens utilized post-guideline (pre 59% vs post 72%, p=0.04). On average, shorter durations of therapy were prescribed post-guideline (pre 6.8 days vs post 5.7 days, p&amp;lt; 0.02). Penicillin-allergic patients were prescribed less clindamycin after guideline implementation. Conclusion ASP initiatives and collaboration with outpatient dental clinics can improve appropriate antibiotic prescribing. As ASPs look to expand into ambulatory care settings, dental clinics should be prioritized. Disclosures All Authors: No reported disclosures

Abbreviated versus standard dual antiplatelet therapy time after PCI in high bleeding risk patients with acute coronary syndrome - a report from the SWEDEHEART registry

Abstract Background The use of a short duration of dual antiplatelet therapy (DAPT) has become increasingly common in patients with high bleeding risk (HBR). This study aimed to evaluate outcomes for an abbreviated DAPT strategy compared to standard DAPT time strategy for high bleeding risk-patients with acute coronary syndrome (ACS) treated with percutaneous coronary intervention (PCI). Methods A total of 22310 patients from the SWEDEHEART-registry with at least one high bleeding risk criteria who underwent PCI for ACS in Sweden between January 1, 2013, until January 15, 2021, were enrolled. Patients were grouped according to their planned DAPT time at discharge: standard DAPT with 12 months of any P2Y12 inhibitor and aspirin or an abbreviated DAPT duration (&amp;lt;6 months DAPT or 12-month single APT) and matched for intended P2Y12 inhibitor type (clopidogrel or prasugrel/ticagrelor). The primary outcome was net adverse clinical events (NACE) at one year defined as the first occurrence of cardiac mortality or hospitalization due to myocardial infarction, ischemic stroke or clinically significant bleeding. Major adverse cardiovascular events and the individual components of NACE were defined as secondary endpoints. Results No significant difference in NACE was observed between the abbreviated compared to standard DAPT time groups, Kaplan-Meier event rate: 12.9% (n = 584) vs 13.1% (n = 594) hazard ratio (HR) 0.99; 95% confidence interval (CI) 0.88-1.11, p=0.83. No differences were observed for MACE (HR 1.08; 95% CI 0.94-1.25) or any of the elements of the primary composite outcome. The results were consistent in all HBR-subgroups. Conclusion For patients with a high bleeding risk undergoing PCI due to an ACS, an abbreviated DAPT strategy was associated with comparable rates of NACE and MACE as compared to a standard DAPT time strategy. The results add real-world evidence that abbreviated DAPT-regimes can be a viable treatment option for patients with ACS with a high bleeding risk.

Short duration of dual antiplatelet therapy following complex percutaneous coronary intervention: A systematic review and meta-analysis

Introduction and aimThe optimal composition and duration of antiplatelet therapy after complex percutaneous coronary intervention (PCI) remains unclear. We conducted a meta-analysis to compare 1–3 months of dual antiplatelet therapy (DAPT) followed by monotherapy vs. 12 months of DAPT. MethodMEDLINE/PubMed, EMBASE, and Cochrane Central Register of Controlled Trials were queried for studies comparing 1–3 months of DAPT followed by monotherapy vs. 12 months of DAPT in the outcomes of complex PCI from inception through January 2023. Outcomes of interest included major bleeding, all-cause mortality, cardiovascular mortality, myocardial infarction (MI), stent thrombosis, target vessel revascularization, and stroke. ResultsCompared to 12 months, 1–3 months of dual antiplatelet therapy had a weak association with less major bleeding (OR 0.67; 95 % CI, 0.44–1.00; p = 0.05; I2 = 28 %). There were no significant differences between the shorter and longer antiplatelet therapy in terms of all-cause mortality (OR 0.83; 95 % CI, 0.59–1.16; p = 0.21; I2 = 17 %), cardiovascular mortality (OR 0.87; 95 % CI, 0.53–0.42; p = 0.50; I2 = 0), MI (OR 0.97; 95 % CI, 0.69–1.35; p = 0.82; I2 = 32 %), stent thrombosis (OR 1.17, 95 % CI, 0.77–1.76; p = 0.38; I2 = 0 %), target vessel revascularization (OR 1.05, 95 % CI, 0.58–1.89; p = 0.82; I2 = 64 %), or stroke (OR 1.10, 95 % CI, 0.55–2.17; p = 0.37; I2 = 7 %);. ConclusionAmong patients undergoing complex PCI, DAPT for 1–3 months may be associated with less major bleeding but similar rates of cardiovascular events (death, MI, stroke, stent thrombosis, and revascularization) compared to DAPT for 12 months.