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Lenvatinib resistance presents a significant challenge in the clinical management of advanced hepatocellular carcinoma (HCC). To address this issue, we established lenvatinib resistant HCC cells and performed high-throughput screening using FDA-approved anti-cancer drug library. Through quantitative selective drug sensitivity scoring (sDSS), pacritinib, a well-known JAK inhibitor, emerged as the top candidate, displaying the highest sDSS score among 219 compounds. We further demonstrated that pacritinib reduced the viability of a panel of HCC cell lines in a dose-dependent manner, while exhibiting minimal effects on normal liver cells. Interestingly, pacritinib, but not other JAK inhibitors such as ruxolitinib, upadacitinib, or filgotinib, acted synergistically with lenvatinib in HCC cells. In lenvatinib-resistant HCC cells, pacritinib significantly decreased proliferation and induced apoptosis. Rescue studies using IL-1 receptor-associated kinase 1 (IRAK1) overexpression and knockdown revealed that pacritinib's effects are mediated through IRAK1, with minimal impact on normal liver cells. In a xenograft model of lenvatinib-resistant HCC, oral administration of pacritinib significantly reduced tumor size without affecting body weight. Immunohistochemical analysis of tumor sections revealed that pacritinib reduced Ki67 staining and phosphorylated IRAK1. Our findings suggest that pacritinib may be a promising therapeutic option for the treatment of advanced HCC, particularly in patients who have developed resistance to lenvatinib., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Several important vaccines differ in immunogenicity and efficacy between populations. We hypothesised that malaria suppresses responses to unrelated vaccines and that this effect can be reversed-at least partially-by monthly malaria intermittent preventive treatment (IPT) in high-transmission settings., Methods: We conducted an individually randomised, double-blind, placebo-controlled trial of the effect of malaria IPT with dihydroartemisinin-piperaquine on vaccine responses among schoolchildren aged 9-17 years in Jinja district, Uganda. Participants were recruited from two schools and did not have exposure to vaccines of interest after the age of 5 years, with the exception of human papillomavirus (HPV). Computer-generated 1:1 randomisation was implemented in REDCap. 3-day courses of dihydroartemisinin-piperaquine (dosage by weight) or placebo were administered monthly, including twice before the first vaccination. Trial participants were vaccinated with the live parenteral BCG vaccine (Serum Institute of India, Pune, India) at week 0; yellow fever vaccine (YF-17D; Sanofi Pasteur, Lyon, France); live oral typhoid vaccine (Ty21a; PaxVax, London, UK), and quadrivalent virus-like particle HPV vaccine (Merck, Rahway, NJ, USA) at week 4; and toxoid vaccines (tetanus-diphtheria; Serum Institute of India) and an HPV booster at week 28. An additional HPV vaccination at week 8 was provided to female participants older than 14 years who had not previously been vaccinated, and a tetanus-diphtheria booster was given after completion of the trial at week 52. Primary outcomes were vaccine responses at week 8 and, for tetanus-diphtheria, at week 52, and analysis was done in the intention-to-treat population. Malaria parasite prevalence at enrolment and during follow-up was determined retrospectively by PCR. The safety population comprised all randomly allocated participants. The trial was registered at the ISRCTN Registry (ISRCTN62041885) and is complete., Findings: Between May 25 and July 14, 2021, we assessed 388 potential participants for eligibility. We enrolled and randomly allocated 341 participants to the two groups (170 [50%] to dihydroartemisinin-piperaquine and 171 [50%] to placebo); 192 (56%) were female and 149 (44%) participants were male. 145 (85%) participants in the dihydroartemisinin-piperaquine group and 140 participants (82%) in the placebo group were followed up until the week 52 endpoint. At enrolment, 109 (64%) of all participants in the dihydroartemisinin-piperaquine group and 99 (58%) of 170 participants in the placebo group had malaria; this reduced to 6% or lower at all follow-up visits in the dihydroartemisinin-piperaquine group. There was no effect of dihydroartemisinin-piperaquine versus placebo on primary outcomes: BCG-specific IFNγ ELISpot response had a geometric mean ratio (GMR) of 1·09 (95% CI 0·93-1·29), p=0·28; yellow fever neutralising antibody was 1·19 (0·91-1·54), p=0·20 for plaque reduction neutralising reference tests (PRNT 50 ) titres (the reciprocal of the last plasma dilution that reduced by 50%) and 1·24 (0·97-1·58), p=0·09 for PRNT 90 titres (reciprocal of the last plasma dilution that reduced by 90%); and IgG to Salmonella enterica serovar Typhi O-lipopolysaccharide was 1·09 (0·81-1·46), p=0·58, HPV-16 was 0·72 (0·44-1·77), p=0·19, HPV-18 was 0·71 (0·47-1·09), p=0·11; tetanus toxoid was 1·22 (0·91-1·62), p=0·18, and diphtheria toxoid was 0·97 (0·83-1·13), p=0·72. There was some evidence that dihydroartemisinin-piperaquine reduced waning of the yellow fever response., Interpretation: IPT for malaria with dihydroartemisinin-piperaquine did not improve peak vaccine responses, despite reducing malaria prevalence. Possible longer-term effects on response waning should be further explored., Funding: UK Medical Research Council., Translation: For the Luganda translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests GN reports funding from the EDCTP2 programme supported by the EU, and from the Wellcome Trust. AME, PK and SC report funding from the UK Medical Research Council (MRC) for conduct of the study; AME reports funding from UK National Institute of Health and care Research (NIHR), Science for Africa Foundation, and DELTAS Africa, outside the submitted work. AME and SC further report support from the Serum Institute of India and Emergent BioSolutions; AME reports support from Uganda National Expanded Program on Immunization; SC reports support from Bliss GVS Pharma, India, for conduct of the study. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Despite breakthroughs of immunotherapy synergistically combined with blockade of vascular endothelial growth factor receptor, several patients with advanced non-small cell lung cancer (NSCLC) experience non-response or followed relapse. Organized lymphoid aggregates, termed tertiary lymphoid structures (TLSs), are found to be associated with improved response to immunotherapy. Here, we explore the landscapes of TLSs in tumour tissues from a real-world retrospective study. Our investigation showed that with a median follow-up of 11.2 months, the ORR was 28.6% (18/63, 95% CI 17.9-41.3) and the median PFS was 6.1 (95% CI 5.5-6.6) months in NSCLC patients treated with PD-1 blockade combined with anlotinib. By multiplex immunofluorescence (mIF) analysis, spatially, more TLSs and high CD20+ B-cell ratio in TLSs were associated with higher ORR. High density of intratumoral CD8+ T cells showed better ORR and PFS. The numbers of CD8+ T cells with a distance within 20 μm and 20-50 μm between tumour cells were higher in responders than non-responders. But responders had significantly higher TLSs within 20 μm rather than within 20-50 μm of tumour cells than non-responders. The inflamed immunophenotyping occupied higher proportions in responders and was associated with better PFS. Besides, tumour cells in non-responders were found more temporal cell-in-cell structures than responders, which could protect inner cells from T-cell attacks. Taken together, landscape of TLSs and proximity architecture may imply superior responses to PD-1 blockade combined with anlotinib for patients with advanced non-small cell lung cancer., (© 2024 John Wiley & Sons Ltd.)

Rationale and Objectives: To compare the treatment efficacy and safety of transarterial chemoembolization (TACE) combined with lenvatinib versus TACE alone in patients with intermediate-stage hepatocellular carcinoma (HCC) beyond up-to-seven criteria., Materials and Methods: A total of 107 newly diagnosed HCC patients with Barcelona Clinic Liver Cancer stage B HCC beyond up-to-seven criteria were included in this retrospective cohort study. These patients were divided into two groups: TACE-Lenv group and TACE alone group. Propensity score matching was used to account for potential confounding factors. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), downstaging rate, liver function, and adverse events (AEs) were recorded and evaluated., Results: Both the median OS and median PFS were significantly longer in the TACE-Lenv group compared to the TACE alone group (median OS: 28.0 vs 12.0 months, P = 0.017; median PFS [mRECIST]: 8.2 vs 3.7 months, P = 0.018; median PFS [RECIST v1.1]: 8.9 vs 3.7 months, P = 0.003). Furthermore, the ORR and DCR were also significantly higher in TACE-Lenv group (ORR: 94% [30/32] vs 47% [15/32], P < 0.001; DCR: 97% [31/32] vs 62% [20/32], P < 0.001). There were no significant differences in terms of liver function and grade 3 or 4 AEs rate between two groups., Conclusion: The combination of TACE and lenvatinib provides clinical benefits for patients with intermediate HCC beyond the up-to-seven criteria, has an acceptable safety profile, shows a trend towards improving liver function, and does not increase the occurrence of grade 3-4 AEs., Key Points: The efficacy of transarterial chemoembolization in intermediate-stage hepatocellular carcinoma patients is partially unsatisfactory. Addition of lenvatinib to transarterial chemoembolization improves OS, PFS, ORR, and DCR for patients with intermediate-stage hepatocellular carcinoma beyond the up-to-seven criteria. This combination therapy is a superior treatment option for intermediate-stage hepatocellular carcinoma patients with high tumor burden., Competing Interests: Declaration of Competing Interest The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Background: The advent of immunotherapy has revolutionized non-small cell lung cancer (NSCLC) treatment. Anlotinib (AN), a multitargeted tyrosine kinase inhibitor, holds promise in combination with PD-1 monoclonal antibody therapy. Understanding the impact of optimal dosage is pivotal., Objective: This study aims to assess the comparative efficacy of high-dose AN versus low-dose AN when combined with PD-1 monoclonal antibody for the treatment of NSCLC., Methods: A total of 70 patients with NSCLC undergoing PD-1 monoclonal antibody therapy at our hospital from June 2020 to January 2022 were selected. The low-dose group (n=33) received AN at 8 mg and 10 mg. In comparison, the high-dose group (n=37) received AN at 12 mg. Comparative analyses included assessment of clinical efficacy, adverse reactions, prognosis, survival, changes in T lymphocyte subsets, inflammatory factors pre and post-chemotherapy, and treatment satisfaction., Results: No significant difference was observed in clinical efficacy and prognosis between the two groups (P > .05). The low-dose group exhibited fewer adverse reactions and inflammatory responses, along with improved immune function post-treatment (P < .05). Treatment satisfaction was higher in the low-dose group compared to the high-dose group (P < .05)., Conclusions: Findings suggest that combining low-dose AN with PD-1 monoclonal antibody therapy is a safer approach in the treatment of advanced NSCLC. These findings advocate for the adoption of a tailored, lower-dose AN regimen, presenting a clinically sound and patient-centered strategy in the ongoing pursuit of optimized treatment modalities for advanced NSCLC.

Purpose: One year of neratinib therapy is known to derive a significant invasive disease-free survival (iDFS) benefit in early-stage, hormone receptor-positive (HR +), HER2 + , node-positive breast cancer after trastuzumab-based adjuvant therapy. Limitations to neratinib use include significant gastrointestinal side effects, which often result in treatment discontinuation. In this study, we aimed to identify clinicopathologic features associated with adjuvant neratinib use and factors impacting treatment completion., Methods: We performed a retrospective review of patients with early-stage HR + HER2 + breast cancer who were prescribed neratinib from 2017 to 2023 at our institution. We used the electronic medical record to extract information on patient characteristics, clinical features, and treatment information. Patients were identified as high risk based on definitions adapted from the standard high-risk definition in HR + HER2- breast cancer combined with studies correlating high Ki67 or high tumor grade with lower recurrence-free survival. Statistical analysis was performed using two-sided T-tests and chi-square tests., Results: We identified 62 eligible patients of whom 55% completed 1 year of neratinib and 45% did not. Sixty percent (N = 37) of patients offered neratinib were considered high risk at diagnosis. The most common reason for neratinib discontinuation was inability to tolerate side effects (54%) followed by pill burden (18%). The most common side effect experienced by patients was diarrhea despite anti-diarrheal prophylaxis (56%), followed by rash (8%). Patients who received an up-titration of neratinib were more likely to complete the full course of neratinib when compared to those who did not (76% vs. 40.5% p = 0.013). The median starting dose of those who completed neratinib treatment was 140 vs. 240 mg in those who did not (p = 0.016). Neither group experienced a statistically significant greater likelihood of treatment holds or dose reductions. In terms of outcomes, 10 patients had progression of disease of whom 7 did not complete neratinib treatment (p = 0.169). Interestingly, those 7 patients developed metastatic disease and 57% (N = 4) had central nervous system metastases., Conclusion: Patients are more likely to complete 1 year of adjuvant neratinib with dose up-titration. Dose reductions and interruptions did not affect neratinib adherence in our patient population. Seven patients (11%) in our study developed metastatic disease, all of whom did not complete adjuvant neratinib treatment., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This open-label, single-arm, phase 2 trial evaluated the efficacy and safety of neoadjuvant sintilimab combined with anlotinib and chemotherapy, followed by adjuvant sintilimab, for resectable NSCLC. Forty-five patients received anlotinib (10 mg, QD, PO, days 1-14), sintilimab (200 mg, day 1), and platinum-based chemotherapy of each three-week cycle for 3 cycles, followed by surgery within 4-6 weeks. Adjuvant sintilimab (200 mg) was administered every 3 weeks. The primary endpoint was achieving a pathological complete response (pCR). From June 10, 2021 through October 10, 2023, 45 patients were enrolled and composed the intention-to-treat population. Twenty-six patients (57.8%) achieved pCR, and 30 (66.7%) achieved major pathological response (MPR). Forty-one patients underwent surgery. In the per-protocol set (PP set), 63.4% (26/41) achieved pCR, and 73.2% achieved MPR. The median event-free survival was not attained (95% CI, 25.1-NE). During the neoadjuvant treatment phase, grade 3 or 4 treatment-related adverse events were observed in 25 patients (55.6%), while immune-related adverse events were reported in 7 patients (15.6%). We assessed vascular normalization and infiltration of immune-related cells by detecting the expression of relevant cell markers in NSCLC tissues with mIHC. Significant tumor microenvironment changes were observed in pCR patients, including reduced VEGF + cells and CD4 + Foxp3 + Treg cells, and increased perivascular CD4 + T cells, CD39 + CD8 + T cells, and M1 macrophages. In conclusion, perioperative sintilimab and neoadjuvant anlotinib plus chemotherapy achieved pCR in a notable proportion of patients with resectable NSCLC and were associated with profound changes in the tumour microenvironment (ClinicalTrials.gov NCT05400070)., (© 2024. The Author(s).)

Background: Recent studies have highlighted that TACE in conjunction with Lenvatinib (TACE-L) offers a promising adjunct therapy for advanced HCC patients, outperforming TACE plus Sorafenib (TACE-S). However, there has been a lack of research comparing these two regimens for intermediate HCC., Aims: This study aims to address the research gap by evaluating the efficacy of TACE-L versus TACE-S in intermediate HCC patients., Methods: A retrospective analysis was conducted on a cohort of consecutive intermediate HCC patients who received either TACE-L or TACE-S from November 2018 to December 2022. Portal vein width was assessed using abdominal NMRI or Doppler ultrasonography, and inflammatory markers were derived from routine blood counts. The primary outcomes of interest were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse drug reactions (ADRs)., Results: The study included 117 patients, with 56 in the TACE-S group and 61 in the TACE-L group. The TACE-S group demonstrated superior OS (HR = 1.704, 95% CI: 1.012-2.870, p = 0.045) compared to the TACE-L group. No significant difference was observed in PFS (HR:1.512, 95% CI: 0.988-2.313, p = 0.057) between the two groups. Subgroup analyses revealed that male patients, those with cirrhosis, and those with more than four tumors had better OS and PFS in the TACE-S group than in the TACE-L group. Inflammatory markers were comparable between the groups. The TACE-S group experienced a higher incidence of palmar-plantar erythrodysesthesia syndrome (PPE) (14/56 [25%] vs. 5/61 [8.1%], p = 0.014) but a lower incidence of hypertension (3/56 [5.3%] vs. 11/61 [18%], p = 0.035) compared to the TACE-L group., Conclusions: In patients with intermediate HCC, TACE-S was found to be more effective in terms of OS than TACE-L. No significant disparity was noted in PFS between the two treatment groups., (© 2024. The Author(s).)

Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive, severe neurodegenerative disease caused by motor neuron death. Development of a medicine for ALS is urgently needed, and induced pluripotent cell-based drug repurposing identified a Src/c-Abl inhibitor, bosutinib, as a candidate for molecular targeted therapy of ALS. A phase 1 study confirmed the safety and tolerability of bosutinib in a 12-week treatment of ALS patients. The objectives of this study are to evaluate the efficacy and longer-term safety of bosutinib in ALS patients., Methods and Analysis: An open-label, multicentre phase 2 study was designed. The study consisted of a 12-week observation period, a 1-week transitional period, a 24-week study treatment period and a 4-week follow-up period. Following the transitional period, patients whose total Revised ALS Functional Rating Scale (ALSFRS-R) score declined by 1 to 4 points during the 12-week observation period were to receive bosutinib for 24 weeks. In this study, 25 ALS patients will be enrolled; patients will be randomly assigned to the following groups: 12 patients in the 200 mg quaque die (QD) group and 13 patients in the 300 mg QD group of bosutinib. The safety and exploratory efficacy of bosutinib in ALS patients for 24 weeks will be assessed. Efficacy using the ALSFRS-R score will be compared with the external published data from an edaravone study (MCI186-19) and registry data from a multicentre ALS cohort study, the Japanese Consortium for Amyotrophic Lateral Sclerosis Research., Ethics and Dissemination: This study was approved by the ethics committees of Kyoto University, Tokushima University, Kitasato University, Tottori University, Nara Medical University School of Medicine, Toho University and Hiroshima University. The findings will be disseminated in peer-reviewed journals and at scientific conferences., Trial Registration Number: jRCT2051220002; Pre-results, NCT04744532; Pre-results., Competing Interests: Competing interests: Kyoto University is the study sponsor. The study drug bosutinib and the pharmacokinetic analysis for only patient-experienced serious adverse events are supported by Pfizer JAPAN INC. under the Clinical Research Collaboration Agreement between Kyoto University and Pfizer JAPAN INC. RTak and NT received research funding and honoraria for lectures from Pfizer., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The majority of metastatic renal cell carcinoma (mRCC) patients receive one or more VEGFR TKI agents, alone or in combination with an immune-oncology (IO) agent or an mTOR inhibitor. To date, the cost of adverse events (AEs) common to VEGFR TKIs has not been quantified. This study estimated the potential impact of differences in VEGFR TKI AE profiles on treatment cost efficiency in the relapsed/refractory (R/R) setting., Methods: Patients with documented mRCC who were treated with VEGFR TKI therapies between Jan 2015 and Mar 2021 were identified using EMR. ICD-10 diagnosis codes were used to identify the first occurrence of each class effect AE. Patients were matched to 3rd party insurance claims, and costs associated to TKI AEs within 90 days of index event were captured. Average per patient AE cost data was calculated and applied to published incidence data to estimate regimen-specific AE total cost burden within a hypothetical commercial plan for mRCC patients undergoing treatment in the R/R setting., Results: The highest total cost for AE management was attributed to lenvatinib and everolimus use at $13,303, followed closely by sunitinib at $13,092. Tivozanib treatment was associated with the lowest total cost of AE management at $7,523, driven by the relatively lower incidence of certain high-cost AEs., Conclusions: The estimated costs of managing VEGFR TKI class-effect AEs were lowest with tivozanib, and highest with lenvatinib and everolimus, indicating potentially differential healthcare resource burden by TKI regimen. The use of tivozanib in the 3 L + mRCC setting suggests potential costs offsets when compared to other TKI regimens., (© 2024. The Author(s).)

Background: This study investigated whether intensive lipid-lowering therapy with pitavastatin and ezetimibe lowers the incidence of heart failure (HF) events in patients with acute coronary syndrome (ACS)., Methods and Results: In the HIJ-PROPER study, 1,734 patients with ACS were randomly assigned to either pitavastatin plus ezetimibe therapy (n=864) or pitavastatin monotherapy (n=857). We examined the incidence of HF between these 2 groups over a 3.9-year period after ACS. The primary endpoint of the study was hospitalization for HF. The mean low-density lipoprotein cholesterol levels during the follow-up period were 65.1 mg/dL in the pitavastatin plus ezetimibe group and 84.6 mg/dL in the pitavastatin monotherapy group. The incidence of HF hospitalization was significantly lower in the pitavastatin plus ezetimibe group than in the pitavastatin monotherapy group (19 [2.2%] vs. 40 [4.7%] patients; hazard ratio 0.47, 95% confidence interval 0.27-0.81; P<0.005). This trend was consistent after multivariable analysis using multiple models., Conclusions: Intensive lipid-lowering therapy with pitavastatin and ezetimibe is associated with a lower incidence of hospitalization for HF in patients with ACS.

Purpose: To assess the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) of gemcitabine and oxaliplatin (GEMOX) plus systemic gemcitabine chemotherapy (GEM-SYS) in combination with lenvatinib and programmed cell death protein-1 (PD-1) inhibitor for patients with large unresectable intrahepatic cholangiocarcinoma (uICC)., Methods: From November 2019 to December 2022, 21 large uICC patients who underwent GEMOX-HAIC (Day 1) and GEM-SYS (Day 8) (3w/cycle) combined with lenvatinib and PD-1 inhibitor were retrospectively enrolled. Local tumor response, progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were analyzed. Tumor response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. AEs were evaluated by the common terminology criteria for adverse events (CTCAE) version 5.0., Results: After a median follow-up duration of 16.0 months (range 5-43.5 months), 17 patients had died. The median OS was 19.5 months (range 9-43.5 months), and the median PFS was 6.0 months (range 2.5-38.5 months). The 1-, 2-, and 3-year OS rates were 71.4 %, 42.9 %, and 19.0 %, respectively. The 1-, 2-, and 3-year PFS rates were 33.3 %, 19.0 %, and 9.5 %, respectively. Complete response, partial response, stable disease, and progressive disease were observed in 0 (0 %), 11 (52.3 %), 5 (23.8 %), and 5 (23.8 %) patients, respectively. The disease control rate and objective response rate were 76.1 % and 52.3 %, respectively. None of the enrolled patients experienced grade 5 AEs., Conclusions: GEMOX-HAIC plus GEM-SYS in combination with lenvatinib and PD-1 inhibitor was effective and well tolerated for patients with large uICC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Amivantamab plus lazertinib (amivantamab-lazertinib) has shown clinically meaningful and durable antitumor activity in patients with previously untreated or osimertinib-pretreated EGFR (epidermal growth factor receptor)-mutated advanced non-small-cell lung cancer (NSCLC)., Methods: In a phase 3, international, randomized trial, we assigned, in a 2:2:1 ratio, patients with previously untreated EGFR -mutated (exon 19 deletion or L858R), locally advanced or metastatic NSCLC to receive amivantamab-lazertinib (in an open-label fashion), osimertinib (in a blinded fashion), or lazertinib (in a blinded fashion, to assess the contribution of treatment components). The primary end point was progression-free survival in the amivantamab-lazertinib group as compared with the osimertinib group, as assessed by blinded independent central review., Results: Overall, 1074 patients underwent randomization (429 to amivantamab-lazertinib, 429 to osimertinib, and 216 to lazertinib). The median progression-free survival was significantly longer in the amivantamab-lazertinib group than in the osimertinib group (23.7 vs. 16.6 months; hazard ratio for disease progression or death, 0.70; 95% confidence interval [CI], 0.58 to 0.85; P<0.001). An objective response was observed in 86% of the patients (95% CI, 83 to 89) in the amivantamab-lazertinib group and in 85% of those (95% CI, 81 to 88) in the osimertinib group; among patients with a confirmed response (336 in the amivantamab-lazertinib group and 314 in the osimertinib group), the median response duration was 25.8 months (95% CI, 20.1 to could not be estimated) and 16.8 months (95% CI, 14.8 to 18.5), respectively. In a planned interim overall survival analysis of amivantamab-lazertinib as compared with osimertinib, the hazard ratio for death was 0.80 (95% CI, 0.61 to 1.05). Predominant adverse events were EGFR -related toxic effects. The incidence of discontinuation of all agents due to treatment-related adverse events was 10% with amivantamab-lazertinib and 3% with osimertinib., Conclusions: Amivantamab-lazertinib showed superior efficacy to osimertinib as first-line treatment in EGFR -mutated advanced NSCLC. (Funded by Janssen Research and Development; MARIPOSA ClinicalTrials.gov number, NCT04487080.)., (Copyright © 2024 Massachusetts Medical Society.)

Vascular endothelial growth factor inhibitors, including tyrosine kinase inhibitors (TKIs), possess immunomodulatory properties and have shown promising outcomes when combined with anti-PD-1 antibodies. The OASIS phase II trial (NCT04503967) is designed to determine the clinical activity and safety of nivolumab (anti-PD-1) and anlotinib hydrochloride (a multi-targets TKI) as second-line or above therapy in patients with advanced gastric adenocarcinoma (GAC) and esophageal squamous cell carcinoma (ESCC). From December 2020 to September 2022, 45 patients with GAC and 3 with ESCC were enrolled in this study. The pre-specified endpoints were reached, with the primary endpoint of overall response rate achieving 29.2%. For secondary objectives, disease control rate was 64.6%; median progression-free survival was 4.0 months; and median overall survival was 11.1 months with a manageable toxicity profile. The exploratory analyses unveiled that the balance of gut bacteria and the presence of a pre-existing immune signature characterized by a high percentage of CD68 + PD-L1 + PD-1 + macrophages and low pretreatment variant allele frequencies (VAF), as well as low expression of certain cytokines were significantly associated with improved clinical outcomes in patients with GAC., (© 2024. The Author(s).)

Context: The relationship between the genomic profile and prognosis of advanced thyroid carcinoma requiring drug therapy has not been reported., Objective: To evaluate the treatment period and overall survival time for each genetic alteration in advanced thyroid carcinoma that requires drug therapy., Methods: We conducted a retrospective observational study using a national database in Japan, which included 552 cases of thyroid carcinoma out of 53 543 patients in the database., Results: The database included anaplastic thyroid carcinoma (23.6%), poorly differentiated thyroid carcinoma (10.0%), and differentiated thyroid carcinoma (66.4%). The most common genetic abnormalities were TERT promoter (66.3%), BRAF (56.7%), and TP53 (32.2%). The typical driver genes were BRAF V600E (55.0%), RAS (18.5%), RET fusion (4.7%), NTRK fusion (1.6%), and ALK fusion (0.4%). The most common regimen was lenvatinib, and the time to treatment failure was not different despite the presence of BRAF or RAS mutations. In differentiated thyroid carcinoma and poorly differentiated thyroid carcinoma, TP53 alterations independently predicted worse overall survival (hazard ratio = 2.205, 95% confidence interval: 1.135-4.283). In anaplastic thyroid carcinoma, no genetic alterations were associated with overall survival., Conclusion: Genetic abnormalities with treatment options were found in 62.7% of advanced thyroid carcinomas. TP53 abnormality was an independent poor prognostic factor for overall survival in differentiated thyroid carcinoma. The time to treatment failure for lenvatinib was not different based on genetic profile., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

This research was intended to compare the clinical efficacy of hepatic arterial infusion chemotherapy (HAIC) in conjunction with lenvatinib and PD1 inhibitors to first-line systemic chemotherapy for advanced intrahepatic cholangiocarcinoma(ICC). The research enrolled advanced ICC patients who underwent HAIC plus lenvatinib and PD1 inhibitor(n = 51) or first-line systemic chemotherapy(cisplatin + gemcitabine, n = 39) between July 2020 to January 2023 in Zhongshan People's Hospital.Their clinical outcomes were assessed through measurement of parameters encompassing objective response rate (ORR), disease control rate (DCR), median overall survival (mOS), median progression-free survival (mPFS), median duration of response (mDOR), and treatment-related adverse events (TRAEs). In accordance with the RECIST1.1, the ORR in the HAIC + L + P and SC groups was 43.1% and 20.5%, while the DCR was 90.2% and 69.2%, respectively (P = 0.04 and = 0.02, respectively). The change in the maximum diameter of intrahepatic target lesions in patients before and after treatment and the diameter of intrahepatic tumors in the HAIC + L + P group were sharply smaller versus the SC group ( P < 0.001). The HAIC + L + P group had prolonged mOS (16.8 months vs. 11.0 months, P = 0.01) and mPFS (12.0 months vs. 6.9 months, P < 0.01) in comparison with the SC group. Compared to first-line systemic chemotherapy(cisplatin + gemcitabine), HAIC plus lenvatinib and PD-1 inhibitors contributes to improvement of tumor response and prolongation of OS and PFS in advanced ICC patients., (© 2024. The Author(s).)

Ovarian cancer is the fifth most prevalent cancer in women. Chemotherapy is a major treatment option for patients with advanced ovarian cancer (OC). Quinoline-2-thione and its derivatives are potential candidates for tumor therapy. In this study, we investigated the anticancer activity of the quinoline-2-thione derivative KA3D against ovarian cancer. The effect of KA3D on the viability of ovarian cancer cells was evaluated using MTT assay, and its effects on apoptosis and the cell cycle were detected using flow cytometry. Western blotting was performed to identify apoptosis-and cell cycle-related proteins altered by KA3D treatment. A xenograft model was used to verify the inhibitory effect of KA3D in vivo. H&E staining, biochemical indicator detection, and blood cell counts were used to observe the toxicity and side effects of KA3D. KA3D treatment impeded cell viability, induced apoptosis, and impeded the G2 phase of the cell cycle in ovarian cancer cells. Mechanistically, we found that KA3D enhanced the expression of proapoptotic molecules such as BAX and Caspase 3, while antiapoptotic proteins such as BCL2 were inhibited. The G0/G1 phase-related protein cyclin D1 was reduced and the G2 phase-related protein cyclin B1 was upregulated. In vivo, KA3D displayed potent anticancer activity, with no apparent toxicity in BABLC/c nude mice bearing SKOV3 cells. KA3D demonstrated remarkable chemotherapeutic drug efficacy in terms of significant cancer suppression in vitro and in vivo with low toxicity., (© 2024. The Author(s).)

Background and Objectives: The purpose of this study was to investigate the survival benefit of Stereotactic Body Radiotherapy (SBRT) versus lenvatinib as first-line therapy in the treatment of hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT)., Materials and Methods: 147 HCC patients with PVTT were included in this retrospective study, 70 were treated with SBRT and 77 of were treated with lenvatinib. Propensity score matching (PSM) analysis was employed to balance the differences in baseline characteristics between the two groups. Overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) were compared between the two groups. In addition, the safety of patients in both groups was also evaluated., Results: After PSM, 38 patients were matched in each of the two groups. The median OS was 14.5 (95% CI: 10.1-18.9) and 11.1 (95% CI: 9.3-12.9) months in the SBRT and lenvatinib groups, respectively (P = 0.014). The median PFS was 6.8 (95% CI: 5.1-8.5) and 5.0 (95% CI: 3.0-7.0) months, respectively (P = 0.010). The 1-, 2-years OS rates in the two groups were 65.8% vs. 39.5% and 31.6% vs. 10.5%, respectively. The 6-, 12-months PFS rates in the two groups were 57.9% vs. 44.7% and 28.9% vs. 10.5%, respectively. In addition, the SBRT group had a better ORR than the lenvatinib group (52.6% vs. 23.7%, P = 0.009). Patients with good response to SBRT had better survival. Cox proportional hazard model showed that SBRT was an important prognostic factor for OS and PFS. The incidence of hypertension (34.2% vs. 0%) was higher in the LEN group, however, both treatment modalities were well tolerated in the two groups of patients., Conclusion: In HCC patients with PVTT, SBRT had a better survival benefit than Lenvatinib treatment as first-line therapy., (© 2024. The Author(s).)

The effect of immune-based therapies on patients with epidermal growth factor receptor (EGFR)-positive advanced non-small cell lung cancer (NSCLC) resistant to EGFR tyrosine kinase inhibitor (TKI) therapy remains unclear. The ALTER-L038 study aimed to evaluate efficacy and safety of a chemotherapy-free combination of benmelstobart, an anti-programmed cell death ligand 1 antibody, and anlotinib, a small-molecule multi-target anti-angiogenic TKI, in EGFR-positive advanced NSCLC patients who progressed after EGFR TKI therapy. Patients were enrolled in a phase I/II study. In phase I (dose-escalation), patients received anlotinib (8, 10, 12 mg) plus benmelstobart (1200 mg). Recommended phase II dose, determined during phase I, was used in phase II dose-expansion cohort. Primary endpoints were maximum tolerable dose in phase I and progression-free survival (PFS) in phase II. At the data cutoff date (March 10, 2024), 55 patients were enrolled in phase II dose-expansion cohort. Median PFS of patients included in phase II cohort was 9.0 months, median overall survival was 28.9 months, objective response rate was 25.5%, disease control rate was 87.3%, and median duration of response was 19.8 months. Incidence of grade ≥3 treatment-related adverse events in study population was 25.5% (14/55), whereas grade ≥3 immune-related adverse events occurred in 10.9% (6/55) of patients. Benmelstobart plus anlotinib showed promising anti-tumor efficacy with tolerable safety profile, supporting the value of further development of this convenient chemotherapy-free regimen for patients with EGFR-positive advanced NSCLC who progressed after EGFR TKI therapy. Trial Registration: ChiCTR1900026273., (© 2024. The Author(s).)

Evidences regarding the feasibility of transcatheter arterial chemoembolization (TACE)-based therapy for unresectable hepatocellular carcinoma (uHCC) remains limited. This study aimed to investigate the efficacy and safety of TACE combined with envafolimab and lenvatinib for uHCC. Eligible patients with uHCC received envafolimab and lenvatinib after TACE until disease progression, conversion to surgery, intolerable toxicities, or death. The primary endpoint was the objective response rate (ORR) assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Between March 2022 and July 2022, 38 patients were included for safety analysis, and 36 patients were included for efficacy analysis. As of the data cutoff (13 December 2023), the median follow-up was 16.9 months. The ORR was 50%, and disease control rate (DCR) was 83.3% per RECIST 1.1 (ORR and DCR of both 83.3% per modified RECIST (mRECIST)). The median progression-free survival (PFS) was 7.58 months. Of 36 patients, 17 patients were converted to resectable HCC with a surgical conversion rate of 47.2%, and 16 patients underwent surgery with R0 resection rate of 100%, pathologic complete response (pCR) rate of 31.3%. Overall incidences of treatment-related adverse events (TRAEs) of any grade was 97.4%. Grade ≥ 3 TRAEs were observed in 52.6% patients. No treatment-related deaths occurred. Image mass cytometry (IMC) analysis revealed that combined treatment improved the immune status of the tumor microenvironment, and resident macrophages had the potential to predict efficacy of this treatment. Envafolimab plus lenvatinib and TACE yielded promising survival outcomes and conversion efficiency with a tolerable safety profile. Trial registration Clinical trials: NCT05213221., (© 2024. The Author(s).)

Background: Embryonal rhabdomyosarcoma (ERMS) is a highly aggressive form of soft-tissue sarcoma that predominantly affects children. Due to limited benefits and resistance to therapy, there is an unmet need to explore alternative therapeutic strategies., Case Presentation: In this report, we present a rare case of pediatric ERMS located on the right side of the maxillary gingiva. A composite reference guide integrating clinical, radiographic, and histopathologic findings was used for a definitive diagnosis. Targeted next-generation sequencing of tumor biopsy was performed to identify genetic alterations. A 12-year-old female was admitted to the Pediatric Intensive Care Unit (PICU) and underwent a tracheotomy to relieve asphyxiation caused by a 5.5 cm diameter mass compressing the tongue root and pharyngeal cavity. Hematoxylin and eosin staining revealed a hybrid morphology characterized by clusters of round and spindle cells. Further immunohistochemistry assays indicated positive immunoreactivity for desmin, myogenin, and MyoD1. Various genetic alterations were identified, including mutations in GNAS, HRAS, LRP1B, amplification of MDM2 and IGF1R, and two novel IGF1R fusions. Negative PAX-FOXO1 fusion status supported the clinical diagnosis of ERMS. Initial treatment involved standard chemotherapy; however, the tumor persisted in its growth, reaching a maximum volume of 12 cm × 6 cm × 4 cm by the completion of treatment. Subsequent oral administration of anlotinib yielded a significant antitumor response, characterized by substantial tumor necrosis and size reduction. Following the ligation of the tumor pedicle and its removal, the patient developed a stabilized condition and was successfully discharged from PICU., Conclusions: Our study highlights the importance of accurate diagnosis established on multifaceted assessment for the effective treatment of ERMS. We present compelling evidence supporting the clinical use of anlotinib as a promising treatment strategy for pediatric ERMS patients, especially for those resistant to conventional chemotherapy., (© 2024. The Author(s).)

Background: Primary liver cancer is the sixth most common cancer worldwide, with hepatocellular carcinoma (HCC) being the most prevalent form. Despite the current availability of multiple immune or immune combination treatment options, the prognosis is still poor, so how to identify a more suitable population is extremely important., Aim: To evaluate the clinical effectiveness of combining lenvatinib with camrelizumab for patients with hepatitis B virus (HBV)-related HCC in Barcelona Clinic Liver Cancer (BCLC) stages B/C, considering various body mass index (BMI) in different categories., Methods: Retrospective data were collected from 126 HCC patients treated with lenvatinib plus camrelizumab. Patients were divided into two groups based on BMI: The non-overweight group (BMI < 25 kg/m 2 , n = 51) and the overweight/obese group (BMI ≥ 25 kg/m 2 , n = 75). Short-term prognosis was evaluated using mRECIST criteria, with subgroup analyses for non-overweight (BMI: 18.5-24.9 kg/m 2 ), overweight (BMI: 25-30 kg/m 2 ), and obese (BMI ≥ 30 kg/m 2 ) patients. A Cox proportional hazards regression analysis identified independent prognostic factors for overall survival (OS), leading to the development of a column-line graph model., Results: Median progression-free survival was significantly longer in the obese/overweight group compared to the non-overweight group. Similarly, the median OS was significantly prolonged in the obese/overweight group than in the non-overweight group. The objective remission rate and disease control rate for the two groups of patients were, respectively, objective remission rate (5.88% vs 28.00%) and disease control rate (39.22% vs 62.67%). Fatigue was more prevalent in the obese/overweight group, while other adverse effects showed no statistically significant differences ( P > 0.05). Subgroup analysis based on BMI showed that obese and overweight patients had better progression-free survival and OS than non-overweight patients, with obese patients showing the best outcomes. Multifactorial regression analysis identified BCLC grade, alpha-fetoprotein level, portal vein tumor thrombosis, and BMI as independent prognostic factors for OS. The column-line graph model highlighted the importance of BMI as a major predictor of patient prognosis, followed by alpha-fetoprotein level, BCLC classification, and portal vein tumor thrombosis., Conclusion: BMI is a long-term predictor of the efficacy of lenvatinib plus camrelizumab, and obese/overweight patients have a better prognosis., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Anlotinib, an oral multitarget tyrosine kinase inhibitor, has shown the ability to inhibit tumor angiogenesis. This study aimed to assess the effectiveness and safety of anlotinib plus docetaxel, epirubicin, and cyclophosphamide (TEC) as a neoadjuvant chemotherapy regimen for locally advanced TNBC., Methods: Locally advanced TNBC patients who had received no prior systemic treatment were eligible for this study. The enrolled patients were scheduled to undergo six cycles of anlotinib (12 mg, d1-14, q3w) plus docetaxel (75 mg/m2, d1, q3w), epirubicin (75 mg/m2, d1, q3w) and cyclophosphamide (600 mg/m2, d1, q3w) prior to surgery, unless there was disease progression or severe toxicity. The primary objective of this study was the safety of this therapeutic regimen, and the secondary objective was the tumor response. The safety of this regimen was assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and the efficacy of this treatment was measured using the Response Evaluation Criteria in Solid Tumors version 1.1., Results: A total of 18 patients were included in this study. Participants completed an average of 5.56 neoadjuvant treatment cycles. The objective response rate (ORR) was 83.33%, and the disease control rate was 100%, respectively. The pCR was 55.6%. No patients discontinued therapy because of Adverse effects (AEs). Grade 3 or 4 AEs were observed in 5 cases (27.8%), with neutropenia and palmar-plantar erythrodysesthesia syndrome being the most common., Conclusions: Anlotinib combined with TEC as neoadjuvant therapy demonstrated manageable toxicity and promising antitumor activity for locally advanced TNBC. Further investigation of this combination regimen is warranted., (© 2024. The Author(s).)

Background: Immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor receptor tyrosine kinase inhibitors are cornerstones of first-line treatment for advanced renal cell carcinoma; however, optimal treatment sequencing after progression is unknown. This study aimed to assess clinical outcomes of tivozanib-nivolumab versus tivozanib monotherapy in patients with metastatic renal cell carcinoma who have progressed following one or two lines of therapy in the post-ICI setting., Methods: TiNivo-2 is a multicentre, randomised, open-label, phase 3 trial at 190 sites across 16 countries, in Australia, Europe, North America, and South America. Patients with advanced renal cell carcinoma and progression during or after one to two previous lines of therapy (including one ICI) were randomised 1:1 to tivozanib (0·89 mg per day, orally) plus nivolumab (480 mg every 4 weeks, intravenously) or tivozanib (1·34 mg per day, orally). Randomisation was stratified by immediate previous therapy (ICI or non-ICI) and International Metastatic Renal Cell Carcinoma Database Consortium risk category. The primary endpoint was progression-free survival (PFS), defined as the time from randomisation to first documentation of objective progressive disease according to RECIST 1·1 or death from any cause, whichever came first, by independent radiology review. Efficacy was evaluated in the intention-to-treat population, and safety was assessed in patients who received one or more doses of the study drug. This trial was registered on ClinicalTrials.gov (NCT04987203) and is active and not recruiting., Findings: From Nov 4, 2021, to June 16, 2023, 343 patients were randomly assigned to tivozanib-nivolumab (n=171) or tivozanib monotherapy (n=172). Median follow-up was 12·0 months. Median PFS was 5·7 months (95% CI 4·0-7·4) with tivozanib-nivolumab and 7·4 months (5·6-9·2) with tivozanib monotherapy (hazard ratio 1·10, 95% CI 0·84-1·43; p=0·49). Among those with an ICI as their immediate previous therapy (n=244), median PFS was 7·4 months (95% CI 5·6-9·6) with tivozanib-nivolumab and 9·2 months (7·4-10·0) with tivozanib monotherapy. With non-ICIs as the most recent therapy, lower median PFS was observed, with no difference between groups (tivozanib-nivolumab 3·7 months [95% CI 2·7-5·4] and with tivozanib monotherapy 3·7 months [1·9-7·2]). Serious adverse events occurred in 54 (32%) of 168 patients receiving tivozanib-nivolumab and 64 (37%) of 171 patients receiving tivozanib monotherapy. One (<1%) treatment-related death occurred (tivozanib group)., Interpretation: These data further support that ICI rechallenge should be discouraged in patients with advanced renal cell carcinoma. Furthermore, these data suggest that tivozanib monotherapy has efficacy in the post-ICI setting., Funding: Aveo Pharmaceuticals., Competing Interests: Declaration of interests TKC reports institutional and personal paid or unpaid support for research, advisory board participation, consultancy, and honoraria within the past 5 years from Alkermes, Arcus Bio, AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers Squibb, Calithera, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, HiberCell, IQVIA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Neomorph, Nuscan and Precede Bio, Novartis, Oncohost, Pfizer, Roche, Sanofi Aventis, Scholar Rock, Surface Oncology, Takeda, and Tempest and equity in Tempest, Pionyr, Osel, Precede Bio, CureResponse, InnDura Therapeutics, and Primium. LA reports consulting fees from Bristol Myers Squibb, Ipsen, Roche, Novartis, Pfizer, Astellas, Merck, MSD, Janssen, Eisai, and Amgen and support for travel expenses from Bristol Myers Squibb, MSD, Ipsen, and Pfizer. PB reports grants or contracts from Roche, Bristol Myers Squibb, MSD, AstraZeneca, Pfizer, Exelixis, Ipsen, Merck, Gilead, Janssen, AAA Pharmaceutical, and Bayer; consulting fees from Astellas, Bayer, Bristol Myers Squibb, Ipsen, Janssen, MSD, Novartis, Pfizer, Merck, Gilead, AAA Pharmaceutical, Eisai, and AstraZeneca; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Astellas, Bayer, Bristol Myers Squibb, Ipsen, Janssen, MSD, Novartis, Pfizer, Merck, Gilead, AAA Pharmaceutical, Eisai, and AstraZeneca; and reports participation on a data safety monitoring board or advisory board for Astellas, Bayer, Bristol Myers Squibb, Ipsen, Janssen, MSD, Novartis, Pfizer, Merck, Gilead, AAA Pharmaceutical, Eisai, and AstraZeneca. SE reports consulting fees from MSD, AstraZeneca, Eisai, Janssen, Bristol Myers Squibb, and Kephren and support for attending meetings and travel from MSD, Chugai, Pfizer, and Janssen. JM-C reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Ipsen, Pfizer, Roche, Bayer, Sanofi, Janssen, Astellas, Eisai, Adacap, Lilly, Novartis, Bristol Myers Squibb, MSD, Adium, and Asofarma; support for attending meetings and travel from Ipsen, Pfizer, Bristol Myers Squibb, and MSD; and participation on a data safety monitoring board or advisory board for Ipsen, Pfizer, Astellas, Eisai, Bristol Myers Squibb, and MSD. BG reports research funding grants from AbbVie, Accutar Biotechnology, Arcus Biosciences, Arvinas, AstraZeneca, AVEO Oncology, CRISPR Therapeutics, Eikon Therapeutics, Exelixis, Roche and Genentech, Flare Therapeutics, Harbour BioMed, IDEAYA Biosciences, Janssen, Janux Therapeutics, Jubilant Therapeutics, Kineta, Kinnate BioPharma, Loxo, Mink Therapeutics, Nuvation Bio, Profound Bio, Takeda Therapeutics, Teon Therapeutics, Tmunity Therapeutics, Xencor, and Zenshine and consulting fees from AbbVie, Adaptimmune, Adicent Therapeutics, AIQ Global, Amgen, Arcus Biosciences, Arvinas, AstraZeneca, AVEO Oncology, Bayer, Bicycle Therapeutics, Eisai, EMD Serono, Exelixis, Janssen, Merck, Novartis, Pfizer, Rondo Therapeutics, Sanofi–Aventis, Seagen, and Xencor. PB reports honoraria from UroToday; consulting or advising fees from Bayer, Bristol Myers Squibb, Pfizer, EMD Serono, Eisai, Caris Life Sciences, AstraZeneca, Exelixis, Aveo, Merck, Ipson, and Dendreon; speakers bureau funding from AstraZeneca, Caris Life Sciences, Bayer, Pfizer and Astellas, and Merck; and research funding from Exelixis, Aveo, Blue Earth, Pfizer, and Merck. AB reports honoraria from Gilead Sciences, Cardinal Health, Eisai, and Natera; consulting or advising fees from EMD Serono, Seattle Genetics, and Bristol Myers Squibb and Pfizer; speakers bureau funds from Eisai; and research funding from Merck, EMD Serono, Natera, Astellas Pharma, Bristol Myers Squibb and Celgene, Genentech and Roche, and Aveo. MTB reports consulting fees, payment or honoraria, and participation on a data safety monitoring board or advisory board from Bristol Myers Squibb. HM reports honoraria from EMD Serono and Pfizer; research funding from Bristol Myers Squibb, Amgen, Genentech, Seattle Genetics, Arcus Bioscience, Apollomics, Nektar, RevImmune, HUYA Bioscience International, Aveo, Xencor, and Pfizer; and travel accommodations or expenses from Aveo, Seagen, Bayer, and Genentech. RR reports honoraria from Ipsen, MSD Oncology, AstraZeneca, Bristol Myers Squibb, Pfizer, Advanced Accelerator Applications, and Eisai; consulting or advisory fees from Astellas Pharma, Pfizer, Ipsen, and MSD; and travel accommodations or expenses from Ipsen, MSD Oncology, and Janssen. RRM reports consulting or advisory roles for Janssen, Novartis, Tempus, Exelixis, Pfizer, Bristol Myers Squibb, Astellas Medivation, Dendreon, Bayer, Sanofi, Merck, Vividion, Calithera, AstraZeneca, Myovant, Caris Life Sciences, Sorrento Therapeutics, Aveo, Seattle Genetics, Telix, Eli Lilly, Blue Earth Diagnostics, Ambrx, Arcus Biosciences, Sumitomo Pharma Oncology, Eisai, and NeoMorph and research funding from Bayer, Tempus, AstraZeneca, Exelixis, Bristol Myers Squibb, Oncternal Therapeutics, and Artera. AC-R reports honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from OncLive and MJH Life Sciences, ASCO Direct, Exelixis, Medical Oncology Association of Southern California, EPG Health, Eisai Co, Aveo, and Seagen. HH reports grants or contracts for clinical trial support from Merck, Bristol Myers Squibb, Eisai, Agenus, Hoosier, and Aveo and advisory consulting fees from Eisai, Aveo, Pfizer, and Bristol Myers Squibb. DYCH reports consultancy fees from Pfizer, Novartis, Bristol Myers Squibb, Janssen, Astellas Pharma, Ipsen, Eisai, and Merck and research funding from Pfizer, Novartis, Exelixis, Bristol Myers Squibb, and Ipsen. EB reports funding for the provision of study materials, medical writing, or article processing charges from Aveo Oncology and stock or stock options from Autolus. KEB reports grants funding from Bristol Myers Squibb–Lung Cancer Foundation of America–International Association for the Study of Lung Cancer, Aravive, Pionyr, and Arsenal Bio; consulting fees from Aravive, Aveo, Alpine Bioscience, Arcus, AstraZeneca, Adicet, Bristol Myers Squibb, Exelixis, Eisai, Merck, Nimbus, and Xencor; and honoraria funding from Merck. BAM reports grants to his institution from Aveo, Bristol Myers Squibb, Exelixis, Gilead, and Pfizer; consulting fees from Arcus, Bristol Myers Squibb, Exelixis, Gilead, Lily, and Pfizer; payments or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Targeted Oncology, Dava Oncology, Aptitude Health, and Curio; and patents planned, issued, or pending with Gilead. RJM reports consulting fees from Aveo, Merck, Exelixis, and Takeda, grants or contracts from Pfizer, Genentech and Roche, Eisai, Merck, Bristol Myers Squibb, and Exelixis; and data safety monitoring and advisory board participation fees from Incyte. RI reports no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Papillary thyroid cancer (PTC) is one of the most treatable forms of cancer, with many cases being fully curable. However, resistance to anticancer drugs often leads to metastasis or recurrence, contributing to the failure of cancer therapy and, ultimately, patient mortality. The mechanisms underlying molecular differences in patients with metastatic or recurrent PTC, particularly those resistant to anticancer drugs through epigenetic reprogramming, remain poorly understood. Consequently, refractory PTC presents a critical challenge, and effective therapeutic strategies are urgently needed. Therefore, this study aimed to identify small-molecule inhibitors to enhance treatment efficacy in lenvatinib-resistant PTC. We observed an increase in sarco/endoplasmic reticulum calcium ATPase (SERCA) levels in patient-derived lenvatinib-resistant PTC cells compared with lenvatinib-sensitive ones, highlighting its potential as a therapeutic target. We subsequently identified two SERCA inhibitors [candidates 40 (isoflurane) and 42 (ethacrynic acid)] through in silico screening. These candidates demonstrated significant tumor shrinkage in a xenograft tumor model and reduced cell viability in patient-derived lenvatinib-resistant PTC cells when used in combination with lenvatinib. Our findings have potential clinical value for the development of new combination therapies to effectively target highly malignant, anticancer drug-resistant cancers.

Background: Treatment options for advanced intrahepatic cholangiocarcinoma (ICC) are currently limited. Chemo-containing regimens are the mainstay treatments but associated with notable toxicity, poor tolerance, and reduced compliance, necessitating exploration of alternative therapies. Lenvatinib plus PD-1 inhibitors has shown substantial clinical activity in preliminary studies. This study aimed to assess the effectiveness and safety of lenvatinib plus toripalimab (a novel PD-1 antibody) as chemo-free therapy in advanced ICC., Methods: This retrospective study included consecutive advanced ICC patients receiving lenvatinib plus toripalimab between February 2019 and December 2023. The main outcomes were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. Prognostic factors and exploratory analyses for genetic alternations were also conducted., Results: A total of 78 patients were included, with a median follow-up of 25.9 months. Median OS and PFS were 11.3 (95% CI: 9.5-13.1) and 5.4 (95% CI: 3.8-7.0) months, respectively. ORR was 19.2% and DCR was 75.6%. The incidence of grade 3 or 4 adverse events (AEs) was 50.0%, with no grade 5 AEs reported. Patients with normal baseline CA19-9 levels exhibited a higher ORR (p = 0.011), longer PFS (11.5 versus 4.6 months; HR 0.47; p=0.005), and OS (21.0 versus 9.7 months; HR 0.43; p=0.003). The presence of IDH1 mutations correlated with increased ORR (60.0% versus 8.9%, p=0.016)., Conclusion: Lenvatinib plus toripalimab represents an effective and well-tolerated chemo-free therapeutic option for advanced ICC. Baseline CA19-9 levels and IDH1 mutations may serve as predictive treatment-related biomarkers., (© 2024. The Author(s).)

Background: Lenvatinib, programmed cell death 1 (PD-1) antibodies, and gemcitabine and oxaliplatin (GEMOX) chemotherapy have shown significant antitumor activity as first-line therapy against biliary tract cancer. This study evaluated their efficacy and safety as non-first-line therapy in advanced gallbladder cancer (GBC)., Methods: Patients with advanced GBC who received lenvatinib combined with anti-PD-1 antibodies and GEMOX chemotherapy as a non-first-line therapy were retrospectively analyzed. The primary endpoints were overall survival (OS) and progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR) and safety., Results: A total of 36 patients with advanced GBC were included in this study. The median follow-up time was 11.53 (95% confidence interval (CI): 2.2-20.9) months, and the ORR was 36.1%. The median OS and PFS were 15.1 (95% CI: 3.2-26.9) and 6.1 (95% CI: 4.9-7.2) months, respectively. The disease control rate (DCR) and clinical benefit rate (CBR) were 75% and 61.1%, respectively. Subgroup analysis demonstrated that patients with programmed cell death-ligand 1 (PD-L1) expression had significantly longer PFS and OS than those without PD-L1 expression. Additionally, patients with a neutrophil-lymphocyte ratio (NLR) < 5.57 had a longer OS than those with an NLR ≥ 5.57. All patients experienced adverse events (AEs), with 61.1% experiencing grade 3 or 4 AEs, including myelosuppression (13.9%) and fatigue (13.3%), alanine transaminase or aspartate transaminase levels (8.3%), and diarrhea (8.3%). No grade 5 AEs were reported., Conclusion: Anti-PD-1 antibodies combined with lenvatinib and GEMOX chemotherapy are effective and well-tolerated as a non-first-line therapy in advanced GBC. PD-L1 expression and baseline NLR may potentially predict treatment efficacy., (© 2024. The Author(s).)

Background: Currently, treatment options for patients with advanced melanoma who experience failed immunotherapy or targeted therapy are lacking. Recent studies suggest the antitumor activity of combined pembrolizumab and lenvatinib in patients with advanced melanoma progressing on immunotherapy. Herein, we report the clinical outcomes of combined lenvatinib and a programmed cell death protein-1 inhibitor (PD-1) in this population., Materials and Methods: This French multicenter real-world study was conducted between September 2020 and July 2023. The primary endpoint was the objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumours (version 1.1). Secondary variables were treatment-related adverse events (TRAEs), progression-free survival (PFS), overall survival (OS), and duration of response (DOR)., Results: Of the 67 patients included (median age, 69 years; median follow-up, 5.0 months), 85% had stage IV-M1c or M1d disease. The overall ORR was 28.4% (95% CI, 18%-41%), including 3 complete (4.5%) and 16 partial (23.9%) responses. Median DOR was 3.1 (interquartile range, 1.3-4.3) months. Median PFS and OS were 3.1 (95% CI, 2.5-3.7) and 9.8 (95% CI, 5.6-13.9) months, respectively. Grades 3-5 TRAEs occurred in 16 (24%) patients; common TRAEs were fatigue (43.3%), nausea/vomiting (26.8%), diarrhea (20.9%), and hypertension (20.9%). No treatment-related deaths occurred., Conclusion: Our real-world study demonstrates an interesting response rate and acceptable safety profile in a population with poor prognostic factors. Our data support this treatment option for refractory melanoma, as it is not approved by the Food and Drug Administration or European Medicines Agency, and highlight the need for new strategies., (© The Author(s) 2024. Published by Oxford University Press.)

Liver cancer is one of the most prevalent malignant tumors worldwide. According to the Barcelona Clinic Liver Cancer staging criteria, clinical guidelines provide tutorials to clinical management of liver cancer at their individual stages. However, most patients diagnosed with liver cancer are at advanced stage; therefore, many researchers conduct investigations on targeted therapy, aiming to improve the overall survival of these patients. To date, small-molecule-based targeted therapies are highly recommended (first line: sorafenib and lenvatinib; second line: regorafenib and cabozantinib) by current the clinical guidelines of the American Society of Clinical Oncology, European Society for Medical Oncology, and National Comprehensive Cancer Network. Herein, we summarize the small-molecule-based targeted therapies in liver cancer, including the approved and preclinical therapies as well as the therapies under clinical trials, and introduce their history of discovery, clinical trials, indications, and molecular mechanisms. For drug resistance, the revealed mechanisms of action and the combination therapies are also discussed. In fact, the known small-molecule-based therapies still have limited clinical benefits to liver cancer patients. Therefore, we analyze the current status and give our ideas for the urgent issues and future directions in this field, suggesting clues for novel techniques in liver cancer treatment., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Importance: The effect of montelukast in reducing symptom duration among outpatients with mild to moderate COVID-19 is uncertain., Objective: To assess the effectiveness of montelukast compared with placebo in treating outpatients with mild to moderate COVID-19., Design, Setting, and Participants: This randomized clinical trial (Accelerating COVID-19 Therapeutic Interventions and Vaccines [ACTIV]-6) was conducted from January 27 through June 23, 2023, during the circulation of Omicron subvariants. Participants aged 30 years or older with confirmed SARS-CoV-2 infection and 2 or more acute COVID-19 symptoms for less than 7 days were included across 104 US sites., Interventions: Participants were randomized 1:1 to receive montelukast, 10 mg once daily, or matched placebo for 14 days., Main Outcomes and Measures: The primary outcome was time to sustained recovery (defined as ≥3 consecutive days without symptoms). Secondary outcomes included time to death; time to hospitalization or death; a composite of health care utilization events (hospitalization, urgent care clinic visit, emergency department visit, or death); COVID-19 clinical progression scale score; and difference in mean time unwell. A modified intention-to-treat approach was used for the analysis., Results: Among 1250 participants who were randomized and received the study drug or placebo, the median age was 53 years (IQR, 42-62 years), 753 (60.2%) were female, and 704 (56.3%) reported receiving 2 or more doses of a SARS-CoV-2 vaccine. Among 628 participants who received montelukast and 622 who received placebo, differences in time to sustained recovery were not observed (adjusted hazard ratio [AHR], 1.02; 95% credible interval [CrI], 0.92-1.12; P = .63 for efficacy). Unadjusted median time to sustained recovery was 10 days (95% CI, 10-11 days) in both groups. No deaths occurred, and hospitalizations were reported for 2 participants (0.3%) in each group; the composite of health care utilization events was reported for 18 participants (2.9%) in the montelukast group and 18 (2.9%) in the placebo group (AHR, 1.01; 95% CrI, 0.45-1.84; P = .48 for efficacy). Five participants (0.4%) experienced serious adverse events (3 [0.5%] in the montelukast group and 2 [0.3%] in the placebo group)., Conclusions and Relevance: In this randomized clinical trial of outpatients with mild to moderate COVID-19, treatment with montelukast did not reduce duration of COVID-19 symptoms. These findings do not support the use of montelukast for the treatment of mild to moderate COVID-19., Trial Registration: ClinicalTrials.gov Identifier: NCT04885530.

Objective: Comparing the efficacy of transarterial chemoembolization (TACE) combined with lenvatinib plus tislelizumab (TLT) with TACE combined with lenvatinib (TL) for unresectable hepatocellular carcinoma, particularly in determining which patients can benefit more from the TLT treatment., Methods: From March 2021 to September 2023, a total of 169 patients from three centers were included in this study, with 103 patients receiving TLT and 66 patients receiving TL. The Kaplan-Meier method was utilized to evaluate the cumulative overall survival (OS) and progression-free survival (PFS) between the two groups and were assessed using the log-rank test. Subgroup analysis on tumor number, maximum tumor diameter, presence of portal vein thrombosis, AFP level, and Child-Pugh class were conducted., Results: The median OS was 26 months in the TLT group, and 20 months in the TL group. The median PFS was 14 months in the TLT group and 9 months in the TL group. The Kaplan-Meier curve demonstrated a significantly superior OS and PFS in the TLT group compared to the TL group. Subgroup analysis showed that for patients with a maximum tumor diameter greater than 7 cm, AFP > 400 ng/ml and accompanied by portal vein tumor thrombus, and Child-Pugh class A, there was a statistically significant difference in OS between TLT and TL groups., Conclusions: OS and PFS were significantly improved in patients who received TLT compared to those who received TL, patients with a largest tumor diameter greater than 7 cm, AFP > 400 ng/ml, Child-Pugh class A and PVTT appeared to derive more benefit., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhao, Wen, Xue, Dang, Nan, Wang, Li, Feng and Chen.)

Background: Although cisplatin plus gemcitabine and other combinations have improved the survival of advanced biliary tract cancer (BTC), high unmet medical needs remain. This study aimed to assess the efficacy and safety of nivolumab plus lenvatinib in the second-line treatment for advanced BTC., Patients and Methods: Nivolumab (240 mg) was administered biweekly. Phase I determined the recommended phase II dose of lenvatinib (20 mg or 14 mg). In phase II, the primary endpoint was the objective response rate (ORR). Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. The planned sample size was 32 patients with a power of 80%, a one-sided alpha error of 5%, threshold ORR of 10%, and expected ORR of 30%., Results: In phase I, the recommended dose of lenvatinib was determined to be 20 mg in six patients, with one dose-limiting toxicity (myocarditis). In phase II, we enrolled 26 patients. ORR, DCR, and median OS and PFS were 9.4% [90% confidence interval (CI) 2.6% to 22.5%], 53.1% (95% CI 34.7% to 70.9%), and 6.4 months (95% CI 4.9-9.7 months) and 2.5 months (95% CI 1.5-4.1 months), respectively. No response was observed in patients with the usage of antibiotics. The grade 3 or 4 adverse events were hypertension (59.4%) and biliary tract infection (37.5%). Rash (28.1%) and hypothyroidism (21.9%) were observed as immune-mediated adverse events of any grade., Conclusions: Nivolumab plus lenvatinib had a manageable safety in advanced BTC, but its efficacy in the second-line treatment was limited., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: High-level resistance to sulfadoxine-pyrimethamine threatens the efficacy of WHO-recommended intermittent preventive treatment in pregnancy (IPTp) with single-dose sulfadoxine-pyrimethamine to prevent malaria. Monthly IPTp with dihydroartemisinin-piperaquine, a 3-day regimen, is an emerging alternative, but this regimen poses potential implementation and adherence challenges. We aimed to assess adherence to a multiday IPTp with dihydroartemisinin-piperaquine regimen and its delivery effectiveness in routine antenatal care settings in western Kenya., Methods: We conducted a pragmatic, three-armed, open-label, cluster-randomised trial in antenatal clinics in 18 health-care facilities (six facilities per group) in Kisumu County and Homa Bay County in western Kenya. Clusters were facilities offering routine antenatal care services provided by trained Ministry of Health staff with 100 or more antenatal clinic attendances per month between July, 2018, and June, 2019. Private or mission hospitals, dispensaries, referral hospitals, and trial sites were excluded. Individuals in their first trimester, living with HIV, or who were not attending a scheduled antenatal clinic visit were excluded. The 18 antenatal clinics were grouped into matched triplets stratified by location and clinics in each matched triplet were randomly assigned to one of the three study groups (1:1:1). Masking was not possible. Two groups were given IPTp with dihydroartemisinin-piperaquine (one group with a targeted information transfer intervention and one group without any additional interventions) and one group was given the standard of care (ie, IPTp with sulfadoxine-pyrimethamine). The primary endpoint, adherence, was defined as the proportion of participants completing their most recent 3-day IPTp with dihydroartemisinin-piperaquine regimen. This completion was verified by pill counts during home visits no more than 2 days after participants' 3-day regimens ended. The secondary endpoint, delivery effectiveness, was defined as the proportion of participants who received the correct number of IPTp tablets and correctly repeated dosing instructions (ie, correctly recalled the instructions they received about self-administered dihydroartemisinin-piperaquine doses and the number of sulfadoxine-pyrimethamine tablets they had received) at their exit from the antenatal clinic. Individuals receiving treatment for malaria, visiting a clinic for registration only, or interviewed during IPTp drug stock-outs were excluded from analyses. We used generalised linear mixed models to compare endpoints among the IPTp with dihydroartemisinin-piperaquine groups. This trial was registered with ClinicalTrials.gov, NCT04160026, and is complete., Findings: 15 facilities (five per group) completed the trial, with 1189 participants having exit interviews (377 in the IPTp with sulfadoxine-pyrimethamine group, 408 in the IPTp with dihydroartemisinin-piperaquine only group, and 404 in the IPTp with dihydroartemisinin-piperaquine plus targeted information transfer intervention group) and 586 participants having home visits (267 in the IPTp with dihydroartemisinin-piperaquine only group and 319 in the IPTp with dihydroartemisinin-piperaquine plus targeted information transfer intervention group) from Sept 8 to Dec 10, 2020. Relative to the IPTp with dihydroartemisinin-piperaquine only group, adherence was 16% higher in the IPTp with dihydroartemisinin-piperaquine plus targeted information transfer intervention group (266 [83%] of 319 participants vs 196 [73%] of 267 participants; adjusted relative risk [RR] 1·16, 95% CI 1·03-1·31; p=0·0140). Delivery effectiveness in the IPTp with dihydroartemisinin-piperaquine plus targeted information transfer intervention group was not significantly different from that in the IPTp with sulfadoxine-pyrimethamine group (352 [87%] of 403 participants vs 335 [89%] of 375 participants; adjusted RR 0·97, 95% CI 0·90-1·05; p=0·4810). However, delivery effectiveness in the IPTp with dihydroartemisinin-piperaquine only group was significantly lower than in the IPTp with sulfadoxine-pyrimethamine group (300 [74%] of 404 participants vs 335 [89%] of 375 participants; 0·84, 0·75-0·95; p=0·0030)., Interpretation: Targeted information transfer interventions to health-care providers and pregnant individuals boost antenatal care delivery adherence to a multiday regimen with dihydroartemisinin-piperaquine., Funding: European and Developing Countries Clinical Trials Partnership 2, UK Joint Global Health Trials Scheme of the Foreign, Commonwealth and Development Office, Medical Research Council, National Institute for Health and Care Research, and Wellcome Trust; and Swedish International Development Cooperation Agency., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To investigate the inhibitory effects of STM2457, which is a novel METTL3 (m 6 A writer) inhibitor, both as a monotherapy and in combination with anlotinib, in the treatment of oral squamous cell carcinoma (OSCC) both in vitro and in vivo., Materials and Methods: The efficacy of STM2457 or STM2457 plus anlotinib was evaluated using two OSCC cell lines by CCK8, transwell, colony formation, would-healing, sphere formation, cell cycle, apoptosis assays, and nude mice tumor xenograft techniques. The molecular mechanism study was carried out by western blotting, qRT-PCR, MeRIP-qPCR, immunofluorescence, and immunohistochemistry., Results: STM2457 combined with anlotinib enhanced inhibition of cellular survival/proliferation and promotion of apoptosis in vitro. Moreover, this combinatorial approach exerted a notable reduction in stemness properties and EMT (epithelial-mesenchymal transition) features of OSCC cells. Remarkably, in vivo studies validated the efficacy of the combination treatment. Mechanistically, our investigations revealed that the combined action of STM2457 and anlotinib exerted downregulatory effects on EGFR (epidermal growth factor receptor) expression in OSCC cells., Conclusions: The combination of STM2457 and anlotinib targeting EGFR exerted a multiple anti-tumor effect. In near future, anlotinib combined with STM2457 may provide a novel insight for the treatment of OSCC., (© 2024 Wiley Periodicals LLC.)

Purpose: Standard treatment for patients with unresectable locally advanced or metastatic soft-tissue sarcoma (LA/M STS) is chemotherapy based on anthracyclines, but patient tolerance of chemotherapy is limited. The present trial (NCT03792542) investigated the use of anlotinib as first-line treatment for patients with advanced STS, in particular liposarcoma., Patients and Methods: Eligible patients were previously untreated, pathologically confirmed, unresectable LA/M STS cases. Anlotinib was given orally at a dose of 12 mg once daily from days 1 to 14 every 3 weeks until disease progression or intolerable adverse events (AE) occurred. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), objective response rate, and disease control rate (DCR). The safety profile was also evaluated., Results: Forty patients were enrolled from April 2019 to June 2022 and are included in the intention-to-treat analysis. The median PFS was 6.83 months [95% confidence interval (CI), 4.17-8.71] and the median OS 27.40 months (95% CI, 16.43-not evaluable); 1 patient reached partial response and 26 attained stable disease, with a DCR of 67.5% (27/40). Median PFS and OS times for liposarcoma patients were 8.71 and 16.23 months, respectively. Ten (25.0%) patients had treatment-related AEs ≥ grade 3, with in particular a higher incidence of hypertension (15.0%) and proteinuria (7.5%)., Conclusions: The findings suggest a potential benefit in using front-line anlotinib to treat patients with STS, who are not eligible for cytotoxic chemotherapy. Of note, the clinical outcomes for the liposarcoma subgroup of patients were encouraging. See related commentary by Napolitano et al., p. 4257., (©2024 The Authors; Published by the American Association for Cancer Research.)

Purpose: The prognosis of patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT) is extremely poor, and systemic therapy is currently the mainstream treatment. This study aimed to assess the efficacy and safety of lenvatinib combined with anti-programmed cell death-1 antibodies and transcatheter arterial chemoembolization (triple therapy) in patients with HCC and PVTT., Materials and Methods: This retrospective multicenter study included patients with HCC and PVTT who received triple therapy, were aged between 18 and 75 years, classified as Child-Pugh class A or B, and had at least one measurable lesion. The overall survival (OS), progression-free survival (PFS), objective response rates, and disease control rates were analyzed to assess efficacy. Treatment-related adverse events were analyzed to assess safety profiles., Results: During a median follow-up of 11.23 months (range, 3.07 to 34.37 months), the median OS was greater than 24 months, and median PFS was 12.53 months. The 2-year OS rate was 54.9%. The objective response rate and disease control rate were 69.8% (74/106) and 84.0% (89/106), respectively; 20.8% (22/106) of the patients experienced grade 3/4 treatment-related adverse events and no treatment-related deaths occurred. The conversion rate to liver resection was 31.1% (33/106), with manageable postoperative complications. The median OS was not reached in the surgery group, but was 19.08 months in the non-surgery group. The median PFS in the surgery and non-surgery groups were 20.50 and 9.00 months, respectively., Conclusion: Triple therapy showed promising survival benefits and high response rates in patients with HCC and PVTT, with manageable adverse effects.

Background: Novel treatments are needed for patients with advanced, triple-negative breast cancer (TNBC) that progresses or recurs after first-line treatment with chemotherapy. The authors report results from the TNBC cohort of the multicohort, open-label, single-arm, phase 2 LEAP-005 study of lenvatinib plus pembrolizumab in patients with advanced solid tumors (ClinicalTrials.gov identifier NCT03797326)., Methods: Eligible patients had metastatic or unresectable TNBC with disease progression after one or two lines of therapy. Patients received lenvatinib (20 mg daily) plus pembrolizumab (200 mg every 3 weeks; up to 35 cycles). The primary end points were the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1, and safety (adverse events graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0). Duration of response, progression-free survival, and overall survival were secondary end points., Results: Thirty-one patients were enrolled. The objective response rate by investigator assessment was 23% (95% confidence interval [CI], 10%-41%). Overall, the objective response rate by blinded independent central review (BICR) was 32% (95% CI, 17%-51%); and, in patients who had programmed cell death ligand 1 combined positive scores ≥10 (n = 8) and <10 (n = 22), the objective response rate was 50% (95% CI, 16%-84%) and 27% (95% CI, 11%-50%), respectively. The median duration of response by BICR was 12.1 months (range, from 3.0+ to 37.9+ months). The median progression-free survival by BICR was 5.1 months (95% CI, 1.9-11.8 months) and the median overall survival was 11.4 months (95% CI, 4.1-21.7 months). Treatment-related adverse events occurred in 94% of patients (grade 3, 52%; grade 4, 0%). One patient died due to a treatment-related adverse event of subarachnoid hemorrhage., Conclusions: The combination of lenvatinib plus pembrolizumab demonstrated antitumor activity with a manageable safety profile in patients with previously treated, advanced TNBC., (© 2024 Merck Sharp & Dohme LLC and The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Currently, the effectiveness of TACE, Lenvatinib, and PD-1/L1 inhibitors used alone or in combination has been thoroughly reported. However, the differences in effectiveness between these treatment protocols require further verification. To this end, this study employs a Bayesian network meta-analysis to compare the efficacy and safety of TACE, Lenvatinib, and PD-1/L1 inhibitors, whether administered by monotherapy or in combination, providing evidence-based medicine for the treatment of unresectable HCC., Purpose: This study employed a network meta-analysis to evaluate the efficacy and safety of trans-arterial chemoembolization (TACE), Programmed Cell Death Protein/Ligand 1 (PD-1/L1) inhibitors, and Lenvatinib in the treatment of advanced HCC., Methods: Literature on the treatment of advanced HCC with TACE, PD-1/L1 inhibitors, and Lenvatinib was searched for in both Chinese and English databases, including PubMed, EMBASE, ClinicalTrials.gov, Cochrane Library, CNKI, and Wanfang. Two researchers conducted independent screening and data extraction, and the meta-analysis was performed using R language with the gemtc package., Results: After retrieval and screening, a total of 21 articles were included, involving 2052 participants and six treatment modalities: Lenvatinib (L), TACE (T), TACE + Lenvatinib (TL), Lenvatinib + PD-1/L1 inhibitors (LP), TACE + Lenvatinib + PD-1/L1 inhibitors (TLP), and TACE + PD-1/L1 inhibitors (TP). In terms of objective response rate (ORR), the TLP regimen provided the optimal effect. In predicting the best ORR, TLP had the highest (75.5%) probability. In terms of disease control rate (DCR), the TLP regimen showed the best effect. In predicting the best DCR, the TLP again offered the highest (76.1%) probability. In terms of overall survival (OS), the best outcome was observed in the TLP protocol. In predicting the best OS, the TLP holds the highest (86.00%) probability. Furthermore, the best outcome in progression-free survival (PFS) was found in the TLP regimen. In predicting the best PFS, the TLP still holds the highest (97.0%) result., Conclusion: The combination of TACE, Lenvatinib, and PD-1/L1 inhibitors appears to provide the maximum benefit for inoperable HCC patients., (© 2024. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Background:  Treatment options for patients with differentiated thyroid cancer (DTC) who experience disease progression on lenvatinib treatment are limited. Although dose escalation of treatment with tyrosine kinase inhibitors at disease progression has been reported across cancer types, clinical significance in patients with DTC has not been investigated., Methods: We retrospectively reviewed patients with DTC who experienced disease progression on lenvatinib treatment from September 2011 to June 2022. We compared subjects who received dose-escalation treatment with standard treatment of termination at the time of initial disease progression. The escalated dose was decided by referencing to the previous effective and tolerated dose., Results: Thirty-three patients were identified, 15 with dose escalation and 18 with lenvatinib termination. In both groups, the starting dose of lenvatinib was 24 mg/day, and the median dose at initial disease progression was 10 mg/day. In the former, the median dose escalation was 6 mg/day (range: 4-12). Objective response rate, clinical benefit rate by escalation, and median treatment duration of the dose-escalation phase were 13.3%, 73.3%, and 9.9 months (95% confidence interval [CI] 5.71-27.6), respectively. Median overall survival from initial disease progression was significantly longer in the dose-escalation group (median OS: 20.4 months [95% CI 7.0-NA] vs. 3.9 months [95% CI 1.7-7.9], log-rank p-value; 0.0004, hazard ratio; 0.22 [95% CI 0.09-0.55]). There were no grade 5 adverse events, and one patient discontinued due to a grade 3 lung abscess., Conclusion: The dose-escalation strategy appears to be a safe and effective treatment option after disease progression in patients treated with lenvatinib for DTC., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Although bosutinib is generally safe and effective, drug-related toxicities (DRTs) such as diarrhea or increased transaminase levels often lead to treatment discontinuation. To clarify whether a lower initial dose of bosutinib (i.e., starting at 200 mg) would reduce rates of discontinuation due to DRTs, we conducted a phase 2 study of BOsutinib Gradual Increase (BOGI trial, UMIN 000032282) as a second/third-line treatment for chronic myeloid leukemia (CML). Between February 4, 2019 and May 24, 2022, 35 patients were enrolled. The rate of bosutinib discontinuation at 12 months was 25.7% vs. 35.9% in a historical control study (Japanese phase 1/2 study) (p = 0.102). The rate of bosutinib discontinuation due to DRTs was significantly lower, at 11.4% vs. 28.2% (p = 0.015). The incidence of grade 3/4 transaminase elevation was 20% vs. 29% (p = 0.427), while the incidence of diarrhea was 3% vs. 25% (p = 0.009). The median dose intensity of bosutinib was higher (391.7 mg/day vs. 353.9 mg/day). Pharmacokinetic analysis of bosutinib showed that patients who achieved a major molecular response tended to have high trough concentrations. Thus, a low initial dose of bosutinib followed by dose escalation reduced discontinuation due to severe DRTs while maintaining high dose intensity and efficacy., (© 2024. The Author(s).)

Immunochemotherapy is the first-line standard for extensive-stage small-cell lung cancer (ES-SCLC). Combining the regimen with anti-angiogenesis may improve efficacy. ETER701 was a multicenter, double-blind, randomized, placebo-controlled phase 3 trial that investigated the efficacy and safety of benmelstobart (a novel programmed death-ligand 1 (PD-L1) inhibitor) with anlotinib (a multi-target anti-angiogenic small molecule) and standard chemotherapy in treatment-naive ES-SCLC. The ETER701 trial assessed two primary endpoints: Independent Review Committee-assessed progression-free survival per RECIST 1.1 and overall survival (OS). Here the prespecified final progression-free survival and interim OS analysis is reported. Patients randomly received benmelstobart and anlotinib plus etoposide/carboplatin (EC; n = 246), placebo and anlotinib plus EC (n = 245) or double placebo plus EC ('EC alone'; n = 247), followed by matching maintenance therapy. Compared with EC alone, median OS was prolonged with benmelstobart and anlotinib plus EC (19.3 versus 11.9 months; hazard ratio 0.61; P = 0.0002), while improvement of OS was not statistically significant with anlotinib plus EC (13.3 versus 11.9 months; hazard ratio 0.86; P = 0.1723). The incidence of grade 3 or higher treatment-related adverse events was 93.1%, 94.3% and 87.0% in the benmelstobart and anlotinib plus EC, anlotinib plus EC, and EC alone groups, respectively. This study of immunochemotherapy plus multi-target anti-angiogenesis as first-line treatment achieved a median OS greater than recorded in prior randomized studies in patients with ES-SCLC. The safety profile was assessed as tolerable and manageable. Our findings suggest that the addition of anti-angiogenesis therapy to immunochemotherapy may represent an efficacious and safe approach to the management of ES-SCLC. ClinicalTrials.gov identifier: NCT04234607 ., (© 2024. The Author(s).)

This final analysis from the phase 4 BYOND trial reports outcomes with bosutinib in patients with previously treated chronic myeloid leukemia (CML); 163 patients with CML resistant/intolerant to previous tyrosine kinase inhibitors received bosutinib (starting dose: 500 mg QD). At study completion (median follow-up, 47.8 months), 48.1% (n = 75/156) of patients with Philadelphia chromosome-positive chronic phase CML were still receiving treatment. Among evaluable patients, 71.8% (95% CI, 63.9-78.9) and 59.7% (95% CI, 51.4-67.7) attained or maintained major molecular response (MMR) and molecular response (MR) 4 , respectively, at any time on treatment. The majority of patients achieved a deeper molecular response relative to baseline while on bosutinib. Kaplan-Meier probabilities (95% CI) of maintaining MMR and MR 4 at 36 months were 87.2% (78.0-92.7) and 80.7% (69.4-88.1), respectively. At 48 months, the Kaplan-Meier overall survival rate was 88.3% (95% CI, 81.8-92.6); there were 17 deaths, including 2 that were considered CML related. Long-term adverse events (AEs) were consistent with the known safety profile of bosutinib, and no new safety issues were identified. The management of AEs through dose reduction maintained efficacy while improving tolerability. These results support the use of bosutinib in patients with previously treated CML.ClinicalTrials.gov, NCT02228382., (© 2024. The Author(s).)

The optimal medical treatment of chemotherapy-ineligible patients affected by advanced soft-tissue sarcomas is unclear. In this population, tyrosine kinase inhibitors represent an appealing alternative treatment strategy. First-line use of the tyrosine kinase inhibitor anlotinib in chemotherapy-ineligible patients with soft-tissue sarcoma showed promising activity across multiple histologies. See related article by Li et al., p. 4310., (©2024 American Association for Cancer Research.)

Aims: To evaluate the impact of elexacaftor/tezacaftor/ivacaftor (ETI) therapy on Cystic Fibrosis Related Diabetes (CFRD) glycemic control and insulin treatment in patients with CFRD during clinical practice., Methods: We carried out a retrospective observational study of 23 adult patients with CFRD who started treatment with ETI. They had, at least, one F508del mutation. Data were collected before ETI initiation and 3, 6, and 12 months after., Results: Glycemic control measured by HbA1c significantly improved by 0.3 % (0.1-0.5) after 3 months of ETI therapy (p = 0.004) and kept this improvement during follow-up (p < 0.001). The proportion of patients needing multiple daily injections of insulin was reduced by 16 % (p = 0.023). Total daily insulin dose dropped by 0.12 (0.05-0.18) UI/kg/day (p < 0.001). Data derived from Flash Continuous Glucose Monitoring (CGM) for patients treated with insulin stayed unchanged after insulin reduction, except for a significant 8 % (0.3-15.6) increase in the Time In Tight Range (TITR) between 70 and 140 mg/dL (p = 0.043)., Conclusion: ETI therapy impacted CFRD in clinical practice reducing insulin needs and improving glycemic control measured by HbA1c and CGM. The improvements can be observed from the first 3 months of treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In the field of chronic myeloid leukemia (CML), new strategies are needed to increase the rate of successful treatment discontinuations, a crucial goal in this disease. Anti-PD-L1 checkpoint inhibitors are a promising therapeutic approach in CML after the demonstration of an increase of these inhibitory molecules in patients with CML. A phase Ib/II (NCT04793399, registration date March 11, 2021) open-label exploratory trial has been conducted to evaluate the safety of atezolizumab, a humanized anti-PD-L1 antibody, in combination with bosutinib in patients with newly diagnosed chronic phase CML. A total of 36 patients were planned to be enrolled, but the study had to be prematurely terminated due to safety concerns. Nine patients were included in the study, and only 8 went on to receive the combination with atezolizumab. There were a total of 44 adverse events (AEs) during the study period. The most frequent were gastrointestinal (50%), mostly mild (86% grade 1-2). The most serious AEs were hepatic. There were 17 hepatic AEs in 5 patients. Of the hepatic AEs 5 were during the bosutinib monotherapy phase and 12 during the combination phase (AST increase x4, ALT increase x4, blood bilirubin increase x1, alkaline phosphatase elevation x2, GGT increase x2), most of them grade 3-4. There were 2 patients who presented a dose-limiting toxicity; a grade 3 elevation of transaminases, that led to premature termination of the study. The combination of atezolizumab with bosutinib presents hepatotoxicity as a dose-limiting effect and therefore we do not recommend to explore this combination in future studies., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Backgrounds & Aim: Placental insufficiency is a serious complication that affects pregnancy and fetal growth. Cyclophosphamide (CYC) is considered one of the chemotherapeutic agents. Unfortunately, CYC not only affects tumor cells but also affects healthy cells causing multiple injuries including the placenta. The present study aimed to evaluate the effect of cysteinyl leukotriene receptor antagonist; montelukast (MK), on CYC-induced placental injury in rats., Materials and Methods: Forty-eight female Wister rats were randomly divided into 8 experimental groups. Group 1: control pregnant group; Group 2: MK 5 mg-treated pregnant rats; Group 3: MK 10 mg-treated pregnant rats; Group 4: MK 20 mg-treated pregnant rats; Group 5: pregnant rats received CYC (20 mg/kg, i.p); Group 6: pregnant rats received MK 5 mg and CYC; Group 7: pregnant rats received MK 10 mg and CYC; Group 8: pregnant rats received MK 20 mg and CYC. Placental malondialdehyde (MDA), reduced glutathione (GSH), total antioxidant capacity (TAC), placental growth factor (PlGF), and Nod-like receptor p3 (NLRP3) inflammasome were measured. Histological changes, interleukin-1β (IL-1β), and cleaved caspase-3 immuno-expressions were also evaluated., Results: CYC showed a significant decrease in placental GSH, TAC, and PlGF with a significant increase in placental MDA, NLRP3, and immuno-expression of IL-1β and caspase-3. MK showed significant improvement in all oxidative stress (MDA, GSH and TAC), inflammatory (NLRP3 and IL-1β), and apoptotic (caspase-3) parameters., Conclusion: According to the findings, MK was proved to have a possible protective role in CYC-induced placental injury via modulation of NLRP3/IL-1β signaling pathway with anti-oxidant, anti-inflammatory, and anti-apoptotic effects., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Objective: To investigate the clinical efficacy and adverse reactions of gemcitabine/nab-paclitaxel (AG regimen) combined with anlotinib and PD-1 inhibitors as a first-line treatment for advanced pancreatic cancer (PC)., Methods: Data of 52 patients with advanced PC who were treated in the Affiliated Hospital of Xuzhou Medical University (Xuzhou, China) between August 2019 and March 2023 were retrospectively analyzed. According to the treatment regimen, patients were divided into two groups, including 27 patients in the chemotherapy group (AG regimen) and 25 patients in the combined treatment group (AG regimen combined with anlotinib and PD-1 inhibitors). Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse reactions were compared between the two groups. The survival curves of the two groups were drawn using the Kaplan-Meier method, and the differences in PFS and OS between the two groups were compared by the log-rank test. Univariate and multivariate Cox regression analyses were performed to identify independent risk factors influencing prognosis., Results: The median OS and PFS in the combined treatment group were significantly longer than those in the chemotherapy group (OS, 12.8 vs. 7.9 months, P = 0.005; PFS, 5.6 vs. 4.4 months, P = 0.003). There was no significant difference in ORR between the two groups (32.0 % vs. 25.9 %, P = 0.629), and DCR in the combined treatment group was significantly better than that in the chemotherapy group (84.0 % vs. 59.3 %, P = 0.049). Grade 1-2 adverse reactions were predominant in both groups, and no adverse reaction-related deaths occurred., Conclusion: Compared with chemotherapy alone, AG regimen combined with anlotinib and PD-1 inhibitors exhibited to have a higher efficacy for the first-line treatment of advanced PC, and the adverse reactions were also controllable., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)