Choice Of Therapy Research Articles

Nutritional support programs in intensive care units patients

Timely and adequate nutritional support is on a par with etiotropic and pathogenetic therapy in terms of effectiveness, especially in intensive care patients. Critical condition and systemic inflammation of any etiology lead not only to primary and secondary damage to organs and tissues, the development of multiple organ failure, but also trigger a cascade of reactions aimed at mobilizing energy substrates to maintain homeostasis and ensure regeneration. This leads to a rapid depletion of endogenous reserves of macro- and microelements and, without proper replenishment, a syndrome of metabolic dysfunction develops, which, in turn, contributes to the progression of multiple organ failure, the development of purulentseptic and metabolic complications, which increases the time of hospitalization and pharmacoeconomical costs, worsens the results of treatment. In everyday clinical practice, when diagnosing nutritional deficiency or the risk of its development, the clinician must determine not only the nutrition program, but also the format of its implementation. This paper presents a critical analysis of the most common ways of providing nutrition and algorithms for personalized choice of nutritional therapy in patients in intensive care units.

Targeting HER2 in Gastroesophageal Cancer: A New Appetite for an Old Plight.

The incidence of gastroesophageal cancers is rising, driven, in part, by an increasing burden of risk factors of obesity and gastroesophageal reflux. Despite efforts to address these risk factors, and a growing interest in methods of population screening, the bulk of these tumours are unresectable at diagnosis. In this setting, effective systemic treatments are paramount to improve survival and quality of life. Early and accurate identification of oncogenic drivers, such as human epidermal growth factor receptor 2 (HER2), present in 5-30% of gastroesophageal adenocarcinomas (GEAs), is integral to guide choice of therapies due to the clear predictive implications that arise from overexpression of this receptor. After trastuzumab, the first anti-HER2 agent with approved use in HER2-positive GEA, the addition of pembrolizumab to first-line trastuzumab-chemotherapy and trastuzumab deruxtecan in the refractory space have more recently changed practice. Yet, the response to these agents has been vastly different across patients with HER2-positive disease, underpinning the need for reliable biomarkers of response. Emergent data have suggested that levels of HER2 expression on tissue or liquid biopsies may predict response to first-generation HER2 therapies while HER2 heterogeneity, receptor changes, co-occurring molecular alterations and oncogenic genomic and metabolic reprogramming may be implicated in resistance. A robust knowledge of the mechanisms of resistance and response to HER2-directed therapies is necessary to inform novel strategies of HER2-targeting and guide choice combinations with other biomarker-directed therapies, to improve outcomes from a new generation of clinical trials in HER2-positive GEA. Understanding and close examination of previous failures in this space form an important part of this assessment, as does correlative biomarker and translational work pertaining to the role of HER2 and dynamic changes that result through treatment exposure. In this review, we aim to provide an overview of strategies for HER2 targeting, summarising both the successes and disappointments in this therapeutic landscape and discuss existing challenges and future perspectives on development in this highly morbid tumour type.

P0918 Identification of a serum proteomics signature linked with anti-TNF therapy response outcomes in Inflammatory Bowel Disease

Abstract Background While treatment options for active disease in IBD become diverse, the choice of therapies is mostly based on patient characteristics, disease course and severity but restrained by economic rationales. To maximize treatment effectiveness, predictive biomarkers are needed to guide therapies either ex ante or at the earliest possible time point after therapy initiation. Previously, we identified dynamic blood-based RNA and DNA methylation signatures that are linked with therapy response to anti-TNF in IBD1. Here, we aim to identify serum proteome biomarkers associated with therapeutic outcomes in IBD patients receiving anti-TNF treatment. Methods 31 ulcerative colitis (UC) and 27 Crohn’s disease (CD) patients with active clinical and endoscopic disease were recruited and followed at baseline (W0) and at weeks 2 (W2), 6 (W6), and 14 (W14) after initiating infliximab therapy. The clinical endpoint of interest was defined as a combination of clinical remission (partial Mayo ≤ 2/CDAI < 150) and endoscopic response (reduction in endoscopic Mayo ≥ 1/SES-CD ≥ 50%) at W14. Serum was collected at each time point and subjected to proximity extension assays (Olink® Explore 3072 panel) to screen for 2,944 proteins. Linear mixed models (LMM) were applied to identify differentially expressed proteins (DEPs) between endpoint achievers/non-achievers over time. Additionally, post-analysis of DEPs was performed using cv.glmnet with least absolute shrinkage and selection operator (LASSO) regression to identify candidate predictive marker sets. Results A total of 229 DEPs were identified over time between UC responders and non-responders: 8 at W0, 22 at W2, 181 at W6, and 78 at W14. In CD patients, 23 DEPs were identified: 9 at W0, 7 at W2, 13 at W6, and 13 at W14. These DEPs were disease-specific and linked to Gene Ontology (GO) terms related to inflammatory response and cell differentiation. Using LMM and machine learning, we identified 5 baseline proteins in UC and 6 in CD patients that differentiated combined endpoint achievers from non-achievers (AUROC: UC: 0.958, CD: 0.800). Additionally, we identified dynamic changes from W0 to W2 in 7 proteins associated with immune regulation in UC patients (1 in CD), which were linked to therapeutic outcomes at W14. Conclusion Detecting specific ex ante biomarkers or early dynamic molecular signatures are critical for precision medicine in IBD. Our data suggest that serum proteomics profiling enables the differentiation of patients who will attain therapeutic success under anti-TNF therapy from those who will not. This study warrants further investigations in larger, independent datasets to confirm the potential clinical utility of the proteomics signature. References (1) Mishra N, et al. Longitudinal multi-omics analysis identifies early blood-based predictors of anti-TNF therapy response in inflammatory bowel disease. Genome Med. 2022 Sep 24;14(1):110. doi: 10.1186/s13073-022-01112-z. PMID: 36153599; PMCID: PMC9509553. This project has received funding from the DFG Cluster of Excellence 2167 "Precision medicine in chronic inflammation", the BMBF (e:Med Network iTREAT 01ZX2202A, and GUIDE-IBD 031L0188A), and the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 831434 (3TR) and No 853995 (ImmUniverse).The JU receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. The content provided in this publication reflects the author’s views only. Neither the Innovative Medicines Initiative (IMI JU) nor the European Commission are responsible for any use that may be made of the information it contains.

P0957 Flow of Advanced Therapy Pathways and Variations over Time in Crohn’s Disease and Ulcerative Colitis: Data from the Persistence Australian National IBD Cohort (PANIC5)

Abstract Background Choice of advanced therapy (AT) in Crohn’s disease (CD) and ulcerative colitis (UC) have increased, however the optimal positioning and sequencing of agents are unknown. We present the first national data on sequencing for all AT treatments in Australia with Sankey diagrams. Methods We analysed the Persistence Australian National IBD Cohort (PANIC) 5 registry, including all UC and CD patients on AT via the Pharmaceutical Benefits Scheme up to December 2021. Sankey diagrams were created using Plotly, a Python-based tool. Each AT was coded as a node along the x-axis, and the y-axis represented patients’ treatment pathways, including sequential switches and stops from first to fifth-line treatments. Patients were divided into tertiles based on first AT commencement date (T1, T2, and T3) for both UC and CD data, and trends across these periods were compared. Statistical analyses were performed using SPSS. Results In a cohort of 9,671 UC patients (23,220 patient-years), 45% (n=539) discontinued first-line treatment in T1, which was 2.8 times more likely compared to 16% in T3 (p < 0.001). Additionally, 15% of patients in T1 transitioned to a second advanced therapy (AT), whereas 35% did so in T3 (p < 0.001). TOF was less frequently used in bio-naïve patients but more commonly prescribed in bio-exposed patients. Notably, in T3, TOF was the only therapy to show a significant increase in use from first- to fifth-line treatment, with the number of patients rising from 84 to 330, a 293% increase. In a cohort of 19,087 CD patients (79,677 patient-years), 48% (n=1465) discontinued first-line TNFi treatment in T1, making them 2.1 times more likely to stop treatment compared to T3 (p < 0.001). Due to limited treatment options in T1, only 20% of patients transitioned to second-line advanced therapy (AT), compared to 38% in T3. Furthermore, with the introduction of UST in T3, it was 2.1 times more likely to be prescribed to bio-exposed patients than ADA, the second most commonly used therapy in this group during T3. Conclusion This study underscores the increasing diversity of AT pathways for IBD patients, resulting in improved treatment retention over time. In both Crohn’s disease and ulcerative colitis, patients in T3 were less likely to discontinue treatment compared to those in T1, largely due to the expanded use of TOF and UST as salvage therapies. These findings provide important insights into the optimal sequencing of AT in IBD, demonstrating that a broader array of treatment options enhances patient adherence by offering more effective salvage strategies. References Ko Y, Paramsothy S, Yau Y, Leong RW. Superior treatment persistence with ustekinumab in Crohn’s disease and vedolizumab in ulcerative colitis compared with anti-TNF biological agents: real-world registry data from the Persistence Australian National IBD Cohort (PANIC) study. Aliment Pharmacol Ther. 2021 Aug;54(3):292-301. doi: 10.1111/apt.16436. Epub 2021 Jun 20. PMID: 34151447.

P1012 Systemic biologic therapies are associated with comparable safety outcomes to vedolizumab for the management of Inflammatory Bowel Disease following liver transplantation

Abstract Background Although the ‘gut-specific’ safety profile of vedolizumab may be considered advantageous in inflammatory bowel disease (IBD) patients on concomitant immunosuppression following liver transplant, the safety of vedolizumab has not been compared with ‘systemic’ biologic therapies in this context. This study aimed to compare the safety of ‘gut-specific’ and ‘systemic’ biologic therapies to manage IBD following liver transplantation (LTx). Methods A retrospective observational study of IBD patients exposed to biologic therapy following LTx was undertaken across two Australian LTx centers. The primary outcome was the incidence rate of safety events per patient-year of biologic exposure, while the secondary outcome was the impact of non-biologic immunosuppression on safety events. Safety events were defined as any documented infection whilst on biologic therapy, and were stratified accordingly to ‘gut-specific’ (vedolizumab) or ‘systemic’ (anti-TNF, ustekinumab) biologic exposure. A severe safety event was defined as one that required hospitalisation. Results Thirty-six patients were exposed to 59 (median 12 (IQR 6-27) months) biologic episodes for IBD following LTx. Most patients had co-existing primary sclerosing cholangitis (88.9%) and ulcerative colitis (72.2%) (Table 1). The cohort were collectively exposed to 44.5 and 44.4 patient-years of ‘gut-specific’ (n=27) and ‘systemic’ (anti-TNF, n=22; ustekinumab, n=10) biologic therapy, respectively. Twenty-seven (45%) biologic episodes were associated with 41 safety events a median of 8 months (IQR 4.5-13.5) following biologic initiation (Table 2A). The incidence rate of safety events were comparable between ‘gut-specific’ and ‘systemic’ biologic exposures (0.43 vs 0.50 per patient-year, p=0.79). Corticosteroid exposure at biologic initiation was the only non-biologic immunosuppressive exposure associated with more frequent severe safety events (incidence ratio 5.40 [95% CI 1.66-17.63, P<0.01]; Table 2B). Conclusion In this study of LTx recipients with IBD, incidence of safety events between those exposed to ‘gut specific’ and ‘systemic’ biologic therapies were comparable. These data suggest that choice of IBD biologic therapy should not be primarily influenced by concurrent transplant immunosuppression. However, corticosteroid co-therapy at biologic initiation may be associated with a higher incidence of severe safety events, highlighting the need to rationalise corticosteroid therapy following biologic initiation. These observations warrant validation in separate cohorts.

P0524 Advanced therapy options, choice, access, and treatment empowerment for Inflammatory Bowel Disease (ADVOCATE-IBD): A UK-wide qualitative study

Abstract Background Inflammatory Bowel Disease (IBD) impairs the quality of life of more than 6.8 million people worldwide1 through symptoms such as severe abdominal pain and faecal urgency. Advanced therapies such as biologics, are increasingly being used in treatment, each holding unique characteristics that influence patient preferences. By understanding these, treatment adherence, long-term health outcomes and shared decision-making can be enhanced2. This study aimed to outline the core domains of patient priorities and values around advanced therapies which influence decision-making. Methods Guided by data saturation3, participants were recruited through social media and Crohn’s and Colitis UK using purposive sampling4. Participants undertook a single semi-structured interview that followed a topic guide informed by the results of a Patient and Public Involvement group. Audio-recordings of interviews were transcribed verbatim prior to undergoing reflexive thematic analysis. Results A total of 26 UK-based participants were recruited who were predominantly female (73.1%) and aged 31-40 (34.6%). The five themes identified were: “Fitting Treatment and Monitoring into Life”, “The influence of Drug Characteristics”, “Balancing Efficacy and Side-effects”, “Optimizing the Quality of Care”, and “Promoting Shared Decision Making and its Value”. Conclusion Patient decision-making and satisfaction with treatment are influenced by multiple factors that evolve in importance over time. For patients, shared decision-making involves having the autonomy to make choices that are disparate from professional recommendations but influenced by open discussions about their care. Shared decision-making also means being actively listened to and their preferences being integrated into their care. Patient decision-making was shaped by the perceived ease of physical drug administration, drug effectiveness at inducing and maintaining remission, and the flexibility of integrating a treatment and its monitoring requirements into their daily lives. Consideration of short- and long-term adverse reactions was generally minimal, as these risks were viewed to be necessary for achieving symptom control. To patients, high-quality care constituted being involved in decisions about their treatment, reliable access to healthcare services in a timely fashion, and comprehensive information about their disease and treatment.

N12 Patient perspectives of switch in route of administration among patients established on long term intravenous Infliximab therapy

Abstract Background An increasing number of patients are switching from intravenous (IV) to subcutaneous (SC) formulations of biologic agents for inflammatory bowel disease (IBD). Research is needed to inform discussions about therapy choices for individual patients switching to SC route from established long term on IV therapy. This study investigates patient preferences, willingness to switch from IV to SC, and factors associated with acceptability of switch. Methods We administered a 6-item questionnaire ranked on Likert’s scale to patients undergoing planned switch from IV to SC Infliximab at our IBD centre. The questionnaire measured patient perspectives in the use of both formulations as well as the acceptability of the process of switching between them. In addition, the overall acceptability rating of the route of administration was measured on a visual analogue scale. Baseline characteristics and disease behaviour was recorded from electronic records. Eligibility to switch was deemed as being clinically stable based on clinicians’ assessment and on maintenance Infliximab therapy for ≥12. Results Eighty eight patients (M: F =1.2:1, UC=35, Crohn’s=53) of the 115 patients (76.5%) who were switched from intravenous to subcutaneous infliximab completed pre and post switch survey. Median age at switch was 32 years (range 17- 76) and median duration of intravenous therapy prior to switch was 156 weeks (IQR 81). Median follow up post switch was 25 weeks (IQR 38). The proportion of patients strongly satisfied with their route of administration increased from 30% to 68% following SC switch. Negative impact on activities of daily living improved from 26% to 1% post switch.11% of patients reported negative financial consequences with IV route while post switch 98% reported no financial consequences. 9% and 8% were not in favour of or neutral to IV route pre-switch. Following switch 98% favoured SC route and 2% were neutral to the route of administration. Mean acceptability score post SC switch (9.5, range 8-10) was better than prior to switch (8, range 5-10) with 86/88 (97.7%) patients reporting equal or higher scores post switch. Conclusion Patients with IBD tend to be more likely to choose SC administration than IV infusion, but preferences and drivers of choice may vary according among individuals. These findings may assist discussions around appropriate treatment choices for each patient.

P0950 Comparing Real-World use of Dietary and Medical Therapies in Children and Adults with IBD

Abstract Background Approximately 10% of people with inflammatory bowel disease (IBD) are diagnosed before 18 years of age. We explored the real-world use of dietary and medical therapies across the age spectrum in people with IBD under routine ambulatory care in Australia and New Zealand (ANZ). Methods Crohn’s Colitis Care (CCCare) is an IBD-specific electronic medical record (EMR) used across ANZ. De-identified data from CCCare’s linked clinical quality registry were analysed in September 2024. All people with IBD under active care (clinical encounter within the prior 14 months) were included. Children were defined as being < 18 years of age at time of extraction. Results A total of 7506 people with IBD were included in the study. In the <18 years age group (n=315), 58.7% were male with a median age of 16 (IQR 14-18). The majority resided in Australia (83.8%, n=264), and most had Crohn’s disease (65.1%, n=205). In the ≥18 years age group (n=7191), 45.6% (n=3494) were male with a median age of 43 years (IQR 32 - 57). The majority (72.6%, n=5223) resided in Australia, and over half had Crohn’s disease (55.4%, n=3982). Interestingly, 5-aminosalicylate use was more prevalent in adults than children (37.2% vs 27.4% respectively, P<0.001), whereas current immunomodulator use was less common in adults compared to children (32.2% vs 61.0% respectively, P<0.001). Steroid use within the past year was close to 10% in both cohorts (11.1% for the paediatrics cohort and 8.5% for adults, P=0.11). Over half of the paediatric and adult cohorts were on an advanced therapy (biologic or novel small molecule) (57.8% and 51.4% respectively, p<0.05). Advanced therapy use by age group is shown below. Anti-TNF therapies (infliximab and adalimumab) predominated in the paediatric cohort. Across the cohort, infliximab use decreased with age, whereas vedolizumab use increased with age. Dietary therapies were infrequently used/documented, with only 13/315 (4.1%) receiving dietary therapy in the paediatric cohort and 53/7191 (0.7%) in the adult cohort (p<0.001). Conclusion This study highlights CCCare’s ability to facilitate clinical research involving individuals of all ages with IBD, as well as to monitor therapy choices within a large, real-world cohort in real time. The findings provide intriguing insights into the variation in the use of dietary and advanced therapies. While certain differences in advanced therapy usage may be attributed to licensing and funding arrangements, others may be linked to concerns over drug safety in older populations. Future efforts aimed at correlating these therapeutic choices with outcomes, complications, and associated costs will soon enable a comparative evaluation of treatment strategies.

The role of a «short-term» preoperative endocrine therapy for adjuvant therapy guidance in early HR+ HER2-negative breast cancer

In the absence of widespread access to genomic tests there is an urgent need for additional methods that influence the choice of adjuvant therapy in patients with early luminal Her2-negative subtype of breast cancer (BC). The IMPACT and POETIC trials have shown that Ki67 level decrease up to ≤10% after a “short-term” (2–4 weeks) preoperative endocrine therapy (ET) is a favorable prognostic factor. This test allows some patients to avoid adjuvant chemotherapy associated with immediate and delayed adverse events.Aims of the study. To evaluate the impact of “short-term” preoperative endocrine therapy for guidance of further treatment for patients with primary operable luminal Her2-negative breast cancer stages T1–3 N0–1 M0.Results. The study included 123 patients, 76 (60.8%) received tamoxifen and 47 (37.6%) – aromatase inhibitors (AI). Most patients – 69 (55.2%) were >50 years old, premenopausal – 58 (46.4%), menopausal – 67 (53.6%). The average age was 52 years (30–82). With the initial Ki67 level>10% (N= 107), Ki67 decreased in 24 (22.4%) up to ≤10% after “short-term” ET, and remained >10% in 83 (77.6%). According to the PREDICT calculator, the benefit of adjuvant chemotherapy (AChT) was assessed as high in 35 (28.5%) patients, and 10 of them (27.8%) were able to avoid Ch T. In 86 patients with a relatively low estimated AChT benefit (<5% at 10 years) there was no response to “short-term” ET, which led to the AChT prescription in 13 cases (15.1%).Conclusions. “Short-term” course of preoperative endocrine therapy is a simple, accessible and reproducible method for personalizing of adjuvant therapy in patients with luminal HER2-negative breast cancer.

Association between empirical antibiotic regimens in emergency department and prognosis of septic patients: A single-Centre real-world study.

In this study, we aimed to explore the association between the choice of empirical antibiotic therapy and outcomes in ED patients with sepsis. Patients admitted to ED with sepsis were identified from a single center in the United States, and the data is stored in the MIMIC-IV-ED database. Propensity score matched model was used to match patients receiving empirical mono or combination antibiotic therapy. Logistic regression model was used to assess the associations between empirical antibiotic therapy and in-hospital mortality. A total of 11,380 ED patients with sepsis were included in the data analysis. After PSM, 3920 pairs of patients were matched between the empirical mono-antibiotic therapy group and combination antibiotic therapy group. No significant benefit was observed among the empirical combination antibiotic therapy patients compared with the mono-antibiotic therapy in in-hospital mortality (OR, 0.96; 95% CI, 0.81-1.15; P: 0.684). Empirical quinolones mono-therapy was associated with significantly lower mortality compared to cephalosporins (OR, 2.12; 95% CI, 1.35-3.50; P:0.002), penicillins (OR, 1.87; 95% CI, 1.08-3.34; P:0.029) and vancomycin mono-therapy (OR, 2.15; 95% CI, 1.19-3.97; P:0.012). Empirical combination antibiotic therapy was not associated with reduced mortality in ED patients with sepsis. Compared with cephalosporins, penicillins and vancomycin, quinolone mono-antibiotic therapy was significantly associated with a decreased risk of in-hospital mortality, especially in patients with respiratory tract infections.

Safety of topical estrogen therapy during adjuvant endocrine treatment among patients with breast cancer: A meta-analysis based expert panel discussion.

Endocrine treatments, such as Tamoxifen (TAM) and/or Aromatase inhibitors (AI), are the adjuvant therapy of choice for hormone-receptor positive breast cancer. These agents are associated with menopausal symptoms, adversely affecting drug compliance. Topical estrogen (TE) has been proposed for symptom management, given its' local application and presumed reduced bioavailability, however its oncological safety remains uncertain. The present systematic review, meta-analysis and expert panel review aimed to evaluate the strength of the available evidence on the risk of recurrence and mortality when TE is utilised in congruence with TAM or AI treatment, among BC survivors. Six databases and two prospective registers, were interrogated from inception to January 3rd, 2024. Search terms were Breast cancer AND Hormone replacement therapy AND topical/vaginal oestrogen AND recurrence/mortality. All study designs reporting the use vs. non-use of TE in breast cancer survivors receiving adjuvant endocrine treatment were included. Six observational studies were deemed eligible for inclusion. Sources of heterogeneity were explored using subgroup analysis by risk of bias, median follow-up period, node positivity and menopausal status. Trial sequential analysis was performed to quantify outcome reliability. A global expert panel was called to deliberate on the data, pinpoint areas of limited understanding, and determine the most important areas for future research. Risk ratio effect sizes (RR) and corresponding 95% Confidence Intervals (CI) of breast cancer recurrence and mortality in survivors on endocrine treatment (TAM and/or AI) exposed to TE were reported. Expert panel appraisal of meta-analysis evidence with definition of current knowledge gaps and future research aims. In 38 050 female patients receiving adjuvant endocrine treatment, of whom 1805 had been exposed to TE, TE exposure of those on AI, did not increase all-cause mortality (RR 0.99 [95%CI 0.58, 1.69], I2=81%, P = 0.96; moderate GRADE certainty). However, such exposure may convey an increased risk of recurrence (RR 2.51 [95% CI 1.10, 5.72], I2=9%, P = 0.03; low-GRADE certainty). Exposure to TE during TAM did not increase either recurrence risk or all-cause mortality. Clinical factors such as lymph node positivity at the time of diagnosis and menopausal status and follow-up time appeared to be significant confounders. The use of TE does not appear to increase either recurrence or mortality risk among BC survivors treated with TAM. An increased recurrence risk, without an increase in mortality, cannot be ruled out when TE is used during AI.

Guidance for Prescribing Oral Antihypertensive Medications in the Emergency Department.

To review the most current recommendations regarding assessment and treatment of asymptomatic hypertension treatment in the emergency department (ED) and to provide guidance for prescribing oral antihypertensive therapy for ED providers. There are varying management strategies for the treatment of asymptomatic hypertension in the ED likely due to a lack of direct guidelines for treatment. There is an increasing body of evidence for the safety of initiating therapy to treat chronic asymptomatic hypertension in the ED. Initiation and optimization of oral antihypertensive therapy in indicated patients can be done by ED providers to enhance and expediate transition of care for patients and can ultimately aid in prevention of cardiovascular disease (CVD). This review provides guidance of when oral antihypertensive therapy can be initiated, medication options depending on the patient's blood pressure and other concurrent medications (if applicable), as well as other factors that may influence choice of therapy are described. Oral antihypertensive therapies can be initiated and optimized in the ED for patients with asymptomatic chronic hypertension.

Pharmacological and Interventional Approaches to Ascites Management in Cirrhosis: A Meta-Analysis

Background: Ascites, a common complication of cirrhosis, significantly impacts patient morbidity and mortality. This meta-analysis evaluated the efficacy and safety of various pharmacological and interventional approaches for ascites management in patients with cirrhosis. Methods: A systematic search of PubMed, Embase, and Cochrane Library databases was conducted from January 2013 to December 2024, identifying randomized controlled trials (RCTs) comparing different pharmacological agents (diuretics, albumin, vasopressin receptor antagonists) and interventional procedures (large-volume paracentesis, transjugular intrahepatic portosystemic shunt [TIPS]) in cirrhotic patients with ascites. The primary outcome was complete ascites resolution. Secondary outcomes included time to ascites recurrence, adverse events, and mortality. A random-effects model was used to pool data, and heterogeneity was assessed using the I² statistic. Results: Twelve RCTs (n=2848 patients) met the inclusion criteria. Diuretics plus albumin was superior to diuretics alone in achieving complete ascites resolution (OR 2.18, 95% CI 1.65-2.88, p<0.001; I²=38%). Vasopressin receptor antagonists were comparable to diuretics plus albumin in terms of ascites resolution (OR 1.09, 95% CI 0.88-1.35, p=0.42; I²=12%) but associated with a lower incidence of hyponatremia (OR 0.52, 95% CI 0.35-0.78, p=0.002; I²=23%). Large-volume paracentesis was more effective than repeated small-volume paracentesis for ascites control (OR 1.75, 95% CI 1.31-2.34, p<0.001; I²=41%). TIPS was associated with a higher rate of complete ascites resolution compared to large-volume paracentesis (OR 2.45, 95% CI 1.78-3.38, p<0001; I²=35%) but a higher risk of hepatic encephalopathy (OR 2.21, 95% CI 1.48-3.30, p<0.001; I²=15%). Albumin reduced mortality in patients undergoing large-volume paracentesis (OR 0.68, 95% CI 0.49-0.94, p=0.02; I²=0%). Conclusion: This meta-analysis supports the use of diuretics plus albumin, vasopressin receptor antagonists, large-volume paracentesis, and TIPS for ascites management in cirrhosis, with the choice of therapy individualized based on patient characteristics, ascites severity, and the risk of complications.

Next-Generation Immunotherapy for Hepatocellular Carcinoma: Mechanisms of Resistance and Novel Treatment Approaches.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, and, with only 15-20% of HCC patients being suitable for potentially curative treatments, the vast majority of patients with HCC ultimately require systemic therapy. For decades, the choice of effective systemic therapy for HCC remained sparse. In recent years, after the combination of atezolizumab and bevacizumab demonstrated superior overall survival over the first-line standard, sorafenib, there has been a major therapeutic paradigm shift to immunotherapy-based regimens for HCC. While representing a great leap forward for the treatment of this cancer, the reality is that less than one-third of patients achieve an objective response to immune checkpoint inhibitor-based therapy, so there remains a significant clinical need for further therapeutic optimization. In this review, we provide an overview of the current landscape of immunotherapy for unresectable HCC and delve into the tumor intrinsic and extrinsic mechanisms of resistance to established immunotherapies with a focus on novel therapeutic targets with strong translational potential. Following this, we spotlight emerging immunotherapy approaches and notable clinical trials aiming to optimize immunotherapy efficacy in HCC that include novel immune checkpoint inhibitors, tumor microenvironment modulators, targeted delivery systems, and locoregional interventions.

Experience of using chemotherapy treatment for the first recurrence of ovarian cancer

Background. The main goal of treating patients with recurrent ovarian cancer is to prolong life and improve its quality. Approaches to the treatment of recurrent ovarian cancer have changed over the past decade. The choice of antitumor drug therapy is determined by the duration of platinum-free interval and the use of targeted therapy with bevacizumab or olaparib. Treatment regimens for relapses are not unified and treatment outcomes are contradictory. Aim: to analyze treatment outcomes of different chemotherapy regimens in patients with the first recurrence of ovarian cancer, depending on the duration of platinum-free interval. Material and Methods. A retrospective analysis of the first recurrence of ovarian cancer in 446 patients treated at the Primorsky Regional Oncology Center in the period 2004–2021 was carried out. All patients were divided into two groups depending on the treatment option for relapse: repeated cytoreduction followed by chemotherapy or only second-line chemotherapy, and into four groups depending on the chemotherapy regimens: 1 – platinum and taxane agents; 2 – platinum and taxane agents with bevacizumab; 3 – platinum agents and non-taxane agents with bevacizumab; 4 – monotherapy with non-platinum agents with bevacizumab. Results. Significant advantages in progression-free survival after second-line chemotherapy (PFS-2) were observed in patients with platinum-resistant relapse after the 4th chemotherapy regimen. Patients with platinum-sensitive relapse had the best treatment outcomes after the 3rd chemotherapy regimen and repeated cytoreduction followed by chemotherapy with a platinum-free interval of 6–12 months and 12–24 months with any platinum-containing chemotherapy regimen. In the platinum-free interval of more than 24 months, significant benefits were observed with a combination of platinum and taxane agents + bevacizumab. In the group of patients without surgery, there were significant benefits in all three intervals when prescribing a combination of platinum and non-oxane agents ± bevacizumab. There was a tendency to increase PFS-2 in patients with low-grade serous ovarian carcinoma compared with patients with high-grade serous carcinoma. The best rates of relapse-free survival were noted with maintenance therapy with olaparib. Conclusion. In patients with localized recurrence of ovarian cancer and a platinum-free interval of more than 6 months, it is advisable to perform repeated cytoreduction followed by chemotherapy, taking into account the duration of the platinum-free interval. The administration of PARP inhibitors in the maintenance therapy of platinum-sensitive recurrence of ovarian cancer improves treatment results.

Comparative Effectiveness of Outpatient COVID-19 Therapies in Solid Organ Transplant Recipients.

Multiple outpatient therapies have been developed for COVID-19 in high-risk individuals, but solid organ transplant (SOT) recipients were not well represented in controlled clinical trials. To date, few comparative studies have evaluated outcomes between outpatient therapies in this population. We performed a retrospective cohort study using de-identified administrative claims data from OptumLabs Data Warehouse. Patients were included if they were age ≥ 18 years, diagnosed with COVID-19 between January 2022 and December 2023, and underwent SOT prior to COVID-19. The primary outcome was 30-day hospitalization. Stabilized inverse probability of treatment weighting was used to account for potential confounding variables. 4192 SOT recipients with COVID-19 were identified. 1403 received an outpatient COVID-19 therapy, including anti-spike monoclonal antibodies (N = 748, 53.3%), molnupiravir (N = 327, 23.3%), ritonavir-boosted nirmatrelvir (N = 217, 15.5%), or remdesivir (N = 141, 10.0%). In weighted analysis compared to no treatment, anti-spike monoclonal antibodies (hazard ratio [HR] 0.39, 95% confidence interval [CI] 0.28-0.55; p < 0.001), molnupiravir (HR 0.56, 95% CI 0.36-0.89; p = 0.013), and nirmatrelvir (HR 0.47, 95% CI 0.25-0.89; p = 0.020) were associated with reduced hospitalization risk, while remdesivir (HR 1.00, 95% CI 0.50-1.98; p = 0.992) was not. Hospitalization rates were similar between the treatment agents, apart from remdesivir showing a higher risk compared to anti-spike monoclonal antibodies. Outpatient COVID-19 therapies were largely associated with improved outcomes among SOT recipients. These treatment agents showed similar rates of 30-day hospitalization, except for remdesivir. The choice of outpatient COVID-19 therapy in SOT recipients should primarily account for patients' individual circumstances and drug-drug interactions rather than differential therapeutic efficacy.

Advancing Prognosis in Behçet's Uveitis: The Role of Biologic Therapies

Behçet’s disease (BD) is a chronic, multi-system inflammatory disease with potentially devastating ocular involvement. Uveitis remains one of the leading causes of blindness in BD patients. The usual remedies, mainly corticosteroids and immunosuppressants, do not effectively work long term and/or stop relapses. New medicines have changed treatment. New therapies for Behçet’s uveitis may just address the cause of the disease process. This paper analyses the continuous evolution of biologics and their contribution towards improving prognosis; specifically it examines tumour necrosis factor (TNF) inhibitors, interleukin (IL) antagonists, and other monoclonal antibodies. Drugs like infliximab and adalimumab have been quite helpful in controlling inflammation, preventing relapses, and saving sight. These agents target immune pathways to ameliorate the systemic and ocular manifestations of BD, and they have a better safety profile than traditional agents. Rising proof points out that IL-17 and IL-1 inhibitors may also work, opening the choice of therapy for resistant cases. Even though they have made progress, there is still a lot of work to do and overcome optimization biologics challenges related to the patient, cost, and adverse effects. This review highlights the value of personalized treatments, offering key recommendations for the use of biologics in their overall management approach depending on the severity. Also, real-world studies and head-to-head trials will help refine therapeutic algorithms in the future directions. Doctors may use biologic therapies to greatly enhance the quality of life and the visual outcome in Behçet’s uveitis. It is an important step toward precision medicine in BD.

Poor agreement among asthma specialists on the choice and timing of initiation of a biologic treatment for severe asthma patients.

As the number of monoclonal antibodies available for severe asthma is growing, specialists currently choose without clear guidelines. Despite increasing knowledge on treatment response to these monoclonal antibodies, making the optimal choice for each individual patient remains a challenge. However, evidence of this daily challenge is lacking. To evaluate inter-observer agreement on the choice of biologic therapy in severe asthma patients among severe asthma specialists, based on clinical cases. This two-phase study included a pilot local study and an international validation study. Asthma specialists were presented 7 real-life asthma cases managed with a monoclonal antibody. Based on the clinical information provided in the cases, they were asked if they would have initiated a monoclonal antibody and, if so, their treatment of choice between a) Omalizumab, b) Mepolizumab, c) Reslizumab, d) Benralizumab and e) Dupilumab. Interobserver agreement for each question was assessed using Gwet's AC1. Sixteen physicians from the Province of Quebec (Canada) completed the pilot survey, and 70 physicians from 26 countries completed the international survey. Gwet's AC1 for the decision to initiate a biological therapy was 0.48 in the pilot survey and 0.33 in the international survey. For the choice of therapy, agreement was 0.33 and 0.26, respectively. The inter-observer agreement among asthma specialists in both the decision to initiate a biological treatment in patients with severe asthma and in the selection of treatment is weak. These results highlight the need for studies seeking reliable predictors for optimal response to biological therapies.

Lymph Node Metastasis for pN+ Superficial Esophageal Squamous Cell Carcinoma.

This study aimed to analyze lymph node metastasis (LNM) distribution in superficial esophageal squamous cell carcinoma (ESCC) and its impact factors on survival. We reviewed 241 pT1N+ ESCC cases between February 2012 and April 2022 from 10 Chinese hospitals with a high volume of esophageal cancer (EC). We analyzed clinicopathological data to identify overall survival (OS) risk factors and LNM distribution in relation to tumor invasion depth. Of the 241 patients, 26 (10.8%) had pT1a cancer and 215 (89.2%) had pT1b cancer. We showed that N3 stage, ≤ 28 lymphadenectomies, and nerve infiltration (NI) were negative factors for OS in superficial pN+ ESCC, whereas the OS was not definitively affected by the tumor depth and the choice of adjuvant therapy. In general, the LNM rates of the 193 pT1N+ ESCC cases can be ranked in the following order: station 106recR > station 106recL > station 1 > station 7 > station 2. With deeper tumor invasion, the higher LNM rate was observed near the bilateral recurrent laryngeal nerves (RLN), but there was no statistically significant difference. In superficial ESCC, LNM was frequently observed along the 106recR (35.8%) and 106recL (25.6%) stations. Advanced N-staging (N3) was a major negative impact factor in prognosis, and adequate lymph nodes dissected (LND) (N > 28) improved OS of pT1N+ ESCC. However, in superficial ESCC, tumor infiltration depth did not affect patients' OS or the distribution of positive LNs. The optimal adjuvant treatment that favors survival for these patients required further investigation.

Lupus Nephritis and Chronic Kidney Disease: A Scoping Review.

Prevention of end-stage kidney disease (ESKD) is a major objective in the management of patients with lupus nephritis (LN). Chronic kidney disease (CKD) of variable severity is common in these patients, but recent literature has mostly focused on novel immunosuppressive treatments for acute LN, while the data on CKD is relatively limited. This scoping review aims to summarise available data on the prevalence and risk factors for CKD in patients with LN. PubMed and Web of Science databases were systematically searched on the 1st November 2024 for 'real world' SLE and LN cohorts with longitudinal follow-up which reported the outcome of CKD or CKD progression and its associated risk factors. Fifteen studies were included. The prevalence of CKD ranged from below 10% to almost 50% across diverse LN and SLE cohorts. Major risk factors for CKD or CKD progression included renal impairment at presentation, renal function at 1 year post-treatment, delayed diagnosis, established chronic pathological lesions on kidney biopsy, unsatisfactory treatment response, nephritic flares, hypertension, and persistent proteinuria during follow-up. Many of the identified risk factors are amenable to therapeutic intervention. CKD not only contributes to morbidity and mortality and inferior quality of life, but also influences the choice of therapy and optimal dosing of medications. Attention to immunomodulatory medications for disease control, and non-immune strategies for renoprotection and prevention of CKD complications, are both important in the management of patients with LN to reduce their life-time risk of ESKD.