First-line Treatment Research Articles

P0811 Comparative efficacy of vedolizumab and infliximab in patients with moderate-to-severe ulcerative colitis: a multicenter real world cohort study

Abstract Background Vedolizumab (VDZ) and infliximab (IFX) are both recognized as first-line treatment options for moderate to severe ulcerative colitis (UC). However, there is a paucity of comparative studies examining their real-world efficacy. Methods Patients with moderate to severe UC were consecutively enrolled from 11 centers. Efficacy were evaluated after 14 and 52 weeks. Logistic regression was conducted to identify independent risk factors for clinical remission. Results A total of 235 patients were enrolled, of which 154 received VDZ treatment and 81 received IFX treatment. 154 (65.5%) were male, with a median age of 40 (32, 49) years, a median disease duration of 7.0 (2.8, 11.9) years. The median baseline Mayo score was 9 (7, 11), and the median baseline partial Mayo score was 6 (4, 8). 16 patients (6.8%) had perianal lesions, and 41 patients (17.4%) had extraintestinal manifestations. At week 14, patients treated with IFX had higher clinical response rate (84.6% vs 66.2%, p = 0.003) but lower endoscopic remission rate (14.5% vs 34.3%, p = 0.003) compared to those treated with VDZ. There were no statistical difference in clinical remission rate between the two groups (39.7% vs 44.8%, p = 0.462). At week 52, there were no statistically difference in the modified Mayo score, partial Mayo score, clinical response rate, clinical remission rate, and endoscopic remission rate between IFX treatment group and VDZ treatment group (p>0.05). Multivariate regression analysis demonstrated that baseline disease extent was a predictor of clinical remission at week 14 of VDZ treatment (OR = 3.55, 95% CI 1.39–9.06, p = 0.008). Conclusion IFX group received higher clinical response rate but not endoscopic remission rate at week 14. The efficacy of IFX was comparable to VDZ at week 52. Disease extent was a predictor of clinical remission at 14 weeks with VDZ.

Real-world short-term outcomes and treatment regimen comparisons in patients with metastatic renal cell carcinoma treated with first-line immune combinations

BackgroundImmune-combinations have recently become the standard first-line treatment for patients with metastatic renal cell carcinoma (mRCC). This study evaluated the applicability of the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk model in predicting outcomes for patients treated with either immune-oncologic drug doublet (IO-IO) or immune-oncologic drug tyrosine kinase inhibitor combinations (IO-TKI). A secondary objective to compare the effectiveness of IO-IO versus IO-TKI within the IMDC risk groups over a short follow-up period.MethodsA retrospective analysis was conducted on 172 patients with mRCC treated with first-line immunotherapy combinations. Progression free survival (PFS), time to treatment failure 2 (TTF2), and overall survival (OS) were compared between IMDC risk categories. Model fit was assessed using the c-index. The inverse probability of treatment weighting (IPTW) method was used to adjust and compare outcomes between IO-IO and IO-TKI, except for IMDC favorable risk patients due to the small number of IO-IO cases.ResultsThe IMDC risk model demonstrated a c-index of 0.684 (OS) for entire cohort, 0.600 (PFS), 0.596 (TTF2), and 0.624 (OS) for IO-IO, and 0.667 (PFS), 0.702 (TTF2), and 0.751 (OS) for IO-TKI. In the IMDC intermediate and poor risk groups after IPTW adjustment, PFS (HR 0.72), TTF2 (HR 0.67), and OS (HR 0.74) did not significantly differ between IO-IO and IO-TKI. Specifically, in the IMDC intermediate risk group, PFS (HR 0.79), TTF2 (HR 0.69), and OS (HR 0.65) were longer in IO-TKI, though the differences were not statistically significant. In the IMDC poor risk group, PFS (HR 0.76), TTF2 (HR 0.77), and OS (HR 1.03) were comparable.ConclusionsThe impact of IMDC risk model on survival was modest in IO-IO, while remained statistically substantial in IO-TKI. Survival outcomes did not significantly differ between IO-IO and IO-TKI during the short follow-up period.

Cross-sectional study of treatment approaches of luminal HER2negative metastatic breast cancer in real practice in Moscow

Introduction: The systemic therapy of patients with metastatic luminal HER2‑negative breast cancer (mBC) in‑ cludes various options, which can be fundamentally divided into endocrine therapy and chemotherapy. According to the Clinical Guidelines, both international and Russian, the “gold standard” of the 1st line therapy for patients with metastatic luminal HER2‑negative breast cancer (mBC) is a combination of cyclindependent kinase inhib‑ itors 4 / 6 (iCDK4 / 6) with endocrine therapy (ET). However, until recently we did not have complete data on the characteristics of the Russian population of patients with luminal HER2‑breast cancer, their treatment options, and the results of this therapy.Aim: To analyze the patients’ profile and current treatment approaches for patients with luminal HER2 mBC in routine clinical practice in Moscow.Materials and methods: The study was performed as an observational, crosssectional and retrospective study. The data of 2,500 patients from medical institutions in Moscow who received systemic therapy for luminal HER2 mBC in AugustOctober 2021 were analyzed.Results: The largest number of patients received iCDK4 / 6 + ET in the first and second lines: 69.0 % and 52.0 %, respectively. In the first line, 54.6 % of patients received ribociclib, 43.1 % palbociclib and 2.3 % abemaciclib. In the second line, 50.6 % of patients received ribociclib, 47.8 % palbociclib and 1.6 % abemaciclib. As the pretreatment of patients increased, preference was given to other treatment methods, therefore the proportion of combined ET decreased to 34.0 % in the third line and 25.0 % in the fourth and subsequent lines.Conclusion: The data obtained indicate that the appointment of iCDK4 / 6 + ET is made in accordance with the Clinical Guidelines for the treatment of breast cancer of the Ministry of Health of the Russian Federation from 2021 and the preferred firstline treatment option for patients with luminal HER2 mBC in Moscow is combined endocrine therapy.

Ravulizumab demonstrates long-term efficacy, safety and favorable patient survival in patients with paroxysmal nocturnal hemoglobinuria.

Ravulizumab is a second-generation complement component 5 (C5) inhibitor (C5i) approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) following positive results from two pivotal trials in patients with PNH originally naive to C5i treatment and eculizumab-experienced patients with PNH. In both trials, after the 26week primary evaluation period, all patients received ravulizumab for up to 6 years. To report ravulizumab treatment outcomes in patients with PNH originally naive to C5i treatment and eculizumab-experienced patients with PNH treated for up to 6 years. Originally C5i-naive (N = 244) and eculizumab-experienced (N = 191) patients with PNH continued ravulizumab treatment for up to 6 years. Major adverse vascular events (MAVEs; including thrombotic events [TEs]) and survival are reported, including a comparison of survival with untreated patients from the International PNH Registry. Laboratory parameters for intravascular hemolysis (IVH) are also described. For up to 6 years (1468.0 patient-years of exposure), ravulizumab provided durable control of terminal complement activity and IVH, resulting in a low incidence of MAVEs (including TEs) reported (MAVE rate: 0.7-1.4 per 100 patient-years) and, compared with untreated patients from the International PNH Registry, reduced the risk of mortality by five-fold. The few breakthrough IVH events reported (N = 122) were commonly associated with complement-amplifying conditions, and only two events (1.8%) were associated with suboptimal inhibition of C5 (i.e. serum free C5 ≥ 0.5µg/mL). These results support the long-term use of ravulizumab as the first-line treatment of choice for patients with PNH. Trial registration details: NCT01374360; registered: October 29, 2004; NCT02946463; registered: October 27, 2016; NCT03056040; registered: June 05, 2017.

P0753 Early surgery in pediatric-onset ileocecal Crohn’s disease is associated with less unfavourable disease course: a retrospective population-based study

Abstract Background Early surgery in Crohn’s disease (CD) seems to be efficient and safe in recently diagnosed adult ileocecal CD as compared to anti-tumor necrosis factor (anti-TNF) therapy. However, its role in the first-line treatment of paediatric-onset CD remains unknown. We aimed to compare long-term disease course in paediatric-onset CD treated within one year of diagnosis with ileocecal resection (ICR) or anti-TNF therapy. Methods We conducted a retrospective study using a population-based cohort of patients aged of less than 17 years old at the diagnosis of ileocecal CD and treated with ICR or anti-TNF therapy within one year of diagnosis. The primary outcome was unfavourable disease course defined as CD-related hospitalization, major CD-related surgery, systemic corticosteroids or perineal CD. We collected ICR characteristics, post-operative complications and clinical remission (Harvey Bradshaw score < 4 without biologic therapy or new surgery). Cumulative incidence was calculated at 1, 3 and 5 years. We performed a Cox regression model with a propensity score. Results are expressed with 95% confidence intervals. Results From January 1988 and December 2011, 1007 patients were identified. 134 patients with ileocecal involvement at diagnosis were included, 67 patients in the ICR group and 67 in the anti-TNF group. The median follow-up was 6.0 years, IQR (3.2-11.1). Only 19% patients in the anti-TNF group had complicated behaviour as compared to 94% in the ICR group (p<0.001) at diagnosis. The mean length of the surgical specimen was 33.5 cm (IQR: (4-95)) and surgeries were performed in emergency in 20% of the patients.The incidence rate of unfavourable disease course was 80 per 1000 person-years [54-113] in the ICR group, and 270 per 1000 person-years [196-363] in the anti-TNF group with a cumulative incidence of 17%, [7-26], 26% [14-37] and 30% [17-41] respectively at 1, 3 and 5 years in the ICR group, versus 24% [13-33], 54% [40-65] and 71% [55-81] in the anti-TNF group (p <0.0001). When including the propensity score, patients in the ICR group had better disease course than patients in the anti-TNF group with a hazard ratio (HR) of 0.16 [0.08-0.35] over time. Clinical remission was achieved in 83% of patients in the ICR group and 41% in the anti-TNF group (p <0.001) at 5 years. Sixteen patients (23%) experienced an early postoperative complication, including 6 (9%) severe complications (Clavien-Dindo ≥ 3). Only emergency surgery was associated with late complications (HR = 6.9 [2.3-20.6]). Conclusion Early surgery in paediatric-onset ileocecal CD was significantly associated with less unfavourable outcome and seemed safe. These data support the role of early elective surgery in the first-line treatment of paediatric-onset ileocecal CD.

P0783 High risk of adrenal insufficiency in patients with Inflammatory Bowel Disease treated with a conventional course of systemic corticosteroids: Results from a prospective study

Abstract Background Corticosteroids (CS) remain the first-line treatment for inflammatory bowel disease (IBD) although they can cause adrenal insufficiency (AI) due to the alteration of the hypothalamic-pituitary-adrenal (HPA) axis. Assessing this risk is essential, as these patients are often in stressful situations, and AI can mimic IBD symptoms, leading to misdiagnosis. However, there is a lack of studies adequately assessing adrenal function in these patients. The objectives of this study were to determine the proportion of IBD patients who present HPA axis suppression following CS treatment, assess the time required for axis recovery, and identify risk factors for AI. Methods A prospective observational study was conducted including adult patients with active IBD who started systemic CS treatment and with no exposure to CS within the last 6 months. They all followed a pre-defined regimen of 1 mg/kg/day of prednisone (maximum 60mg) for 2 weeks, tapering by 10 mg weekly until reaching 20 mg, then tapering by 5 mg weekly. The HPA axis was assessed 24 hours after CS discontinuation by the measurement of baseline cortisol and ACTH, and cortisol 30 and 60 minutes after stimulation with 250 mcg of ACTH. HPA axis recovery was evaluated 3 and 6 months after CS discontinuation. The association between clinical and demographic variables and the occurrence of AI was analysed. Results Ninety-two patients were included (58% Crohn's disease, 39% ulcerative colitis, mean age 39.8±16 years, 50% women), who received a total CS dose of 2000.7±543.1 mg for 63.5±14.1 days. Forty patients (43.5%) were diagnosed with AI (32 partial, 8 complete). The recovery test was not performed in 10/40 patients (5 due to loss of follow-up, 5 due to need of a new course of CS). 23/30 patients recovered the adrenal function 3 months after stopping CS, and 27/30 patients after 6 months. In the univariate analysis, only fecal calprotectin at the end of CS treatment was associated with AI (P=0.026). Conclusion A high proportion of IBD patients treated with a conventional CS treatment schedule develop HPA axis suppression, although most of them recover adrenal function within six months. The development of AI was not associated with any of the studied variables, except for faecal calprotectin levels. Our results highlight the potential risks associated with prolonged CS use and underscore the importance of considering AI in this context, particularly when the patient faces physical stress.

P0846 A patient’s perspective on the use of exclusive enteral nutrition (EEN) for the treatment of paediatric Crohn’s Disease

Abstract Background Crohn’s Disease (CD) is a chronic condition and can result in the inflammation of any part of the gut. If left untreated, children diagnosed with CD are at increased risk of nutrient malabsorption and poor growth. The first-line treatment for CD is a 6-week dietary treatment called Exclusive Enteral Nutrition (EEN). This diet requires patients to stop eating food and switch to taking prescribed nutritional drinks, to achieve outcomes of resolving malabsorption symptoms and improving growth. This treatment is managed exclusively by dietitians. The aim of this study is to acquire an in depth understanding of the paediatric patient experience with EEN; identifying challenges and empowerment strategies that help increase patient adherence to the EEN treatment course. Methods Ethical approval was obtained from the CHI Ethics Committee in October 2023. The design of this study is a mixed-research method that focuses on collecting both qualitative and quantitative data. Participants of the study include patients of both sexes and all ethnicities, between 1-17years old, who were diagnosed with CD and advised to complete their first course of EEN during January 2022 and October 2023. An anonymised survey with 25 questions total was used to gather the information. Results Of the 116 patients who were approached to take part in the study, 47% of participants completed it. Two main themes were identified: (i) barriers to EEN compliance (subthemes included “feelings of isolation, taste/texture/smell of drinks and missing food), (ii) empowerment strategies for EEN (subthemes included drink preparation techniques, eliminating temptation, wide flavour choice, external support and health improvements). Of the 79% of patients who completed a full course of EEN; 55% found it ‘difficult’ and 60% reported that "they would attempt it again if required". Conclusion This study shows that patients find EEN to be a challenging diet which can have physical, emotional, and social impacts on aspects of the child’s life. Empowerment strategies such as external support (from family, friends and dietitians), adequate drink preparation and an awareness of associated health outcomes are imperative to help patients complete EEN. These findings are a valuable addition to the current limited knowledge base in this area.

P0791 Development and validation of a nomogram for predicting the short-term effectiveness of Ustekinumab in patients with moderate to severe Crohn's disease

Abstract Background Ustekinumab (UST) is recommended as the first-line treatment for patients with moderate to severe Crohn's disease (CD). The effectiveness of certain patients, however, may be suboptimal and necessitate intensive treatment or modification of the treatment regimen. We sought to establish a nomogram model to predict the short-term effectiveness of UST in moderate to severe CD patients. Methods We established a derivation cohort comprising patients diagnosed with CD and treated with UST at the Sixth Affiliated Hospital of Sun Yat-sen University between May 2020 and July 2023. The patient data, including demographic and clinical characteristics as well as treatment details, were systematically collected. The achievement of clinical remission (Crohn's Disease Activity Index, CDAI < 150) after induction therapy was the endpoint observed during follow-up. Potential predictors were selected using the Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis. Multivariate logistic regression analysis was performed to develop a nomogram model. The predictive accuracy and discriminative power of the model were evaluated using Receiver Operating Characteristics (ROC) curves and calibration curves. Decision curve analysis (DCA) was employed to assess the clinical utility of the model. Results A total of 162 moderate to severe CD patients were included in the derivation cohort. Prognostic factors, including duration, body mass index (BMI), smoking, extraintestinal manifestations (EIMs), perianal lesions (P), history of Vedolizumab therapy, and albumin levels (ALB), were identified and included in the nomogram. The model showed good discrimination and calibration on internal validation based on the bootstrap method (C-index: 0.843, 95% confidence interval [CI]: 0.768-0.903). Moreover, DCA demonstrated that the nomogram was clinically beneficial. Conclusion Our model is a useful tool for accurately predicting the short-term effectiveness of UST in moderate to severe CD patients and aids clinicians in formulating personalized treatment plans.

Reanalysis of Urothelial Cancer Chemoimmunotherapy Trials With Differential Censoring

Three similar phase 3 randomized clinical trials have investigated PD-1/PD-L1 (programmed cell death 1 protein/programmed cell death 1 ligand 1) inhibitors in combination with platinum-based chemotherapy vs chemotherapy alone as first-line treatment for advanced urothelial carcinoma (IMvigor130, atezolizumab; KEYNOTE-361, pembrolizumab; and CheckMate901, nivolumab). Only CheckMate901 reported overall survival (OS) benefit for the combination. The reason for these inconsistent results is unclear. To explore whether differential censoring-that is, censoring imbalance between the study groups-is a possible explanation for these inconsistent findings. This comparative effectiveness study involved a censoring analysis of data from IMvigor130, KEYNOTE-361, and CheckMate901, which enrolled patients between 2016 and 2022. Participants included patients in these 3 trials. Participation in 1 of the 3 trials. The primary outcomes were censoring rates adjusted for treatment effects. Censoring rates were calculated from the Kaplan-Meier (KM) curves. When excess censoring in the control group of open-label trials was found, the hypothesis was that better-performing patients might be dropping out to seek alternative treatments; a sensitivity analysis was conducted in which their survival was assumed to be similar to that of the longest surviving patients in the control group. Treatment effects of the censoring-adjusted KM curves were calculated using the 2-sided log-rank test. The 3 trials involved a total of 2162 patients (1640 male [76%]; age range, 65-69 years) Analysis of progression-free survival (PFS) curves demonstrated no differential censoring in IMvigor130, but there was more than 30% excess censoring in the chemotherapy-only groups in KEYNOTE-361 and CheckMate901 trials. After sensitivity analysis, the PFS benefit was no longer significant in either study (KEYNOTE-361, adjusted hazard ratio [HR], 1.13 [95% CI, 0.95-1.35]; CheckMate901, adjusted HR, 1.17 [0.96-1.44]). Analysis of OS curves demonstrated no differential censoring in IMvigor130 or KEYNOTE-361, but there was more censoring in the chemotherapy-only group in CheckMate901. After sensitivity analysis, the OS benefit of adding nivolumab to chemotherapy was lost (before adjustment, HR, 0.77 [95% CI, 0.63-0.95]; P = .01; adjusted HR, 0.95 [95% CI, 0.77-1.17]; P = .64). In this comparative effectiveness study, differential censoring explained the inconsistent results reported in the evaluated trials. The term perceived-inferiority censoring is suggested to describe a phenomenon wherein better-performing patients are aware of their treatment and drop out to pursue alternative therapeutic options; it is possible that this occurred in the open-label KEYNOTE-361 and CheckMate901 trials. Such censoring confounds randomization and interpretation of clinical trials, since a larger experimental group is compared with a selected group of controls with poorer prognosis.

Impact of Genomic Classifiers on Risk Stratification and Treatment Intensity in Patients With Localized Prostate Cancer : A Systematic Review.

Tissue-based genomic classifiers (GCs) have been developed to improve prostate cancer (PCa) risk assessment and treatment recommendations. To summarize the impact of the Decipher, Oncotype DX Genomic Prostate Score (GPS), and Prolaris GCs on risk stratification and patient-clinician decisions on treatment choice among patients with localized PCa considering first-line treatment. MEDLINE, EMBASE, and Web of Science published from January 2010 to August 2024. Two investigators independently identified studies on risk classification and treatment choice after GC testing for patients with localized PCa considering first-line treatment. Relevant data extracted by 1 researcher and overread by a second. Risk of bias (ROB) was assessed in duplicate. Ten studies reported risk reclassification after GC testing. In low ROB observational studies, very low- or low-risk patients with PCa were more likely to have their risk levels classified as the same or lower (GPS, 100% to 88.1%; Decipher, 87.2% to 82.9%; Prolaris, 76.9%). However, 1 randomized trial found that GC testing with GPS reclassified 34.5% of very low-risk and 29.4% of low-risk patients to a higher risk category. Twelve observational studies indicated that treatment decisions after GC testing either remained unchanged or slightly favored active surveillance. In contrast, analyses from a single randomized trial found fewer choices for active surveillance after GPS testing. Heterogeneity in screening patterns, risk-determination cutoffs, pathology, and clinical practices. Studies on treatment choice were moderate to high ROB. Although GC tests do not consistently influence risk classification or treatment decisions, the differences observed between observational and randomized studies highlight a need for well-designed trials to explore the role of GC tests in patients with newly diagnosed PCa considering first-line treatment. U.S. Department of Veterans Affairs. (PROSPERO: CRD42022347950).

Efficacy and Safety of Immunotherapy Combined with Anlotinib as FirstLine Treatment in Older NSCLC Patients with PD-L1 Expression

Non-small cell lung cancer (NSCLC) predominantly affects older adults; these patients have significant comorbidities, making them unsuitable for chemotherapy. This study aimed to evaluate the efficacy and safety of immune checkpoint inhibitor (ICI) along with anlotinib combination therapy as a first-line treatment in older NSCLC patients with programmed death ligand-1(PD-L1) expression＜50%. We conducted a retrospective observational study including 73 patients with advanced NSCLC treated at Nanjing Brain Hospital. All patients were aged 75 years or older and received first-line systemic therapy with a combination of PD-1 inhibitors and anlotinib. Clinical data were obtained from electronic medical records and analyzed through Kaplan-Meier estimates and Cox proportional hazards models to assess progression-free survival (PFS), overall survival (OS), and the influence of different variables. The patients had a median age of 80 years. The median PFS was 9.8 months (95% CI: 7.9-11.7), and the median OS was 19.5 months (95% CI: 17.3-21.7). PD-L1 tumor proportion score (TPS) <1% (χ2=10.263, P=0.001) and absence of treatment-induced hypertension (χ2=12.804, P<0.001) were identified as independent risk factors for poor PFS. Advanced disease stage (χ2=11.900, P=0.001), PD-L1 TPS <1% (χ2=6.643, P=0.010), and having two or more chronic comorbidities (χ2=9.011, P=0.003) were independent risk factors for poor OS. Treatment-related hypertension was observed in 25% of patients and was associated with better PFS. ICI-anlotinib combination therapy showed promising efficacy and an acceptable safety profile in older NSCLC patients. Future studies involving larger populations are necessary to validate these findings and determine the potential of PD-L1 levels as a biomarker for treatment stratification.

Analysis of the efficiency of integrated chemotherapy in the treatment of patients with non-small cell lung cancer with EGFR L858R mutation in exon 21 using first- and second-generation tyrosine kinase inhibitors

General data. The article presents the results of a comparative analysis of the effectiveness of integrated chemotherapy in targeted anti-EGFR therapy for patients with non-small cell lung cancer (NSCLC) with a mutation in exon 21 of the EGFR gene compared to monotherapy with firstand second-generation tyrosine kinase inhibitors (TKIs).Material: From 2015 to 2021, the study included 45 patients with metastatic NSCLC with the L858R mutation in exon 21 for the first line of treatment, distributed into an experimental group and a control group of 23 and 22 people, respectively. Patients in the experimental group received therapy with tyrosine kinase inhibitors for the first 2 months, followed by discontinuation of targeted drugs and 3 courses of chemotherapy according to the paclitaxel and carboplatin regimen. Targeted therapy was then resumed until disease progression. Patients in the control group received only monotherapy with first- or second-generation TKIs. The median follow-up was 36 months.Result. The objective response rate (ORR) was 59.1 % for the experimental group and 27.3 % for the control group, disease stabilization was achieved in 9 (40.9%) patients and 14 (63.6%), respectively. The median progression-free survival (PFS) for the experimental group was 23 months [95% CI: 16–36], for the control group 13 [95% CI: 11–17] (p=0.004). The median overall survival (OS) for the experimental group was statistically higher than in the control group and was 43 [lower limit of 95% CI – 38] months versus 32 [95% CI: 23–44] months (p=0.008).Conclusion. The results of our study showed that the integration of chemotherapy into targeted treatment of this category of patients may become a new worthy option that allows for a statistically significant increase in both the median PFS and the median OS.

Prognostic value of clinical complete response for patients with initially unresectable hepatocellular carcinoma after conversion with triple therapy

Introduction: Accurately predicting the outcomes of conversion therapy among patients with initially unresectable hepatocellular carcinoma (uHCC) remains a challenge. Clinical complete response (cCR) has been proposed as a predictor of prognosis. However, information on its prognostic value in these patients is limited. We aimed to explore the prognostic value of cCR in patients with uHCC following conversion therapy and identify predictors of cCR. Methods: We included 241 patients with uHCC who underwent transcatheter arterial chemoembolization combined with lenvatinib and PD-1 inhibitors (triple therapy) as first-line treatment. The prognostic value of cCR, predictive factors of cCR, and the relationship between cCR and pathological complete response (pCR) were analyzed. Results: The cCR rate of the 241 patients included was 17.4%. Patients with cCR showed better overall survival (OS) (p &lt; 0.001) and progression-free survival (PFS) (p &lt; 0.001) than those without. cCR was an independent risk factor for OS (hazard ratio [HR]: 0.11, 95% confidence interval [CI]: 0.03–0.42, p = 0.001) and PFS (HR: 0.29, 95% CI: 0.15–0.56, p &lt; 0.001). Serum α-fetoprotein levels ≥400 ng/mL (odds ratio [OR]: 0.47, 95% CI: 0.22–0.95, p = 0.040) and extrahepatic metastasis (OR: 0.13, 95% CI: 0.01–0.62, p = 0.046) were independent negative predictors of cCR. A total of 107 patients (44.4%) underwent conversion surgery. Among these patients, cCR was associated with better OS (p =0.009) and recurrence-free survival (p = 0.007). cCR was significantly correlated with pCR (Φ = 0.61, p &lt; 0.001). Albumin levels ≥35 g/L (OR: 0.12, 95% CI: 0.02–0.69, p = 0.018) and cCR (OR: 30.32, 95% CI: 9.19–128.00, p &lt; 0.001) were independent predictors of pCR. Conclusion: cCR after triple therapy has an excellent long-term survival advantage and is significantly related to pCR. cCR may be a surrogate marker for predicting prognosis and pCR in patients with uHCC receiving triple therapy.

Comparative effectiveness of bictegravir versus dolutegravir, raltegravir, and efavirenz-based antiretroviral therapy among treatment-naïve individuals with HIV.

Bictegravir or dolutegravir based antiretroviral therapy are first-line HIV treatments. However, no trial has recruited enough participants to estimate the most effective treatment, and there is little evidence on the comparative effectiveness of bictegravir and other available antiretrovirals, like efavirenz and raltegravir. We emulated a four-arm target trial using country-wide data from Mexico. The eligibility criteria of the target trial were people with HIV, treatment naïve with viral load >500 copies/mL, without tuberculosis, not pregnant, and started either bictegravir, dolutegravir, efavirenz or raltegravir-based treatment between July 2019 and September 2021. The main outcome was the probability of viral suppression (HIV-RNA <50 copies/mL) at three months estimated using an adjusted logistic regression model, with assignment assumed to be random within levels of adjusted covariates. Probabilities were compared via differences and non-parametric bootstrapping was used to calculate 95 % confidence intervals. 20,285 individuals were included, of whom 84.3 % started bictegravir, 7.2 % dolutegravir, 6.6 % efavirenz, and 1.8 % raltegravir. The adjusted probability of viral suppression at 3 months was 79.4 % (79.4 %, 80.2 %) with bictegravir, 78.5 % (76.2 %, 81.1 %) with dolutegravir, 63.9 % (60.6 %, 67.7 %) with efavirenz, and 69.8 % (63.8 %, 76.1 %) with raltegravir. When compared with bictegravir, this resulted in differences of -0.8 % (-3.5 %, 1.9 %) for dolutegravir, -15.5 % (-19 %, -11.7 %) for efavirenz, and -9.6 % (-15.9 %, -3.3 %) for raltegravir. Differences shrank at twelve months and with a higher viral threshold (200 copies/mL). Bictegravir was similar to dolutegravir and slightly more effective than efavirenz or raltegravir at three months, but differences became negligible at twelve months.

Insights into the future of first-line advanced hepatocellular carcinoma treatment.

Insights into the future of first-line advanced hepatocellular carcinoma treatment.

Multicenter Phase 2 Trial of Second-Line Regorafenib in Patients with Unresectable Hepatocellular Carcinoma After Progression on Atezolizumab Plus Bevacizumab (REGONEXT)

Introduction: Atezolizumab-bevacizumab (Atezo-Bev) has become the standard first-line treatment for patients with unresectable hepatocellular carcinoma (uHCC). However, data on subsequent treatment after Atezo-Bev failure are lacking. We aimed to investigate the efficacy and safety of regorafenib for uHCC progression after first-line Atezo-Bev. Methods: This investigator-initiated, single-arm, phase 2 trial involved two academic centers in Korea. Eligibility criteria included a diagnosis of HCC, prior treatment with at least 2 cycles of Atezo-Bev, and Child-Pugh A liver function. Eligible patients received regorafenib 160 mg once daily for 3 weeks of every 4-week cycle (i.e., 3 weeks on, 1 week off) until progressive disease or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate, disease control rate according to RECIST v1.1, overall survival (OS), and treatment-related adverse events. Results: Forty patients were enrolled from December 2021 through May 2023. The median follow-up duration was 10.1 months (95% confidence interval [CI], 8.3-12.0). The median PFS was 3.5 months (95% CI, 3.0-3.9). The median OS was 10.5 months (95% CI, 7.1-13.8), and the 6-month OS rate was 65.0%. The objective response rate and disease control rate were 10.0% and 82.5%, respectively. The most common grade 3-4 treatment-related adverse event was thrombocytopenia (5.0%). When stratified according to time to progression on prior Atezo-Bev (first quartile [&lt; 2.3 months] vs. second to fourth quartiles [≥ 2.3 months]), patients with longer time to progression on prior Atezo-Bev had better OS (15.0 vs. 3.6 months, p&lt;0.001), objective response rate (13.3% vs. 0%, p=0.009), and a tendency toward better PFS with regorafenib (3.8 vs. 2.5 months; p=0.054). Conclusions: Second-line regorafenib was effective for treating uHCC progression after first-line Atezo-Bev. The efficacy and safety outcomes from our study were consistent with those observed in the pivotal phase 3 RESORCE trial, which included sorafenib-tolerant/progressed patients.

Gemcitabine and ATR inhibitors synergize to kill PDAC cells by blocking DNA damage response.

The DNA-damaging agent Gemcitabine (GEM) is a first-line treatment for pancreatic cancer, but chemoresistance is frequently observed. Several clinical trials investigate the efficacy of GEM in combination with targeted drugs, including kinase inhibitors, but the experimental evidence for such rationale is often unclear. Here, we phenotypically screened 13 human pancreatic adenocarcinoma (PDAC) cell lines against GEM in combination with 146 clinical inhibitors and observed strong synergy for the ATR kinase inhibitor Elimusertib in most cell lines. Dose-dependent phosphoproteome profiling of four ATR inhibitors following DNA damage induction by GEM revealed a strong block of the DNA damage response pathway, including phosphorylated pS468 of CHEK1, as the underlying mechanism of drug synergy. The current work provides a strong rationale for why the combination of GEM and ATR inhibition may be useful for the treatment of PDAC patients and constitutes a rich phenotypic and molecular resource for further investigating effective drug combinations.

IL-21 and IL-33 May Be Effective Biomarkers to Predict the Efficacy of PD-1 Monoclonal Antibody for Advanced Cholangiocarcinoma.

Background and Objective: Treatment options for patients with advanced biliary tract cancer (BTC) are limited. The programmed cell death protein-1 (PD-1) inhibitors may have synergistic effects with chemotherapy. Therefore, the aim of our study was to provide real-world data on treatment outcomes in BTC patients receiving chemotherapy alone versus a combination of chemotherapy and PD-1 inhibitors. Additionally, we explored potential markers predictive of PD-1 inhibitor efficacy in this combined therapy. Methods: We conducted a review of patients at Changzhou First People's Hospital who received PD-1 inhibitors in combination with chemotherapy or chemotherapy alone as first-line treatment for advanced BTC. The primary endpoints of the study were progression-free survival (PFS) and overall survival (OS). Kaplan-Meier survival curves and the log-rank test were used to analyze the data. Immunohistochemistry showed the expression of interleukin-21 (IL-21), interleukin-33 (IL-33), and Eomes in the tumor tissue of patients who received PD-1 inhibitors in combination with chemotherapy. Results: The study enrolled 61 patients receiving PD-1 inhibitors combined with chemotherapy and 65 receiving chemotherapy alone. The median OS and PFS for patients receiving PD-1 inhibitors in combination with chemotherapy were 11.7 and 6.7 months, respectively. These durations were significantly longer than those for chemotherapy alone: OS of 10.3 months (95% CI: 0.16-0.21, p = 0.031) and PFS of 5.3 months (95% Confidence interval (CI) 0.25-0.32, p = 0.018). High IL-21 expression or low IL-33 expression in tumor tissue correlated with better response rates to chemotherapy combined with PD-1 inhibitors. Conclusions: Combining PD-1 inhibitors with chemotherapy shows good antitumor activity, making it an effective way to treat BTC. The expression profiles of IL-21 and IL-33 hold promise as potential markers for guiding the chemotherapy combined with immunotherapy in BTC patients.

POEMS Syndrome.

POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Protein, Skin changes) is a syndrome that involves a monoclonal B-cell proliferation, most often plasmacytic, and a variable number of manifestations listed or not in the acronym. These manifestations include sclerotic bone lesions, plasmacytic Castleman disease, papillary edema, peripheral edema, ascites, thrombocytosis and/or polycythemia, venous and/or arterial thrombosis, and renal, pulmonary, and cardiac impairments [1]. Diagnosis is often delayed due to the rarity of this entity and its clinical polymorphism, which can mimic other neurological disorders. First-line treatment for patients without bone marrow involvement and with a limited number of bone lesions is radiation. Patients with diffuse bone lesions or bone marrow involvement should receive systemic treatment, ideally intensive treatment with autologous stem cell transplantation (ASCT) when possible. Lenalidomide and bortezomib appear to be very promising, showing very rapid efficacy on neuropathy. Early initiation of treatment, before the development of severe neurological damage, along with supportive care, especially physiotherapy, is crucial for optimal neurological recovery.

Safety and Tolerability of Pivmecillinam During More Than Four Decades of Clinical Experience: A Systematic Review.

The recent US Food and Drug Administration approval of pivmecillinam-an oral prodrug of the amidinopenicillin antibiotic mecillinam-presents a valuable opportunity to address the need for new treatments for uncomplicated urinary tract infection (uUTI). We report findings of a systematic literature review of the safety profile of pivmecillinam/mecillinam based on more than 40 years' experience, mainly in Europe and Canada, to describe its tolerability profile and identify any important safety signals. In total, 110 eligible publications were identified describing use of pivmecillinam/mecillinam as monotherapy or in combination, for treatment of uUTI or other infectious conditions. These studies revealed a benign safety and tolerability profile, awareness of which will inform treatment decisions as pivmecillinam is made available in the United States. Together with the evidence for efficacy of, and minimal resistance to, pivmecillinam, the findings of this review support the position of pivmecillinam as a first-line treatment for uUTI.