Therapy In High-risk Patients Research Articles

Ruxolitinib plus basiliximab therapy for steroid-refractory acute graft-versus-host disease in unrelated cord blood transplantation: a large-scale study

Steroid-refractory (SR) acute graft-versus-host disease (aGVHD) is a major cause of mortality after allogeneic stem cell transplantation (allo-HSCT). We aimed to evaluate the effectiveness and safety of ruxolitinib plus basiliximab for treating SR-aGVHD after unrelated cord blood transplantation (UCBT). Among the 1154 patients with hematological malignancies who underwent UCBT between February 2014 and May 2022, 198 patients with grade II to IV SR-aGVHD were enrolled, 112 of whom were treated with basiliximab alone (basiliximab group) and 86 of whom received basiliximab plus ruxolitinib (combined therapy group). The combined therapy group demonstrated a significantly higher complete response rate (CRR) on day 28 (36.0%) than did the basiliximab group (12.5%, P < 0.001). SR-aGVHD patients were further stratified into standard-risk and high-risk groups using the refined Minnesota aGVHD risk score. For standard-risk patients, combined therapy significantly improved the CRR (51.1% versus 13.6%, P < 0.001) and 3-year overall survival (74.5% versus 52.4%, P = 0.033). However, high-risk patients did not exhibit the same benefits. Compared with basiliximab monotherapy, ruxolitinib plus basiliximab therapy was an effective therapy for patients with standard-risk SR-aGVHD following UCBT. The effectiveness of combined therapy in high-risk patients was not apparent, indicating the need for other treatments.

COVID-19 therapeutics.

SUMMARYSince the emergence of COVID-19 in 2020, an unprecedented range of therapeutic options has been studied and deployed. Healthcare providers have multiple treatment approaches to choose from, but efficacy of those approaches often remains controversial or compromised by viral evolution. Uncertainties still persist regarding the best therapies for high-risk patients, and the drug pipeline is suffering fatigue and shortage of funding. In this article, we review the antiviral activity, mechanism of action, pharmacokinetics, and safety of COVID-19 antiviral therapies. Additionally, we summarize the evidence from randomized controlled trials on efficacy and safety of the various COVID-19 antivirals and discuss unmet needs which should be addressed.

Robotic 8-mm trocar fascial wounds: To close or not to close?

The aim of this study was to investigate 8-mm robotic trocar site hernia (TSH) rate over the short and long term, providing aids to manage the related fascial wounds. A retrospective analysis of 320 patients undergoing robotic surgery was conducted. The primary outcome was 8-mm TSH rate with a minimum follow-up of 12months. The secondary outcome was the rate of haematomas and infections related to 8-mm wounds and their association with patient comorbidities and trocar position. One case of TSH was observed (0.31%). There were 15 cases of wound infection (4.68%) and 22 cases of wound haematoma (6.87%). Trocar related complications were significantly associated with patient comorbidities, not with trocar position. Our results do not justify the 8-mm fascial wound closure. Data concerning the association between trocar-related complications and patient comorbidities strengthen the need to implement the control of metabolic state and correct administration of perioperative therapy in high-risk patients.

Outcome of Atezolizumab Plus Bevacizumab Combination Therapy in High-Risk Patients with Advanced Hepatocellular Carcinoma.

Real-world data regarding treatment with atezolizumab plus bevacizumab in high-risk patients with advanced HCC are lacking. In this multicenter retrospective cohort study, a total of 215 patients with advanced HCC received atezolizumab plus bevacizumab treatment at four tertiary hospitals. High-risk patients were those with grade Vp4 portal vein thrombus, bile duct invasion, or more than 50% liver infiltration. In total, 98 (45.6%) were the high-risk population, 186 (86.5%) were considered to be Child-Pugh class A, and 128 (59.5%) had previously received neoadjuvant or concomitant radiation treatment. Median overall survival (OS) was 11.25 months (95% CI, 9.50-13.10), and the median progression-free survival (PFS) was 8.00 months (95% CI, 6.82-9.18). In the high-risk population, the median OS was 10 months (95% CI, 8.19-11.82) and the median PFS was 6.50 months (95% CI, 3.93-9.08). In the high-risk population, multivariate analysis indicated that radiation therapy and lower ALBI grade were associated with better OS and PFS. A total of 177 (82.3%) patients experienced adverse events of any grade, the most common being proteinuria (23.7%). Atezolizumab plus bevacizumab treatment showed consistent efficacy and tolerability in both the total and high-risk population. Radiation therapy combined with atezolizumab plus bevacizumab treatment might be helpful to improve PFS and OS in high-risk populations.

HER2 positivity predicts BCG unresponsiveness and adaptive immune cell exhaustion in EORTC risk-stratified cohort of bladder cancer.

Predicting the response to Bacillus Calmette-Guérin (BCG) therapy in high-risk patients with non-muscle invasive bladder cancer (NMIBC) is crucial, as failure may necessitate interventions, such as radical cystectomy or salvage therapy. With the recent classification of genetic class 2a (which has HER2 protein abundance as its signature mutation of ERBB2), evaluating its prognostic role and relationship with BCG response could yield important results. This retrospective study included 160 patients with NMIBC who underwent transurethral resection of bladder tumors at Gangneung Asan Hospital between 2000 and 2013 and were stratified based on the European Organization for Research and Treatment of Cancer (EORTC) risk criteria. In addition, we analyzed a subset of 67 patients who had received BCG induction therapy to identify factors predictive of BCG treatment response. Univariate and multivariate analyses were used to assess the impact of clinicopathological factors, HER2 positivity, and EORTC risk on recurrence, progression, survival, and BCG response. Each variable's prognostic significance was determined using the Kaplan-Meier analysis. The tumor microenvironments (TMEs) were evaluated in relation to HER2 and EORTC risk. Patients with HER2+ had a higher median age, a greater prevalence of high-grade tumors, and more frequent recurrences. The univariate analysis demonstrated that the HER2+, intermediate (vs. low-risk) high (vs. low-risk), and EORTC recurrence risk groups were significantly associated with recurrence. In patients treated with BCG, only the HER2+ status predicted recurrence. In the univariate analysis for progression, age, high EORTC progression risk (vs. low-to-intermediate), HER2+, and programmed death-ligand 1 positive (PD-L1+) were significant factors. In multivariate analyses for progression, age, high EORTC progression risk, and PD-L1+ were significant factors for progression. HER2 expression was associated with the TME, influencing the proportion of PD-L1+ cells, as well as other markers of PD-1, CD8, and Ki67. The HER2+ status may be related to genetic characteristics that appear more frequently in older age, which suggests a potential for predicting the recurrence and response to BCG treatment. Additionally, analyzing TME trends of aggressive adaptive immune response characterized by HER2 expression provides insight into recurrence and BCG response mechanisms.

Prophylactic Use of Negative Pressure Wound Therapy in High-risk Patients Undergoing Oncoplastic and Reconstructive Breast Surgery.

Negative pressure wound therapy (NPWT) has emerged as an adjunct to reduce wound complication rates in many surgical domains. This study investigated the prophylactic use of PICO NPWT in high-risk patients undergoing oncoplastic and reconstructive breast surgery. This was a prospective multicenter national audit. The findings were compared against Association of Breast Surgery/British Association of Plastic, Reconstructive and Aesthetic Surgeons (ABS/BAPRAS) Oncoplastic Guidelines for best practice. Data from 267 patients were included from seven centers. All patients had at least one high-risk factor for postoperative wound complications, whereas 78 patients (29.2%) had more than one. Thirty-six patients (13.5%) developed postoperative wound complications. An estimated 16 (6%) developed skin flap necrosis, wound dehiscence occurred in 13 patients (4.9%), and 15 patients (5.6%) developed postoperative wound infection. Eleven patients (4.1%) required further surgery due to wound complications. In total, 158 patients underwent mastectomy with immediate implant reconstruction. Postoperative wound complication rate was comparable in this subgroup (n = 22; 13.9%). Implant loss rate was 3.8%, which was within the 5% target mentioned in the ABS/BAPRAS guidelines. The estimated total cost saving was US $105,600 (£84,613) and US $395.50 (£316.90) per patient. Wound infection rate (5.6%) was much lower than the 25% reported by both iBRA study and National Mastectomy and Breast Reconstruction Audit. Our study suggests that prophylactic use of NPWT in oncoplastic and reconstructive breast surgery results in low rates of wound-related complications with associated healthcare cost benefits in patients with high-risk factors for wound-related complications. However, a prospective randomized control trial is required.

Comparison of Maintenance Therapy Regimens of Patients Treated for Multiple Myeloma

Background: Despite significant progress in treatment modalities and improved survival and response rates in patients diagnosed with multiple myeloma (MM), it remains an incurable disease with a poor outcome, especially in high-risk groups. Though not all patients are eligible, autologous stem-cell transplantation (ASCT) remains an integral part of the treatment of patients with both newly diagnosed and relapsed MM. Regardless of whether patients receive a transplant, they do receive maintenance therapy, and recent evidence has demonstrated that maintenance therapies offer an advantage in progression free and overall survival. While Revlimid is the standard of care, data regarding the specifics of maintenance therapy in high-risk patients is limited and the overall impact of various regimens on survival needs to be further investigated. In our retrospective chart review we reviewed all adult patients with advanced MM within Henry Ford Cancer Institute in the last 10 years to determine the impact of maintenance therapy on progression free survival (PFS) and overall survival (OS). Methods: We conducted a retrospective chart review of adult patients with MM who underwent ASCT between January 1, 2012 to December 31, 2022. Those who received maintenance chemotherapy after transplant were included in the study. Patients who were lost to follow-up or who had largely incomplete records were excluded. Data points including age, ethnicity, cytogenetic analysis, risk category, maintenance regimen after transplant, last chemotherapy regimen, last follow-up, and date of death (if applicable) were recorded. Maintenance chemotherapy regimens were recorded as Revlimid versus other. Patients were split into 2 categories based on risk - high risk and standard risk. Kaplan-Meier plots were used to illustrate overall survival and time to relapse between groups for various variables. Statistical significance was set at p&amp;lt;0.05 Results: 158 patients were included in the study of which 44 were considered high-risk based on cytogenetics, 106 were standard-risk and 8 were missing. Most of the patients (n=137, 87.3%) received Revlimid, while 20 (12.7%) received maintenance therapy other than Revlimid, and for 1 patient, the type of maintenance therapy was unknown. Within the high-risk group, no statistical significance in OS or PFS was found between patients that received Revlimid versus those that did not. Furthermore, there was no statistical significance in OS and PFS within high risk versus standard cytogenetic risk groups. Conclusions: We did not see a difference in outcome based on risk and believe all patients would derive equal benefit from maintenance therapy We also did not see a difference in outcome between high and standard risk patients, and for the high-risk subgroup, there was a separation in curves suggesting that maintenance therapy has benefit compared to no maintenance.

Guideline adherence to statin therapy and association with major adverse cardiac events in high-risk patients following major noncardiac surgery

Abstract Introduction Statins are widely used for the prevention of coronary artery disease (CAD) and associated secondary cardiovascular complications. Despite established evidence in acute and chronic cardiovascular disease, the optimal perioperative use of statins remains uncertain. We aimed to evaluate adherence to current guideline recommendations regarding statin therapy in high-risk patients undergoing major noncardiac surgery and its association with major adverse cardiac event (MACE). Methods Class I indications for statin therapy according to current ESC clinical practice guidelines were assessed among consecutive high-risk patients undergoing major noncardiac surgery enrolled in a prospective multicentre cohort study. The primary endpoint MACE, a composite of cardiovascular death and spontaneous acute myocardial infarction, was recorded during 120-day follow up and centrally adjudicated by cardiologists blinded to statin therapy. As a co-primary endpoint, perioperative myocardial infarction/injury (PMI) due to a type 1 MI (T1MI) or likely type 2 MI (lT2MI) within the first three postoperative days was used. After multivariable adjustment with inverse probability of treatment weighting (IPTW) to account for differences between statin and non-statin users, we performed a Cox proportional hazard model with MACE and a logistic regression model with PMI due to T1MI or lT2MI as endpoints. Results Between October 2014 and February 2018, we included 8116 high-risk patients undergoing major noncardiac surgery. 4227 of 8116 patients (52.1%) had at least one class I indication for statin therapy. The most common indication for statin use was CAD in 2235 patients (52.9%) followed by diabetes with comorbidities in 1676 patients (39.6%) and peripheral artery disease in 1514 patients (35.8%). From all patients with a class I indication for statin use, only 2440 (57.7%) were on statins preoperatively. Usage was highest in patients with prior myocardial infarction (828/1110 [74.6%]) and lowest in patients with chronic kidney disease stage 3-5 (494/996 [49.6%]). During the follow up of 120 days, 192 MACE occurred (4.6%) including 116 cardiovascular deaths. After multivariable adjustment, preoperative use of statins was associated with a reduced risk of MACE (weighted hazard ratio 0.59, 95% confidence interval [CI] 0.41-0.86; p = 0.006). PMI due to T1MI or lT2MI occurred in 508 of 4170 (12.2%) patients. After IPTW, the weighted odds ratio for PMI in patients receiving preoperative statin therapy was 1.15 (95%CI 1.01-1.31; p = 0.036). Conclusion Current adherence to guideline-recommended statin therapy in the noncardiac surgery population is suboptimal. The use of statins was associated with reduced rates of adverse cardiac events within 120 days, but not with cardiac PMI.Percentage of patients receiving statinsMACE within 120 days

Comparison of therapeutic strategies for aortic stenosis between transcatheter and surgical aortic valve implantation: a retrospective cohort study in Japanese dialysis patients

BackgroundAlthough transcatheter aortic valve implantation (TAVI) is assumed to be a less invasive therapy in high-risk patients with aortic valve stenosis (AS), there have been limited data suggesting its beneficial effects on cardiovascular mortality in Japanese patients receiving dialysis therapy.MethodsHemodialysis patients with severe AS underwent either TAVI (n = 33) or surgical aortic valve replacement (SAVR, n = 25). We compared the postoperative outcomes and perioperative complications, including dialysis-associated parameters [e.g., intradialytic hypotension (IDH)], between TAVI and SAVR.ResultsA 30-day and 1-year mortality rate was nearly the same among the TAVI and the SAVR group. Incidence of permanent pacemaker implantation or other events, including stroke, bleeding and vascular complications, in the TAVI group were not different from those in SAVR patients during the 30-day or 1-year postoperative period. The incidence of IDH was increased following SAVR (odds ratio (OR) = 11.29 [95% CI 1.29–98.89]) but was not affected by TAVI (OR = 1.55 [95% CI 0.24–9.94]). Among the patients aged 75 or older, the incidence of IDH was particularly conspicuous in the SAVR group (OR = 15.75 [95% CI 2.30–107.93]). Because there were differences in background data (age, EuroSCORE II, and dialysis duration) between these groups, propensity score-matched analysis was conducted and showed no difference in the composite event-free probability between the TAVI and the SAVR group over one year (p = 0.816).ConclusionsTAVI offers an alternative strategy to Japanese hemodialysis patients with severe AS, with nearly the same incidence of complications as SAVR during 1-year observation.

Diagnosis and treatment in a case of uterine leiomyosarcoma - case report and review of the literature

Introduction: Uterine leiomyosarcoma accounts for approximately 3%–7% of all uterine cancers and it is the most common subtype of uterine sarcoma. They are associated with high potential to both local recurrence and distant metastases, and they contribute to a significant proportion of uterine cancer deaths. Tumor stage is the single most important prognostic factor for uterine sarcomas. Presenting symptoms may be vague and mimic other benign uterine conditions.The aim of the study: This study aims to describe a case of uterine leiomyosarcoma and summarize current knowledge about classification, diagnostics and treatment.Materials and methods: The research method was a case study. This review was based on available data collected in the PubMed database and Google Scholar web search engine, using the key words: uterine leiomyosarcoma, uterine sarcoma, hysterectomy, gynecologic oncology.Conclusion: Surgery is considered the mainstay of treatment for sarcomas limited to the uterus. In patients with carcinosarcomas postoperative radiotherapy increases the local control. High rate of distant metastases suggests potential role of systemic therapy. However, the benefits of postoperative chemotherapy and endocrine therapy in high-risk patients are of no proven value in the adjuvant setting. These methods, in addition to palliative radiotherapy and surgery are used in recurrent and advanced disease.Keywords: uterine leiomyosarcoma, uterine sarcoma, hysterectomy, gynecologic oncology

Adenosine Triphosphate Citrate Lyase and Fatty Acid Synthesis Inhibition

Adenosine triphosphate citrate lyase (ACLY) is a key regulatory enzyme of glucose metabolism, cholesterol and fatty acid synthesis, and the inflammatory cascade. Bempedoic acid, an ACLY inhibitor, significantly reduces atherogenic lipid markers, including low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol, and apolipoprotein B. Additional effects of ACLY inhibition include antitumor growth; reduction of triglycerides and proinflammatory molecules such as high-sensitivity C-reactive protein; less insulin resistance; reduction of hepatic lipogenesis; and weight loss. While numerous ACLY inhibitors have been identified, most of the clinical data have focused on bempedoic acid. The Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen (CLEAR) program was a series of phase 3 clinical trials that evaluated its effects on lipid parameters and safety, leading to US Food and Drug Administration approval in 2020. CLEAR Outcomes was a phase 3, double-blind, randomized, placebo-controlled trial in individuals with a history of statin intolerance, serum LDL-C level of 100 mg/dL or higher, and a history of, or at high risk for, cardiovascular disease. Bempedoic acid modestly reduced the primary 4-way cardiovascular composite end point as well as the individual components of myocardial infarction and coronary revascularization but did not reduce stroke, cardiovascular death, or all-cause mortality. Rates of gout and cholelithiasis were higher with bempedoic acid, and small increases in serum creatinine, uric acid, and hepatic-enzyme levels were also observed. ACLY inhibition with bempedoic acid has been established as a safe and effective therapy in high-risk patients who require further LDL-C lowering, particularly for those with a history of statin intolerance. The recently published CLEAR Outcomes trial revealed modest reductions in cardiovascular events with bempedoic acid, proportional to its LDL-C lowering, in high-risk individuals with statin intolerance and LDL-C levels of 100 mg/dL or higher. The additional effects of ACLY inhibition have prompted a more thorough search for novel ACLY inhibitors for conditions such as cancer, hypertriglyceridemia, chronic inflammation, type 2 diabetes, fatty liver disease, obesity, and metabolic syndrome. Similarly, therapies that reduce fatty acid synthesis are being explored for their use in cardiometabolic conditions.

Efficacy of Left Atrial Appendage Closure and Oral Anticoagulation After Atrial Fibrillation Catheter Ablation

Left atrial appendage closure (LAAC) proved to be noninferior to oral anticoagulation (OAC) in nonablated patients with atrial fibrillation (AF). This study aimed to compare the efficacy and safety of LAAC with those of OAC therapy in patients after AF ablation. This study included patients who underwent catheter ablation (CA) of AF between January 2016 and December 2020. The cohort was divided into CA+LAAC and CA+OAC, where propensity score matching was used to select controls, and each group contained 682 subjects. The enrolled patients' mean age was 70.34 ± 8.32years, and 47.3% were female; their CHA2DS2-VASc score was 3.48 ± 1.17. Baseline characteristics were similar between groups. After a 3-year mean follow-up, the incidence of thromboembolic events was 1.25 and 1.10 and that of major bleeding events was 0.65 and 1.72 per 100 patient-years in the CA+LAAC, and CA+OAC groups, respectively. The rate of thromboembolisms and major adverse cardiovascular events was similar between the 2 groups (hazard ratio [HR] 1.162, 95% confidence interval [CI] 0.665 to 2.030, p=0.598, HR 0.711, 95% CI 0.502 to 1.005, p=0.053); however, that of major bleeding and all-cause death was significantly reduced with LAAC (HR 0.401, 95% CI 0.216 to 0.746, p=0.004, HR 0.528, 95% CI 0.281 to 0.989, p=0.046). There was no significant difference in periprocedural complications (p >0.05) and the rate of AF recurrence (OAC vs LAAC: 39.44% vs 40.62%, p=0.658). LAAC is a reasonable and safer alternative to OAC therapy in high-risk patients after AF ablation.

Opportunistic In-hospital Initiation of Lipid-Lowering Therapy in High-risk Patients With Atherosclerotic Cardiovascular Disease—A Catalyst for Achieving Secondary Prevention

Opportunistic In-hospital Initiation of Lipid-Lowering Therapy in High-risk Patients With Atherosclerotic Cardiovascular Disease—A Catalyst for Achieving Secondary Prevention

Epinephrine injection monotherapy shows similar hemostatic efficacy to epinephrine injection combined therapy in high-risk patients (Forrest Ib) with bleeding ulcers.

Whether combination therapy has higher hemostatic efficacy than epinephrine injection monotherapy in different Forrest classifications is not clear. This study aimed to compare hemostatic efficacy between epinephrine injection monotherapy (MT) and combination therapy (CT) based on different Forrest classifications. We retrospectively analyzed peptic ulcer bleeding (PUB) patients who underwent endoscopic epinephrine injections or epinephrine injections combined with a second therapy between March 2014 and June 2022 in our center, and the patients were divided into MT group or CT group. Subsequently, a propensity score matching analysis (PSM) was performed and rebleeding rates were calculated according to Forrest classifications via a stratified analysis. Overall, 605 patients who met the inclusion criteria were included, and after PSM, 173 patients in each of the CT and MT groups were included. For PUB patients with nonbleeding visible vessels (FIIa), the rebleeding rates by Days 3, 7, 14, and 30 after PSM were 8.8%, 17.5%, 19.3%, and 19.3% in the MT group, respectively, and rates were 0%, 4.1%, 5.5%, and 5.5% in the CT group, respectively, with significant differences observed between the two groups by Days 3, 7, 14, and 30 (P = 0.015, P = 0.011, P = 0.014, and P = 0.014, respectively). However, for PUB patients with oozing bleeding (FIb), the rebleeding rates by Days 3, 7, 14, and 30 after PSM were 14.9%, 16.2%, 17.6%, and 17.6% in the MT group, respectively, and rates were 13.2%, 14.7%, 14.7%, and 16.2% in the CT group, respectively, with no significant differences observed between the two groups by Days 3, 7, 14, and 30 (P = 0.78, P = 0.804, P = 0.644 and P = 0.825). Combined therapy has higher hemostatic efficacy than epinephrine injection monotherapy for PUB patients with visible blood vessel (FIIa) ulcers. However, epinephrine injection monotherapy is equally as effective as combined therapy for PUB patients with oozing blood (FIb) ulcers.

Advances in molecular characterization of pediatric acute megakaryoblastic leukemia not associated with Down syndrome; impact on therapy development.

Acute megakaryoblastic leukemia (AMKL) is a rare subtype of acute myeloid leukemia (AML) in which leukemic blasts have megakaryocytic features. AMKL makes up 4%-15% of newly diagnosed pediatric AML, typically affecting young children (less than 2years old). AMKL associated with Down syndrome (DS) shows GATA1 mutations and has a favorable prognosis. In contrast, AMKL in children without DS is often associated with recurrent and mutually exclusive chimeric fusion genes and has an unfavorable prognosis. This review mainly summarizes the unique features of pediatric non-DS AMKL and highlights the development of novel therapies for high-risk patients. Due to the rarity of pediatric AMKL, large-scale multi-center studies are needed to progress molecular characterization of this disease. Better disease models are also required to test leukemogenic mechanisms and emerging therapies.

A cuproptosis-related lncRNA signature to predict prognosis and immune microenvironment of colon adenocarcinoma

Cuproptosis is a novel cell death modality but its regulatory role in the colon cancer remains obscure. This study is committed to establishing a cuproptosis-related lncRNA (CRL) signature to forecast the prognosis for colon adenocarcinoma (COAD). The Cancer Genome Atlas (TCGA) samples were randomly divided into training and validation cohorts. LASSO-COX analysis was performed to construct a prognostic signature consisting of five CRLs (AC015712.2, ZEB1-AS1, SNHG26, AP001619.1, and ZKSCAN2-DT). We found the patients with high-risk scores suffered from poor prognosis in training cohort (p < 0.001) and validation cohort (p = 0.004). Nomogram was created based on the 5-CRL signature. Calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA) demonstrated the nomogram performed well in 1‑, 3‑, and 5‑year overall survival (OS). Subsequently, we observed increased infiltration of multiple immune cells and upregulated expression of immune checkpoints and RNA methylation modification genes in high-risk patients. Additionally, gene set enrichment analysis (GSEA) revealed two tumor-related pathways, including MAPK and Wnt signaling pathways. Finally, we found AKT inhibitors, all-trans retinoic acid (ATRA), camptothecin, and thapsigargin had more sensitivity to antitumor therapy in high-risk patients. Collectively, this CRL signature is promising for the prognostic prediction and precise therapy of COAD.

Abemaciclib: A Review in Early Breast Cancer with a High Risk of Recurrence.

Abemaciclib [Verzenio® (USA) or Verzenios® (EU)] is a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor approved in combination with adjuvant endocrine therapy for patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), node-positive, early breast cancer with a high risk of recurrence. In a phase III trial, abemaciclib plus endocrine therapy reduced the risk of recurrence of breast cancer compared with endocrine therapy alone, including in patients who had previously received neoadjuvant chemotherapy, in patients with high- and low-scoring Ki-67 tumours, and in both premenopausal and postmenopausal patients. The tolerability profile of abemaciclib plus endocrine therapy was acceptable and manageable, with diarrhoea, infections and neutropenia being the most common adverse events. Thus, abemaciclib in combination with standard endocrine therapy is a valuable additional treatment option for patients with HR+, HER2-, node-positive early breast cancer with a high risk of recurrence.

Benefit of Combination Ezetimibe/Simvastatin Among High-Risk Populations: Lessons from the IMPROVE-IT Trial.

The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) demonstrated the clinical benefit of the combination of ezetimibe-simvastatin compared to placebo-simvastatin following acute coronary syndrome (ACS). This review highlights key findings from this study with particular attention to the practice-changing impact on guidelines for low-density lipoprotein cholesterol (LDL-C) reduction after ACS, especially among high-risk populations. Consistent reductions in LDL-C have been reported with newer lipid-lowering therapies (proprotein convertase subtilisin/kexin type 9 inhibitors, cholesterol ester transfer proteins, bempedoic acid) in combination with statin in high-risk subgroups. Since high-risk subgroups remain a focus of guidelines, exploration of high-risk subgroups can help define the optimal use of new therapies. Ezetimibe reduced the LDL-C by 16.7mg/dL compared to placebo at 1year, resulting in a significant reduction in the primary composite endpoint (absolute risk difference 2.0%; relative risk difference 6.4%, hazard ratio, 0.936; 95% confidence interval, 0.89 to 0.99; P = 0.016). The benefits achieved with ezetimibein both LDL-C reduction and the primary clinical composite across 10 pre-specified high-risk subgroups, including the elderly; women; patients with diabetes, prior coronary artery bypass graft, history of stroke, polyvascular disease, low baseline LDL-C, renal dysfunction, prior heart failure, and an elevated TIMI risk score for secondary prevention, were similar or greater than in the corresponding non-high-risk subgroups. Safety events were similar between ezetimibe and placebo across the high-risk subgroups. These data support the addition of ezetimibe to statin therapy in high-risk patients who require additional therapy to lower the LDL-C post-ACS.

CXCR3 Expression Is Associated with Advanced Tumor Stage and Grade Influencing Survival after Surgery of Localised Renal Cell Carcinoma

Surgery is the standard treatment in localized renal cell carcinoma (RCC). Pembrolizumab is now approved for adjuvant therapy in high-risk patients. However, inhomogeneity of studies gives ambiguity which patient benefit most from adjuvant therapy. A high infiltration of CD8+ T cells is known to be linked with poor prognosis in RCC. CXCR3 is a key player of CD8+ T cell differentiation and infiltration. We aimed to evaluate CXCR3 as a potential marker for predicting recurrence. CXCR3 and immune cell subsets (CD4, CD8, CD68 and FoXP3) were measured on RCC samples by multiplex immunofluorescence (mIF) staining. Cellular localization of CXCR3 was evaluated using single-cell RNA analysis on a publicly available dataset. Tumor samples of 42 RCC patients were analyzed, from which 59.5% were classified as clear-cell RCC and of which 20 had recurrence. Single-cell RNA analysis revealed that CXCR3 was predominantly expressed in intratumoral T cells and dendritic cells. CXCR3 expression was higher in advanced tumors stages (p = 0.0044) and grade (p = 0.0518), correlating significantly with a higher CD8+ T cell expression (p < 0.001). Patients with CXCR3high RCCs had also a significant shorter RFS compared to CXCR3low (median: 78 vs. 147 months, p = 0.0213). In addition, also tumor stage pT3/4 (p < 0.0001) as well as grade G3/4 (p = 0.0008) negatively influenced RFS. CXCR3high cell density was associated with high T cell infiltration and advanced tumor stage, worsening RFS in surgically resected RCC patients. Beside its prognostic value, CXCR3 might be a predictive biomarker to guide therapy decision for adjuvant therapy in localized RCC.

P603 Real-world Scottish experience of anti-TNF therapy in paediatric Crohn’s disease 2016-2020 against the ECCO-ESPGHAN recommendations

Abstract Background ECCO-ESPGHAN updated the guideline on the management of paediatric Crohn’s disease (CD) in 2021. This promoted a move to early risk stratification and a ‘top-down’ (anti-TNF within 4 weeks of diagnosis) approach for patients who were deemed high-risk. High-risk was defined by extensive panenteric or severe disease, perianal, stricturing and/or penetrating behaviour. We sought to compare the use of anti-TNF therapy against the new guidance by conducting a Scottish nationwide retrospective multi-centre study (all three regional PGHAN units). Methods We analysed a prospectively identified nationwide cohort of all new paediatric CD patients (&amp;lt;18 years) diagnosed in Scotland between 01/01/16 and 31/12/20. We retrospectively collected data from electronic medical records on the use of anti-TNF therapy (infliximab or adalimumab) within 18 months of diagnosis. Paris location and behaviour at diagnosis were determined, allowing us to split the patient group into high-risk or low/medium-risk as per latest ECCO-ESPGHAN guidance. Data regarding surgical intervention was collected and defined as: Perianal (Seton suture or drainage of abscess) and/or bowel resection +/- stoma formation. Results 419 patients were included (259/419 male; median age at diagnosis 13.2 yrs). Disease phenotype and behaviour are shown in tables 1 and 2. 225/419 (54%) were classified as high-risk and 194/419 (46%) as low/medium-risk. 171/225 (76%) high-risk and 78/194 (40%) low/medium-risk patients received anti-TNF within 18 months of diagnosis, with median start at 5 months (IQR: 1- 8 m) and 6.5 months (IQR: 3 – 13 m) respectively. Figure 1 demonstrates cumulative anti-TNF new starts by month. Of these patients, 49/171 (40%) high-risk and 12/78 (15.3%) low-risk received anti-TNF within 4 weeks of diagnosis. High-risk patients were more likely to receive anti-TNF (76.0% vs 40.2%, p&amp;lt;0.0001). 37 (8.8%) patients underwent surgical intervention; 31/225 (13.7%) high-risk and 6/194 (3.1%) low/medium-risk (13.7% vs 3.1%, p= 0.0002). Conclusion The ECCO-ESPGHAN guidance seeks to shift practice towards “top-down” anti-TNF therapy in high-risk patients. Our real-world data supports this view by showing that high-risk patients are more likely to require biologics within 18 months and more likely to require surgery than low/medium-risk patients. The ECCO-ESPGHAN approach would however have led to unnecessary anti-TNF in 24% of our high-risk cohort within 18 months of diagnosis. The financial cost and risk:benefit profile of this group should be considered carefully both in clinical practice and future guidance.